Meningococcus

J Immunol, 2004 Feb 15, 172(4), 2461 - 8
Protective immunization against group B meningococci using anti-idiotypic mimics of the capsular polysaccharide; Beninati C et al.; Use of the serogroup B meningococcal capsular polysaccharide (MenB CP) as a vaccine is hampered by the presence of epitopes that cross-react with human polysialic acid . As non-cross-reactive, protective capsular epitopes have also been described, we set out to develop protein mimics of one of such epitopes using as a template a highly protective mAb (mAb Seam 3) raised against a chemically modified form of the MenB CP (N-Pr MenB CP) . Using phage display, anti-idiotypic single-chain Ab fragments (scFvs) were obtained from spleen cells of mice immunized with the Seam 3 mAb . Two Seam 3-specific scFvs competed with N-Pr MenB CP for binding to either mAb Seam 3 or rabbit Abs present in typing sera . Moreover, in mice and rabbits the scFvs elicited the production of Abs reacting with both N-Pr MenB CP and whole meningococci, but not with human polysialic acid . These scFv-induced Ab responses were boostable and of the Th1 type, as shown by a predominance of IgG2a . In addition, passive immunization with sera from scFv-immunized animals partially protected neonatal mice from experimental infection with group B meningococci . In conclusion, we have produced anti-idiotypic scFvs that mimic a protective MenB CP epitope and may be useful in the development of an alternative group B meningococcal vaccine.

Expert Rev Vaccines, 2004 Feb, 3(1), 77 - 87
Serologic correlates of protection for evaluating the response to meningococcal vaccines; Balmer P et al.; Meningococci cause serious disease worldwide and the organism remains the most common cause of bacterial meningitis in children and young adults . The only effective means of controlling disease is through vaccination . Although polysaccharide vaccines have been available for serogroup A, C, Y and W135 for many years, serogroup C polysaccharide-protein conjugate vaccines have only recently been licensed in many countries . Conjugate vaccines for combinations of serogroup A, C, Y and W135 are progressing through clinical trials and major efforts are being made to develop a safe and efficacious vaccine against serogroup B . To assess the quality of the immune response after vaccination, laboratory correlates of protection are needed . For serogroups A and C, serum bactericidal antibody is a well established predictor for protection but for serogroup B, other mechanisms besides serum bactericidal antibody may also be involved in conferring protection against disease . The serologic correlates of protection for evaluating the response to meningococcal vaccines are described in this review.

Bull World Health Organ, 2003, 81(10), 745 - 50; discussion 751-5 Epub 2003 Nov 25.
Meningococcal meningitis in sub-Saharan Africa: the case for mass and routine vaccination with available polysaccharide vaccines; Robbins JB et al.; Endemic and epidemic group A meningococcal meningitis remains a major cause of morbidity and mortality in sub-Saharan Africa, despite the availability of the safe and inexpensive group A meningococcal polysaccharide vaccine, which is protective at all ages when administered as directed . Despite optimal therapy, meningococcal meningitis has a 10% fatality rate and at least 15% central nervous system damage . WHO's policy of epidemic containment prevents, at best, about 50% of cases and ignores endemic meningitis, which is estimated at 50,000 cases per year . The effectiveness of group A, C, W135, and Y capsular polysaccharides is the basis for recommending universal vaccination with group A meningococcal polysaccharide twice in infancy, followed by the four-valent vaccine in children aged two and six years . This could eliminate epidemic and endemic disease, prepare for the use of conjugates when they become available, and probably could have prevented the recent epidemics of groups A and W135 meningitis in Burkina Faso.

Crit Care Med, 2004 Feb, 32(2), 433 - 8
Plasma interferon-gamma and interleukin-10 concentrations in systemic meningococcal disease compared with severe systemic Gram-positive septic shock; Bjerre A et al.; OBJECTIVE: To analyze plasma interferon-gamma and interleukin-10 concentrations in patients with systemic meningococcal disease and patients with severe Gram-positive septic shock caused by Streptococcus pneumoniae or Staphylococcus aureus . To study the in vitro cytokine (interferon-gamma and interleukin-10) responses in a whole blood model boosted with heat-killed Neisseria meningitidis, S . pneumoniae, and S . aureus before and after treatment with recombinant interleukin-10 or recombinant interferon-gamma . DESIGN: Experimental study . SETTING: Laboratory . SUBJECTS: Plasma samples were collected from patients with systemic meningococcal disease (n = 66) and patients with severe Gram-positive septic shock caused by S . pneumoniae (n = 4) or S . aureus (n = 3) . INTERVENTIONS: Whole blood was boosted with heat-killed N . meningitidis, S . pneumoniae, and S . aureus (1 x 106 colony forming units/mL), and plasmas were analyzed for interleukin-10 or interferon-gamma at 0, 5, 12, and 24 hrs . Furthermore, recombinant interleukin-10 or recombinant interferon-gamma was added before bacteria, and the effect on the secretion of interferon-gamma and interleukin-10, respectively, was analyzed after 24 hrs . MEASUREMENTS AND MAIN RESULTS: The median concentration of interferon-gamma was 15 pg/mL and of interleukin-10 was 10,269 pg/mL in patients with meningococcal septic shock (n = 24) compared with median interferon-gamma concentration of 3400 pg/mL and interleukin-10 concentration of 465 pg/mL in patients with severe Gram-positive shock (p =.001) . Increased interferon-gamma concentrations were associated with case fatality (p =.011) . In a whole blood model we demonstrated that 1 x 106 colony forming units/mL of N . meningitidis induced more interleukin-10 but less interferon-gamma than S . pneumoniae . S . aureus induced minimal secretion of both cytokines . Recombinant interleukin-10 efficiently down-regulated the secretion of interferon-gamma, and vice versa, as shown in a whole blood model . CONCLUSION: We speculate whether high concentrations of interleukin-10 contribute to the low concentrations of interferon-gamma in fulminant meningococcal septicemia . In addition, it appears as if interferon-gamma plays a minor role in the pathophysiology of meningococcal septic shock.

Eur J Pharm Sci, 2004 Feb, 21(2-3), 131 - 41
Immunogenicity of meningococcal PorA formulations encapsulated in biodegradable microspheres; Arigita C et al.; The purpose of our study was to investigate the possibility to microencapsulate liposomes and meningococcal outer membrane vesicles (OMV), both containing neisserial pore protein A (PorA), in biodegradable dextran- and mannan-based microspheres and to study the immunogenicity of the encapsulated PorA formulations . PorA-liposomes and OMV were encapsulated in dextran- or mannan-based microspheres by using an aqueous two-phase system consisting of a polyethylene glycol solution and a methacrylated dextran or mannan solution . The formulations were characterized for size distribution, PorA structure and antigen recovery after release . Calcein-containing model liposomes were used to establish the encapsulation efficiency and release profiles from both types of microspheres . The immunogenicity of the PorA-containing formulations was determined in mice after subcutaneous immunization . Liposomes were encapsulated in dextran and mannan microspheres with a high efficiency (70-90%) . Calcein liposomes, after a 5-day lag period, exhibited apparent zero-order release kinetics from both types of microspheres between Days 5 and 10 of incubation in vitro . The total release was 80 and 100% from mannan and dextran microspheres, respectively . The trimeric PorA conformation was preserved in the released liposomes and OMV and the antigen was partly recovered . The immunogenicity of PorA-liposomes and OMV encapsulated in dextran or mannan microspheres was preserved . In conclusion, PorA-liposomes and OMV could be encapsulated in dextran- and mannan-based microspheres with high efficiency . The immunogenicity of encapsulated antigen was preserved.

J Lipid Res, 2004 Apr, 45(4), 742 - 9 Epub 2004 Feb 01.
Human lipoproteins have divergent neutralizing effects on E . coli LPS, N . meningitidis LPS, and complete Gram-negative bacteria; Sprong T et al.; The use of lipoproteins has been suggested as a treatment for Gram-negative sepsis because they inhibit lipopolysaccharide (LPS)-mediated cytokine production . However, little is known about the neutralizing effects of lipoproteins on cytokine production by meningococcal LPS or whole Gram-negative bacteria . We assessed the neutralizing effect of LDLs, HDLs, and VLDLs on LPS- or whole bacteria-induced cytokines in human mononuclear cells . A strong inhibition of Escherichia coli LPS-induced interleukin-1beta (IL-1beta), tumor necrosis factor-alpha, and IL-10 by LDL and HDL was seen, whereas VLDL had a less pronounced effect . In contrast, Neisseria meningitidis LPS, in similar concentrations, was neutralized much less effectively than E . coli LPS . Effective neutralization of meningococcal LPS required a longer interaction time, a lower concentration of LPS, or higher concentrations of lipoproteins . The difference in neutralization was independent of the saccharide tail, suggesting that the lipid A moiety accounted for the difference . Minimal neutralizing effects of the lipoproteins were observed on whole E . coli or N . meningitidis bacteria under all conditions tested . These results indicate that efficient neutralization of LPS depends on the type of LPS, but a sufficiently long interaction time, a low LPS concentration, or high lipoprotein concentration also inhibited cytokines by the less efficiently neutralized N . meningitidis LPS . Irrespective of these differences, whole bacteria showed no neutralization by lipoproteins.

Immunol Allergy Clin North Am, 2003 Nov, 23(4), 769 - 86
Meningococcal immunology; Lepow ML et al.; There is a major need for an effective vaccine against serogroup B disease . The long-term efficacy of the serogroups A, C, Y and W135 conjugate vaccines and the need for booster vaccines has to be determined, as does the effect of changing epidemiology in the United States and worldwide . Control of serogroup A disease in sub-Saharan Africa is a major challenge.

Acta Med Port, 2003 Sep-Oct, 16(5), 321 - 6
{Assessment of severity of meningococcal sepsis in children}; Oom P et al.; Despite advances in critical care medicine, acute meningococcal infection remains complicated by high mortality . Different prognostic scoring systems have been developed but none of them is largely used . The objective of this study was to evaluate the performance at admission to the pediatric intensive care unit (PICU) of five severity scores in children with proven and unproven meningococcal infection . Our results seem to indicate that the Neisseria Sepsis Index (NESI) and the Rotterdam Score (RS) perform better than the other scores, being appropriate tools to assess severity of illness at admission to the PICU in children with proven or presumed meningococcal infection.

J Clin Pathol, 2004 Feb, 57(2), 208 - 9
Waterhouse-Friderichsen syndrome as a result of non-meningococcal infection; Hamilton D et al.; Waterhouse-Friderichsen syndrome--massive adrenal haemorrhage in the setting of overwhelming clinical sepsis--is usually taken at necropsy to indicate meningococcal infection, and may be the only evidence of this pathogen . This report describes three fatal cases of the syndrome in which the causative organism proved to be a streptococcus . The organisms were detected during routine coroners' autopsies with histology and microbiological investigations . In two cases, the syndrome followed Streptococcus pneumoniae infection and in a third beta haemolytic streptococcus group A . Thus, adrenal haemorrhage alone cannot be taken to indicate meningococcal disease and other pathogens, particularly streptococcus, must be considered.

Annu Rev Med, 2004, 55, 333 - 53
Opportunities for control of meningococcal disease in the United States; Raghunathan PL et al.; The United States currently has relatively low rates of meningococcal disease caused by Neisseria meningitidis . Serogroups Y, C, and B are most common . Although most cases are sporadic, a minority are associated with outbreaks . Pediatric populations have disproportionately higher rates of disease, but nearly two thirds of all cases occur in persons aged 15 years and older . The major challenge to control of domestic meningococcal disease is the absence of a vaccine to prevent sporadic cases spanning many age groups . The quadrivalent A/C/Y/W-135 meningococcal polysaccharide vaccine is licensed in the United States, but because of its limited efficacy in children under two years of age, it is recommended for high-risk groups and outbreak response rather than routine childhood immunization . New conjugate meningococcal vaccines have successfully reduced endemic disease in the United Kingdom, and similar vaccines promise to have a dramatic impact on the burden of meningococcal disease in the United States.

Vaccine, 2004 Jan 26, 22(5-6), 629 - 42
Stability of mono- and trivalent meningococcal outer membrane vesicle vaccines; Arigita C et al.; The stability during storage of outer membrane vesicles (OMVs) of Neisseria meningitidis group B was studied . Three types of OMVs were compared for their stability, containing either one (monovalent) or three different PorA subtypes (trivalent), the latter with and without class 4 outer membrane protein (OMO, RmpM) . Aqueous formulations were stored freeze-dried (4 degrees C), frozen (-70 degrees C) and in liquid form at 4, 37 and 56 degrees C . Physico-chemical properties and immunogenicity of the OMVs as well as PorA conformation and antigenicity (P1.7-2,4, the subtype present in all formulations) were monitored during 1 year . At -70 or 4 degrees C, the structure and immunogenicity of OMVs was preserved . Storage of OMVs at high temperatures (37 or 56 degrees C) induced destruction of the OMV structure and denaturation of PorA, followed by chemical degradation . Immunogenicity decreased or was lost completely . Changes observed in the fluorescence spectra of degraded OMVs were also seen in tryptophan (Trp) and tyrosine (Tyr) derivatives incubated at 56 degrees C, indicating the occurrence of chemical degradation of tryptophan and tyrosine residues in PorA . Trivalent OMVs were slightly more stable at 37 degrees C than monovalent OMVs as assessed by in vitro methods, but these differences did not result in differences in the immunogenicity . The stability of trivalent OMVs was not affected by the presence of RmpM . Both trivalent and monovalent OMVs could be freeze-dried with preservation of their immunogenicity . In conclusion, OMVs are sensitive to elevated temperatures, but are stable in the frozen or freeze-dried state or when stored at 4 degrees C in the liquid state.

Lancet, 2004 Jan 17, 363(9404), 203 - 9
Role of interleukin 6 in myocardial dysfunction of meningococcal septic shock; Pathan N et al.; BACKGROUND: Myocardial failure has a central role in the complex pathophysiology of septic shock and contributes to organ failure and death . During the sepsis-induced inflammatory process, specific factors are released that depress myocardial contractile function . We aimed to identify these mediators of myocardial depression in meningococcal septic shock . METHODS: We combined gene-expression profiling with protein and cellular methods to identify a serum factor causing cardiac dysfunction in meningococcal septic shock . We identified genes that were significantly upregulated in blood after exposure to meningococci . We then selected for further analysis those genes whose protein products had properties of a myocardial depressant factor--specifically a 12-25 kDa heat-stable protein that is released into serum shortly after onset of meningococcal infection . FINDINGS: We identified 174 significantly upregulated genes in meningococcus-infected blood: six encoded proteins that were of the predicted size and had characteristics of a myocardial depressant factor . Of these, interleukin 6 caused significant myocardial depression in vitro . Removal of interleukin 6 from serum samples of patients with meningococcaemia and from supernatants of inflammatory cells stimulated by meningococci in vitro abolished the negative inotropic activity . Furthermore, concentrations in serum of interleukin 6 strongly predicted degree of myocardial dysfunction and severity of disease in children with meningococcal septic shock . INTERPRETATION: Interleukin 6 is a mediator of myocardial depression in meningococcal disease . This cytokine and its downstream mediators could be a target for future treatment strategies.

Rev Med Interne, 2004 Jan, 25(1), 3 - 7
{Extra-meningeal meningococcal infection: report of 14 cases}; Guignard S et al.; INTRODUCTION AND METHOD: Fifty-five patients (17 adults, 38 children) with meningococcal infection were admitted between 1986 and 2002 in a university hospital (500 beds) . Fourteen of them (nine adults, five children) presented with an extra-meningeal infection . We compared adults and children presentations . RESULTS: All adults had immunodeficiency . Septic locations were various (three bacteriemia, four pneumoniae, one infected ascitis, one cutaneous abscess) . All patients received amoxicillin or third generation cephalosporin . Hospitalisation was prolonged (mean: 47 days) . Seven patients required intensive care unit admission, and two of them died . All children (all were less than 36-month-old) presented with fever . Only one was immunodeficient (infected by human immunodeficiency virus) . Neisseria meningitidis grew from blood in four, and in the throat for the remaining one . Hospitalisation was of short duration (mean: 4 days) and none of the children required intensive care unit . All the children recovered rapidly with antibiotics . CONCLUSION: Outcome of extra-meningeal infection with N . meningitidis is different in adults and children . Adults present with immunodeficiency, infection is severe and patients present with various clinical features; children have a more homogeneous clinical presentation (fever) and outcome is excellent.

Infection, 2003 Dec, 31(6), 392 - 7
Meningococcal disease in catalonia 1 year after mass vaccination campaign with meningococcal group C polysaccharide vaccine; Cardenosa N et al.; BACKGROUND: The aim of this study was to investigate the clinical and epidemiological characteristics of meningococcal disease in Catalonia (Spain) after vaccination with the polysaccharide vaccine . PATIENTS AND METHODS: Cases were collected by the Statutory Diseases Reporting System . RESULTS: 176 cases were reported, an overall incidence of 2.9/100,000 persons/year . 60% of cases occurred during winter and spring . The case fatality rate was 6.3% . The highest age incidence was in children under 2 years of age (48/100,000 persons/year) . Comparison of the cases detected by the Statutory Diseases Reporting System with those obtained by the Microbiological Reporting System shows that meningococcal disease surveillance in Catalonia was relatively complete (95.7%), with a positive predictive value of 66.3% . 115 cases (65%) were culture-confirmed with a rate of 1.9/100,000 persons/year . 86 (75%) cases were due to Neisseria meningitidis serogroup B and 21 to serogroup C (18%) . CONCLUSION: Although infections due to serogroup C have decreased after mass vaccination with the polysaccharide vaccine, it is likely that the number of infections will decrease further with the conjugate meningococcal group C vaccine.

FEMS Immunol Med Microbiol, 2004 Jan 15, 40(1), 89 - 94
Analysis of Moraxella catarrhalis outer membrane antigens cross-reactive with Neisseria meningitidis and Neisseria lactamica; Troncoso G et al.; Mouse sera against outer membrane proteins from Moraxella catarrhalis, Neisseria meningitidis and Neisseria lactamica, and human sera from both healthy individuals and patients convalescing from meningococcal meningitis were used to identify cross-reactive antigens . Mouse anti-N . meningitidis and anti-N . lactamica sera recognized 77, 62 and 32 kDa outer membrane antigens in M . catarrhalis strains; on the contrary, the meningococcal porin PorB (38-42 kDa) was recognized by one of the two anti-M . catarrhalis sera . Human sera from both healthy individuals and patients convalescing from meningococcal meningitis also showed cross-reactive antibodies against these proteins . The existence of cross-reactive antigens in M . catarrhalis and N . meningitidis (as well as in N . lactamica) could favor the development of natural immunization against both pathogens.

J Endotoxin Res, 2003, 9(6), 401 - 8
Regulation of interactions of endotoxin with host cells; Gioannini TL et al.; Potent Toll-like receptor 4 (TLR4)-dependent cell activation by endotoxin requires lipopolysaccharide-binding protein (LBP) and CD14-dependent delivery of endotoxin to cells containing MD-2 and TLR4 . We have used metabolically labeled {(14)C} meningococcal lipooligosaccharide (LOS), purified recombinant endotoxin-binding proteins, and cultured endothelial cells to better define protein:endotoxin intermediates key in cell activation in the absence of functional membrane (m) CD14 . Protein:endotoxin complexes or aggregates (agg) were purified by gel sieving and characterized by immunocapture and bio-assays . Cell activation closely correlated with LBP, albumin and soluble (s) CD14-dependent conversion of endotoxin agg (M(r) > or = 20 x 10(6)) to monomeric (M(r) approximately 55 x 10(3)) endotoxin:sCD14 complexes . Ordered interaction of LBP (+ albumin) and sCD14 with LOSagg was required for the efficient formation of a bioactive endotoxin:sCD14 complex and potent cell activation . Increasing the ratio of LBP/sCD14 or addition of bactericidal/permeability-increasing protein (BPI) reduced accumulation of endotoxin:sCD14 complexes and instead yielded aggregates of endotoxin (M(r) approximately 1-20 x 10(6)) containing LBP or BPI that were taken up by cells in a CD14- and TLR4-independent manner without inducing pro-inflammatory responses . These findings strongly suggest that host machinery linked to TLR4-dependent cellular activation or TLR4-independent cellular clearance of endotoxin selectively recognizes different protein:endotoxin complexes . At the outset of infection, the low concentrations of LBP present and absence of extracellular BPI favor formation of pro-inflammatory endotoxin:CD14 complexes . The mobilization of LBP and BPI that is triggered by inflammation directs endotoxin for clearance and hence resolution of endotoxin-triggered inflammation.

Arzneimittelforschung, 2003, 53(12), 805 - 13
Development of new vaccines against meningococcal disease; Broker M; Meningococcal diseases continue to have a major public health impact in many countries . Five major groups of Neisseria meningitidis (A, B, C, Y and W135) are responsible for most meningoccocal diseases . Plain polysaccharides vaccines for Nelsseria meningitidis groups A, C, Y and W-135 have been in use for approximately 20 years, both to prevent invasive disease in high-risk population and to control disease outbreaks . However, these conventional meningococcal vaccines induce a relatively short-lasting T-cell independent immune response, are not effective in children under two years of age and can induce hyporesponsiveness . New meningococcal group C conjugate vaccines have since been developed, which offer solid advantages over the currently licensed plain polysaccharide vaccines . There is still no vaccine available against the serogroup B, which is a major cause of invasive disease . This report summarises the different approaches to the development of vaccines against the pathogenic meningococci.

J Bacteriol, 2004 Feb, 186(3), 870 - 4
DNA binding by the meningococcal RdgC protein, associated with pilin antigenic variation; Moore T et al.; The RdgC protein of Neisseria gonorrhoeae is required for efficient pilin antigenic variation, although its precise role has yet to be established . We demonstrate that the nearly identical RdgC from Neisseria meningitidis binds DNA with little specificity for sequence or structure, like the Escherichia coli protein . We also show that neither protein is able to constrain torsional tension in relaxed DNA . These data exclude several possible roles for RdgC in pilin antigenic variation and suggest that RdgC performs a similar function in both E . coli and the Neisseria spp.

Br J Biomed Sci, 2003, 60(4), 204 - 9
Irish strains of Neisseria meningitidis: characterisation using multilocus sequence typing; Murphy KM et al.; A total of 56 Neisseria meningitidis strains are analysed using multilocus sequence typing (MLST) . Twenty-nine distinct sequence types (STs) were identified, eight of which were new . Four known hypervirulent clones--ST-11 (electrophoretic type {ET}-37) complex, ST-44 complex (lineage 3), ST-32 (ET-5) complex and ST-8 complex (cluster A4)--were identified by MLST in 35 disease-associated and four carrier strains . Two other clones (ST-22 complex and ST-269 complex) were identified in nine disease-associated and one carrier strain . The remaining strains were heterogeneous . Additional sequencing within the FumC gene further distinguished the ET-15 clone within the ST-11 (ET-37) clonal complex . This resolution of isolates into genetic clones by MLST enhances the more traditional techniques of serotyping and serosubtyping . The data obtained established that hyperendemic meningococcal disease in Ireland could be attributed to strains belonging to four major hypervirulent clones, all of which account for elevated levels of disease worldwide . The extra information provided by MLST will be used to study the population structure and epidemiology of N . meningitidis and will allow a comparison of Irish strains with those circulating globally.

Scand J Immunol, 2004 Jan, 59(1), 34 - 9
The four mouse IgG isotypes differ extensively in bactericidal and opsonophagocytic activity when reacting with the P1.16 epitope on the outer membrane PorA protein of Neisseria meningitidis; Michaelsen TE et al.; Mouse monoclonal antibodies (MoAbs) of the four IgG isotypes, all specific for the P1.16 epitope on the meningcoccal PorA protein, were tested for functional activities . The avidities of the antibodies, measured by NH4SCN elution in enzyme-linked immunosorbent assay, showed similar values for all the MoAbs . The serum bactericidal activity (SBA) defined as the lowest concentration of antibodies giving 50% reduction in the number of meningococcal colony-forming units using human serum as complement, showed a hierarchy of IgG3 >> IgG2b > IgG2a >> IgG1 . For the opsonophagocytosis (OP), the hierarchy was IgG3 > IgG2b = IgG2a >> IgG1 . OP was measured in flow cytometry using log-phase live meningococci as target cells, normal human peripheral blood polymorphonuclear cells (PMNs) as effector cells and human serum as a complement source . The mouse MoAbs were negative in OP when using human PMNs in the absence of complement . The results demonstrate the importance of choosing the right isotype of mouse MoAbs when using them to judge the potential vaccine importance of their corresponding antigen . If such MoAbs should be used for passive vaccination against infectious diseases, the isotype would presumably play an important role for their anticipated clinical effects.

J Thromb Haemost, 2004 Jan, 2(1), 54 - 7
A functional single nucleotide polymorphism in the thrombin-activatable fibrinolysis inhibitor (TAFI) gene associates with outcome of meningococcal disease; Kremer Hovinga JA et al.; In meningococcal sepsis, disseminated intravascular coagulation with deposition of fibrin and formation of microthrombi occurs in various organs and enhanced inhibition of fibrinolysis is associated with adverse outcome . Recently, TAFI (thrombin-activatable fibrinolysis inhibitor) was identified as a link between coagulation and fibrinolysis, as TAFI can be activated by thrombin and once activated potently attenuates fibrinolysis . On the basis of this one would predict that DNA polymorphisms that increase TAFI activity would deteriorate the outcome in meningococcal sepsis . Therefore, we studied the prevalence of the Thr325Ile dimorphism in the TAFI gene, which is associated with increased TAFIa stability and activity in 50 patients who survived meningococcal disease, in 176 first-degree relatives of a consecutive patient series with meningococcal disease and 212 controls from the same geographic region . The TAFI 325 Ile/Ile genotype was slightly more common among parents of patients with meningococcal disease than in controls (11% vs . 7.1%, P= 0.24) . This difference was pronounced among the subgroup of parents of non-surviving patients (19.2%, P= 0.03) . Patients whose parents were carriers of the TAFI 325 Ile/Ile genotype had a 1.6-fold (95% CI 0.7-3.7) higher risk to contract meningococcal disease and a 3.1-fold (95% CI 1.0-9.5) increased risk to die from the infection compared with all other genotypes . Survivors had a genotype frequency (4.0%) that was lower than in the general population . TAFI 325 variants affect the outcome of meningococcal disease.

J Am Coll Health, 2003 Jul-Aug, 52(1), 41 - 3
The impact of educational efforts on first-year university students' acceptance of meningococcal vaccine; Collins L et al.; The authors measured the impact of educational efforts on the number of college students who received meningococcal vaccine . First-year Brown University students from the classes of 2004 (n = 1,562) and 2005 (n = 1,518) received educational vaccine materials before they arrived on campus, whereas students from the class of 2003 (n = 1.441) did not . Students in the class of 2003, 13% (n = 184) of whom had received vaccine before their arrival on campus, served as the baseline . These educational efforts by the college health services before students arrived on campus increased the number of students immunized before campus arrival to 46% (n = 724) for the class of 2004, and 60% (n = 913) for the class of 2005 . Education about the benefits of meningococcal vaccine before students' arrival on campus increased both the number of immunized students and the overall immunization rate among students.

J Clin Microbiol, 2004 Jan, 42(1), 320 - 8
Use of real-time PCR to resolve slide agglutination discrepancies in serogroup identification of Neisseria meningitidis; Mothershed EA et al.; Neisseria meningitidis is a leading cause of bacterial meningitis and septicemia in children and young adults in the United States . Rapid and reliable identification of N . meningitidis serogroups is crucial for judicious and expedient response to cases of meningococcal disease, including decisions about vaccination campaigns . From 1997 to 2002, 1,298 N . meningitidis isolates, collected in the United States through the Active Bacterial Core surveillance (ABCs), were tested by slide agglutination serogrouping (SASG) at both the ABCs sites and the Centers for Disease Control and Prevention (CDC) . For over 95% of isolates, SASG results were concordant, while discrepant results were reported for 58 isolates . To resolve these discrepancies, we repeated the SASG in a blinded fashion and employed ctrA and six serogroup-specific PCR assays (SGS-PCR) to determine the genetic capsule type . Seventy-eight percent of discrepancies were resolved, since results of the SGS-PCR and SASG blinded study agreed with each other and confirmed the SASG result at either state health laboratories or CDC . This study demonstrated the ability of SGS-PCR to efficiently resolve SASG discrepancies and identified the main cause of the discrepancies as overreporting of these isolates as nongroupable . It also reemphasized the importance of adherence to quality assurance procedures when performing SASG and prompted prospective monitoring for SASG discrepancies involving isolates collected through ABCs in the United States.

Clin Diagn Lab Immunol, 2004 Jan, 11(1), 83 - 8
Immunologic hyporesponsiveness to serogroup C but not serogroup A following repeated meningococcal A/C polysaccharide vaccination in Saudi Arabia; Jokhdar H et al.; In Saudi Arabia, vaccination with the meningococcal A/C polysaccharide (MACP) vaccine is advised every 3 years . A clinical outcome study was performed to test the effect of repeat vaccination with the MACP vaccine on the immune responses among Saudi nationals who live in the Makkah and Jeddah areas . Subjects (n = 230) aged 10 to 29 years were selected: 113 subjects with two or more prior vaccinations with the MACP vaccine, 79 subjects with one prior vaccination with the MACP vaccine, and 38 subjects naive to vaccination with the MACP vaccine . All subjects received the MACP vaccine in 2002, and serum bactericidal antibody (SBA) titers were measured before and 1 month after vaccination with the MACP vaccine . For serogroup C, geometric mean SBA titers 1 month following vaccination with the MACP vaccine were 708.6 (95% confidence interval {CI}, 217.5 to 2,308.9) for those naive to prior vaccination with the MACP vaccine, and they were significantly higher (P < 0.0001) than 25.0 (95% CI, 12.4 to 50.2) for those who had received one prior vaccination with the MACP vaccine and 32.4 (95% CI, 18.7 to 56.4) for those who had received two or more doses of the MACP vaccine . For serogroup A, the geometric mean SBA titer 1 month after receipt of the MACP vaccine was 1,649.3 (95% CI, 835.2 to 3,256.9) for those naive to prior vaccination, and the titers were lower (P = 0.67) than 2,185.7 (95% CI, 1,489.4 to 3,207.7) for those who had received one prior dose of the MACP vaccine and significantly lower (P = 0.042) than 3,540.8 (95% CI, 2,705.2 to 4,634.5) for those who had received two or more doses of the MACP vaccine . For serogroup C, the proportions of nonresponders (SBA titers, <8) were 19% for the naive cohort, 52% for the cohort with one prior vaccination, and 49% for the cohort with two or more prior vaccinations . Following repeated doses of the MACP vaccine, hyporesponsiveness to serogroup C is evident, with high percentages of MACP vaccinees having SBA titers below the putative protective SBA titer . Serogroup A responses following vaccination with the MACP vaccine were boosted . Introduction of the serogroup C conjugate vaccine would provide long-term protection against serogroup C disease; however, quadrivalent conjugate vaccines are required to provide long-time protection against disease caused by serogroups A, W135, and Y.

Clin Diagn Lab Immunol, 2004 Jan, 11(1), 1 - 5
Assignment of Neisseria meningitidis serogroups A, C, W135, and Y anticapsular total immunoglobulin G (IgG), IgG1, and IgG2 concentrations to reference sera; Joseph H et al.; Meningococcal serogroup-specific immunoglobulin G (IgG), IgG1, and IgG2 concentrations were assigned to three reference sera, CDC 1992, 89-SF, and 96/562, for meningococcal serogroups A, C, Y, and W135 via the method of cross standardization . The sum of the serogroup-specific IgG1 and IgG2 concentrations determined for the four meningococcal serogroups showed good agreement with the serogroup-specific IgG either determined here or as previously represented . Following the assignment of meningococcal serogroup-specific IgG1 and IgG2 concentration to these reference sera, a meningococcal serogroup-specific IgG1 and IgG2 enzyme-linked immunosorbent assay protocol was developed . The serogroup A and C specific subclass distribution of a panel of adult sera collected following vaccination with any combination of meningococcal serogroup C conjugate, bivalent, or tetravalent polysaccharide vaccines was determined . For the determination of serogroup W135 and Y specific subclass distribution, an adolescent panel 28 days following a single dose of either tetravalent polysaccharide or conjugate vaccine was used . The sum of the serogroup-specific IgG1 and IgG2 showed strong correlation with the serogroup-specific total IgG determined . The assignment here of IgG1 and IgG2 subclasses to these reference sera will allow more detailed evaluation of meningococcal conjugate and polysaccharide vaccines.

Expert Rev Vaccines, 2003 Aug, 2(4), 571 - 82
Neisseria meningitidis serogroup A vaccines: an overview; Vergnano S et al.; A recent report by the Weekly Epidemiological Record of an outbreak of Neisseria meningitidis serogroup A in the Great Lakes region shows that meningococcal epidemics are an unsolved problem in resource-poor countries, particularly in Africa {1} . During the last epidemic wave in the 1990s, about 350,000 people developed meningitis and 1000 people died {101} . An effective polysaccharide vaccine has been available since the early 1970s . Unfortunately, attempts to contain the epidemics by timely detection of cases through active surveillance and prompt mass vaccination campaigns have failed to prevent the deaths of thousands of people in several African countries in the 1980s and 1990s . This article describes the epidemiology of N . meningitidis serogroup A, the available polysaccharide vaccines, their advantages and limitations . The current vaccination policies and their economic implications are discussed, to clarify why the use of an effective vaccine has, to date, been disappointing . The recent exciting developments with respect to conjugate vaccines are described.

Expert Rev Vaccines, 2003 Oct, 2(5), 673 - 81
Meningococcal serogroup B infections: a search for a broadly protective vaccine; Vermont CL et al.; Meningococcal disease is mainly caused by serogroup B in many West European countries . Recently, a highly efficacious vaccine against infections caused by serogroup C has been introduced in the UK and The Netherlands . However, an effective vaccine against serogroup B has not yet become available . Outer membrane vesicle vaccines against serogroup B were previously tested in large Phase III trials but showed a low efficacy in young children . In addition, the high variability of the vaccines' main component, porin A, potentially diminishes its efficacy . Therefore, several approaches in either optimizing these outer membrane vesicle vaccines or searching for novel, highly conserved antigens are currently under investigation . The sequencing of the meningococcal genome has provided new opportunities to detect additional immunogenic epitopes . In this review, the developments in the search for a broadly protective meningococcal serogroup B vaccine will be discussed.

Nurs Times, 2003 Dec 2-8, 99(48), 48 - 50
Aspergillus: the invisible threat; Kibbler C; Although the media constantly regales the public with stories of 'killer' infections, few people are aware of their daily exposure to a fungus that can cause fatal infections in a susceptible host . It has been estimated that at least as many die from invasive aspergillosis each year as from meningococcal sepsis.

Antimicrob Agents Chemother, 2004 Jan, 48(1), 358 - 9
Sequencing of Neisseria meningitidis penA gene: the key to success in defining penicillin G breakpoints; Arreaza L et al.; Testing of susceptibility to penicillin G by E-test and sequencing of an internal fragment of the penA gene were done for 43 meningococcal strains . Those strains for which the MIC was >/=0.094 micro g/ml showed mosaic alleles, so 0.094 micro g/ml is suggested as the penicillin G intermediate breakpoint when E-test is used.

Clin Infect Dis, 2003 Dec 15, 37(12), 1639 - 42 Epub 2003 Nov 17.
The role of particular strains of Neisseria meningitidis in meningococcal arthritis, pericarditis, and pneumonia; Vienne P et al.; The clinical presentations of meningococcal diseases other than meningitis or meningococcemia may lead to erroneous diagnosis . Although several reports have described unusual meningococcal diseases, the Neisseria meningitidis strains involved in these forms have been poorly characterized . In this study, meningococcal arthritis and pericarditis were confirmed by isolation of N . meningitidis and/or detection of meningococcal DNA in synovial or pericardial fluid, respectively, and meningococcal pneumonia was detected by isolation of N . meningitidis from blood . From 1999 through 2002, meningococcal disease was bacteriologically confirmed in 26 cases of arthritis, 6 cases of pericarditis, and 33 cases of pneumonia by the National Reference Center for the Meningococci in Paris . We found a statistically significant association between strains of serogroup W135, mostly of the clonal complex ET-37, and arthritis . Pneumonia was most frequently diagnosed in patients aged >70 years, and 54.5% of the strains belonged to serogroup W135, although these strains had heterogeneous phenotypes . Bacteremia is a key step in the pathophysiology of meningococcal disease and precedes any form of invasive infection.

Infect Immun, 2004 Jan, 72(1), 559 - 69
Development, characterization, and functional activity of a panel of specific monoclonal antibodies to inner core lipopolysaccharide epitopes in Neisseria meningitidis; Gidney MA et al.; A panel of six murine monoclonal antibodies (MAbs) recognizing inner core lipopolysaccharide (LPS) epitopes of Neisseria meningitidis was prepared and characterized in order to determine the diversity of inner core LPS glycoforms among disease and carrier isolates . Two of these MAbs, L2-16 (immunoglobulin G2b {IgG2b}) and LPT3-1 (IgG2a), together with a third, previously described MAb, L3B5 (IgG3), showed reactivity, either individually or in combination, with all except 3 of 143 disease and carriage isolates (125 of 126 strains from blood, cerebrospinal fluid, or skin biopsy samples and 15 of 17 from nasopharyngeal cultures) . MAbs L3B5, L2-16, and LPT3-1 were further characterized in an indirect immunofluorescence assay . All three MAbs bound to the bacterial cell surface, findings that correlated strongly with whole-cell enzyme-linked immunosorbent assay and immunodot blots . However, in contrast to our findings with L3B5, cell surface binding of L2-16 or LPT 3-1 did not correlate with functional activity as determined by bactericidal or infant rat passive protection assays against wild-type N . meningitidis strains . These findings are provocative with respect to the requirements for protective activity of antibodies and the development of inner core LPS vaccines against invasive meningococcal disease.

Infect Immun, 2004 Jan, 72(1), 371 - 80
Neisseria meningitidis lipooligosaccharide structure-dependent activation of the macrophage CD14/Toll-like receptor 4 pathway; Zughaier SM et al.; Meningococcal lipopoly(oligo)saccharide (LOS) is a major inflammatory mediator of fulminant meningococcal sepsis and meningitis . Highly purified wild-type meningococcal LOS and LOS from genetically defined mutants of Neisseria meningitidis that contained specific mutations in LOS biosynthesis pathways were used to confirm that meningococcal LOS activation of macrophages was CD14/Toll-like receptor 4 (TLR4)-MD-2 dependent and to elucidate the LOS structural requirement for TLR4 activation . Expression of TLR4 but not TLR2 was required, and antibodies to both TLR4 and CD14 blocked meningococcal LOS activation of macrophages . Meningococcal LOS alpha or beta chain oligosaccharide structure did not influence CD14/TLR4-MD-2 activation . However, meningococcal lipid A, expressed by meningococci with defects in 3-deoxy-D-manno-octulosonic acid (KDO) biosynthesis or transfer, resulted in an approximately 10-fold (P < 0.0001) reduction in biologic activity compared to KDO2-containing meningococcal LOS . Removal of KDO2 from LOS by acid hydrolysis also dramatically attenuated cellular responses . Competitive inhibition assays showed similar binding of glycosylated and unglycosylated lipid A to CD14/TLR4-MD-2 . A decrease in the number of lipid A phosphate head groups or penta-acylated meningococcal LOS modestly attenuated biologic activity . Meningococcal endotoxin is a potent agonist of the macrophage CD14/TLR4-MD-2 receptor, helping explain the fulminant presentation of meningococcal sepsis and meningitis . KDO2 linked to meningococcal lipid A was structurally required for maximal activation of the human macrophage TLR4 pathway and indicates an important role for KDO-lipid A in endotoxin biologic activity.

Infect Immun, 2004 Jan, 72(1), 345 - 51
Vaccination with attenuated Neisseria meningitidis strains protects against challenge with live Meningococci; Li Y et al.; Meningococcal disease is a life-threatening infection caused by Neisseria meningitidis . Currently, there are no vaccines to prevent infection with serogroup B N . meningitidis strains, the leading cause of meningococcal meningitis in Europe and North America . Here we describe the construction and characterization of two attenuated serogroup B N . meningitidis strains, YH102 (MC58deltasia deltarfaF) and YH103 (MC58deltasia deltametH) . Both strains are markedly attenuated in their capacity to cause bacteremia in rodent models and have a reduced ability to survive in a human whole-blood assay . Immunization of adult mice with these strains leads to the development of bactericidal antibodies and confers sterilizing protection against challenge with homologous live bacteria . Furthermore, we show that the strains confer protection against infection by other serogroups . Use of the attenuated strains in animals with gene knockouts or after depletion of immunological effectors could be used to define the basis of protection, and human volunteer studies could be undertaken to examine the immune response following exposure to this important human pathogen.

Infect Immun, 2004 Jan, 72(1), 338 - 44
Infection with an avirulent phoP mutant of Neisseria meningitidis confers broad cross-reactive immunity; Newcombe J et al.; Successful vaccines against serogroup A and C meningococcal strains have been developed, but current serogroup B vaccines provide protection against only a limited range of strains . The ideal meningococcal vaccine would provide cross-reactive immunity against the variety of strains that may be encountered in any community, but it is unclear whether the meningococcus possesses immune targets that have the necessary level of cross-reactivity . We have generated a phoP mutant of the meningococcus by allele exchange . PhoP is a component of a two-component regulatory system which in other bacteria is an important regulator of virulence gene expression . Inactivation of the PhoP-PhoQ system in Salmonella leads to avirulence, and phoP mutants have been shown to confer protection against virulent challenge . These mutants have been examined as potential live attenuated vaccines . We here show that a phoP mutant of the meningococcus is avirulent in a mouse model of infection . Moreover, infection of mice with the phoP mutant stimulated a bactericidal immune response that not only killed the infecting strain but also showed cross-reactive bactericidal activity against a range of strains with different serogroup, serotype, and serosubtyping antigens . Sera from the mutant-infected mice contained immunoglobulin G that bound to the surface of a range of meningococcal strains and mediated opsonophagocytosis of meningococci by human phagocytic cells . The meningococcal phoP mutant is thus a candidate live, attenuated vaccine strain and may also be used to identify cross-reactive protective antigens in the meningococcus.

Infect Immun, 2004 Jan, 72(1), 332 - 7
Immune response to meningococcal serogroup C conjugate vaccine in asplenic individuals; Balmer P et al.; Asplenic individuals are known to be at increased risk of infection with encapsulated bacteria . Recent United Kingdom recommendations stated that this at-risk group should receive one dose of the meningococcal serogroup C conjugate (MCC) vaccine . However, the immune response of asplenic individuals to MCC vaccine is unknown . The immune response of asplenics (n = 130) to immunization with the MCC vaccine was investigated . Asplenic individuals had a significantly lower geometric mean titer (GMT) (157.8; 95% confidence interval {CI}, 94.5 to 263.3) of bactericidal antibody in serum (SBA) than an age-matched control group (n = 48) (1448.2; 95% CI, 751.1 to 2792.0) . However, 80% of asplenic individuals achieved the proposed protective SBA titer of > or =8 . No differences were observed between the two groups in the serogroup C-specific immunoglobulin G geometric mean concentration . A significant reduction in SBA GMT or the number of responders achieving an SBA titer of > or =8 was observed if the reason for splenectomy was a medical cause or if MCC vaccination occurred <10 years after splenectomy . Individuals (n = 29) who did not achieve an SBA titer of > or =16 were offered a second dose of MCC vaccine . Analysis of the SBA response revealed that 61% (14 of 23) of the individuals who received a second dose achieved a protective titer . In total, 93% of asplenic individuals achieved a titer of > or =8 following MCC vaccination (one or two doses combined) . We recommend that, following vaccination of asplenics, either the level of functional antibody should be determined, with a second dose of MCC vaccine offered to nonresponders, or two doses of MCC vaccine should be routinely offered.

Infect Immun, 2004 Jan, 72(1), 187 - 95
Immunization of female mice with glycoconjugates protects their offspring against encapsulated bacteria; Richter MY et al.; The immune system of the newborn is immature, and therefore it is difficult to induce protective immunity by vaccination in the neonatal period . Immunization of mothers during pregnancy against infections caused by encapsulated bacteria could thus be particularly attractive, as infants do not respond to polysaccharide (PS) antigens . Transmission of maternal vaccine-specific antibodies and protection of offspring against pneumococcal bacteremia and/or lung infection were studied in a neonatal murine model of pneumococcal immunization and infections . Adult female mice were immunized with native pneumococcal PS (PPS) of serotypes 1, 6B, and 19F or PPS conjugated to tetanus protein (Pnc-TT), and PPS-specific antibodies were measured in sera of mothers and their offspring . Effective transmission of maternal antibodies was observed, as PPS-specific immunoglobulin G levels in 3-week-old offspring of immunized mothers were 37 to 322% of maternal titers, and a significant correlation between maternal and offspring antibody levels was observed . The PPS-specific antibodies persisted for several weeks but slowly decreased over time . Offspring of Pnc-TT-immunized mothers were protected against pneumococcal infections with homologous serotypes, whereas PPS immunization of mothers did not protect their offspring, in agreement with the low titer of maternal PPS specific antibodies . When adult female mice were immunized with a meningococcal serogroup C conjugate vaccine (MenC-CRM), antibody response and transmission were similar to those observed for pneumococcal antibodies . Importantly, bactericidal activity was demonstrated in offspring of MenC-CRM-immunized mothers . These results demonstrate that this murine model of pneumococcal immunization and infections is suitable to study maternal immunization strategies for protection of offspring against encapsulated bacteria.

Clin Microbiol Infect, 2003 Dec, 9(12), 1245 - 7
Primary meningococcal conjunctivitis; Orden B et al.; Neisseria meningitidis is an uncommon cause of acute bacterial conjunctivitis . One case of primary meningococcal conjunctivitis in a healthy 6-year-old boy is reported . The patient was initially treated with a topical instillation of polymyxin B, neomycin and gramicidin in ophthalmic solution, and this was followed by systemic rifampin once the diagnosis had been established . No ocular or systemic complications developed.

J Pediatr (Rio J), 1998 Jul-Aug, 74(4), 306 - 14
{Evaluation of the therapeutic efficacy of dexamethasone in meningococcal meningitis}; Osmo AA et al.; OBJECTIVE: To evaluate the efficacy of dexamethasone as an auxiliary therapeutic tool to the antibiotics in hospitalized children with meningococcal meningitis . METHODS: A retrospective clinical comparative study was undertaken with children from a pediatric ward affected by laboratory proved meningococcal meningitis at a university hospital . Cases of children in state of shock at admission or deceased in the first 24 hours were excluded . During the period from 1987 to 1989 33 children were treated only with antibiotics (group A), while from 1990 to 1993 other 66 children received additionally dexamethasone (12mg/m2/24h) by intravenous route during four days beginning at the admission to the hospital (group B) . The two groups were evaluated at baseline through prognostic scores and analysis of their clinical and laboratorial characteristics obtained from data recorded at the admission . The parameters to evaluate dexamethasone efficacy were the comparative number of neurologic and systemic complications detected at the hospital, and the liquoric profile (leukocyte count, glucose and protein content) verified between day 9 and day 11 of hospitalization . RESULTS: The profile of the two groups (A and B) were homogeneously evaluated by the illness severity scores and their clinical and laboratorial characteristics . Nine complications were recognized in group A (27.2%) and 21 (31.8%) among those of group B, difference not significant . Likewise, there were not observed liquoric differences between the two groups related to the chimiocytologic pattern . CONCLUSIONS: No effect of dexamethasone therapy to prevent neurologic and systemic meningococcal meningitis complications was observed during hospitalization . Similarly no favorable effect in relation to the liquoric pattern verified between day 9 and day 11 of hospitalization was recognized.

Am J Med Genet A, 2004 Jan 1, 124(1), 60 - 6
Metaphyseal chondrodysplasia with cone-shaped epiphyses: a specific form involving the lower limbs; Dieux-Coeslier A et al.; Three unrelated patients affected by a characteristic metaphyseal chondrodysplasia with cup-shaped metaphyses of the knees are described . Lower femoral and upper tibial cone-shaped epiphyses were embedded in the metaphyses . Main clinical features are short stature, shortening of the lower limbs, limitation of knee extension, and normal hands length . Radiographs of skull, spine, and hands showed no abnormality . This particular appearance of the knees has been seldom described in acquired disease such as repeated injuries, meningococcemia, scurvy, and hypervitaminosis A . Metaphyseal dysplasias with these distinctive radiological findings of the knees are uncommon . Differential diagnosis includes trichoscyphodysplasia and acroscyphodysplasia among others . Two other cases reported by Kozlowski showed the most similarities to our three cases and defined a new form of metaphyseal dysplasia with specific lower limbs involvement and cup-shaped metaphyses .

J Bacteriol, 2004 Jan, 186(1), 244 - 7
Necessity of meningococcal gamma-glutamyl aminopeptidase for Neisseria meningitidis growth in rat cerebrospinal fluid (CSF) and CSF-like medium; Takahashi H et al.; The growth of a gamma-glutamyl aminopeptidase (GGT)-deficient Neisseria meningitidis strain was much slower than that of the parent strain in rat cerebrospinal fluid (CSF) and in a synthetic CSF-mimicking medium, and the growth failure was suppressed by the addition of cysteine . These results suggested that, in the environment of cysteine shortage, meningococcal GGT provided an advantage for meningococcal multiplication by supplying cysteine from environmental gamma-glutamyl-cysteinyl peptides.

Clin Exp Immunol, 2004 Jan, 135(1), 85 - 93
High-level endothelial E-selectin (CD62E) cell adhesion molecule expression by a lipopolysaccharide-deficient strain of Neisseria meningitidis despite poor activation of NF-kappaB transcription factor; Dixon GL et al.; Binding of host inflammatory cells to the endothelium is a critical contributor to the vascular damage characteristic of severe meningococcal disease and is regulated by endothelial cell adhesion molecules such as ICAM-1, VCAM-1 and CD62E . Intact meningococci induce far higher levels of CD62E than lipopolysaccharide (LPS) alone, whereas LPS is at least as potent as meningococci at inducing both VCAM-1 and ICAM-1 expression . This suggests that meningococci possess additional factors other than LPS present in whole bacteria that result in differential adhesion molecule expression . To investigate this possibility, we studied the capacity of an LPS-deficient isogenic strain of serogroup B Neisseria meningitidis H44/76 (lpxA-) to induce endothelial cell adhesion molecule expression and translocation of the transcription factor NF-kappaB, and compared it to both parent and unencapsulated strains of both B1940 and H44/76 and purified LPS . Although the LPS-deficient isogenic mutant of strain H44/76 was found to be a poor inducer of NF-kappaB, it induced higher levels of CD62E expression than LPS alone . These data provide evidence that intact meningococci induce a range of signals in the endothelium that are distinct from those seen with purified LPS alone and that they occur in a LPS-dependent and LPS-independent manner . These signals may explain the potent effects of N . meningitidis on CD62E expression on vascular endothelium and provide a basis for the complex endothelial dysregulation seen in meningococcal sepsis.

Vaccine, 2004 Jan 2, 22(3-4), 335 - 44
Quantification of O-acetyl, N-acetyl and phosphate groups and determination of the extent of O-acetylation in bacterial vaccine polysaccharides by high-performance anion-exchange chromatography with conductivity detection (HPAEC-CD); Kao G et al.; The O-acetyl groups in meningococcal A and typhoid Vi polysaccharides (PSs) are functional immunogenic epitopes in humans . To quantify and determine the extent of O-acetylation in these and other bacterial vaccine PSs, anion-exchange HPLC methods have been developed for quantification of O-acetyl, N-acetyl, and phosphate groups in the PSs after these groups were hydrolyzed into anions . The O-acetylation in meningococcal A, C, Y and W-135, pneumococcal 9 V and 18C and typhoid Vi PSs were analyzed . The O-acetyl group was selectively released from a PS as acetate by mild alkaline hydrolysis in 10 or 20 mM NaOH at 37 degrees C until maximum release . The acetate in the hydrolysate was then quantified by high-performance anion-exchange chromatography with conductivity detection (HPAEC-CD) after removal of the PS by filtration with a 10,000 molecular-weight-cut-off membrane . Since the extent of O-acetylation on the PSs depends on bacterial species, strains and growth conditions, the N-acetyl group of amino-sugars, phosphate or monosaccharide components of the PSs were also quantified using HPAEC with conductivity or amperometry detection to determine the molar ratios of the O-acetyl group to these components . The average numbers of O-acetyl molecules in one PS repeating unit of the PSs were obtained from the molar ratios . Besides the O-acetyl determination, the pyruvate component in non-O-acetylated pneumococcal type 4 PS was analyzed by the HPAEC method . The HPAEC method can quantify the O-acetyl content in 0.2 microg of the meningococcal C PS and has a sensitivity at least 10 times higher than that of the colorimetric Hestrin assay . The method can be used for routine analysis of O-acetylation of PSs for quality control of vaccine PSs.

Crit Care Med, 2003 Dec, 31(12), 2788 - 93
Role of functional plasminogen-activator-inhibitor-1 4G/5G promoter polymorphism in susceptibility, severity, and outcome of meningococcal disease in Caucasian children; Haralambous E et al.; OBJECTIVE: Meningococcal sepsis invariably is associated with coagulopathy . We have previously reported an association between mortality rate in meningococcal disease and the functional 4G/5G promoter polymorphism of the plasminogen-activator-inhibitor (PAI)-1 gene in a small patient cohort . In a much larger cohort, we aimed to confirm these results and further investigate the role of the 4G/5G polymorphism in determining susceptibility, outcome, and complications of disease.DESIGN Susceptibility was investigated in two separate studies, a case-control study and a family-based transmission study, each test using a separate patient cohort . Severity was investigated using clinical diagnosis, the presence of vascular complications, Pediatric Risk of Mortality (PRISM)-predicted morality, and actual mortality . SETTING: University hospital and laboratories . SUBJECTS: Subjects were 510 UK pediatric patients, 210 parents of patients, and 155 UK Caucasian controls . INTERVENTIONS: DNA extraction and 4G/5G PAI-1 genotyping was carried out using published techniques . MEASUREMENTS AND MAIN RESULTS: Predicted mortality distribution differed significantly between genotypes (p =.05) with a significantly higher median PRISM in the 4G/4G (41.1%) than the 4G/5G (23.4%) and 5G/5G (19.0%) genotyped patients combined (p =.02) . Actual mortality rate was significantly associated with both genotype (chi-square = 14.8, p =.001) and allele frequencies (chi-square = 14.0, p <.0001), with more deaths in the 4G/4G (28.4%) than the 4G/5G and 5G/5G genotyped patients combined (14.9%; chi-square = 7.9; p =.005; risk ratio, 1.9; 95% confidence interval, 1.2-3.0) . Logistic regression indicated a 40% and 91% reduction in the odds of dying if a patient was either 4G/5G or 5G/5G, respectively, in comparison to a 4G homozygous patient . When analyzed by clinical diagnosis, the association with death was found only in the sepsis group (chi-square = 18.7, p <.0001; risk ratio, 2.7; 95% confidence interval, 1.6-4.6) . In survivors of disease, a significantly higher proportion of 4G/4G patients suffered from vascular complications (chi-square = 6.7, p =.03; risk ratio, 2.4; 95% confidence interval, 1.1-5.0) . The 4G/5G polymorphism was not associated or linked with susceptibility (case-control result, p =.6; family-based transmission study results, p =.2) . CONCLUSIONS: This study confirms that Caucasian pediatric patients carrying the functional PAI-1 4G/4G genotype are at an increased risk of developing vascular complications and dying from meningococcal disease.

Clin Ther, 2003 Oct, 25(10), 2614 - 30
Epidemiologic impact and cost-effectiveness of universal infant vaccination with a 7-valent conjugated pneumococcal vaccine in the Netherlands; Bos JM et al.; BACKGROUND: Streptococcus pneumoniae is one of the main causes of bacterial meningitis, bacteremia, pneumonia, and otitis media in the Netherlands . These diseases lead to substantial mortality, morbidity, and costs . The societal impact is especially severe because most cases occur in very young infants . OBJECTIVE: The aim of this study was to estimate the epidemiological impact and cost-effectiveness of universal infant vaccination with a 7-valent conjugated pneumococcal vaccine in the Netherlands . METHODS: Decision analysis was performed using epidemiological data and data on health care resource use from 1996 to 2001 . A model was used to project the impact of pneumococcal vaccination on the incidence of pneumococcal infections in infants and children from birth to age 10 years . Costs, benefits, and health gains were estimated, and cost-effectiveness was calculated . All analyses were performed from a societal perspective . RESULTS: On average, 339 cases per year of invasive pneumococcal infection occurred in infants and children from birth to age 10 years in the Netherlands from 1996 to 2001 . The model predicted that introduction of the 7-valent conjugated pneumococcal vaccine would prevent 48 cases of bacterial meningitis and 88 cases of pneumococcal bacteremia per year, as well as 42,695 cases of pneumococcal otitis media and 3411 cases of invasive pneumococcal pneumonia . The model also predicted that vaccination would save 13 lives per year and prevent 31 cases of lifelong sequelae, rendering 382 discounted quality-adjusted life-years (QALYs) gained or 329 discounted life-years gained per year . Considering these health gains, vaccination would prevent Euro 9,453,600 of direct and indirect medical costs of meningococcal and pneumococcal infections in the Netherlands, including acute medical care, management of sequelae, and lost time at work . With a vaccine price of Euro 40 per dose, the base-case cost-effectiveness ratio would be Euro 71,250 per QALY . The model was sensitive to changes in incidence of infections, vaccine effectiveness, and vaccine price . CONCLUSIONS: Our analytic model predicted that universal pneumococcal vaccination of infants in the Netherlands could prevent a large number of pneumococcal infections and considerably reduce related mortality and morbidity . However, the baseline cost-effectiveness ratio of such a vaccination program would be relatively unfavorable compared with other interventions implemented in the Netherlands.

Carbohydr Res, 2003 Nov 21, 338(24), 2905 - 12
Phase-variation of the truncated lipo-oligosaccharide of Neisseria meningitidis NMB phosphoglucomutase isogenic mutant NMB-R6; Monteiro MA et al.; The detection of antibodies specific to meningococcal lipo-oligosaccharides (LOSs; outer-core-->inner-core-->lipid A) in sera of patients convalescent from meningococcal infection suggests the potential use of LOS as a vaccine to combat pathogenic Neisseria spp . Removal of the outer-core region, which expresses glycans homologous to human blood-group antigens, is a required first-step in order to avoid undesirable immunological reactions following vaccination . To this end, we describe here the structural makeup of the LOS produced by serogroup B N . meningitidis NMB isogenic phosphoglucomutase (Pgm) mutant (NMB-R6) . The dominant LOS types produced by NMB-R6 expressed a deep-truncated inner-core region, GlcNAc-(1-->2)-LDHepII-(1-->3)-LDHepI-(1-->5)-{Kdo-2-->4}-Kdo-->lipid A, with one PEA unit attached at either O-6 or O-7 of LDHepII, or with two simultaneously PEA moieties attached at O-3 and O-6 or O-3 and O-7 of the same unit . Unexpectedly, this mutation did not completely deactivate the production of Glc, as some LOS molecules were observed to carry Glc at O-4 of LDHepI and at O-3 of LDHepII . A glycoconjugate vaccine comprised of NMB-R6 LOSs is currently being evaluated in our laboratory.

Can J Microbiol, 2003 Oct, 49(10), 633 - 8
Characterization of Neisseria meningitidis strains isolated from invasive meningococcal disease cases in Canada in 2001; Tsang RS et al.; With the recent introduction of polysaccharide-protein conjugated vaccines for the control of serogroup C meningococcal disease and the emergence of different variants of serogroup C meningococci, it is likely the epidemiology of meningococcal disease in many countries may be affected . We have therefore analysed and reported the characteristics of Neisseria meningitidis strains collected in 2001 from the Canadian surveillance program on invasive meningococcal disease . Only strains collected from normally sterile clinical sites of patients were studied . Of the 289 isolates obtained from individual patients, 173 (59.9%) were serogroup C, 76 (26.3%) were serogroup B, 30 (10.4%) were serogroup Y, and 10 (3.5%) were serogroup W135 . Ninety-six percent of the serogroup C isolates belonged to the ET-15 clone, with an additional 2.3% belonging to other electrophoretic types within the ET-37 clonal complex . Different antigenic variants of the endemic serogroup C ET-15 clone were responsible for localized outbreaks in different parts of the country . One novel variant with the antigenic composition of C:2a:P1.1,7 was reported in two provinces, Quebec and Ontario . Eighteen percent of the meningococci isolated from patients in Ontario belonged to serogroup Y, compared with only 8% in the rest of Canada . The current data highlight the importance of strain characterization by serogroup, serotype, and serosubtype antigens in providing useful information for the surveillance of meningococcal disease in Canada.

J Immunol Methods, 2003 Dec, 283(1-2), 247 - 59
Direct isolation of recombinant human antibodies against group B Neisseria meningitidis from scFv expression libraries; Stacy JE et al.; The successful generation of human antibodies from large nai;ve antibody libraries requires iterative selection steps . Here, we describe a new and fast method for the isolation of high affinity antibodies directly from human single chain Fv antibody (scFv) expression libraries . Escherichia coli scFv expression libraries were made from peripheral blood lymphocytes from four individuals vaccinated with group B Neisseria meningitidis outer membrane vesicle (OMV) vaccine . Forty thousand clones were directly screened for antibodies binding N . meningitidis strain 44/76 (B:15:P1.7,16) . Of 430 specific clones detected, 225 candidates were isolated and re-screened against the N . meningitidis strains NZ-98/254 (B:4:P1.7b,4) giving 4% cross-reactive clones . Antibodies were further characterized by DNA sequencing, ELISA and surface plasmon resonance (SPR) analysis, showing broad V-gene diversity and nanomolar scFv affinities . Antibodies derived by this method may assist in the discovery and development of new vaccine antigens as well as therapeutic antibody agents for the treatment of meningococcal diseases.

J Virol Methods, 2004 Jan, 115(1), 41 - 9
A dengue-2 Envelope fragment inserted within the structure of the P64k meningococcal protein carrier enables a functional immune response against the virus in mice; Hermida L et al.; A gene fragment encoding for the amino acids (aa) 286-426 from the dengue Envelope (E) protein was expressed in Escherichia coli as two forms of fusion proteins . In one case, the E fragment was fused to the first 45 aa of the P64k protein from Neisseria meningitidis (PD2) while, in the other, it was inserted within the lipoil-binding domain of the aforementioned bacterial protein (PD3) . PD2 was obtained as insoluble form within the cytoplasm of the bacteria while PD3 was distributed equally as soluble and insoluble forms . The insoluble forms of each protein as well as the soluble fraction of PD3 were semipurified to test the antigenicity and the immunogenicity in mice . The forms containing the entire P64k protein exhibited the highest recognition with different polyclonal and monoclonal antibodies . Consequently, the neutralizing antibodies elicited by the recombinant proteins were higher in the case of PD3 forms than with PD2, independently of the solubility status . In addition, mice inoculated with the semipurified insoluble form of PD3 were partially protected against lethal challenge with dengue-2 virus, administered by intracerebral inoculation . The results suggested the folding and carrier capacity of the P64k protein over the E fragment, converting PD3 as an attractive vaccine candidate against dengue-2 virus.

Pediatrics . 2003 Dec;112(6 Pt 1):e491.
Henoch-Schonlein purpura following a meningococcal vaccine; Lambert EM et al.; We report a 17-year-old girl who developed Henoch-Schonlein purpura 10 days after receiving a meningococcal vaccine (Menomune) . To our knowledge, this is the first case report of Henoch-Schonlein purpura temporally associated with the tetravalent serogroups A, C, W-135, and Y meningococcal vaccine administered in the United States.

Hunan Yi Ke Da Xue Xue Bao, 2003 Aug, 28(4), 412 - 4
{Etiology of infectious diseases in the central nervous system}; Yu JL et al.; OBJECTIVE: To determine the etiological characteristics of infectious diseases in the central neural system (CNS) . METHODS: The serum and cerebral spinal fluid of acute patients in the CNS were detected for virus-specific IgM, IgG and pathogens with enzyme-linked immunosorbent assay as well as traditional bacterial and fungal culture . RESULTS: Of the 823 patients, 126 (15.3%) patients were positive herpes simplex virus (HSV)-specific IgM and/or IgG, of which the maximum morbidity was under 10 years; 10(1.2%) were positive cytomegalovirus specific IgM and/or IgG; 8 (0.97%) were positive varicella-zoster virus specific IgM and/or IgG; 7 (0.85%) were diagnosed as tubercular meningitis; 6 (0.72%) as cryptocococes meningitis and 1 (0.12%) as meningococcic meningitis . CONCLUSION: Viruses, especially herpes simplex viruses are the common causative agents of infectious diseases of the CNS, in which mycobacterium tuberculosis and cryptocococcus neoformans are conspicuous.

Mol Microbiol, 2004 Jan, 51(1), 227 - 39
Genetics of capsule O-acetylation in serogroup C, W-135 and Y meningococci; Claus H et al.; Capsular polysaccharides of serogroup C, W-135 and Y meningococci were previously reported to be O-acetylated at the sialic acid residues . There is evidence that O-acetylation affects the immunogenicity of polysaccharide vaccines . We identified genes indispensable for O-acetylation of serogroup C, W-135 and Y meningococci downstream of the capsule synthesis genes siaA-D . The genes were co-transcribed with the sia operon as shown by reverse transcription polymerase chain reaction analysis . The putative capsular polysaccharide O-acetyltransferases were designated OatC and OatWY . The protein OatWY of serogroups W-135 and Y showed sequence homologies to members of the NodL-LacA-CysE family of bacterial acetyltransferases, whereas no sequence homology with any known protein in the different databases was found for the serogroup C protein OatC . In serogroup W-135 and Y meningococci, several clonal lineages either lacked OatWY or OatWY was inactivated by insertion of IS1301 . For serogroup C meningococci, we observed in vitro phase variation of O-acetylation, which resulted from slipped-strand mispairing in homopolymeric tracts . This finding explains the observation of naturally occurring de-O-acetylated serogroup C meningococci . Our report is the first description of sequences of sialic acid O-acetyltransferase genes that have not been cloned from either other bacterial or mammalian organisms.

Genes Immun, 2003 Dec, 4(8), 533 - 40
Genomic polymorphic profiles in an Irish population with meningococcaemia: is it possible to predict severity and outcome of disease?
Balding J, Healy CM, Livingstone WJ, White B, Mynett-Johnson L, Cafferkey M, Smith OP.
Patients with meningococcal disease have increased plasma levels of proinflammatory cytokines IL-6, IL-1beta, and TNF-alpha, with higher levels associated with fatal outcome . This study investigated whether polymorphisms in genes encoding these cytokines, and in those encoding anti-inflammatory IL-10 and IL-1Ra, are associated with the outcome in patients with meningococcal disease . Seven polymorphisms were genotyped in 183 meningococcal disease patients and 389 controls . The IL-6 -174 G/G and IL-10 -1082 A/A genotypes were more frequent in nonsurvivors compared with survivors (P=0.023 IL-6, 0.25 IL-10), and in patients with severe disease compared to those with mild disease (P=0.037 IL-6, 0.0078 IL-10) . An association was also found between meningococcal disease and the IL-1RN VNTR polymorphism, but no association was observed with the LTA +252, TNF -308, IL-10 -592, or IL-1B +3953 polymorphisms . We conclude that genetic variability in the IL-6, IL-10, and IL-1RN genes is associated with a poor outcome in meningococcal disease.

Enferm Infecc Microbiol Clin, 2003 Dec, 21(10), 557 - 62
{Meningococcal disease: clinicopathological correlation}; Stella-Silvaa N et al.; INTRODUCTION: Clinicopathological correlation studies of cases admitted as meningococcal disease are scarce, although they can serve to elucidate clinically obscure cases . METHODS: A descriptive approach was used to analyze 42 necropsies following clinical diagnosis of meningococcal disease, verifying the agreement between histopathological and clinical findings evaluated according to three clinical forms of meningococcal disease (MD) in children and adults: septicemic meningococcal disease (MD-S), meningococcal disease with meningitis and septicemia (MD-MS), and meningococcal disease with meningitis/meningoencephalitis alone (MD-M) . RESULTS: Of the total, 81% met the confirmatory clinical criteria; 56% were 14 years of age or less and 44% were over 14 years . The principal causes of death included multiple organ failure (59%) (associated with shock in 65% of cases); cerebral edema (29%); and myocarditis (12%) . There was a high clinicopathological correlation between septic shock and diffuse adrenal hemorrhage (77%) and between respiratory failure and pulmonary alterations (77%), and a low correlation between heart failure and cardiac involvement (27%) and between diarrhea and enteritis (25%) . Myocarditis and disseminated fibrin thrombi, especially in the skin, lungs, and kidneys, predominated in the MD-S and MD-MS forms, while diffuse adrenal hemorrhage and enteritis predominated in MD-S . The correlations between the clinical and pathological diagnoses of the MD forms were: MD-S, 17/11 (65%), MD-MS, 14/14 (100%), and MD-M, 3/2 (67%) . CONCLUSION: There was significant correlation between clinical and pathological diagnoses (P <.0001) according to the various forms of MD . However, histopathological analysis did not differentiate between the MD-S and MD-MS forms, which merely represented variations in severity.

Pediatr Nephrol, 2004 Feb, 19(2), 237 - 9 Epub 2003 Nov 25.
Fulminant meningococcemia and acute renal failure in a 3-year-old boy; Akil I et al.; Acute renal failure is a common occurrence in sepsis, but is rarely reported in meningococcemia . We present a young child diagnosed with fulminant meningococcemia who had several poor prognostic factors, including hypotension, thrombocytopenia, purpura fulminans, seizures, the absence of meningitis with meningococcemia, and acute renal failure, which was successfully treated with peritoneal dialysis . Peritoneal dialysis was started on the 5th day because the patient had been anuric for 48 h . At that time, analysis showed that the child was both hypokalemic and hypophosphatemic . His serum blood urea nitrogen was 61 mg/dl, creatinine 2.75 mg/dl, potassium 2.8 mEq/l, and phosphorus 0.7 mg/dl . Urine output began on the 12th day post admission and normalization of serum creatinine was achieved on the 26th day . In conclusion, renal failure is an important complication of meningococcemia and, to be effective, sometimes long-term peritoneal dialysis is required . Profound metabolic abnormalities, such as hypokalemia and hypophosphatemia, may occur paradoxically in the presence of oliguria.

Trop Med Int Health, 2003 Dec, 8(12), 1118 - 23
Outbreaks of serogroup X meningococcal meningitis in Niger 1995-2000; Djibo S et al.; In the African meningitis belt, the recurrent meningococcal meningitis epidemics are generally caused by serogroup A . In the past 20 years, other serogroups have been detected, such as X or W135, which have caused sporadic cases or clusters . We report here 134 meningitis cases caused by Neisseria meningitidis serogroup X that occurred in Niamey between 1995 and 2000 . They represented 3.91% of the meningococcal isolates from all CSF samples, whereas 94.4% were of serogroup A . Meningococcal meningitis cases were detected using the framework of the routine surveillance system for reportable diseases organized by the Ministry of Public Health of Niger . The strains were isolated and determined by the reference laboratory for meningitis in Niamey (CERMES) and further typed at the WHO collaborating center of the Pharo in Marseille and at the National Reference Center for the Meningococci at the Institut Pasteur . Reference laboratories in Marseille and Paris characterized 47 isolates having the antigenic formula (serogroup:serotype:sero-subtype) X:NT:P1.5 . Meningitis cases due to meningococcus serogroup X did not present any clinical or epidemiological differences to those due to serogroup A . The seasonal incidence was classical; 93.3% of the cases were recorded during the dry season . The mean age of patients was 9.2 years (+/- 6 years) . The sex ratio M/F was 1.3 . Case fatality rate was 11.9% without any difference related to age or sex . The increasing incidence of the serogroup X was not related to the decrease of serogroup A, but seemed cyclic, and evolved independently of the recurrence of both serogroups A and C.

J Infect Dis, 2003 Dec 1, 188(11), 1730 - 40 Epub 2003 Nov 19.
Antibody to genome-derived neisserial antigen 2132, a Neisseria meningitidis candidate vaccine, confers protection against bacteremia in the absence of complement-mediated bactericidal activity; Welsch JA et al.; Genome-derived neisserial antigen 2132 (GNA2132) is a novel vaccine candidate that was identified during the Neisseria meningitidis group B strain MC58 genome-sequencing project . To assess the vaccine potential of GNA2132, we prepared antisera from mice immunized with recombinant GNA2132 (gene from strain NZ394/98) . Anti-GNA2132 antibody bound to the surface of live bacteria from all 7 capsular group B or C strains tested and elicited deposition of human C3b on the bacterial surface . However, with human or infant-rat complement, anti-GNA2132 had no detectable bactericidal activity (titer, <1:4) against the nominal strain, NZ394/98, and was bactericidal against only 2 of the other 6 strains tested . These differences between strains were unrelated to GNA2132 amino acid sequence or level of protein expression . Despite lack of bactericidal activity, anti-GNA2132 antiserum passively protected infant rats against meningococcal bacteremia after challenge with all 5 resistant strains . GNA2132 is thus a promising vaccine candidate for prevention of disease caused by N . meningitidis.

Infect Immun, 2003 Dec, 71(12), 6712 - 20
Genetic basis for biosynthesis of the (alpha 1-->4)-linked N-acetyl-D-glucosamine 1-phosphate capsule of Neisseria meningitidis serogroup X; Tzeng YL et al.; The genetic basis for biosynthesis of the (alpha1-->4)-linked N-acetyl-D-glucosamine 1-phosphate capsule of Neisseria meningitidis serogroup X was defined . The biosynthesis gene cassette was a approximately 4.2-kb region located between ctrA of the capsule transport operon and galE, which encodes the UDP-glucose-4-epimerase . This location was identical to the locations of the biosynthesis cassettes in other meningococcal serogroups . Three open reading frames unique to meningococcus serogroup X were identified . Deletion-insertion mutation and colony immunoblotting confirmed that these three genes were essential for serogroup X capsule expression, and the genes were designated xcbA, xcbB, and xcbC (serogroup X capsule biosynthesis) . Reverse transcriptase PCR indicated that the xcbABC genes form an operon and are cotranscribed divergently from ctrA . XcbA exhibited 52% amino acid similarity to SacB, the putative capsule polymerase of meningococcus serogroup A, suggesting that it plays a role as the serogroup X capsule polymerase . An IS1016 element was found within the intergenic region separating ctrA and xcbA in multiple strains, and this element did not interfere with capsule expression.

Hosp Q, 2003, 6(4), 55 - 8, 4
SARS: a health system's perspective; Beard L et al.; Effective communications with different stakeholders was critical for health systems everywhere during the worldwide SARS outbreak earlier this year . For Capital Health in Edmonton, Alberta, the health system was able to build on its past experiences in dealing with meningococcal outbreaks and its planning for a pandemic flu.

Ann Acad Med Singapore, 2003 Sep, 32(5), 706 - 9
Primary meningococcal arthritis and endogenous endophthalmitis: a case report; Cheng YK et al.; INTRODUCTION: Arthritis and endophthalmitis are both recognised complications of meningococcal infection . They may occur in the presence or absence of meningitis or meningococcaemia . Primary meningococcal arthritis (PMA) and endophthalmitis are important diagnoses to recognise as delayed treatment would result in permanent joint and eye damage . We report the first patient with both PMA and meningococcal endophthalmitis and present a review of the literature . CLINICAL PICTURE: An afebrile, non-toxic, 54-year-old female presented with arthritis and a painful red left eye following an episode of diarrhoea . An initial diagnosis of reactive arthritis with uveitis was made . However, subsequent microbiological investigations isolated Neisseria meningitides thus confirming the final diagnosis . TREATMENT: Antibiotics were instituted . OUTCOME: There was complete resolution of the arthritis but her left eye vision had deteriorated to just perception of light . CONCLUSION: The presentations of PMA and meningococcal endophthalmitis are often confusing . This should be considered in the differential diagnosis of reactive arthritis and acute dermatitis-arthritis syndrome.

Eur J Epidemiol, 2003, 18(11), 1073 - 7
An outbreak of serogroup C meningococcal disease in the province of Antwerp (Belgium) in 2001-2002; De Schrijver K et al.; In 2001 an outbreak of Neisseria menigitidis serogroup C occurred in the province of Antwerp (Belgium) . Over a year the incidence rate of meningococcal disease (MD) increased from 3.9 per 100,000 to 9.1 per 100,000 with a shift from serogroup B (87%) in 2000 to serogroup C (66%) in 2001 . The most prominent phenotype was C:2a:P1.2,5 . The incidence rate for serogroup C MD increased from 0.4 per 100,000 to 4.5 per 100,000 in 2001 . The case fatality rate was 6.7% in 2001 . After the introduction of a mass vaccination campaign with a conjugated vaccine against serogroup C MD the incidence of serogroup C MD fell from 4.5 to 1.8 per 100,000 . As a result of the analysis of this outbreak, it was proposed to offer a vaccine against serogroup C to all people under 19 years of age . Part of this plan has been implemented to date in Belgium.

Scand J Infect Dis, 2003, 35(9), 608 - 13
Contacting the host: insights and implications of pathogenic Neisseria cell interactions; Plant L et al.; Neisseria is a highly adapted human specific pathogen that initiates infection at the mucosal epithelia by using multiple adhesins to interact with host cell receptors . Colonization begins at the apical cell surface with a multi-step adhesion cascade, followed by invasion and persistence within the cell and finally transcytosis at the basolateral surface . The type IV pill are implicated in mediating the initial attachment of both meningococci and gonococci, and this association has been shown to involve contact with the cellular receptor CD46 . In this review we describe the initial events in the adhesion, invasion and signaling of pathogenic Neisseria focusing on the initial attachment and signaling induced by the interaction of the type IV pili with CD46.

Scand J Infect Dis, 2003, 35(9), 563 - 7
Lps2 and signal transduction in sepsis: at the intersection of host responses to bacteria and viruses; Beutler B et al.; A phenotype-driven approach led to the first understanding of precisely what the Toll-like receptors (TLR) did, when it was determined that the mammalian endotoxin (lipopolysaccharide; LPS) receptor is encoded by TLR4 . The TLRs are the primary sensors of the innate immune system, and without them, small inocula of microorganisms pose a major threat to the host, growing unchecked for a long period before they are recognized . Mutations that affect innate immune sensing may account for a substantial fraction of sepsis, and a highly significant excess of mutations in TLR4 has been identified in patients with systemic meningococcal disease . As such, it is important to understand the pathways that are responsible for innate immune sensing, including the signaling intermediates utilized by the TLRs . Random germline mutagenesis identified a locus, Lps2, which is required for normal responses to double-stranded RNA and LPS . Hence, a single transducer was found to serve both the TLR3 and TLR4 response pathways . The Lps2 mutation was found to ablate entirely the MyD88-independent pathway for LPS sensing, indicating that two and only two branches of the LPS sensing pathway exist in macrophages, and homozygotes for the mutation were resistant to LPS, but markedly susceptible to infection with mouse cytomegalovirus . Remarkably, Lps2 mutant mice entirely failed to produce type I interferons in response to a viral infection . It would appear that Lps2 is the most proximal component of a signal integration system required for innate immune responses to both viral and bacterial diseases . Positional cloning revealed that the TIR adapter protein Trif/Ticam-1 is structurally altered by the Lps2 mutation . This adapter is responsible for shared effects of responses to viral and bacterial pathogens.

Mol Cell Biochem, 2003 Nov, 253(1-2), 179 - 90
The role of pilin glycan in neisserial pathogenesis; Banerjee A et al.; The pilus of pathogenic Neisseria is a polymer composed mainly of the glycoprotein, pilin . Recent investigations significantly enhanced characterization of pilin glycan (Pg) from N . gonorrhoeae (gonococcus, GC) and N . meningitidis (meningococcus, MC) . Several pilin glycosylation genes were discovered recently from these bacteria and some of these genes transfer sugars previously unknown to be present in neisserial pili . Due to these findings, glycans of GC and MC pilin are now considered more complex . Furthermore, various Pg can be expressed by different strains and variants of GC, as well as MC . Intra-species variation of Pg between different groups of GC or MC can partly be due to polymorphisms of glycosylation genes . In pilus of pathogenic Neisseria, alternative glycoforms are also produced due to phase-variation (Pv) of pilin glycosylation genes . Most remarkably, the pgtA (pilin glycosyl transferase A) gene of GC can either posses or lack the ability of Pv . Many GC strains carry the phase-variable (Pv+) pgtA, whereas others carry the allele lacking Pv (Pv-) . Mostly, the GC isolates from disseminated gonococcal infection (DGI) carry Pv+ pgtA but organisms from uncomplicated gonorrhea (UG) contain the Pv- allele . This data suggests that Pv of pgtA facilitates DGI, whereas constitutive expression of the Pv- pgtA may promote UG . Additional implications of Pg in various physiological and pathogenic mechanisms of Neisseria can also be envisaged based on various recent data.

Mol Microbiol, 2003 Nov, 50(3), 1005 - 15
Mapping the binding domains on meningococcal Opa proteins for CEACAM1 and CEA receptors; de Jonge MI et al.; The opacity (Opa) proteins of pathogenic Neisseria spp . are adhesins, which play an important role in adhesion and invasion of host cells . Most members of this highly variable family of outer membrane proteins can bind to the human carcinoembryonic antigen-related cell adhesion molecules (CEACAMs) . Several studies have identified the Opa-binding region on the CEACAM receptors; however, not much is known about the binding sites on the Opa proteins for the corresponding CEACAM-receptors . The high degree of sequence variation in the surface-exposed loops of Opa proteins raises the question how the binding sites for the CEACAM receptors are conserved . Neisseria meningitidis strain H44/76 possesses four different Opa proteins, of which OpaA and OpaJ bind to CEACAM1, while OpaB and OpaD bind to CEACAM1 and CEA . A sequence motif involved in binding to CEACAM1 was identified by alanine scanning mutagenesis of those amino acid residues conserved within the hypervariable (HV) regions of all four Opa proteins . Hybrid Opa variants with different combinations of HV-1 and HV-2 derived from OpaB and OpaJ showed a reduced binding to CEACAM1 and CEA, indicating that particular combinations of HV-1 and HV-2 are required for the Opa binding capacity . Homologue scanning mutagenesis was used to generate more refined hybrids containing novel combinations of OpaB and OpaJ sequences within HV-1 and HV-2 . They could be used to identify residues determining the specificity for CEA binding . The combined results obtained with mutants and hybrids strongly suggest the existence of a conserved binding site for CEACAM receptors by the interaction of HV-1 and HV-2 regions.

Clin Microbiol Infect, 2003 Oct, 9(10), 1062 - 4
Infective endocarditis due to Neisseria meningitidis: two case reports; Benes J et al.; Two cases of meningococcal endocarditis are described . An 84-year-old man developed sepsis and septic shock and died 15 h after admission to the department . The autopsy revealed aortic endocarditis . Blood and vegetation culture yielded Neisseria meningitidis B:16:P1.5 . A 37-year-old man was admitted for fever and rash lasting several weeks . Endocarditis of the bicuspid aortic valve caused by N . meningitidis C:2a:P1.2,5 was found . The patient was successfully treated with penicillin G for 4 weeks . Brief epidemiologic characteristics of invasive meningococcal disease in the Czech Republic are given.

Br J Clin Pharmacol, 2003 Dec, 56(6), 658 - 63
The involvement of nurses in reporting suspected adverse drug reactions: experience with the meningococcal vaccination scheme; Ranganathan SS et al.; AIMS: In order to aid the monitoring of the new Meningococcal serogroup C Conjugate (Men C) vaccine, the Yellow Card Scheme was extended to allow nurses for the first time to report any suspected adverse reactions associated with these vaccines . We have analysed the Yellow Cards received by the Committee on Safety of Medicines (CSM) Wales from nurses reporting a suspected reaction in association with these vaccines during the first 16 months of the programme . METHODS: CSM Wales receives Yellow Cards from healthcare professionals in Wales . Details of Yellow Cards reporting a suspected adverse reaction associated with Men C vaccines during the study period were extracted from the CSM Wales database and analysed according to health professional category {nurses, General Practitioners (GP), hospital doctors or pharmacists} . RESULTS: During the study period 534 117 doses of Men C vaccines were administered in Wales; in the same period CSM Wales received 1095 Yellow Cards containing 1952 suspected reactions . Nurses completed 529 {48.3%, 95% confidence interval (CI) 43.6, 53.1} Yellow Cards compared with 294 (26.8%, 95% CI 22.7, 30.8) from GPs, 262 (23.9%, 95% CI 20.1, 27.6) from hospital doctors and 10 (0.91%, 95% CI 0.43, 1.73) from others, which include hospital pharmacists, community pharmacists and health visitors . The proportion of Yellow Cards sent by nurses was significantly higher than those sent by GPs and hospital doctors . Ninety-five percent CIs for differences in proportions (CI diff prop) were (0.175, 0.254) and (0.204, 0.282), respectively . The majority (90.9%, 95% CI 88.7, 93.5) of the Yellow Cards from nurses reported suspected reactions children in over the age of 5 (95% CI diff prop 0.861, 0.917) . The spectrum of suspected adverse drug reactions (ADRs) involved the skin and subcutaneous tissue, central nervous system, general reactions, and the gastrointestinal tract . Of the suspected reactions reported by nurses, GPs and hospital doctors, 13.4% (95% CI 10.5, 15.8), 12.9% (95% CI 9.6, 16.8) and 9.1% (95% CI 6.5, 11.8), respectively, were of serious reactions . Nurses reported 52.5% (95% CI 45.4, 60.6) of all the suspected serious reactions, which was statistically more significant than hospital doctors {chi2 = 5.864, degree of freedom (DF) = 1, P < 0.05} but not GPs (chi2 = 0.066, DF = 1, P > 0.05) . CONCLUSIONS: Nurses were the health professionals who provided the largest proportion of reports of suspected ADRs and almost half of all reports during the Men C vaccination campaign . Their reports contained an equal proportion of serious suspected ADRs and the reports were documented as completely as those from GPs and hospital doctors.

Clin Infect Dis, 2003 Dec 1, 37(11), 1496 - 505 Epub 2003 Nov 06.
Impact of mannose-binding lectin on susceptibility to infectious diseases; Eisen DP et al.; When the adaptive immune response is either immature or compromised, the innate immune system constitutes the principle defense against infection . Mannose-binding lectin (MBL) is a C-type serum lectin that plays a central role in the innate immune response . MBL binds microbial surface carbohydrates and mediates opsonophagocytosis directly and by activation of the lectin complement pathway . A wide variety of clinical isolates of bacteria, fungi, viruses, and parasites are bound by MBL . Three polymorphisms in the structural gene MBL2) and 2 promoter gene polymorphisms are commonly found that result in production of low serum levels of MBL . Clinical studies have shown that MBL insufficiency is associated with bacterial infection in patients with neutropenia and meningococcal sepsis . Low MBL levels appear to predispose persons to HIV infection . Numerous other potential infectious disease associations have been described . Therapy to supplement low MBL levels is being explored using either plasma-derived or recombinant material.

J Med Microbiol, 2003 Dec, 52(Pt 12), 1077 - 81
Description of new mutations in the rpoB gene in rifampicin-resistant Neisseria meningitidis selected in vitro in a stepwise manner; Nolte O et al.; Fourteen meningococcal strains were selected towards rifampicin resistance in a stepwise manner in vitro; final MICs were between 8 and >256 microg ml(-1) . Sequence analysis of a 295 bp subgenic fragment of the RNA polymerase beta-subunit (rpoB) gene from the original and the fully resistant strains revealed that, with one exception, the strain pairs differed by just one position in the deduced amino acid sequence . Transformation of a PCR-amplified subgenic rpoB fragment harbouring the mutated site into a susceptible strain demonstrated the resistance-conferring mechanism.

Arch Pediatr, 2003 Nov, 10(11), 1013 - 5
{Respiratory virosis and invasive bacterial superinfections . The case for influenza and meningococcal diseases}; Alonso JM et al.; The pathophysiology of bacterial superinfections of influenza, including meningococcal diseases, remains obscure . Mice, normally resistant to the meningococcus, become susceptible after previous influenza A virus infection . This immunosuppressive effect is transitory and is associated with the peak of the inflammatory anti-virus reaction . These results underline the importance of preventing bacterial superinfections of influenza by the surveillance of any relapse of fever after improvement of the influenza syndrome . At the community level, influenza vaccine, beside its specific effects, might also prevent many cases of invasive superinfections, including meningococcal diseases.

Med Sci (Paris), 2003 Oct, 19(10), 1011 - 5
{Public health: the control of meningococcal disease in Quebec}; De Wals P et al.; A first outbreak of serogroup C meningococcal disease occurred in the province of Quebec in 1990-1992 and lead to a mass immunization campaign using polysaccharide vaccines . In 2001, a second outbreak was identified and a mass vaccination campaign was carried out, using the newly licensed conjugate vaccine . Clinical, epidemiological, economic and social studies were instrumental in the decision making for implementing these control programs.

Clin Diagn Lab Immunol, 2003 Nov, 10(6), 1136 - 40
Effect of antigen coating conditions on enzyme-linked immunosorbent assay for detection of immunoglobulin G antibody to Neisseria meningitidis serogroup Y and W135 capsular polysaccharide antigens in serum; Giardina PC et al.; Human sera collected from 28 consenting adult volunteers were used to define assay conditions for meningococcal vaccine clinical trial serology . Immunoassay parameters were optimized with these test sera and the standard reference serum, CDC1992 . Coating conditions for serogroup Y and W135 polysaccharide antigens were found to influence the predicted serum immunoglobulin G (IgG) antibody concentrations . Sera that displayed IgG antibody binding profiles most unlike that of CDC1992 were influenced the most by coating conditions . Our results suggest that presentation of specific epitopes is influenced by antigen-coating concentrations for serogroup Y and W135 polysaccharides.

Scand J Infect Dis, 2003, 35(10), 719 - 23
PCR of cerebrospinal fluid for diagnosis of bacterial meningitis during meningococcal epidemics; an example from Sudan; Issa M et al.; Meningococcal disease is feared due to its rapid progression and high case fatality rate, especially in the African meningitis belt, where epidemics of meningococcal meningitis appear cyclically . Culture, direct microscopy and antigen detection are the basic methods for diagnosis and species identification of bacterial meningitis . These methods are known to have limitations, especially in developing countries . The aim of the present study was to document the application of PCR technology for the diagnosis of bacterial meningitis in cerebrospinal fluid (CSF) samples (n = 52) collected during epidemics in Sudan . In the application of PCR for detection of the causative agent of bacterial meningitis (based on the 16S rRNA gene), bacterial DNA was identified in 49 samples . Common bacterial species causing bacterial meningitis could be detected in 31 of the CSF samples (27 meningococci), while 18 contained DNA, mainly from normally contaminating bacteria . A specific PCR for group A meningococci (based on the sacC gene) was positive in 27 of the CSF samples . The results show that PCR technology is a sharp-edged tool for confirmation of a diagnosis of meningococcal meningitis and for obtaining a direct genogrouping of group A meningococci in CSF . It is important to stress the use of direct and specific PCRs to avoid interference by contaminating bacteria, a great problem in samples from areas in the meningitis belt.

Br J Gen Pract, 2003 Aug, 53(493), 626 - 31
Management of diagnostic uncertainty in children with possible meningitis: a qualitative study; Brennan CA et al.; BACKGROUND: Neisseria meningitidis serogroup B is the most common cause of bacterial meningitis in children and young adults . Early recognition and prompt intervention with antibiotics are thought to be key to preventing serious complications . AIM: Explore how general practitioners evaluate and manage febrile children with possible meningitis or meningococcal septicaemia . DESIGN OF THE STUDY: Qualitative study using one-to-one, semi-structured interviews . SETTING: General practices in the Avon Health Authority district . METHOD: Twenty-six general practitioners were purposefully sampled, using a sampling frame to ensure a range of experience and practices in a variety of settings Data management and analysis were conducted using a grounded theory approach . RESULTS: Key themes to emerge were the effect that fear of meningitis has upon parents and general practitioners; the difficulties associated with reaching a diagnosis; and the existence of barriers to the use of guidelines and pre-hospital penicillin . When assessing a febrile child, participating general practitioners rarely thought that meningitis or meningococcal septicaemia were likely, but were aware that this was frequently the principal parental concern . They relied upon intuitive rather than systematic methods to distinguish serious from self-limiting conditions, rarely making a definitive diagnosis . Although concerned about 'missed cases', interviewees doubted that current management could be improved . They questioned the assumption that guidelines could be sufficiently discriminating to be helpful and thought it unlikely that they would be followed in everyday clinical practice . Pre-hospital penicillin was only given if the diagnosis of meningitis or septicaemia was thought to be certain . CONCLUSIONS: There is a substantial gap in perception between primary and secondary care in the diagnostic and management approach to children who may have meningitis or meningococcal septicaemia . Until this is addressed, further attempts to improve early intervention in primary care are unlikely to succeed.

An Pediatr (Barc), 2003 Nov, 59(5), 491 - 6
{Treatment of septic shock with continuous plasmafiltration and hemodiafiltration}; Lopez-Herce Cid J et al.; Despite recent therapeutic advances, mortality due to septic shock remains high . The most important causes of mortality are refractory shock, uncontrollable alterations of coagulation, and multiorgan failure . Some authors have proposed the early use of plasmafiltration and high flow hemodiafiltration for refractory septic shock . Most authors initiate treatment with a short session of plasmafiltration followed by continuous hemodiafiltration . A 13-year-old girl presented refractory meningococcal septic shock, disseminated intravascular coagulation, and acute renal failure unresponsive to volume expansion and high doses of adrenalin and noradrenaline . She received simultaneous treatment with plasmafiltration and continuous venovenous hemodiafiltration for 30 hours . Two pumps of extrarenal purification placed in parallel through the same double line catheter were used . Fast hemodynamic stabilization and control of the coagulopathy were achieved . The patient survived with progressive recovery of renal function but required amputation of the inferior left limb . Continuous plasmafiltration and venovenous hemodiafiltration can be used simultaneously for the treatment of older children with septic shock, severe coagulopathy, and hypervolemia.

N Z Med J . 2003 Sep 26;116(1182):U603.
Pre-hospital antibiotic treatment of meningococcal disease: scope for improvement; Riddell T et al.; AIM: To determine the extent to which Auckland general practitioners (GPs) follow Ministry of Health guidelines recommending the administration of pre-hospital antibiotic treatment to suspected cases of meningococcal disease . METHODS: Retrospective audit of notified cases of meningococcal disease referred by Auckland GPs from 1 May 2001 to 30 April 2002 . RESULTS: Of 142 meningococcal disease cases that were referred to hospital by GPs, 111 (78%) were 'eligible' or met Ministry of Health guideline criteria for pre-hospital antibiotic treatment . Of these, only 33 (30%) were given parenteral antibiotics . Those with a rash were twice as likely as those without a rash to receive antibiotics (RR 2.1; 95% CI 1.7-2.7) . There was no difference in antibiotic administration by age, sex, ethnicity, or where there was an estimated delay of greater than 30 minutes to assessment in hospital . CONCLUSIONS: The findings of this audit reinforce the need for GPs to have a higher index of suspicion and lower threshold for treatment for suspected cases of meningococcal disease and to give antibiotics more often than they do at present.

Methods Enzymol, 2003, 363, 340 - 54
Characterization of polysaccharide conformational epitopes by surface plasmon resonance; MacKenzie CR et al.; SPR techniques can provide a wealth of insight into the nature of protein-carbohydrate interactions . Information not obtained readily by other methodologies can be gathered relatively quickly in a label-free manner with low sample consumption . This chapter focused on two applications in which SPR has been used to map conformational epitopes on bacterial polysaccharides recognized by protective antibodies . In one example, methods for demonstrating the conformational nature of the epitope recognized by an anti-GBS antibody were described . Dramatic epitopic stabilization at 2 repeating units with further significant stabilization between 7 and 20 repeating units was demonstrated . In a second example, SPR methods were employed in characterization of the epitope recognized by a protective antibody against the group B meningococcus . It was shown that the antibody bound a long epitope, in excess of eight monosaccharides and probably helical, on NPr-GBMP but did not bind to GBMP . The binding of the protective antibody to GBMP only when GBMP is cell associated, or with an attached lipid, indicated that the protective GBM epitope consists of more than GBMP . NPr-GBMP mimics a cell surface complex consisting of extended helical portions of the GBMP in association with a second molecule, possibly a phosphoglycerolipid . SPR experiments indicated that the protective nature of certain antibodies induced by the NPr-GBMP vaccine is attributable to their recognition of an abundant internal epitope on NPr-GBMP and cell-associated GBMP . A nonprotective antibody, specific for NPr-GBMP, recognized a terminal and consequently minor epitope on the polysaccharide . Low levels of this nonprotective antibody binding to cells and unpurified polysaccharide confirmed recognition of a minor epitope on the natural antigen as well . In contrast, a protective antibody exhibited a high level of binding to the cell-associated antigen.

Antimicrob Agents Chemother, 2003 Nov, 47(11), 3430 - 4
Interlaboratory comparison of agar dilution and Etest methods for determining the MICs of antibiotics used in management of Neisseria meningitidis infections; Vazquez JA et al.; Previous studies have shown that there is considerable variation in the methods and media used to determine the susceptibility of Neisseria meningitidis to antimicrobial agents in different countries . In this study, national and regional reference laboratories used a standardized methodology to determine the MICs of antibiotics used in the management of meningococcal infection . Fourteen laboratories participated in the study, determining the susceptibility to penicillin G, rifampin, cefotaxime, ceftriaxone, ciprofloxacin, and ofloxacin of a collection of 17 meningococci, of which 11 strains were previously defined as having intermediate resistance to penicillin (Pen(I)) by sequencing and restriction fragment length polymorphism analysis of the penA gene . The MIC was determined by agar dilution and Etest with Mueller-Hinton agar (MH), MH supplemented with sheep blood (MH+B), and MH supplemented with heated (chocolated) blood . Several laboratories encountered problems obtaining confluent growth with unsupplemented MH . MH+B was considered to give the most congruent and reproducible results among the study laboratories . The modal MIC for MH+B for each antibiotic and method was calculated to define the MIC consensus, allowing assessment of each individual laboratory's data in relation to the others . The agreement in each antibiotic/method/medium combination was defined as the percentage of laboratories with a result within one dilution of the modal result . For the whole study, an agreement of 90.6% was observed between agar dilution and Etest methods . The agreement in each laboratory/antibiotic/method combination ranged from 98.2% to 69.7%, with six laboratories demonstrating agreement higher than 90% and 11 more than 80% . The ability of the laboratories to detect the Pen(I) isolates ranged from 18.2% to 100% . The apparent difficulty in interpreting susceptibility to rifampin, particularly with the Etest method, is very interesting.

Vaccine, 2003 Nov 7, 21(31), 4576 - 87
Phase I study of detoxified Escherichia coli J5 lipopolysaccharide (J5dLPS)/group B meningococcal outer membrane protein (OMP) complex vaccine in human subjects; Cross AS et al.; We previously observed that a detoxified Escherichia coli O111, Rc chemotype J5 lipopolysaccharide (J5dLPS)/group B meningococcal outer membrane protein (OMP) vaccine protected animals from experimental lethal sepsis when immune antibodies were given passively as treatment at the onset of fever or when vaccine was given actively as prophylaxis . To test the safety and immunogenicity of this vaccine, we administered doses of 5, 10 and 25 microg (based on dLPS) of vaccine at days 0, 28 and 56 to 24 human subjects (8 per group) . Temperatures of 100.3, 99.5 and 99.4 degrees F occurred in three subjects . At 24h, pain at the injection site was moderate in 38%, mild in 44% and not present in 18%, while at 48 h, it was 1, 25 and 73%, respectively . No alterations in baseline renal, hepatic or hematologic functions occurred . There were two to three times mean-fold increases in anti-J5dLPS IgG (range: 1.9-5.1) and IgM (range: 1.2-9.2) levels in subjects receiving the 10 and 25 microg doses . At 12-month follow-up, three of the original responders had continued elevation of antibody levels . A 25 microg booster dose of vaccine did not increase antibody levels among those responders and did not elicit antibodies among three subjects with no previous antibody response . The plasma from the six volunteers inhibited LPS-induced cytokine generation in human whole blood ex vivo . We conclude that this J5dLPS/OMP vaccine was safe and well-tolerated with transient, local pain at the injection site . Vaccine formulations with different adjuvants are currently under investigation.

Infect Immun, 2003 Nov, 71(11), 6367 - 71
Relative immunogenicity of PorA subtypes in a multivalent Neisseria meningitidis vaccine is not dependent on presentation form; Luijkx TA et al.; The hexavalent meningococcal vaccine HexaMen, containing six PorAs on two vesicles, was tested in clinical studies . Although fourfold increases in serum bactericidal activity (SBA) titers against all of the PorAs were observed, there were significant differences between PorA-specific SBA titers . SBA titers were mainly directed against one PorA from each vesicle, P1.5-2,10 and P1.5-1,2-2, and were lower against the other PorAs, especially P1.7-2,4 and P1.19,15-1 . We investigated whether these differences were due to immunological interference that resulted in competition between the three PorAs on the same vesicle or whether they were caused by a difference in the immunogenicities of the separate PorAs . Therefore, mice were immunized either with HexaMen, with six monovalent outer membrane vesicles (OMVs) representing the same six PorAs simultaneously (HexaMix), or with only one of the monovalent OMVs . The immunoglobulin G and SBA titers after HexaMen immunization in mice resembled the results obtained in clinical studies . Although immunization with HexaMix gave higher titers than immunization with HexaMen for some PorAs, the pattern of high and low titers was the same . Similar differences in immunogenicity between subtypes were seen after monovalent immunization when interference was eliminated as a cause of the differences . Monovalent immunization resulted in higher titers for P1.5-1,2-2 and P1.7,16 than immunization with HexaMen . However, no significant differences were found for the weakly immunogenic PorAs, P1.7-2,4 and P1.19,15-1 . Since immunization with the six PorAs in the trivalent presentation form (HexaMen) and in the mixture of monovalent vesicles (HexaMix) resulted in the same pattern of high and low titers, we concluded that the differences between the PorA-specific responses are due to differences in the immunogenicities of the various PorAs and not due to interference that results in competition between different PorAs.

Enferm Infecc Microbiol Clin, 2003 Nov, 21(9), 513 - 9
{Active immunization against serogroup B Neisseria meningitidis}; Navarro-Alonso JA; Serogroup B Neisseria meningitidis causes high morbidity and mortality rates over the world . This article reviews the current vaccination strategies against this microorganism, including vaccines already tested on a large scale, particularly those based on class 1 outer membrane proteins, and vaccines in different stages of development . The latter involve several approaches, such as modification of the polysaccharide capsule composition or conjugation with proteins, and the use of recombinant DNA techniques to obtain vaccines that express the prevalent sero-subtypes in a particular geographical area . The challenges that have emerged with the sequencing of the meningococcus B genome are also addressed.

Minerva Anestesiol, 2003 Sep, 69(9), 691 - 3, 693-5
Replacement treatment with protein C in an 18-year-old man with meningococcal sepsis and purpura fulminans; Vaccarella G et al.; In separate studies on Neisseria meningitidis sepsis, Powars and Fiynvandraat suggested that low protein C levels may be responsible for disseminated intravascular coagulopathy and purpura fulminans . Following on this observation, we used protein C concentrate in an 18-year-old male patient with septic shock and purpura fulminans . The patient's coagulation parameters were seriously altered: AT 45%; protein C 21%; PT 50%; platelets 55000; D-dimer 2400 . Early treatment included immediate administration of 3000 IU of antithrombin and intensive therapy: antibiotic therapy, volemic replacement, supported by inotropic drugs and oxygen therapy . Given the patient's low protein C levels and the progression of purpura, replacement therapy with protein C concentrate was instituted . The initial dose of 80 IU/kg/bw (5600 IU) in bolus, was adjusted according to blood laboratory values and then set at 2000 IU every 8 hours for 4 days . An increase in protein C was observed (78%) after the 1st administration, while the D-dimer levels fell by 50% . By day 7, the patient's cardiocirculatory conditions had stabilized and the coagulation parameters had normalized; the patient was discharged from the intensive care unit . Protein C replacement therapy normalized the coagulation parameters and blocked the evolution of the skin injuries.

Clin Infect Dis, 2003 Nov 1, 37(9), 1183 - 8 Epub 2003 Oct 03.
Neisseria meningitidis carriage during an outbreak of serogroup C disease; Patrick DM et al.; During 2001, an outbreak of serogroup C meningococcal disease led to immunization of individuals aged 13-29 years in Abbotsford, British Columbia, Canada . This study addresses the distribution of Neisseria meningitidis carriage in this population and the implications of that distribution for the targeting of the immunization campaign . Pharyngeal swabs were obtained at immunization from 2004 people . Colonies were identified and serogrouped using standard agglutination methods and by PCR . Isolates were characterized using pulsed-field gel electrophoresis (PFGE) . The prevalence of N . meningitidis carriage was 153 carriers per 2004 subjects (7.6%; 95% confidence interval, 6.5%-8.9%) . Only 6 (4%) of the isolates from these carriers were found to be serogroup C by agglutination or PCR testing, and all of these were from individuals within the age group targeted for immunization . Only 1 of these 6 isolates was found to be identical to the outbreak strain by PFGE . The observation that a virulent strain is not circulating widely suggests the possibility of low background immunity in the population at risk and emphasizes the importance of vaccination in controlling epidemic group C meningococcal disease.

Clin Infect Dis, 2003 Nov 1, 37(9), 1155 - 64 Epub 2003 Oct 07.
Protective efficacy of a second pneumococcal conjugate vaccine against pneumococcal acute otitis media in infants and children: randomized, controlled trial of a 7-valent pneumococcal polysaccharide-meningococcal outer membrane protein complex conjugate vaccine in 1666 children; Kilpi T et al.; To assess the efficacy of a 7-valent pneumococcal polysaccharide-meningococcal outer membrane protein complex conjugate vaccine (PncOMPC) against acute otitis media (AOM), 1666 infants were randomly assigned to receive either PncOMPC or control vaccine (hepatitis B vaccine) at 2, 4, 6, and 12 months of age . Of the 835 children assigned to receive PncOMPC, 187 received a 23-valent pneumococcal polysaccharide vaccine (PncPS) at 12 months of age instead . Whenever AOM was diagnosed, middle ear fluid was aspirated for bacterial culture . In the PncOMPC and control groups, there were 110 and 250 AOM episodes, respectively, in children between 6.5 and 24 months of age that could be attributed to vaccine serotypes, which indicates a vaccine efficacy of 56% (95% confidence interval, 44%-66%) . The serotype-specific efficacy ranged from 37% for 19F to 82% for 9V . The 2 boosters seemed to provide equal protection against AOM, but PncPS induced markedly higher antibody concentrations . The efficacy of PncOMPC was comparable to that of the recently licensed pneumococcal conjugate vaccine.

FEMS Immunol Med Microbiol, 2003 Oct 24, 39(1), 31 - 6
Evaluation of non-culture diagnosis of invasive meningococcal disease by polymerase chain reaction (PCR); Tzanakaki G et al.; Antibiotic treatment prior to transport or admission to hospital has reduced the proportion of cases of invasive meningococcal disease (IMD) from which Neisseria meningitidis can be isolated by standard microbiological techniques . Identification of meningococci by polymerase chain reaction (PCR) was assessed in relation to microbiological diagnosis for cases over a 4-year period between 1998 and 2001 . A screening assay for the IS1106 gene was used to detect meningococcal DNA and five additional assays for siaD and orf-2 genes were performed to determine the serogroup . PCR results were compared with results of bacteriological culture, other laboratory test results and clinical data . The sensitivity of the PCR assay for culture-confirmed cases was 98.5% . The specificity of the assay was 96% based on test results for patients from whom other bacteria were isolated, children with viral meningitis and afebrile negative controls . The siaD B/C/W-135 and Y as well as the orf-2 gene for serogroup A PCR assays were able to determine the serogroup for 75.2% of cases that were positive by PCR screening assay . When isolates from patients with IMD were tested by both agglutination and PCR, the results agreed in all cases . PCR is a useful tool for diagnosis of IMD when Gram stain and culture tests are negative due to antibiotic treatment prior to collection of samples for microbiological analyses.

FEMS Immunol Med Microbiol, 2003 Oct 24, 39(1), 23 - 9
Carriage of Neisseria meningitidis and Neisseria lactamica in northern Greece; Kremastinou J et al.; In response to an increase in the number of cases of invasive meningococcal disease (IMD) in northern regions of Greece, a survey was carried out to determine if there was an increase in carriage of Neisseria meningitidis, particularly in areas where there have been increases in immigrant populations from neighbouring countries . The second objective was to determine if there was an increase in the serogroup C:2a:P1.5,2 a phenotype associated with recent outbreaks or changes in antibiotic sensitivities . As carriage of Neisseria lactamica is associated with development of natural immunity to IMD, the third objective was to determine the carriage rate of N . lactamica in this population . Among 3167 individuals tested, meningococci were isolated from 334 (10.5%) . Compared with our previous studies, the proportion of meningococcal carriers was significantly increased among children in secondary education (11.3%) (chi2=9.67, P<0.005) and military recruits (37.4%) (chi2=21.11, P<0.000) . Only 5/334 (1.5%) isolates expressed the phenotype associated with the increase in IMD in Greece . N . lactamica was isolated from 146/3167 (4.6%) participants . It was isolated from 71/987 (7.2%) children attending primary or nursery schools; however, the highest proportion of carriers (11.3%) was found in the boarding school for young Albanian men . In the 21-59-year age range, the majority of N . lactamica isolates (22/25, 88%) were from women, probably due to closer or more prolonged contact with children in the primary school age range . Smoking was significantly associated with isolation of meningococci from men but not from women . Penicillin-insensitive strains (25/334, 7.5%) were identified in all four regions examined; the majority (14/25, 56%) were obtained from military personnel . We conclude that there was a higher proportion of carriers in the population of northern Greece; however, the increase in carriage rate was not associated with the influx of immigrants from neighbouring countries, and there was not a higher incidence of the C:2a:P1.5,2 strain responsible for increased disease activity in Greece in either the immigrant or local populations.

Pediatr Infect Dis J, 2003 Oct, 22(10), 868 - 73
Age dependence of in vitro survival of meningococci in whole blood during childhood; Ison CA et al.; OBJECTIVES: To determine the association between the ability of a different strains of meningococci to survive in whole blood and the age of the donor . METHODS: A panel of serogroup B and a serogroup C strain of Neisseria meningitidis was tested in an ex vivo whole blood model . Blood from 81 healthy children and 20 adults and from children during convalescence from serogroup B (55 patients) or serogroup C (43 patients) meningococcal infection was assessed . RESULTS: Age-dependent acquisition of whole blood killing of serogroup B and C bacterial isolates was demonstrated in healthy children with an inverse relationship to the reported incidence of disease . After infection with serogroup B or C meningococci, evidence of whole blood killing of the bacteria was found even in blood from children <2 years of age, the survival of a serogroup B strain, MC58, being reduced compared with that in healthy children (median, 64% compared with 194.5% survival at 90 min) . In both affected children and controls, there was a significant correlation between whole blood killing of strain MC58 and of other serogroup B and C meningococci . CONCLUSIONS: The whole blood model measures both humoral and cellular mechanisms responsible for the bactericidal activity of blood . The model was first described 80 years ago, but this is the first description of its age dependency . Acquisition of bactericidal activity was more rapid in children infected and is directed at various strains of meningococci, indicating the presence of a cross-reactive antigen(s).

Rev Hosp Clin Fac Med Sao Paulo, 2003 Jul-Aug, 58(4), 231 - 40 Epub 2003 Sep 30.
Critical analysis of old and new vaccines against N . meningitidis serogroup C, considering the meningococcal disease epidemiology in Brazil; Bricks LF; Worldwide, the impact of meningococcal disease is substantial, and the potential for the introduction and spread of more virulent strains of N . meningitidis or strains with increased resistance to current antibiotics causes concern, making prevention essential . OBJECTIVES: Review the indications for meningococcal disease vaccines, considering the epidemiological status in Brazil . METHODS: A critical literature review on this issue using the Medline and Lilacs databases . RESULTS: In Brazil, MenB and MenC were the most important serogroups identified in the 1990s . Polysaccharide vaccines available against those serogroups can offer only limited protection for infants, the group at highest risk for meningococcal disease . Additionally, polysaccharide vaccines may induce a hypo-responsive state to MenC . New meningococcal C conjugate vaccines could partially solve these problems, but it is unlikely that in the next few years a vaccine against MenB that can promote good protection against multiple strains of MenB responsible for endemic and epidemic diseases will become available . CONCLUSIONS: In order to make the best decision about recommendations on immunization practices, better quality surveillance data are required . In Brazil, MenC was responsible for about 2,000 cases per year during the last 10 years . New conjugate vaccines against MenC are very effective and immunogenic, and they should be recommended, especially for children less than 5 years old . Polysaccharide vaccines should be indicated only in epidemic situations and for high-risk groups . Until new vaccines against MenC and MenB are available for routine immunization programs, the most important measure for controlling meningococcal disease is early diagnosis of these infections in order to treat patients and to offer chemoprophylaxis to contacts.

Adv Exp Med Biol, 2001, 491, 543 - 50
NMR and molecular modeling of complex carbohydrates and carbohydrate-protein interactions . Applications to anti-bacteria vaccines; Brisson JR et al.; In order to characterize the conformational epitope of the group B meningococcal polysaccharide and of the type III group B Streptococcus capsular polysaccharide NMR measurements were done on a wide variety of native and modified polysaccharides and oligosaccharides . Since these saccharides are highly mobile and exist as random coils in solution, the analysis of the NMR data and molecular modeling was done to take into account this inherent flexibility . The conformational model of extended high-order helices being selected upon binding to a protein, although still hypothetical at this stage, has proven useful in explaining the serology for the conformational epitopes for polysaccharides of group B Neisseria meningitidis, group B Streptococcus type III and Streptococcus pneumoniae type 14.

J Clin Microbiol, 2003 Oct, 41(10), 4666 - 70
Prediction of decreased susceptibility to penicillin of Neisseria meningitidis strains by real-time PCR; Stefanelli P et al.; Sequence analysis of the penA gene, encoding penicillin-binding protein 2 (PBP2), in 30 penicillin-intermediate (PenI) Neisseria meningitidis strains showed altered gene sequences due to the translocation of exogenous DNA blocks derived from commensal neisseriae, which are known to have PBP2 proteins with decreased affinity for the antibiotic . In order to obtain a rapid and reproducible method for predicting the PenI phenotype, a real-time PCR assay was set up with primers and probes designed on the basis of the penA gene . The A-->G mutation at codon 566, in the transpeptidase domain of the penA gene (which is present in the whole sample of 30 PenI strains and in all the 41 sequences of PenI meningococci isolated worldwide and has been deposited in the sequence databank), was chosen as a marker of penA translocations . Two hybridization probes were designed to distinguish the wild-type penA gene in penicillin-susceptible (PenS) meningococci from the mutated penA gene at codon 566 in PenI strains . Thermal analysis of probe hybridization revealed a melting temperature difference of at least 6 degrees C between PenI and PenS strains . This real-time PCR protocol characterizes the penicillin phenotype of N . meningitidis in a few hours without DNA sequencing and is useful for rapid screening of the penicillin-intermediate genotype among meningococcal isolates.

Cad Saude Publica, 1995 Jun, 11(2), 332 - 5 Epub 2003 Sep 29.
On the controversy about the efficacy of the antimeningococcal B vaccine: methodological pitfalls; Costa Ed Ede A; The present communication analyses methodological problems related to evaluating the protection given by the antimeningococcal B vaccine to children under four years of age in a case-control study carried out in Sao Paulo, Brazil . Detection of a hospital selection bias, among other disturbing features of the study, suggests that the efficacy of the vaccine was underestimated . Altogether, data presented support a wider use of the Cuban-produced vaccine to reduce morbidity and mortality from serogroup B meningococcal disease.

J Bacteriol, 2003 Oct, 185(20), 6032 - 41
The iron-responsive regulator fur is transcriptionally autoregulated and not essential in Neisseria meningitidis; Delany I et al.; Fur is a well-known iron-responsive repressor of gene transcription, which is used by many bacteria to respond to the low-iron environment that pathogens encounter during infection . The fur gene in Neisseria meningitidis has been described as an essential gene that may regulate a broad array of genes . We succeeded in obtaining an N . meningitidis mutant with the fur gene knocked out and used it to undertake studies of fur-mediated iron regulation . We show that expression of both Fur and the transferrin binding protein Tbp2 is iron regulated and demonstrate that this regulation is Fur mediated for the Tbp2 protein . Footprinting analysis revealed that Fur binds to two distinct sites upstream of its coding region with different affinities and that these binding sites overlap two promoters that differentially control transcription of the fur gene in response to iron . The presence of two independently regulated fur promoters may allow meningococcus to fine-tune expression of this regulator controlling iron homeostasis, possibly during infection.

J Biol Chem, 2003 Dec 19, 278(51), 50853 - 62 Epub 2003 Oct 02.
Neisserial lipooligosaccharide is a target for complement component C4b . Inner core phosphoethanolamine residues define C4b linkage specificity; Ram S et al.; We identified Neisseria meningitidis lipooligosaccharide (LOS) as an acceptor for complement component C4b (C4b) . Phosphoethanolamine (PEA) residues on the second heptose (HepII) residue in the LOS core structure formed amide linkages with C4b . PEA at the 6-position of HepII (6-PEA) was more efficient than 3-PEA in binding C4b . Strains bearing 6-PEA bound more C4b than strains with 3-PEA and were more susceptible to complement-mediated killing in serum bactericidal assays . Deleting 3-PEA from a strain that expressed both 3- and 6-PEA simultaneously on HepII did not decrease C4b binding . Glycose chain extension of the first heptose residue (HepI) influenced the nature of the C4b-LOS linkage . Predominantly ester C4b-LOS bonds were seen when lacto-N-neotetraose formed the terminus of the glycose chain extension of HepI with 3-PEA on HepII in the LOS core . Related LOS species with more truncated chain extensions from HepI bound C4b via amide linkages to 3-PEA on HepII . However, 6-PEA in the LOS core bound C4b even when the glycose chain from HepI bore lacto-N-neotetraose at the terminus . The C4A isoform exclusively formed amide linkages, whereas C4B bound meningococci preferentially via ester linkages . These data may serve to explain the preponderance of 3-PEA-bearing meningococci among clinical isolates, because 6-PEA enhances C4b binding that may facilitate clearance of 6-PEA-bearing strains resulting from enhanced serum killing by the classical pathway of complement.

Pediatr Crit Care Med, 2003 Oct, 4(4), 471 - 5
Cardiac rescue with enoximone in volume and catecholamine refractory septic shock; Ringe HI et al.; In December 2000 and February 2001, two children with suspected meningococcal disease were admitted to our pediatric intensive unit . Their Glasgow Meningococcal Septicaemia Prognostic score was 12 points . General treatment including antibiotics, steroids in case of meningitis, and fluid replacement, was performed . Despite appropriate volume replacement, intubation and ventilation, noradrenaline and adrenaline continuous infusions < or =1.0 microg/kg/min, and additional bolus infusions, cardiac output deteriorated within minutes in both children . Calcium and bicarbonate were given without sustained effect . Echocardiography demonstrated no pericardial effusion and shortening fraction was <10% . External cardiac massage had to be performed immediately in one case for electromechanical uncoupling . Both patients received a bolus of enoximone 2 mg/kg and 5 mg/kg body weight, respectively, followed by a continuous infusion of 20-23 microg/kg/min . Thereafter, both children had an adequate blood pressure and their shortening fraction increased to >30% . Within minutes, the catecholamine infusion could be reduced in both patients . The children completely recovered from their life-threatening situations . In patients with severe prolonged catecholamine and volume refractory endotoxin shock in Waterhouse-Friderichsen syndrome, even with electromechanical uncoupling and complete myocardial arrest, enoximone can immediately restore myocardial contractility.

Immunology, 2003 Oct, 110(2), 242 - 9
Induction of a protective capsular polysaccharide antibody response to a multiepitope DNA vaccine encoding a peptide mimic of meningococcal serogroup C capsular polysaccharide; Prinz DM et al.; Systemic infection by encapsulated organisms, such as Neisseria meningitidis, is a major cause of morbidity and mortality worldwide, especially in individuals less than 2 years of age . Antibodies directed at the capsular polysaccharide are shown to be protective against disease by inducing complement-dependent bactericidal activity . The current polysaccharide vaccine has been shown to be poorly immunogenic in high-risk groups and this is probably related to its T-independent properties . An alternative approach to eliciting a T-dependent serum immunoglobulin G (IgG) antibody response to encapsulated pathogens is DNA vaccination . We assessed the immunogenicity of a multiepitope DNA vaccine encoding a T-cell helper epitope and a peptide mimic of N . meningitidis serogroup C . The DNA construct induced a significant anti-polysaccharide antibody response that was bactericidal . Mice immunized with the DNA construct were subsequently protected against challenge with a lethal dose of N . meningitidis serogroup C.

Commun Dis Intell, 2003, 27(3), 342 - 51
Surveillance of invasive meningococcal disease in Queensland, 2002; Pugh RE et al.; During 2002, 124 cases of invasive meningococcal disease were notified in Queensland . This was similar to the previous year (n = 128) . Four (3.2%) of the cases died . Trends by age and serogroup were generally similar to previous years and were consistent with the overall patterns of this disease in Australia . However, an apparent increase in serogroup C, which infected 41 per cent of cases, needs continued monitoring . This report highlights the need for continued surveillance of morbidity and mortality patterns and management of this disease . Ongoing surveillance will monitor the impact of the National Meningococcal C Vaccination Programme, commenced in early 2003 . This report also highlights the need for ongoing community education to ensure people seek medical attention early after onset of the illness . This report shows that when general practitioners considered meningococcal disease as a diagnosis, their patients were admitted to hospital sooner than patients in whom this diagnosis was not initially considered . Acknowledging that early disease may present diagnostic difficulties, further awareness raising amongst general practitioners is required to promote early recognition and referral.

Vaccine, 2003 Oct 1, 21(27-30), 4437 - 47
Long term effects of vaccination of patients deficient in a late complement component with a tetravalent meningococcal polysaccharide vaccine; Platonov AE et al.; Of 45 Russian patients with late complement component deficiency (LCCD) who experienced one to five meningococcal infections, 31 were immunised with a meningococcal A/C/W135/Y polysaccharide vaccine and were followed for 3-8 years . Total and immunoglobulin (Ig) class specific concentration of antibodies to meningococcal polysaccharides in sera of LCCD patients increased significantly 1 month after vaccination and remained elevated for 3 years . Revaccination of LCCD patients 3 years after the first dose restored the total Ig concentrations to those observed 1 year after the first vaccination . Six new episodes of meningococcal infection in four patients developed in the group of 31 vaccinees; six episodes in six patients developed in the same time in the group of 14 non-vaccinated LCCD persons . Survival analysis demonstrated the risk to contract meningococcal disease decreased significantly for vaccinees in comparison to non-vaccinees (P<0.05) . Vaccination with of meningococcal tetravalent polysaccharide vaccine decreases the risk of meningococcal infection in LCCD patients.

Vaccine, 2003 Oct 1, 21(27-30), 4145 - 52
Invasive meningococcal and pneumococcal disease in Switzerland: cost-utility analysis of different vaccine strategies; Ruedin HJ et al.; We performed a cost-utility analysis for various vaccination strategies against meningococcal and pneumococcal diseases (MenC or MenC/PCV-9) in Switzerland . The analysis compared the current recommendations of vaccinating only children with medical risks to the introduction of the vaccination with either the MenC or the MenC/PCV-9 vaccine, administered at 12 or 2, 4 and 6 months of age, into the existing immunisation programme . For a birth cohort of 80,000 children and assuming a vaccine coverage of 80%, the introduction of a generalised vaccination would be cost-effective . The strategy using three doses of MenC/PCV-9 would achieve the highest health benefit, with 440 quality-adjusted life years (QALYs) gained at costs of 34,000 per QALY.

Biochem Soc Trans, 2003 Oct, 31(Pt 5), 1032 - 5
Binding properties and anti-bacterial activities of V-region identical, human IgG and IgM antibodies, against group B Neisseria meningitidis; Michaelsen TE et al.; We have constructed chimaeric (ch) mouse/human antibodies with identical binding regions isolated from the V-genes of two mouse parent hybridoma cell lines, with specificity against the P1.7 and P1.16 epitopes on the outer-membrane protein PorA on meningococci . The chimaeric antibodies can be used to analyse relationships between specificity, binding activity (avidity and kinetics), isotype (antibody class and antibody subclass) and in vitro anti-bacterial activity of meningococcal antibodies . The antibody sets represented the human isotypes IgG1, IgG3 and IgM, which dominate during immune response against protein antigens . The binding activities were quite similar for all these isotypes, surprisingly also for the pentameric IgM . Interestingly, monomeric IgM, prepared from pentameric IgM by partially reduction and alkylation, had similar binding activities as the original pentameric IgM . Regarding in vitro anti-bacterial activity, chIgG1 was superior in SBA (serum bactericidal activity) compared with chIgG3, while chIgG3 was more efficient in OP (opsonophagocytosis; measured by flow cytometry) than chIgG1 . ChIgM showed slightly higher SBA than chIgG1 on molar basis, and much higher OP than chIgG3 and chIgG1 . A lower concentration of antibodies was needed against the P1.16 than against the P1.7 epitope to induce SBA, but this was not the case for OP.

Int J Med Microbiol, 2003 Aug, 293(4), 241 - 9
The role of human dendritic cells in meningococcal and listerial meningitis; Kolb-Maurer A et al.; Few bacteria are capable of causing infections of the central nervous system (CNS), one of the most subtly shielded anatomical structures within the human body . Neisseria meningitidis is an important cause of bacterial meningitis and commonly affects otherwise healthy infants and adolescents . In contrast, Listeria monocytogenes is a cause of septicaemia and meningitis in neonates and immunocompromised adults . Dendritic cells (DCs) provide the physical link between the innate and adaptive immune system and play a crucial role in host defence against invading bacterial pathogens . The mechanisms of interaction of L . monocytogenes and N . meningitidis with DCs are entirely distinct . Whereas L . monocytogenes is readily phagocytosed by DCs by a serum-dependent mechanism, N . meningitidis is largely protected against phagocytotic uptake by its polysaccharide capsule . In addition, the pattern of secreted cytokines induced by L . monocytogenes is dominated by interleukin (IL)-12 and IL-18, capable of initiating a Th-1 response, whereas N . meningitidis induces high levels of proinflammatory cytokines . Therefore, we propose distinct functions of DCs in both types of bacterial meningitis.

Curr Opin Infect Dis, 2003 Oct, 16(5), 369 - 74
Current immunizations for travel; Kirkpatrick BD et al.; PURPOSE OF REVIEW: International travelers may be at risk from a variety of potentially severe and life-threatening infections . Some of these diseases are preventable, and vaccination remains a cornerstone of travel medicine . Vaccines that are important for international travel are reviewed, in a succinct update based on the most recent literature . RECENT FINDINGS: Discussed are vaccines for enteric infections (polio, cholera, hepatitis A, and typhoid), as well as those for hepatitis B, Japanese encephalitis, yellow fever, and meningococcal vaccines . The controversial end to the polio eradication campaign and the recognition of vaccine-derived polioviruses are discussed . New monovalent cholera vaccines, including the live attenuated Peru-15 and CVD 103-HgR and the oral killed whole cell B subunit vaccine are reviewed, as well as a new oral bivalent vaccine that may offer protection against Vibrio cholerae 0139 . Advances in typhoid vaccination include promising preclinical and clinical trial results of recombinant ZH9 and CVD 908-htrA vaccines, which, in addition to providing protection against typhoid fever, may be useful vectors for heterologous antigens . A growing recognition of rare adverse reactions to the 17D yellow fever vaccine, especially postvaccinal encephalitis, has led to a reassessment of its risks and benefits . Development of a novel chimeric vaccine may improve the safety and efficacy of the current Japanese encephalitis vaccine . Vaccination for meningococcal disease is characterized by the need for polyvalent, conjugate vaccines as well as a product that affords protection against serotype B . SUMMARY: This travel vaccination review highlights progress in new travel-related vaccine development and updates the reader on issues surrounding licensed products . It will be useful for generalists, infectious disease physicians, and travel medicine specialists.

Infect Immun, 2003 Oct, 71(10), 5714 - 23
Construction and functional activities of chimeric mouse-human immunoglobulin G and immunoglobulin M antibodies against the Neisseria meningitidis PorA P1.7 and P1.16 epitopes; Michaelsen TE et al.; We studied the in vitro protective activities of human immunoglobulin G1 (IgG1), IgG3, and IgM antibodies against group B meningococci by constructing sets of chimeric mouse-human antibodies (chIgG1, chIgG3, and chIgM, respectively) with identical binding regions against the P1.7 and P1.16 epitopes on PorA . This was done by cloning the V genes of three mouse hybridoma antibodies and subsequently transfecting vectors containing the homologous heavy- and light-chain genes into NSO cells . Cell clones secreting intact human chIgG1, chIgG3, or chIgM antibodies originating from three parent mouse antibodies were isolated . The functional affinities appeared to be similar for all human isotypes and surprisingly also for the pentameric chIgM antibody . chIgG1 exhibited greater serum bactericidal activity (SBA) than chIgG3, while chIgG3 was more efficient in inducing a respiratory burst (RB) associated with opsonophagocytosis than chIgG1 was . On the other hand, chIgM exhibited SBA similar to that of chIgG1, but it exhibited much higher RB activity than chIgG3 and chIgG1 exhibited . The antibodies against the P1.16 epitope were more efficient in terms of SBA than the antibodies against the P1.7 epitope were; thus, 10- to 40-fold-lower concentrations of antibodies against P1.16 than of antibodies against P1.7 were needed to induce SBA . On the other hand, antibodies against these epitopes were equally effective in inducing RB . Our results revealed differences in the functional activities of human chIgG1, chIgG3, and chIgM antibodies against meningococci, which might influence their protective effects against meningococcal disease.

Infect Immun, 2003 Oct, 71(10), 5590 - 7
Activation of human dendritic cells is modulated by components of the outer membranes of Neisseria meningitidis; Al-Bader T et al.; Neisseria meningitidis serogroup B is a major cause of life-threatening meningitis and septicemia worldwide, and no effective vaccine is available . Initiation of innate and acquired immune responses to N . meningitidis is likely to be dependent on cellular responses of dendritic cells (DC) to antigens present in the outer membrane (OM) of the meningococcus . In this study, the responses of human monocyte-derived DC (mo-DC) to OM isolated from parent (lipopolysaccharide {LPS}-replete) meningococci and from a mutant deficient in LPS were investigated . Parent OM selectively up-regulated Toll-like receptor 4 (TLR4) mRNA expression and induced mo-DC maturation, as reflected by increased production of chemokines, proinflammatory cytokines, and CD83, CD80, CD86, CD40, and major histocompatibility complex (MHC) class II molecules . In contrast, LPS-deficient OM selectively up-regulated TLR2 mRNA expression and induced moderate increases in both cytokine production and expression of CD86 and MHC class II molecules . Preexposure to OM, with or without LPS, augmented the allostimulatory properties of mo-DC, which induced proliferation of naive CD4+ CD45RA+ T cells . In addition, LPS-replete OM induced a greater gamma interferon/interleukin-13 ratio in naive T cells, whereas LPS-deficient OM induced the reverse profile . These data demonstrate that components of the OM, other than LPS, are also likely to be involved in determining the levels of DC activation and the nature of the T-helper immune response.

Infect Immun, 2003 Oct, 71(10), 5549 - 55
Immunogenicity of, and immunologic memory to, a reduced primary schedule of meningococcal C-tetanus toxoid conjugate vaccine in infants in the United kingdom; Borrow R et al.; It has been previously shown that one of the three meningococcal C conjugate (MCC) vaccines introduced in the United Kingdom proved highly immunogenic after the first dose of a three-dose schedule, with evidence of immune memory after dose 3 . Thus, in infants a one- or two-dose schedule of this MCC vaccine, conjugated to tetanus toxoid (TT), may suffice . Healthy infants (n = 586) were randomized to receive either one (group 1), two (group 2), or three (group 3) doses of MCC-TT vaccine with a 10- micro g polysaccharide booster given at 13 to 14 months of age . Serum bactericidal antibody (SBA) levels were measured by utilizing rabbit complement (rSBA), meningococcal C-specific immunoglobulin G (IgG), and avidity indices (AIs) . For groups 1, 2, and 3, the percentages of infants with an rSBA level of > or =8 against strain C11 were 98.4, 100, and 99.4%, respectively . Infants in group 1 with prevaccination rSBA titers of > or =8 had post-primary MCC rSBA geometric mean titers (GMTs) significantly lower than those infants with prevaccination rSBA titers of <8 . One dose of MCC-TT vaccine given to infants at 2 months of age yielded significantly lower SBA GMTs and geometric mean AIs (GMAIs) than two or three doses but elicited a significantly greater response after boosting, as reflected by rSBA levels and GMAI . This study provides the first evidence that the number of doses of MCC-TT used in infant immunization schedules could be decreased.

Arch Dis Child, 2003 Oct, 88(10), 927 - 30
Immune complex associated complications in the subacute phase of meningococcal disease: incidence and literature review; Goedvolk CA et al.; AIM: To determine the incidence of immune complex associated complications (IAC) after severe meningococcal disease (SMD) in a group of Dutch children admitted to a paediatric intensive care unit (PICU) . METHODS: Retrospective chart analysis and follow up of 130 survivors of SMD admitted to PICU . Signs of IAC, inflammatory parameters, and temperature profile were reviewed . RESULTS: Of 130 children with SMD, 20 (15.3%) showed one or more of the three manifestations of IAC: 18 (13.8%) developed arthritis (effusion, with or without erythema/arthralgia), 11 (8.4%) vasculitis, and five (3.8%) pleuritis . Eighteen of 20 (90%) patients with IAC had a secondary rise in temperature; in patients with no IAC this was 48 of 110 (43.6%) . IAC was associated with leucocytosis in 82.3% versus 47.7% in patients without IAC, and with increased CRP in 86.6% versus 47.2% in patients without IAC . Leucocytes on admission were significantly lower in patients who would later develop IAC (mean 8.6 versus 13.8x10(9)/l) . CONCLUSION: IAC is a common complication of SMD, mainly occurring 4-10 days after systemic disease . IAC presents clinically as arthritis or vasculitis, mostly accompanied by secondary fever and raised inflammatory parameters.

Eur J Pediatr, 2003 Nov, 162(11), 785 - 7 Epub 2003 Sep 17.
Early onset neonatal infection with Neisseria meningitidis serogroup C: case report and literature review; Lo WT et al.; Although Neisseria meningitidis is one of the major causes of meningitis in children and adolescents, meningococcal disease should also be considered as part of the differential diagnoses in the newborn period.

Clin Infect Dis, 2003 Oct 1, 37(7), 912 - 20 Epub 2003 Sep 09.
Neisseria meningitidis strains isolated from invasive infections in France (1999-2002): phenotypes and antibiotic susceptibility patterns; Antignac A et al.; Infections due to Neisseria meningitidis are a major public health concern . In France, during 1999-2002, a total of 2167 clinical isolates of N . meningitidis from invasive infections were studied at the National Reference Center for Meningococci (Paris) . Serogroup B strains were the most common (58%), followed by serogroup C strains (29%) and serogroup W135 strains (8%) . Various phenotypes were observed, reflecting heterogeneity in the meningococcal population . Strains were susceptible to antibiotics currently used for treatment and chemoprophylaxis of meningococcal infections . However, the prevalence of meningococci with reduced susceptibility to penicillin is increasing . Such strains were heterogeneous and accounted for approximately 30% of isolates during this period, warranting continued surveillance of this phenomenon.

FEMS Microbiol Lett, 2003 Sep 12, 226(1), 51 - 6
Insertional inactivation of the lpxA gene involved in the biosynthesis of lipid A in Neisseria meningitidis resulted in lpxA/lpxA::aph-3' heterodiploids; Zarantonelli ML et al.; The lpxA gene is known to be involved in the biosynthesis of lipid A in Gram-negative bacteria and thought to be an essential gene . However, viable meningococcal lpxA mutants devoid of detectable endotoxin (lipooligosaccharide) have been reported . We characterised such mutants in strains of Neisseria meningitidis belonging to serogroups B and C using molecular and biochemical analysis . While lpxA mutants with no detectable or a low level of lipooligosaccharide could be obtained in N . meningitidis, the simple insertional inactivation of lpxA was not possible . In all mutants, we obtained lpxA/lpxA::aph-3' heterodiploids harbouring one copy of the wild-type lpxA gene and one copy of the inactivated lpxA gene by insertion of the kanamycin resistance cassette, aph-3' . The absence of lipooligosaccharide in these mutants may result from a negative transdominance effect of a truncated LpxA protein on the wild-type LpxA protein.

Aust Fam Physician, 2003 Aug, 32(8), 597 - 601, 603-5
Meningococcal disease; Daley AJ; BACKGROUND: Despite significant advances in the prevention and management of Neisseria meningitidis infection, invasive meningococcal disease continues to occur with significant morbidity and mortality . OBJECTIVE: This article aims to provide an overview of the aetiology, pathogenesis, transmission, epidemiology, clinical presentation, diagnosis, treatment and prevention of meningococcal disease . DISCUSSION: Neisseria meningitidis is now the commonest cause of meningitis and is a significant cause of septicaemia, particularly in children and young adults . The initial diagnosis may be difficult but early recognition and treatment is essential . Transmission occurs during close contact and prophylaxis is important to prevent invasive disease in contacts . The conjugate meningococcal C vaccine has recently been funded for all children aged 1-19 years in Australia.

Southeast Asian J Trop Med Public Health, 2002, 33 Suppl 3, 127 - 30
Surveillance for meningococcal carriage by Muslims returning from the Hajj to Hat Yai Airport, Thailand; Phrom-in S; This study had three objectives: firstly, it aimed to examine an appropriate model for preventing and controlling the risk of meningococcal disease as a result of an epidemic carrying by returning pilgrims at Hat Yai International Airport; secondly, it aimed to establish the number of meningococcal carriers among pilgrims returning from Saudi Arabia; thirdly, it considered the health problems that arose during the Hajj pilgrimage . A structured questionnaire was used to collect data from 374 pilgrims at the Hat Yai airport checkpoint between March 15th and April 2nd, 2001 . Each subject provided a naso-pharyngeal swab and reported on their health status by postcard once they had reached their homes 7-10 days later . It was found that most of the pilgrims were from Satun Province (23%) . The average age was 50.5 years (range 20 to 86; SD 12.8) . More than half of the pilgrims had some knowledge of meningococcal meningitis . Most, about 80.7%, knew that vaccination against meningococcal infection is required before traveling to Saudi Arabia . About 77.8% were vaccinated at the Provincial Health Office (PHO) in their hometown . Nearly 19% had underlying diseases such as chronic cough, asthma, diabetes, hypertension, headache and rheumatism . During their pilgrimage some were troubled by symptoms of respiratory tract disease, fever and headache . All had negative laboratory results . Only 16.6% returned postcards describing their self-assessed health status . About 30.6% described themselves as healthy . Among those who reported sick, coughs, sore throats and stomach aches were prevalent . Health education and public information about vaccine need to be strengthened . The best place to get the vaccination is their hometown PHO . Trained health personnel, instead of tour leaders or guides, should pay attention to the health of the pilgrims . The tour leaders are an important target group for improved health knowledge because most pilgrims will trust and follow them . Even though there were negative laboratory results, it is worth having a good surveillance system for meningococcal meningitis in order to prevent epidemics and reduce mortality among returning pilgrims.

Clin Diagn Lab Immunol, 2003 Sep, 10(5), 780 - 6
Validation of serological correlate of protection for meningococcal C conjugate vaccine by using efficacy estimates from postlicensure surveillance in England; Andrews N et al.; Meningococcal C conjugate (MCC) vaccines were licensed on the basis of serological correlates of protection without efficacy data . The original correlate of protection was established by using a serum bactericidal antibody assay (SBA) with human complement (hSBA), with titers > or =4 predicting protection . However, the antibody data supporting licensure were largely generated by SBA with rabbit complement (rSBA), which gives higher titers than hSBA . While rSBA titers > or =128 reliably predict protection, as measured by hSBA, sera with rSBA titers in the range of 8 to 64 may not have hSBA titers > or =4 . For rSBA titers in this equivocal range, a fourfold rise pre- to postvaccination with the MCC vaccine and/or a characteristic booster response to a polysaccharide challenge was proposed as a correlate of protection . To validate this proposed rSBA correlate, age-specific efficacy estimates for MCC vaccines obtained from postlicensure surveillance in England were compared with the efficacy predicted by the percentage of individuals in these age groups with rSBA titers above different cutoffs at 4 weeks and at 7 to 9 months after vaccination with the MCC vaccine . The average time since vaccination in the cohorts in whom efficacy was measured ranged from 8 to 10 months . The rSBA cutoff of > or =128 was shown to significantly underestimate efficacy, with rSBA cutoffs of > or =4 or > or =8 at 4 weeks postvaccination with the MCC vaccine being the most consistent with observed efficacy . When the levels obtained 7 to 9 months postvaccination with the MCC vaccine were used, all rSBA cutoffs significantly underestimated efficacy, suggesting that continuing protection is less dependent on the SBA level at the time of exposure but is more reliant on immunologic memory.

J Clin Microbiol, 2003 Sep, 41(9), 4411 - 4
Outbreak of serogroup C meningococcal disease caused by a variant of Neisseria meningitidis serotype 2a ET-15 in a community of men who have sex with men; Tsang RS et al.; We describe an outbreak, in a community of men who have sex with men, of serogroup C meningococcal disease caused by a genetic variant of the serotype 2a ET-15 Neisseria meningitidis characterized by a point mutation in the gene coding for the serotype 2a antigen . A microbiological characterization of the outbreak strain is presented in this report.

Lancet Infect Dis, 2003 Sep, 3(9), 565 - 77
Host genetic determinants of Neisseria meningitidis infections; Emonts M et al.; The clinical presentation of infections caused by Neisseria meningitidis is highly diverse . Some patients develop meningitis, and others present with sepsis or even septic shock . After invasion of the bloodstream by the bacteria, three main cascade pathways are activated . These are the complement system, the inflammatory response, and the coagulation and fibrinolysis pathway . These pathways do not act independently but are able to interact with each other . Genetic polymorphisms among components of these pathways have been shown to be involved in the susceptibility, severity, and outcome of meningococcal disease . We review knowledge of genetic variations associated with susceptibility to and severity of meningococcal infection . Complement deficiencies and defects in sensing or opsonophagocytic pathways, such as the rare Toll-like receptor 4 single nucleotide polymorphisms (SNPs) and combinations of inefficient variants of Fcgamma-receptors, seem to have the most important role in genetically established susceptibility . Effect on severity has repeatedly been reported for FcgammaRIIa and plasminogen activator inhibitor type 1 (PAI1) polymorphisms . Outcome effects have been confirmed for SNPs in properdin deficiencies, PAI1 and combination of the -511C/T SNP in interleukin 1beta, and the +2018C/T SNP in interleukin RN . Conflicting results are reported for the effect of the -308G/A promoter polymorphism in tumour necrosis factor (TNF) alpha . These differences may reflect discrepancies in group definitions between studies or the influence of additional SNPs in the TNFalpha promoter, which can form haplotypes representing different cytokine production capacity . For several SNPs, the potential effect on susceptibility, severity, or outcome has not yet been confirmed in an independent study.

Scand J Infect Dis, 2003, 35(6-7), 418 - 9
Chronic meningococcaemia; Hansen L et al.; Chronic meningococcaemia is a rare disorder . A patient was admitted to hospital with intermittent fever and arthralgia of a migratory nature for 1 week . Maculopapular lesions were present . His temperature was 38.5 degrees C . Physical examination revealed a patient without any signs of severe illness . Blood cultures grew Neisseria meningitides.

Clin Infect Dis, 2003 Sep 1, 37(5), 658 - 62 Epub 2003 Aug 13.
Three days of intravenous benzyl penicillin treatment of meningococcal disease in adults; Ellis-Pegler R et al.; New Zealand has experienced an epidemic of predominantly serogroup B meningococcal disease during the past decade . In a prospective study, we treated adults (age, >15 years) with meningococcal disease with intravenous benzyl penicillin (12 MU {7.2 g} per day) for 3 days . Sixty-one adults with suspected meningococcal disease were consecutively admitted during the 33-month period; 3 patients were excluded . The 58 patients had a mean age (+/- standard deviation {SD}) of 27.9+/-14.5 years (median, 21 years; range, 15-70 years) . Forty-four patients had confirmed and 14 patients had probable meningococcal disease . Fifty-seven patients received 12 MU (7.2 g) and 1 received 8 MU (4.8 g) of benzyl penicillin per day . Thirteen patients received additional antibiotics within the first 24 h because of diagnostic uncertainties . Patients received a mean (+/-SD) of 3.0+/-0.5 days of treatment . No patients relapsed . Five patients died . All but 1 death occurred during benzyl penicillin treatment, and the only posttreatment death was not due to meningococcal disease . Three days of intravenous benzyl penicillin is sufficient treatment for adults with meningococcal disease . The usual recommendations for duration of treatment are excessive.

Med Sci Monit, 2003 Aug, 9(8), BR316 - 24
Expression and involvement of Toll-like receptors (TLR)2, TLR4, and CD14 in monocyte TNF-alpha production induced by lipopolysaccharides from Neisseria meningitidis; Mirlashari MR et al.; BACKGROUND: The present study was undertaken to examine the ability of lipopolysaccharide-containing outer membrane vesicles (OMV-LPS) and purified LPS (P-LPS) from the same meningococcal strain to induce the expression of Toll-like receptors (TLR2 and TLR4) and TNF-alpha production in leukocytes, and further to study the involvement of TLRs, and CD14 in monocyte TNF- alpha production in an ex vivo human whole blood system . MATERIAL/METHODS: OMV-LPS or P-LPS were added to human whole blood and expression of TLR2/4 and production of TNF- alpha in leukocytes were measured by flow cytometry . To study involvement of TLRs and CD14 in monocyte cytokine production we used monoclonal antibodies against TLR2/4 and CD14 . RESULTS: OMV-LPS and P-LPS induced surface expression (maximal at 120 min) of TLR2 and TLR4 on granulocytes and monocytes . LPS incorporated in OMV was less potent (weight basis) than P-LPS in inducing monocyte TNF- alpha production . When inducing monocyte TNF-alpha by OMV-LPS, antibodies directed against TLR2 and TLR4 caused 45 and 78% inhibition, respectively . When inducing TNF- alpha by P-LPS, antibodies against TLR2 had no effect, whereas anti-TLR4 antibodies caused 63% inhibition . Antibodies against CD14 inhibited nearly completely the monocyte TNF- alpha response induced by meningococcal LPS irrespective of whether LPS was presented in purified form or incorporated in membrane vesicles . CONCLUSIONS: OMV-LPS and P-LPS from the same meningococcal strain induced expression of TLR2/4 on monocytes and granulocytes . Surface receptors TLR2/4 and CD14 are essential for in vitro cellular activation induced by OMV-LPS and P-LPS, but the functional significance of these receptors during meningococcal infections remains elusive.

Mol Microbiol, 2003 Sep, 49(5), 1213 - 25
Recognition of sialylated meningococcal lipopolysaccharide by siglecs expressed on myeloid cells leads to enhanced bacterial uptake; Jones C et al.; Sialic acid-binding immunoglobulin-like lectins (siglecs) are expressed predominantly in the haemopoietic and immune systems and exhibit specificities for both the linkage and the nature of sialic acids in N-glycans, O-glycans and glycolipids . Several siglecs, including sialoadhesin (Sn, siglec-1) and siglec-5, bind to NeuAcalpha2,3Gal, a terminal capping structure that can also be displayed on the lipopolysaccharide (LPS) of Neisseria meningitidis (Nm) . In the present study, we examined the potential of siglecs expressed on cells of the immune system to function as receptors for sialylated Nm . We used sialylated and non-sialylated LPS derivatives of two serogroups (A and B) of Nm in this study . Using recombinant chimeric soluble receptors, siglec-transfected cell lines and macrophages from wild-type and Sn-deficient mice, we observed that sialylated but not non-sialylated variants of either genetic background were specifically recognized by Sn and siglec-5, whereas other siglecs examined were ineffective . In addition, macrophages expressing Sn, as well as transfectants expressing Sn or siglec-5, bound and phagocytosed sialylated bacteria in a siglec- and sialic acid-dependent manner . This study demonstrates that Nm LPS sialylation can lead to increased bacterial susceptibility to phagocytic uptake, a phenomenon in direct contrast to previously reported protective effects of LPS sialylation.

Eur J Clin Microbiol Infect Dis, 2003 Sep, 22(9), 566 - 8 Epub 2003 Aug 21.
Long-term predominance of a rare meningococcal phenotype in a small geographical area; Stefanelli P et al.; Reported here is a predominant clone of Neisseria meningitidis B:14:P1.13 that persisted over a 6-year period in the northernmost province of Italy, where it was responsible for a higher incidence of meningococcal disease compared to the rest of the country . Genetic relatedness of isolates was confirmed by multilocus sequence typing, pulsed-field gel electrophoresis and PorA variable region typing . All strains examined belonged to the ST44 complex/lineage III . Risk factors for infection were evaluated through a case-control study conducted with 21 cases and 63 age- and sex-matched controls . Risk factors for infection in the seven patients younger than 13 years were (i) residence in a rural area, (ii) exposure to passive smoke, and (iii) living in a home with rooms rented to tourists (all odds ratios infinite) . The only risk factor for the older patients was previous influenza-like illness (odds ratio, 41.9; 95% confidence interval, 1.6-1068.9) . Guidelines for the early treatment of patients and public information campaigns were successfully implemented to reduce disease transmission and the case fatality rate in the region.

Infect Immun, 2003 Sep, 71(9), 5210 - 8
Liposomal meningococcal B vaccination: role of dendritic cell targeting in the development of a protective immune response; Arigita C et al.; The effect of targeting strategies for improving the interaction of liposomal PorA with dendritic cells (DC) on the immunogenicity of PorA was investigated . PorA, a major antigen of Neisseria meningitidis, was purified and reconstituted in different types of (targeted) liposomes, i.e., by using mannose or phosphatidylserine as targeting moieties, or with positively charged liposomes . We studied the efficiency of liposome uptake and its effect on the maturation of and interleukin 12 (IL-12) production by murine DC . Moreover, mice were immunized subcutaneously to study the localization and immunogenicity of PorA liposomes . Uptake of liposomes by DC was significantly increased for targeted liposomes and resulted in the maturation of DC, but to various degrees . Maturation markers (i.e., CD80, CD86, major histocompatibility complex class II, and CD40) showed enhanced expression on DC incubated with targeted PorA liposomes relative to those incubated with nontargeted PorA liposomes . Moreover, only the uptake of targeted PorA liposomes induced production of IL-12 by DC, with levels similar to those produced by lipopolysaccharide (LPS)-pulsed DC . Mannose-targeted PorA liposomes administered subcutaneously had an increased localization in draining lymph nodes compared to nontargeted PorA liposomes . Liposomes in draining lymph nodes interacted preferentially with antigen-presenting cells, an effect that was enhanced with targeted PorA liposomes . Immunization studies showed an improvement of the bactericidal antibody response (i.e., increased number of responders) generated by targeted PorA liposomes compared to that generated by nontargeted ones or LPS-containing outer membrane vesicles . In conclusion, the use of targeted PorA liposomes results in an improved uptake by and activation of DC and an increased localization in draining lymph nodes . These effects correlate with an enhanced immune response toward the vaccine.

Infect Immun, 2003 Sep, 71(9), 5115 - 20
Preparation and characterization of group A meningococcal capsular polysaccharide conjugates and evaluation of their immunogenicity in mice; Jin Z et al.; Epidemic and endemic meningitis caused by group A Neisseria meningitidis remains a problem in sub-Saharan Africa . Although group A meningococcal capsular polysaccharide (GAMP) vaccine confers immunity at all ages, the improved immunogenicity of a conjugate and its compatibility with the World Health Organization's Extended Program on Immunization offers advantages over GAMP alone . Conjugates of GAMP bound to bovine serum albumin (BSA) were synthesized, characterized, and evaluated for their immunogenicities in mice . Two methods, involving adipic acid dihydrazide (ADH) as a linker, were used . First, ADH was bound to GAMP activated with cyanogen bromide (CNBr) or with 1-cyano-4(dimethylamino)-pyridinium tetrafluoroborate (CDAP) to form GAMP(CNBr)AH and GAMP(CDAP)AH . These derivatives were bound to BSA by 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide (EDC) to form GAMP(CNBr)AH-BSA and GAMP(CDAP)AH-BSA . Second, ADH was bound to BSA with EDC to form AHBSA . AHBSA was bound to activated GAMP to form GAMP(CNBr)-AHBSA and GAMP(CDAP)-AHBSA . The yield of GAMP(CDAP)-AHBSA (35 to 40%) was higher than those of the other conjugates (5 to 20%) . GAMP conjugates elicited immunoglobulin G (IgG) anti-GAMP in all mice after three injections of 2.5 or 5.0 microg of GAMP: the geometric mean (GM) was highest in recipients of GAMP(CDAP)-AHBSA (11.40 enzyme-linked immunosorbent assay units) . Although the difference was not statistically significant, the 5.0- microg dose elicited a higher GM IgG anti-GAMP than the 2.5- microg dose . Low levels of anti-GAMP were elicited by GAMP alone . GAMP(CDAP)-AHBSA elicited bactericidal activity roughly proportional to the level of IgG anti-GAMP.

Lancet, 2003 Aug 9, 362(9382), 449 - 50
Risk of relapse after meningococcal C conjugate vaccine in nephrotic syndrome; Abeyagunawardena AS et al.; In November, 1999, all children under age 18 years in the UK were offered immunisation with the newly introduced meningococcal C conjugate vaccine (MCCV) . In a cohort of 106 patients with nephrotic syndrome, there were 63 relapses during the 12 months before vaccination, and 96 during the equivalent period postvaccination (p=0.009) . The relapse rate of nephrotic syndrome increased significantly after administration of MCCV . Whether to vaccinate such children needs to be carefully considered.

Commun Dis Intell, 2003, 27(2), 196 - 208
Annual report of the Australian Meningococcal Surveillance Programme, 2002; Australian Meningococcal Surveillance Programme; Since 1994, The National Neisseria Network, a nationwide collaborative laboratory program, has examined and analysed isolates of Neisseria meningitidis from cases of invasive meningococcal disease in Australia . The phenotypes (serogroup, serotype and serosubtype) and antibiotic susceptibility of 393 isolates of N . meningitidis from invasive cases of meningococcal disease were determined in 2002 . Most disease was caused by serogroup B (210 isolates, 53%) or serogroup C (162 isolates, 41%) meningococci . An increased number of isolates in Victoria (129 from 77 in 2001) accounted for most of the increased national total . A diversity of phenotypes circulated in the different states and territories . Serogroup B strains predominated in all jurisdictions except Victoria, Tasmania and the Australian Capital Territory and were isolated from sporadic cases of invasive disease . Serogroup B phenotypes B:4:P1.4(7) and B:15:P1.7 were the most common and widely distributed . The common serogroup C phenotype in Victoria, C:2a:P1.4(7), was also common in Tasmania . Elsewhere in Australia it was detected only in low numbers . Other C:2a serosubtypes were prominent in other jurisdictions . About two-thirds of all isolates showed decreased susceptibility to the penicillin group of antibiotics (MIC 0.06 to 0.5 mg/L) . Two isolates, one each from Darwin and Sydney, had MICs of 1 mg/L . From 1999, reports have also included diagnoses made by non-culture-based methods in these analyses . Data relating to 187 laboratory-confirmed but culture-negative cases supplemented information on culture confirmed cases in this report.

Hamostaseologie, 2003 Aug, 23(3), 125 - 30
Disseminated intravascular coagulation in meningococcal sepsis . Case 7; Zeerleder S et al.; We report on a man (age: 49 years), who died from severe meningococcal sepsis with disseminated intravascular coagulation (DIC), multiple organ dysfunction syndrome and extended skin necrosis . We discuss in detail the pathophysiology of the activation of coagulation and fibrinolysis during sepsis . The article discusses new therapeutic concepts in the treatment of disseminated intravascular coagulation in meningococcal sepsis, too.

Vaccine, 2003 Sep 8, 21(25-26), 3837 - 44
The concomitant use of the LTK63 mucosal adjuvant and of chitosan-based delivery system enhances the immunogenicity and efficacy of intranasally administered vaccines; Baudner BC et al.; In this paper we evaluated chitosan microparticles as a vaccine delivery system as well as the mucosal adjuvant LTK63, a nontoxic Escherichia coli enterotoxin (LT) mutant for the intranasal immunization with the group C meningococcal conjugated vaccine (CRM-MenC) . Mice receiving intranasally the CRM-MenC vaccine formulated with chitosan microparticles and the LTK63 mutant showed higher titers of systemic and mucosal antibodies specific for the group C meningococcal polysaccharide as compared to those receiving the vaccine subcutaneously . In addition, high bactericidal activity was found in serum samples of mice immunized intranasally with the conjugated vaccine formulated together with the microparticles and the LT mutant . These results demonstrate that the concomitant use of chitosan microparticles and the LTK63 mutant significantly enhances the immunogenicity and the protective efficacy of vaccines given intranasally.

Intensive Care Med, 2003 Oct, 29(10), 1770 - 3 Epub 2003 Aug 15.
Gender-based differences in children with sepsis and ARDS: the ESPNIC ARDS Database Group; Bindl L et al.; Male gender predisposes to severe sepsis and septic shock . This effect has been ascribed to higher levels of testosterone . The ESPNIC ARDS database was searched, to determine if there was evidence of a similar male preponderance in severe sepsis in prepubertal patients in spite of low levels of male sex hormones at this age . A total of 72 patients beyond neonatal age up to 8 years of age with sepsis were identified . The male/female (M/F) ratio was 1.7 (1.0;2.7) and differed significantly from non-septic ARDS patients in this age group {n = 209; M/F = 1.0 (0.8;1.3)} . The highest M/F-ratio was observed in the first year of life . The gender-ratio was the same as reported in adult patients with sepsis . In infants between 1 month and 12 months of age, the ratio was 2.8 (1.2;6.1) (Chi2= 5.6; P< 0.01), in children from 1 year to 8 years of age it was 1.2 (0.7;2.2) (n.s.) . In a subgroup of patients with severe sepsis or septic shock, caused by other bacteria than Neisseria meningitidis, the M/F-ratio was 2.1 (1.2;3.6) (Chi2= 4.9; P<0.05), while in patients with meningococcal sepsis (n=20) the M/F-ratio was 1.0 (0.4;2.3) . In prepubertal ARDS patients with sepsis an increased frequency of male patients is found, comparable to adults . No male preponderance exists in patients with ARDS due to meningococcal septic shock . Since levels of testosterone and other sex hormones are extremely low at this age, we conclude that factors others than testosterone are involved in the male preponderance in severe sepsis.

Adv Exp Med Biol, 2003, 531, 351 - 5
A case of familial meningococcal disease due to deficiency in mannose-binding lectin (MBL); Kuipers S et al.; A case of familial meningococcal meningitis is described, which involved a 18-year old boy, his mother, and his grandfather, from who all three suffered from meningococcal disease at about similar age (17-19 y), albeit with one or two generations in between . By studying the genetic variants of MBL, we found out that all three family members described carried the B, D variant mbl genes instead of the homozygous mbl A, A trait . Serum MBL levels within the family varied from <0.15 microgs per ml (for the B, D variant) up to 7.0 microgs per ml with 1.67 microgs per ml as mean serum level of a control population (n = 216); in the normal population, also incidental cases with serum levels of up to 16 (!) microg-equivalents per ml were observed, which occurred predominantly in elderly people and which are most likely to be explained by the acute-phase reactant behavior of MBL protein.

Med Trop (Mars), 2003, 63(2), 191 - 3
{Description of the first cases of serotype A, sequence type (ST)-11 meningococcal meningitis in Senegal}; Ndoye B et al.; Senegal is located in the African meningitis belt and meningococcal meniningitis outbreaks are yearly events . Occurrence of an epidemic involving serogroup W135 in 2000 and its spread following the Hajj (pilgrimage to Mecca) exposed the strongly Moslem population of Senegal to the risk of early infection . Indeed the first two cases in Dakar occurred simultaneously with the spread of this epidemic strain . The purpose of this article is to describe clinical, laboratory, and therapeutic findings in these two cases and the results of the ensuing epidemiological survey . The relationship with the pilgrimage and consequences on public health in Senegal are discussed.

J Med Microbiol, 2003 Sep, 52(Pt 9), 793 - 9
Direct-test PCR for detection of meningococcal DNA and its serogroup characterization: standardization and adaptation for use in a public health laboratory; Baethgen LF et al.; A direct PCR test (DT-PCR) was established to detect Neisseria meningitidis DNA in clinical samples from patients with suspected bacterial meningitis . Specific primers for the 16S rDNA of N . meningitidis were designed to amplify a 600 bp DNA fragment . One hundred and ninety-three clinical samples were analysed, corresponding to 114 samples from patients diagnosed as positive and 79 as negative for infection by N . meningitidis using conventional methods (culture, latex agglutination and counterimmunoelectrophoresis) . These samples were submitted to PCR by two different clinical sample preparation approaches (with and without DNA extraction and purification) and submitted to different PCR protocols to improve the results . In agarose gel detection, the sensitivity value for DT-PCR was 88.5 % and, using dot-blot DNA detection, the sensitivity increased to 96.4 % . The detection limit for meningococcus in cerebrospinal fluid was 2x10(2) c.f.u . ml(-1) . Serogroup prediction was done using a multiplex PCR protocol and the sensitivity was 83 % for agarose gel DNA detection and 96.4 % using dot-blot DNA detection.

Expert Rev Vaccines, 2002 Jun, 1(1), 75 - 84
Meningococcal vaccines; Bethell D et al.; The successful introduction of a protein-polysaccharide conjugate vaccine against serogroup C meningococci into the UK infant immunization schedule, in combination with a catch-up campaign for individuals less than 18 years of age, has seen virtually all group C disease eliminated in childhood . From being a devastating disease with a very high mortality, the possibility of eradicating invasive meningococcal disease now seems eminently feasible . Since similar technology is likely to facilitate prevention of disease caused be serogroup A, Y and W135 meningococci, the major hurdle in achieving the goal of eradication is development of a safe and immunogenic vaccine against serogroup B infections . Outer membrane vesicle vaccines remain in development and further trials are anticipated . Through the recent availability of the meningococcal genome sequence, many new vaccine candidates are being identified and there is increasing optimism that a solution to the problem can be found.

Lancet, 2003 Aug 2, 362(9381), 355 - 61
Efficacy and safety of seven-valent conjugate pneumococcal vaccine in American Indian children: group randomised trial; O'Brien KL et al.; BACKGROUND: Streptococcus pneumoniae is the main cause of invasive bacterial disease in children aged younger than 2 years . Navajo and White Mountain Apache children have some of the highest rates of invasive pneumococcal disease documented in the world . We aimed to assess the safety and efficacy of a seven-valent polysaccharide protein conjugate pneumococcal vaccine (PnCRM7) against such disease . METHODS: In a group-randomised study, we gave this vaccine to children younger than 2 years from the Navajo and White Mountain Apache Indian reservations; meningococcal type C conjugate vaccine (MnCC) served as the control vaccine . Vaccine schedules were determined by age at enrollment . We recorded episodes of invasive pneumococcal disease and serotyped isolates . Analyses were by intention to treat and per protocol . FINDINGS: 8292 children enrolled in the trial . In the per protocol analysis of the primary efficacy group (children enrolled by 7 months of age) there were eight cases of vaccine serotype disease in the controls and two in the PnCRM7 group; in the intention-to-treat analysis we noted 11 cases of vaccine serotype disease in the MnCC control group and two in the PnCRM7 group . After group randomisation had been controlled for, the per protocol primary efficacy of PnCRM7 was 76.8% (95% CI -9.4% to 95.1%) and the intention-to-treat total primary efficacy was 82.6% (21.4% to 96.1%) . INTERPRETATION: PnCRM7 vaccine prevents vaccine serotype invasive pneumococcal disease even in a high risk population . Other regions with similar disease burden should consider including this vaccine in the routine childhood vaccine schedule.

J Clin Microbiol, 2003 Aug, 41(8), 3873 - 6
Identification of the hypervirulent lineages of Neisseria meningitidis, the ST-8 and ST-11 complexes, by using monoclonal antibodies specific to NmeDI; Claus H et al.; Most cases of serogroup C meningococcal disease are caused by the clonal lineages ST-8 and ST-11 . The gene encoding the putative restriction-modification system NmeDI is specific to these lineages . We report here a monoclonal antibody directed against the NmeDI endonuclease as a tool for their rapid and spe-cific identification.

J Clin Microbiol, 2003 Aug, 41(8), 3851 - 3
Evaluation of a rapid PCR assay for diagnosis of meningococcal meningitis; Richardson DC et al.; We compared the results of Gram staining and culture of cerebrospinal fluid to results obtained with a rapid PCR assay for the diagnosis of meningococcal meningitis in 281 cases of suspected bacterial meningitis . PCR had a sensitivity of 97% compared to a sensitivity of 55% for culture, and the PCR specificity was 99.6% . PCR results were available within 2 h of the start of the assay.

J Biol Chem, 2003 Nov 7, 278(45), 44025 - 32 Epub 2003 Aug 06.
Nramp1-mediated innate resistance to intraphagosomal pathogens is regulated by IRF-8, PU.1, and Miz-1; Alter-Koltunoff M et al.; Natural resistance-associated macrophage protein 1 (Nramp1) is a proton/divalent cation antiporter exclusively expressed in monocyte/macrophage cells with a unique role in innate resistance to intraphagosomal pathogens . In humans, it is linked to several infectious diseases, including leprosy, pulmonary tuberculosis, visceral leishmaniasis, meningococcal meningitis, and human immunodeficiency virus as well as to autoimmune diseases such as rheumatoid arthritis and Crohn's disease . Here we demonstrate that the restricted expression of Nramp1 is mediated by the macrophage-specific transcription factor IRF-8 . This factor exerts its activity via protein-protein interaction, which facilitates its binding to target DNA . Using yeast two-hybrid screen we identified Myc Interacting Zinc finger protein 1 (Miz-1) as new interacting partner . This interaction is restricted to immune cells and takes place on the promoter Nramp1 in association with PU.1, a transcription factor essential for myelopoiesis . Consistent with these data, IRF-8 knockout mice are sensitive to a repertoire of intracellular pathogens . Accordingly, IRF-8-/- mice express low levels of Nramp1 that can not be induced any further . Thus, our results explain in molecular terms the role of IRF-8 in conferring innate resistance to intracellular pathogens and point to its possible involvement in autoimmune diseases.

Expert Opin Drug Saf, 2003 Jan, 2(1), 7 - 19
Safety and efficacy of meningococcal group C conjugate vaccines; Ruggeberg J et al.; The UK was the first country to implement a universal vaccination programme with conjugate polysaccharide vaccines against Neisseria meningitidis group C . This article reviews the pre- and postlicensure data on their efficacy and safety 3 years after the introduction of the programme . Local reactogenicity data compare favourably with other routine vaccinations and no specific increase in adverse reactions has been associated with their use in infant vaccination programmes . Self-limiting systemic reactions such as fever, myalgia, headaches and irritability have commonly been observed in prelicensure studies . Passive postlicensure safety monitoring of suspected adverse reactions has identified a large number of reports, generally of reactions deemed non-serious and reversible . An Expert Working Group has concluded the balance of benefits and risks to be overwhelmingly favourable . Further safety data are expected from large data-linkage studies . Present efficacy estimates, based on active surveillance of case numbers, vaccine failures and coverage rates, are approximately 90% for all age groups . A significant fall in the number of cases attributable to meningococcal group C infection has been observed in the age group of < 20 years . The annual number of fatalities from confirmed meningococcal C disease in the same population has fallen from 67 to 5 cases within a 2-year period.

Expert Rev Vaccines, 2002 Dec, 1(4), 433 - 42
Emerging issues in vaccine economics: perspectives from the USA; Lieu TA et al.; Economic studies of vaccines, including vaccine development and delivery issues, are increasingly needed to inform policy recommendations and programmatic decisions in the USA . This need arises from the increasing costs of vaccines, the complexity of the US healthcare system and the limited number of vaccine manufacturers in the market . We have developed a national research agenda in domestic and global vaccine economics by conducting key informant interviews with 42 experts and inviting ideas from an additional 128 experts . To assess priorities among the 129 ideas that were generated, we asked 15 experts representing a broad range of perspectives to rank the ideas and we analyzed their votes . The highest-ranking domestic research ideas included evaluating: the costs of vaccine shortages, the cost-effectiveness of potential human papillomavirus vaccination and adult and adolescent pertussis vaccination programs and the cost-effectiveness of universal vaccine purchase programs for adults as well as children . The highest-ranking globally-oriented ideas included developing a resource allocation model to support the best vaccination program decisions with limited funds and assessing the cost-effectiveness of HIV, rotavirus, meningococcal and malaria vaccines in developing countries . To optimize the usefulness of vaccine economics research, conceptual issues, such as how to set values for the prevention of illness and how to maximize social equity through investments in vaccines, must be addressed.

Expert Rev Vaccines, 2002 Aug, 1(2), 227 - 32
Can nonliving nasal vaccines be made to work?
Haneberg B, Holst J.
Nasal vaccines consisting of nonliving particulate formulations can induce immune responses of importance for protection against infection . The most promising results have been obtained with vaccines against influenza, pertussis and group B meningococcal disease . So far, however, the results do not challenge the standing of corresponding injectable vaccines, although results of experiments in animals do indicate that effective nonliving nasal vaccines may soon be developed . This will depend on refined immunization schedules to benefit from immunological memory and on formulations to make the vaccines more accessible to the immune system by way of mucosal adjuvants or immune modulators.

Am Fam Physician, 2003 Jul 15, 68(2), 299 - 304
Vaccinations in pregnancy; Sur DK et al.; Adult immunization rates have fallen short of national goals partly because of misconceptions about the safety and benefits of current vaccines . The danger of these misconceptions is magnified during pregnancy, when concerned physicians are hesitant to administer vaccines and patients are reluctant to accept them . Routine vaccines that generally are safe to administer during pregnancy include diphtheria, tetanus, influenza, and hepatitis B . Other vaccines, such as meningococcal and rabies, may be considered . Vaccines that are contraindicated, because of the theoretic risk of fetal transmission, include measles, mumps, and rubella; varicella; and bacille Calmette-Guerin . A number of other vaccines have not yet been adequately studied; therefore, theoretic risks of vaccination must be weighed against the risks of the disease to mother and fetus . Inadvertent administration of any of these vaccinations, however, is not considered an indication for termination of the pregnancy.

Acta Paediatr, 2003 Jul, 92(7), 854 - 6
Seven-year review of paediatric bacteraemias diagnosed in a Spanish university hospital; Perez Lopez A et al.; This study analysed the clinical and bacteriological patterns of paediatric bacteraemia in a university hospital, by a review of 213 episodes over a period of 7 y . Streptococcus pneumoniae was the most frequent aetiological agent after the neonatal period and Streptococcus agalactiae in neonatal sepsis . Almost half of pneumococci and meningococci were penicillin non-susceptible . Four neonatal deaths attributed to bacteraemia were recorded . CONCLUSION: Streptococcus pneumoniae is the leading cause of community-acquired bacteraemia . Mortality due to bacteraemia in children without underlying conditions is rare.

An Sist Sanit Navar, 1997 Sep-Dec, 20(3), 363 - 71
{State of the meningococcal disease in Navarra}; Barricarte A et al.; The incidence of meningococcal disease in Navarra and Spain is determined for the 1991-1997 period, with a detected density of incidence of 5.46 per 100,000 in the 1987-1991 period . In Navarra the incidence in the 1991-1997 period was of 3.26 per 100,000 inhabitants, of which 1.91 per 100,000 corresponded to serogroup B, 0.77 per 100,000 corresponded to serogroup C, and a rate of 0.57 per 100,000 were non-grouped . During the year 1997 (weeks 1 to 35) the accumulated incidence in the period of MD serogroup C was of 0.38 per 100,000 (2 cases), the Ratio of Rates Navarra/Spain was 0.21 . Considering that the last case of MD occurred in week 8, in an adult woman of 39 years and nonexistence of serogroup A in Navarra, it can bi concluded that there is no justification for a strategy of mass or routine vaccination with respect to meningococcus C.

An Sist Sanit Navar, 1997 Sep-Dec, 20(3), 357 - 62
{State of infectious disease notification (I.D.N.'s) in Navarra . 1996}; Ederra M et al.; The System of Infectious Disease Notification (I.D.N.) encompasses the notification of 41 infectious transmissible diseases to which are added epidemic outbreaks of any etiology or cause . In Navarra, the I.D.N.'s are reported to the Section of Vigilance and Epidemiological Control of the Public Health Institute . A sharp increase of alimentary toxic-infections is observed due to two community outbreaks produced by Salmonella enteritidis that affected 410 persons . The incidence of pulmonary tuberculosis, 15.37 cases per 100,000 inhabitants has remained at the same levels as previous years and with lower rates than those published in neighbouring Autonomous Communities such as La Rioja and the Autonomous Community of the Basque Country . In the group of Exanthematic Diseases, an outbreak of German measles is noteworthy that affected males between the ages of 16 and 20 . During the year 1996 there were 17 cases of Meningococcal Disease that meant a rate of 3.27 per 100,000 inhabitants, the second lowest rate in the last 25 years after the rate of 2.29 of 1994 . With respect to the causative serogroup, serogroup C was isolated on 7 occasions, serogroup B on four occasions and on 6 it could not be grouped . Hydatidosis through reports of I.D.N.'s and active search in the hospitals remained steady, with 26 cases, remaining within the regular values of recent years . An important decline with respect to recent years was observed in cases of hepatitis A, hepatitis B and brucellosis.

An Sist Sanit Navar, 1998 May-Aug, 21(2), 211 - 5
{Situation of Diseases of Compulsory Declaration (DCDs) in Navarra . 1997}; Urtiaga M et al.; The system of Diseases of Compulsory Declaration (DCDs) encompasses, until the end of 1997, the notification of 41 transmittable infectious diseases, to which are added epidemic outbreaks of any etiology and cause . In Navarra, the DCDs are declared to the Vigilance and Epidemiological Control Section of the Public Health Institute on a weekly basis by the doctors of Primary and Specialised Care . Subsequently, the information is sent to the National Centre of Epidemiology where the data from the autonomous communities is centralised . The only disease that has shown an epidemic index higher than 1.25 is varicella, with 3,817 declared cases (EI:1.68), with a clear seasonal component--onset at the end of February (week 7) and conclusion towards mid-June (week 24) . Between these two dates 80% of annual cases are declared . During 1997 there were 17 cases of Meningococcal Disease, (3.27 cases per 100,000 inhabitants), identical to the number declared in 1996 and the second lowest in the last 25 years after the rate of 2.29 in 1994 . With respect to the causative serogroup, on 5 occasions serogroup C was isolated and was responsible for the death of a girl aged 3 months . On 9 occasions Neisseria meningitis serogroup B was isolated, also responsible for the death of a woman of 65 . On three occasions grouping was not possible.

Commun Dis Public Health, 2003 Jun, 6(2), 157 - 60
Meningitis C vaccine uptake by British undergraduates; Thirlaway K et al.; A new conjugated meningococcal group C vaccine became available in November 1999 . This study set out to record the vaccination status of all first year undergraduates attending a university in South Wales in 2000-01 and to identify socio-demographic factors that might influence vaccine uptake . Vaccination status of 1,120 first year undergraduates (aged between 18-21 inclusive) was assessed by a questionnaire . Eight hundred and eighty-seven (79.1%) had been vaccinated prior to coming to university . Vaccinated undergraduates showed significantly more knowledge about meningitis than unvaccinated students . Both groups had only limited understanding . The vaccination rate was significantly higher (96.3%) among students offered vaccination in school compared to students not offered vaccination there (19.7%) . This finding demonstrates the effectiveness of the school-based immunisation programme . Many of our sample did not understand that they had only been vaccinated for meningitis C . This, coupled with their poor understanding of meningitis symptoms, may result in students failing to respond appropriately to such symptoms.

J Paediatr Child Health, 2003 Jul, 39(5), 390 - 1
Red eyes as the initial presentation of systemic meningococcal infection; Yeung WL et al.; The present paper is a report of a 14-month-old boy who presented with fever, coryzal symptoms and red eyes . The patient developed a generalized tonic clonic convulsion on day 2 of his illness . Ophthalmological assessment demonstrated bilateral hypopyon and vitreous opacity resulting from endophthalmitis . Cerebrospinal fluid was positive for Neisseria meningitidis (A, C, Y, W 135) by latex agglutination . He was treated with high dose intravenous cefotaxime and intravitreal ceftazidime . He made good recovery and his vision was preserved . In view of the potential morbidity and mortality associated with systemic meningococcal infection, the presence of red eye and hypopyon provides important diagnostic clues indicating the need to investigate beyond superficial conjunctivitis . It should prompt the clinician to recognize endopthalmitis early and accurately diagnose this serious disease.

Biotechnol Appl Biochem, 2004 Feb, 39(Pt 1), 107 - 14
A fragment of the envelope protein from dengue-1 virus, fused in two different sites of the meningococcal P64k protein carrier, induces a functional immune response in mice; Hermida L et al.; Previously we have reported the capacity of the fusion protein PD3, composed of the P64k protein and the envelope (E) fragment from amino acids (aa) 286-426 of dengue-2 virus (DEN-2), to induce a functional immune response in mice against the homologous virus . In that case, the E fragment was inserted within the lipoyl-binding domain of the meningococcal P64k protein . In the present study, to test the functionality of the same E region from dengue-1 (DEN-1), a similar construct was made . Furthermore, another alternative of fusion protein was also constructed where the same E fragment from DEN-1 was fused to the C-terminus of the P64k protein . The recombinant proteins obtained (PD11 and PD10) were semi-purified and analysed for their antigenicity, immunogenicity and the ability to protect mice against lethal challenge . Both molecules exhibited the same recognition patterns against anti-DEN-1 polyclonal antibodies . In addition, when administered to mice, they elicited high levels of neutralizing antibodies and induced significant protection against lethal challenge with DEN-1 after intracerebral inoculation . These results reveal the availability of two sites within the P64k for the further insertion of DEN fragments, enabling a construct carrying two fragments from heterologous serotypes within the same molecule of this protein carrier.

Biochem Soc Trans, 2003 Aug, 31(Pt 4), 770 - 3
Clinical potential of mannose-binding lectin-replacement therapy; Summerfield JA; Mannose-binding lectin (MBL; also known as mannan-binding lectin) is an important component of innate immunity . MBL levels are mainly genetically determined . Low serum MBL levels and their cognate haplotypes have been associated with a wide range of infections . However, most subjects with MBL deficiency remain healthy . MBL deficiency is also associated with non-infectious diseases including systemic lupus erythematosus, rheumatoid arthritis, cystic fibrosis and common variable immunodeficiency . MBL deficiency may affect susceptibility to (e.g . meningococcal disease), or alter the natural history of (e.g . rheumatoid arthritis, cystic fibrosis), a disease . MBL (plasma-derived or recombinant) therapy has yet to be shown to be safe and effective . Potentially it may be useful in MBL-deficient patients to reduce susceptibility to, or enhance recovery from, bacterial infection or to alter the natural history of a disease (disease-modifying drug) . In practise the place of MBL therapy may be as a disease-modifying drug to reduce the severity of rheumatoid arthritis and to preserve lung and liver function in cystic fibrosis . MBL therapy may also ameliorate various immunodeficiency syndromes . A potential hazard of MBL therapy is enhanced complement-mediated host damage . The place of MBL therapy will await results of randomized controlled clinical trials.

Pediatr Infect Dis J, 2003 Jul, 22(7), 659 - 61
Immunologic memory with no detectable bactericidal antibody response to a first dose of meningococcal serogroup C conjugate vaccine at four years; McVernon J et al.; Fourteen children with no detectable bactericidal antibody response to a first dose of meningococcal C conjugate vaccine at 4 years of age were given a booster dose of the same vaccine 2 years later . A rapid 1000-fold rise in postimmunization bactericidal antibody titers, a measured either 7 or 14 days later, suggested previous immunologic priming.

An Sist Sanit Navar, 1999 May-Aug, 22(2), 241 - 8
{Situation of Diseases of Compulsory Declaration (DCDs) in Navarra . 1998}; Urtiaga M et al.; The System of Epidemiological Vigilance of Navarra comprises the notification of 33 transmissible infectious diseases, to which are added epidemic outbreaks of any etiology or cause . Notification to the system is carried out on a weekly basis by any doctor who suspects or diagnoses any of the processes . In our Autonomous Community, the Diseases of Compulsory Declaration (DCDs) are reported to the Section of Vigilance and Epidemiological Control of the Institute of Public Health, on a weekly basis by the doctors of Primary and Specialised Care . Subsequently, the information is sent to the National Centre of Epidemiology, where data from the Autonomous Communities is centralised . In 1998, with respect to the heading of diseases of respiratory transmission, the only disease that showed an epidemic index higher than 1 was Flu, with 44,666 reported cases, (Estimated Incidence: 1.15), and which has a clear seasonal component nin the first 8 weeks of the year 67% of the cases corresponding to the yearly total were reportedn with a maximum in week 4 with 6,361 reported cases . Fifteen cases of meningococcal disease were diagnosed, (Rate 2.88 cases per 100,000 inhabitants), lower to that declared in 1997 and the second lowest in the last 25 years after the rate of 2.31 in 1994 . All of the cases were confirmed microbiologically and appeared in a sporadic way . With respect to the causative serogroup, on 9 occasions serogroup C was isolated, with the latter responsible for the death of a girl and an elderly woman . On 6 occasions Neisseria meningitidis serogroup B was isolated . By age group, 4 cases were declared in children under 2 years of age (46.1 per 100,000), nine cases in children between 2 and 19 years of age (8.65 per 100,000) and the two remaining cases in persons of 20 years or above (0.49 per 100,000) . The predominant clinical form was sepsis in 9 cases and meningitis in the 6 remaining cases . Six cases of Legionnaire's disease were declared in 1998, all under the clinical form of pneumonia; these were isolated cases of middle-aged persons resident, in five cases, in different localities in the south of Navarra without any antecedents of travelling.

An Sist Sanit Navar, 2000 May-Aug, 23(2), 293 - 9
{Surveillance report on Diseases of Compulsory Notification in Navarra . 1999}; Urtiaga M et al.; The Epidemiological Surveillance System of Navarra includes the notification of 33 transmissible infectious diseases, to which epidemic outbreaks of any aetiology and cause are added . Reporting to the system is carried out on a weekly basis by every doctor who suspects or diagnoses any of these processes . In our autonomous community, Diseases of Compulsory Notification (DCN) are reported to the Section for the Control of Infectious Diseases and Outbreaks of the Public Health Institute on a weekly basis by the doctors of Primary and Specialised Care . Subsequently, the information is sent to the National Epidemiology Centre where data from the autonomous communities is centralised . In 1999, under the heading of diseases of respiratory transmission, 59,159 cases of Flu were reported; 65% of total annual cases were reported in the first 9 weeks of the year, with a maximum in week 4 when 6,826 cases were reported . 18 cases of Meningococcal Disease were reported to the system . Sixteen cases were confirmed microbiologically and appeared in a sporadic way . With respect to the causative serogroup, serogroup C was isolated on 8 occasions . On 7 occasions Neisseria meningitidis serogroup B was isolated . By age groups, 4 cases were declared in infants of 2 years of age (Rate: 46.1 per 100,000), nine cases in children between 2 and 9 years of age (1.53 per 100,000) and the remaining 2 cases in persons aged 20 years or over (0.49 per 100,000) . 15 cases of Legionellosis were declared in 1999, all under the clinical form of pneumonia . These were isolated cases in persons of middle or advanced age . No indication was found of prior tourist trips to areas of high prevalence . In the majority of cases the origin was considered to be in the community, while one outbreak was identified as nosocomial . Similarly, there was a notable increase in the declaration of cases of Paludism, with 16 cases (EI: 5.33) affecting travellers and immigrants.

Blood, 2003 Nov 15, 102(10), 3702 - 10 Epub 2003 Jul 24.
Inhibition of C5a-induced inflammation with preserved C5b-9-mediated bactericidal activity in a human whole blood model of meningococcal sepsis; Sprong T et al.; The complement system plays an important role in the initial defense against Neisseria meningitidis . In contrast, uncontrolled activation in meningococcal sepsis contributes to the development of tissue damage and shock . In a novel human whole blood model of meningococcal sepsis, we studied the effect of complement inhibition on inflammation and bacterial killing . Monoclonal antibodies (mAbs) blocking lectin and alternative pathways inhibited complement activation by N meningitidis and oxidative burst induced in granulocytes and monocytes . Oxidative burst was critically dependent on CD11b/CD18 (CR3) expression but not on Fc gamma-receptors . Specific inhibition of C5a using mAb 137-26 binding the C5a moiety of C5 before cleavage prohibited CR3 up-regulation, phagocytosis, and oxidative burst but had no effect on C5b-9 (TCC) formation, lysis, and bacterial killing . An mAb-blocking cleavage of C5, preventing C5a and TCC formation, showed the same effect on CR3, phagocytosis, and oxidative burst as the anti-C5a mAb but additionally inhibited TCC formation, lysis, and bacterial killing, consistent with a C5b-9-dependent killing mechanism . In conclusion, the anti-C5a mAb 137-26 inhibits the potentially harmful effects of N meningitidis-induced C5a formation while preserving complement-mediated bacterial killing . We suggest that this may be an attractive approach for the treatment of meningococcal sepsis.

An Sist Sanit Navar, 2001 Jan-Apr, 24(1), 67 - 74
{Surveillance report on Diseases of Compulsory Declaration (DCD) in Navarra . 2000}; Urtiaga M et al.; The Epidemiological Surveillance System of Navarra includes the notification of 34 transmissible infectious diseases, to which epidemic outbreaks of any aetiology and cause are added . In 2000, under the heading of diseases of respiratory transmission, 31,106 cases of flu were reported; 80% of total annual cases were reported in the first 6 weeks of the year, with a maximum in week 1 when 7,949 cases were reported . Twelve cases of meningococcal disease were reported to the system . Eight cases were confirmed microbiologically and appeared in a sporadic way . With respect to the causative serogroup, Neisseria meningitidis serogroup B was isolated on 5 occasions . On 2 occasions serogroup C was isolated, and serogroup Y was isolated on 1 occasion . By age groups, 5 cases were declared in infants of 2 years of age (Rate: 57.6 per 100,000), two cases in children between 2 and 4 years of age (14.7 per 100,000), one case in children between 5 and 9 years of age (3.5 per 100,000), two cases between 10 and 19 years of age (2.5 per 100,000) and the remaining 2 cases in persons aged 20 years or over (0.50 per 100,000) . Twenty three cases of legionellosis were declared in 2000, all under the clinical form of pneumonia . These were isolated cases in persons of middle or advanced age . No indication was found of prior tourist trips to areas of high prevalence . In the majority of cases the origin was considered to be in the community, while one outbreak was identified as nosocomial . Similarly, there was a notable increase in the declaration of cases of hepatitis A, with 24 cases (EI: 2.00), pertussis, with 23 cases (EI: 1.64) and varicella, with 4,232 reported cases (EI: 1.86).

Scand J Infect Dis, 2003, 35(5), 345 - 8
A premature infant with fulminant meningococcal septicaemia; Selander B et al.; The case is described of a 10-week-old preterm infant, a twin boy born at 34 weeks of gestational age . The day after a hernia operation he had a rapidly progressive fulminant Neisseria meningitidis serogroup B septicaemia, of which he died despite immediate and adequate treatment . No secondary cases occurred among other infants on the neonatal intensive care unit . Epidemiological investigation revealed that of 185 bacterial throat cultures performed on 17 infants on the ward, 37 close relatives to the infants and 131 medical personnel in contact with the deceased patient, 4 (2.2%) were asymptomatic carriers of N . meningitidis . Serotyping and pulsed-field gel electrophoresis of the genomic DNA of the N . meningitidis isolates revealed that the infant and his father had closely related strains.

Science, 2003 Jul 18, 301(5631), 373 - 5
CD46 in meningococcal disease; Johansson L et al.; The human-specific bacterial pathogen Neisseria meningitidis is a major cause of sepsis and/or meningitis . The pili of N . meningitidis interact with CD46, a human cell-surface protein involved in regulation of complement activation . Transgenic mice expressing human CD46 were susceptible to meningococcal disease, because bacteria crossed the blood-brain barrier in these mice . Development of disease was more efficient with piliated bacteria after intranasal, but not intraperitoneal, challenge of CD46 transgenic mice, suggesting that human CD46 facilitates pilus-dependent interactions at the epithelial mucosa . Hence, the human CD46 transgenic mice model is a potentially useful tool for studying pathogenesis and for vaccine development against meningococcal disease.

Clin Exp Immunol, 2003 Aug, 133(2), 240 - 6
Complement component C7 deficiency in a Spanish family; Vazquez-Bermudez MF et al.; Different genetic mutations have been described in complement component C7 deficiency, a molecular defect which is clinically associated with an increased susceptibility to neisserial recurrent infections, although some cases remain asymptomatic . In this work we report the genetic bases of C7 deficiency in one Spanish family . Exon-specific PCR and sequencing revealed a novel point mutation at nucleotide 615 (exon 6) leading to a stop codon (UGG to UGA) in the patient, his mother, and sister . This transversion causes the premature truncation of the C7 protein (W183X) . Additionally, we detected a missense mutation at position 1135 (exon 9) located in the first nucleotide of the codon GGG (CGG), resulting in an amino acid change (G357R) in the patient, his father, as well as in his sister . This latter mutation had been previously described in individuals from Moroccan Sephardic Jewish ancestry . Since both heterozygous mutations were found in the patient as well as in his asymptomatic sister, we analyse other meningococcal defence mechanisms such as polymorphisms of the opsonin receptors on polymorphonuclear cells . Results showed that the patient and his sister bore identical combinations of FcgammaRIIA-H/R131 and FcgammaRIIIB-NA1/2 allotypes . Our results provide further evidence that the molecular pathogenesis of C7 deficiency as well as susceptibility to meningococcal disease are heterogeneous, since different families carry different molecular defects, although many of the C7 defects appear to be homogeneous in individuals from certain geographical areas . The missense mutation G357R would make an interesting topic of analysis with regard to meningococcal disease susceptibility in the Spanish population.

Mol Microbiol, 2003 Aug, 49(3), 833 - 47
Genetic characterization of pilin glycosylation and phase variation in Neisseria meningitidis; Power PM et al.; Pili of Neisseria meningitidis are a key virulence factor, being the major adhesin of this capsulate organism and contributing to specificity for the human host . Pili are post-translationally modified by addition of either an O-linked trisaccharide, Gal (beta1-4) Gal (alpha1-3) 2,4-diacetamido-2,4,6-trideoxyhexose or an O-linked disaccharide Gal (alpha1,3) GlcNAc . The role of these structures in meningococcal pathogenesis has not been resolved . In previous studies we identified two separate genetic loci, pglA and pglBCD, involved in pilin glycosylation . Putative functions have been allocated to these genes; however, there are not enough genes to account for the complete biosynthesis of the described structures, suggesting additional genes remain to be identified . In addition, it is not known why some strains express the trisaccharide structure and some the disaccharide structure . In order to find additional genes involved in the biosynthesis of these structures, we used the recently published group A strain Z2491 and group B strain MC58 Neisseria meningitidis genomes and the unfinished Neisseria meningitidis group C strain FAM18 and Neisseria gonorrhoeae strain FA1090 genomes to identify novel genes involved in pilin glycosylation, based on homology to known oligosaccharide biosynthetic genes . We identified a new gene involved in pilin glycosylation designated pglE and examined four additional genes pglB/B2, pglF, pglG and pglH . A strain survey revealed that pglE and pglF were present in each strain examined . The pglG, pglH and pglB2 polymorphisms were not found in strain C311 musical sharp 3 but were present in a large number of clinical isolates . Insertional mutations were constructed in pglE and pglF in N . meningitidis strain C311 musical sharp 3, a strain with well-defined lipopolysaccharide (LPS) and pilin-linked glycan structures . Increased gel migration of the pilin subunit molecules of pglE and pglF mutants was observed by Western analysis, indicating truncation of the trisaccharide structure . Antisera specific for the C311 musical sharp 3 trisaccharide failed to react with pilin from these pglE and pglF mutants . GC-MS analysis of the sugar composition of the pglE mutant showed a reduction in galactose compared with C311 musical sharp 3 wild type . Analysis of amino acid sequence homologies has suggested specific roles for pglE and pglF in the biosynthesis of the trisaccharide structure . Further, we present evidence that pglE, which contains heptanucleotide repeats, is responsible for the phase variation between trisaccharide and disaccharide structures in strain C311 musical sharp 3 and other strains . We also present evidence that pglG, pglH and pglB2 are potentially phase variable.

An Sist Sanit Navar, 2002 Jan-Apr, 25(1), 47 - 58
{Surveillance report on Diseases of Compulsory Declaration (DCD) in Navarra . 2001}; Urtiaga M et al.; The Epidemiologic Surveillance System of Navarra includes the notification of 34 communicable diseases, to which are added epidemic outbreaks of any aetiology and cause . Every doctor who suspects, or diagnoses, any of the processes carries out reporting to the system on a weekly basis . In 2001, under the heading of diseases of respiratory transmission, 7,779 cases of Flu were reported (EI: 0.20), with the particular circumstance that the winter epidemic peak did not occur; 48% of total annual cases were reported in the first 12 weeks of the year, with a maximum in week 4 when only 449 cases were reported . 10 cases of Meningococcal Disease were reported to the system (EI: 0.59), a figure that is considered to be an historical minimum . Nine cases were confirmed microbiologically and all appeared in a sporadic way . With respect to the causative serogroup, on 6 occasions Neisseria meningitidis serogroup B was isolated and in the 3 remaining cases serogroup C was isolated . By age groups, 3 cases were declared in infants of less than 2 years of age (Rate: 34.6 cases per 100,000), 2 cases in children between 2 and 5 years (11.0 cases per 100,000), 4 cases in the age group of 6 to 10 years (Rate: 4.7 per 100,000) and the remaining case in the age group of persons aged 20 years or over (0.24 per 100,000) . 42 cases of Legionellosis were declared in 2001, all under the clinical form of pneumonia . Twenty-five of them were presented in a context of outbreak; three community outbreaks and one with a nosocomial origin, which affected 19 persons . Similarly, there was a notable increase in the declaration of cases of Hepatitis A, with 33 cases (EI: 2.06), brucellosis, with 9 cases (EI: 0.81) and above all parotiditis, with 267 notified cases (EI: 8.34).

Acta Anaesthesiol Scand, 2003 Aug, 47(7), 897 - 900
Low utilisation of unactivated protein C in a patient with meningococcal septic shock and disseminated intravascular coagulation; Lignell A et al.; BACKGROUND: Activated protein C has recently been shown in a multicentre trial to significantly reduce mortality in patients with septic shock . There are also some case reports and minor studies demonstrating promising results with the unactivated form of protein C . However, in children with severe meningococcal infection, skin biopsies have demonstrated low expression of endothelial thrombomodulin and protein C receptors, suggesting low protein C activation capacity in severe meningococcal sepsis . METHODS: A patient with meningococcal septic shock was treated with two doses of the unactivated form of protein C, the first during intense activation of the coagulation system and the second during a phase of low grade or no activation . Repeated plasma samples were analysed for protein C concentration, which made it possible to compare pharmacokinetics and half-lives of the two administrations . A shorter half-life during intense coagulation was expected if there was an activation and consumption of the protein C administered . RESULTS: The calculated half-lives of protein C during intense and low grade activation were 32 h and 19 h, respectively, a magnitude similar to that reported in protein C-deficient patients without infection . CONCLUSION: The result indicates that whole body utilisation of the unactivated protein C was low . Endothelial impairment of protein C activation does not seem to be restricted to the skin vessels only.

Intensive Care Med, 2003 Aug, 29(8), 1339 - 44 Epub 2003 Jul 10.
Admission plasma vasopressin levels in children with meningococcal septic shock; Leclerc F et al.; OBJECTIVE: Vasopressin (AVP) response has been reported to be inappropriately low in adult established septic shock . We studied admission AVP levels in children with meningococcal septic shock (MSS) . PATIENTS AND METHODS: All children with meningococcal infection admitted to our PICU between May 2001 and August 2002 were classified as MSS (persistent hypotension despite fluid therapy, with perfusion abnormalities and the need for vasoactive drug infusion for at least 24 h or until death), or meningococal infection without shock (fever and purpura, with or without meningitis) . Blood samples were collected at admission and AVP levels were subsequently determined using Nichols Institute Diagnostics vasopressin assay . Eighteen of 19 children with MSS (7 deaths) and 15 without shock (no death) were included . RESULTS: In children with MSS median admission AVP level was 41.6 pg/ml (1.4-498.9) and in those without 3.3 pg/ml (1.6-63.8) . In children with MSS the AVP level was not correlated with duration of shock and fluid expansion prior to AVP sampling, or with age-adjusted blood pressure and natremia at the time of blood sampling . AVP levels were higher in nonsurvivors, but not significantly so . Only one nonsurvivor had an admission AVP level below 30 pg/ml . CONCLUSIONS: In our children with established MSS who died the admission AVP level Delta were not inappropriately low . Further studies including serial AVP level assessments are needed before concluding that AVP administration is of little interest in children with MSS.

Microbiology, 2003 Jul, 149(Pt 7), 1859 - 69
Production of the signalling molecule, autoinducer-2, by Neisseria meningitidis: lack of evidence for a concerted transcriptional response; Dove JE et al.; Neisseria meningitidis is a Gram-negative bacterium which is an important causative agent of septicaemia and meningitis . LuxS has been shown to be involved in the biosynthesis of a quorum sensing molecule, autoinducer-2 (AI-2), known to play a role in virulence in Escherichia coli, as well as other bacteria . Evidence that serogroup B of N . meningitidis produces AI-2, along with the observation that a luxS mutant of this strain had attenuated virulence in an infant rat model of bacteraemia, led to further investigation of the role of this quorum sensing molecule in N . meningitidis . In this study, it is demonstrated that AI-2 is not involved in regulating growth of meningococci, either in culture or in contact with epithelial cells . Furthermore, transcriptional profiling using DNA microarrays shows an absence of the concerted regulation seen in other bacteria . Taken together, these data suggest that in N . meningitidis, AI-2 may be a metabolic by-product and not a cell-to-cell signalling molecule.

Microbiology, 2003 Jul, 149(Pt 7), 1849 - 58
Antigenic diversity of meningococcal enterobactin receptor FetA, a vaccine component; Thompson EA et al.; Meningococcal FetA (FrpB), an iron-regulated outer-membrane protein and vaccine component, was shown to be highly diverse: a total of 60 fetA alleles, encoding 56 protein sequences, were identified from 107 representative Neisseria meningitidis isolates . Phylogenetic analysis established that the allelic variants had been generated by both point mutation and horizontal genetic exchange . Nucleotide substitution was unevenly distributed in the gene, which contained both conserved and variable sequence regions . The most conserved region of the translated peptide sequence corresponded to an amino-terminal domain of the protein and the most diverse region to a previously identified variable region (VR) . A nomenclature system for the peptides encoded by the VR was devised which classified 24 variants into 5 FetA variant families . On the basis of these data, murine polyclonal sera specific for four FetA variants were generated . The reactivities of these sera in whole-cell ELISA experiments were consistent with the hypothesis that the VR encoded an immunodominant epitope and indicated that the sera reacted mainly with variants against which they were raised . The diversity of this protein is likely to limit its effectiveness as a vaccine component.

Ann R Coll Surg Engl, 2003 Jul, 85(4), 252 - 5
An audit of post-splenectomy prophylaxis--are we following the guidelines?
Ramachandra J, Bond A, Ranaboldo C, Cullis J.
INTRODUCTION: Asplenic individuals have major difficulties coping with specific infections (e.g . Streptococcus pneumoniae) . This is an audit to look at a district general hospital's compliance with published guidelines for immunisations and antibiotic prophylaxis post-splenectomy . PATIENTS AND METHODS: A retrospective review of hospital records of consecutive splenectomy patients from January 1996 to March 2001 . RESULTS: Of 76 patients, 72% were vaccinated (30/76 with pneumococcal, HIB and meningococcal vaccines, 15/76 with Pneumovax and HIB, 10/76 with Pneumovax only), 63% were discharged on prophylactic antibiotics, and 81% of surviving patients had adequate communication with the GP regarding splenectomy . Patients undergoing non-elective splenectomy were less likely to be vaccinated or receive prophylactic antibiotics when compared with elective splenectomy patients . CONCLUSIONS: Results are comparable with other published studies, but are still unsatisfactory for many splenectomy patients . Vaccination rates must be improved and more information given to patients and GPs to allow for appropriate follow-up care.

J Infect, 2003 Jul, 47(1), 12 - 8
Pneumococcal bacteraemia: clinical and microbiological epidemiology in Dundee, Scotland; Maddox JM et al.; OBJECTIVE: To report the incidence of drug resistant Streptococcus pneumoniae isolated from blood culture in Dundee, Scotland . We shall also review the clinical and laboratory findings in these cases.METHODS: A retrospective review was undertaken of all cases of S . pneumoniae bacteraemia identified in our local area during a three year period from August 1st, 1997 to July 31st, 2000 (107 cases.) Data was obtained from patient medical records, blood culture reports and results of Stoke's disk testing . Many organisms were also sent to the Scottish Meningococcus and Pneumococcus Reference Laboratory for serogrouping and determination of the minimum inhibitory concentration of common antibiotics.RESULTS: Annual incidence of bacteraemia was approximately 15.9-17.8 per 100000 population . Mortality was 33% (34 and 30% for those with pneumonia or meningitis, respectively) . No relationship was seen between patient age and overall mortality . Factors relating to increased mortality were a high respiratory rate (p=0.01), high blood urea level (p=0.05) and the presence of confusion (p<0.01) on admission to hospital.The incidence of penicillin resistant S . pneumoniae was 7%, all of these isolates having low level resistance . Macrolide resistance was 8% . Neither were found to be increasing over the three year period . The most common serogroups were 23 (18%) and 14 (12%).CONCLUSIONS: The incidence of penicillin resistant S . pneumoniae isolated from blood culture in Dundee, Scotland, is similar to the UK average and did not appear to be rising between 1997 and 2000.

Scand J Infect Dis, 2003, 35(4), 230 - 3
Neisseria meningitidis serogroup W-135 isolated from healthy carriers and patients in Sudan after the Hajj in 2000; Issa M et al.; The first epidemic in the world of meningococcal disease due to serogroup W-135 was reported during the Hajj in 2000, with subsequent spread . The aims of the present study were to investigate whether the Hajj 2000 Neisseria meningitidis serogroup W-135 had also been carried to Sudan in the eastern part of the African meningitis belt, by examining healthy Sudanese pilgrims (Hajj 2000) and members of their families, and whether the strain was causing meningitis . The phenotypic character of W-135 meningococci from Sudanese carriers (n = 5) and patients (n = 2) 1 y later was similar to W-135 strains associated with Hajj 2000 . The present study, using the combination of the 2 molecular techniques; sequencing of the porA gene for variable regions (VR1, VR2 and VR3) and pulsed-field gel electrophoresis of the entire genome (using SpeI and NheI), shows that the Hajj 2000 serogroup W-135 clone (P1.5,2,36-2 of the ET-37 complex) most probably was introduced into Sudan, by pilgrims returning from the Hajj 2000 . This strain has not been diagnosed before in Sudan . Close epidemiological surveillance is required to identify a possible new emerging meningitis epidemic.

Scand J Infect Dis, 2003, 35(4), 226 - 9
Seasonal variation in meningococcal disease in Denmark: relation to age and meningococcal phenotype; Jensen ES et al.; Seasonal variation has been shown in meningococcal disease (MD), but it is not known whether seasonal variation depends on age, gender and meningococcal phenotype . Based on complete registration of MD in North Jutland County, Denmark, during 1980-1999 (n = 413 cases), a Poisson regression model of a sinusoidal form was used to examine: (i) whether the seasonal variation in MD follows a sinusoidal pattern; (ii) the magnitude of seasonal variation in MD; and (iii) whether seasonal variation is related to age and gender and meningococcal phenotype . The peak-to-trough ratio (PTR) was used as a measure of the magnitude of seasonal variation . An overall seasonal variation in MD was found {PTR 2.0, 95% confidence interval (95% CI) 1.5-2.6} . There were differences between age groups and between phenotypes, but not between genders . The highest PTRs were observed for the age groups 5-9 y (PTR 4.9, 95% CI 2.1-11.9) and 10-14 y (PTR 3.7, 95% CI 1.4-9.7) . No seasonal variation was found for children < 1 y (PTR 1.4, 95% CI 0.6-3.2) or teenagers 15-19 y (PTR 1.6, 95% CI 0.8-3.0) . Among phenotypes the highest PTR was observed for C:2a:P1.2,5 (PTR 3.8, 95% CI 1.3-11.2) . Thus, seasonal variation depended on age and meningococcal phenotype, the most pronounced seasonality being in 5-14-y-olds and in cases with phenotype C:2a:P1.2,5.

J Biochem Biophys Methods, 2003 Jun 30, 56(1-3), 291 - 6
Simple and rapid technique for monitoring the quality of meningococcal polysaccharides by high performance size-exclusion chromatography; von Hunolstein C et al.; The molecular size of meningococcal polysaccharides is an important physico-chemical parameter which correlates with immunogenicity . This paper describes the experimental conditions for high-performance size-exclusion chromatography on a PL Aquagel-OH 60 column to follow changes in the size distribution and therefore in the distribution coefficient (K(D)) of the meningococcal polysaccharides of groups A, C, Y and W-135 used to formulate anti-Neisseria meningitidis vaccines . The experimental conditions were also found to be suitable for a rapid monitoring of the quality (no group A polysaccharide depolymerization) of the tetravalent meningococcal polysaccharide vaccine.

J Endotoxin Res, 2003, 9(3), 155 - 63
Identification of meningococcal LPS as a major monocyte activator in IL-10 depleted shock plasmas and CSF by blocking the CD14-TLR4 receptor complex; Bjerre A et al.; We have examined the in vitro stimulatory effects of lipopolysaccharide (LPS)-containing samples (meningococcal shock plasma, n = 10; non-shock plasma, n = 10; cerebrospinal fluid (CSF), n = 7) before and after immunodepletion of interleukin (IL)-10 in a monocyte target assay . We also studied the stimulatory effects of plasma collected from 3 patients with lethal septicemia caused by Streptococcus pneumoniae without detectable LPS but with 100-fold increased levels of heat-shock protein 70 (HSP70) . HSP70 may, like LPS, activate monocytes via the Toll-like receptor 4 (TLR4) . The samples were analyzed for LPS, tumor necrosis factor (TNF)-alpha, IL-10 and HSP70; applied on human monocytes (purity > 95%) before and after IL-10 immunodepletion, in the absence or presence of CD14 blocking mAb (60bca) or the lipid A antagonist, Rhodobacter sphaeroides diphosphoryl lipid A (RsDPLA) which blocks TLR4 . Monocyte activation was measured by increased TNF-alpha secretion and tissue factor (TF) up-regulation by monocyte procoagulant activity (PCA) . There was a positive correlation between patient plasma LPS levels (n = 10) and increases in TNF-alpha secretion by the monocytes after immunodepletion of IL-10 (r = 0.82) . Pretreatment of the monocytes with mAbCD14 or RsDPLA reduced TNF-alpha secretion to median 5% and 12%, respectively, of the levels before the receptor complex was blocked . The median levels of HSP70 were 543 ng/ml (range, 468-962 ng/ml) in pneumococcal shock plasma, 81.5 ng/ml (range, 41-331 ng/ml) in meningococcal shock plasma and 24 ng/ml (range, < 0.8-41 ng/ml) in meningococcal non-shock plasma . Pneumococcal septic shock plasmas with significantly higher levels of HSP70 (P < 0.05) did not induce TNF-alpha secretion in the monocytes . The results strongly suggest that LPS in meningococcal shock plasma is the major activator of monocytes whereas HSP70 (in plasma concentrations up to 963 ng/ml) does not activate monocytes in this assay.

Epidemiol Infect, 2003 Jun, 130(3), 413 - 8
Sibling familial risk ratio of meningococcal disease in UK Caucasians; Haralambous E et al.; To quantify the host genetic component of meningococcal disease (MD) susceptibility, the sibling risk ratio (lambdaS) was calculated as the ratio of observed MD cases among 845 siblings of 443 UK Caucasian cases to that expected, calculated from age-calendar year specific rates for England and Wales . Twenty-seven siblings contracted MD compared with an expected 0.89, generating a lambdaS value of 30.3 . Overestimation of lambdaS due to Neisseria meningitidis exposure was minimized by excluding siblings with MD onset within set time points of the index case . Irrespective of whether siblings contracted MD more than 1, 3, 6, 9 or 12 months after the index case, the lambdaS varied slightly (lambdaS range: 8.2-11.9), suggesting that host genetic factors may contribute approximately one third of the total lambdaS . Social class distribution did not differ between MD cases and the general population of England and Wales . This study is the first to calculate lambdaS for MD and establishes that susceptibility to MD has a significant host genetic component.

Prescrire Int, 2003 Jun, 12(65), 109 - 10
When to vaccinate travellers against meningococci; Why do parents decide against immunization? The effect of health beliefs and health professionals; Child Health Department, City and Hackney Primary Care Trust, St Leonards, London, UKOBJECTIVES: To explore the knowledge, attitudes and concerns with respect to immunization and vaccine-preventable infections in parents whose children have not completed the recommended course of immunization . SETTING: Parents of children resident in the London Borough of Hackney . METHODS: Children born between 1 January 1999 and 15 February 1999 were identified from the child health database, and cases were defined as those who had defaulted for one or more primary immunization by 18 months of age . After validation of immunization status from health records, questionnaires were sent to parents . Ten respondents from this sample were interviewed . RESULTS: Questionnaires were sent to 129 parents of children identified as not completing the recommended immunization course . Nine questionnaires were returned 'address unknown', and 76 parents returned the completed questionnaire . The response rate from known residents was 76/110 (69%) . Eight parents stated that their child had been immunized, leaving 68 questionnaires available for further analysis . Measles, mumps, rubella (MMR) and meningococcal C were most frequently omitted, usually because of concerns about vaccine safety . Twenty-three out of 68 respondents perceived that having their child immunized with a particular vaccine was more risky than non-immunization, particularly for MMR and meningococcal C vaccines . Those who agreed to be interviewed were notably concerned about the MMR vaccine, but not immunization in general . They perceived the information provided by health professionals to be poor . CONCLUSIONS: The decision-making process around childhood immunization is complex . Parents require information that is up to date, tailored to their individual needs and provided by health professionals who are well informed.

Ned Tijdschr Geneeskd, 2003 Jun 7, 147(23), 1132 - 5
{The first effect of the national vaccination campaign against meningococcal-C disease: a rapid and sharp decrease in the number of patients}; de Greeff SC et al.; OBJECTIVE: To describe the initial effects of the large-scale vaccination campaign in June-July of 2002 (1-5- and 15-18-year-olds) and September-November of 2002 (6-14-year-olds) on the incidence of group-C meningococcal disease in the Netherlands . DESIGN: Descriptive . METHOD: The incidence of meningococcal disease and the serogroup distribution were determined on the basis of the patient data associated with isolates of Neisseria meningitidis that were sent to the Netherlands Reference Laboratory for Bacterial Meningitis during the period from 1 January 1999 to 31 January 2003 . RESULTS: The highest monthly incidence of serogroup-C disease was reported in January-April 2002 (2.2-3.1/100,000), after which the incidence remained more or less unchanged after September at a level of 0.1-0.4/100,000 . The incidence of meningococcal-C disease was 73% lower in August-October 2002 compared with the same period in 2001 . In the same months, the incidence of meningococcal-C disease for the 0, 1-5, 6-14, 15-18 and > 18 year-olds was 49%, 80%, 89%, 89% and 42%, respectively, lower than in the same months in the previous year . The percentage of meningococcal disease caused by serogroup-C fluctuated from 35 to 49% in January-August 2002 and decreased to 9-19% in September-December 2002 . There was also a decrease in the unvaccinated age groups . CONCLUSION: The vaccination campaign led almost immediately to a sharp decrease in the number of patients with meningococcal serogroup-C disease.

Infect Immun, 2003 Jul, 71(7), 4217 - 21
Asymmetrical distribution of Neisseria miniature insertion sequence DNA repeats among pathogenic and nonpathogenic Neisseria strains; De Gregorio E et al.; Neisseria miniature insertion sequences (nemis) are miniature DNA insertion sequences found in Neisseria species . Out of 57 elements closely flanking cellular genes analyzed by PCR, most were conserved in Neisseria meningitidis but not in N . lactamica strains . Since mRNAs spanning nemis are processed by RNase III at hairpins formed by element termini, gene sets could selectively be regulated in meningococci at the posttranscriptional level.

Infect Immun, 2003 Jul, 71(7), 3775 - 81
Antibody specificities and effect of meningococcal carriage in icelandic teenagers receiving the Norwegian serogroup B outer membrane vesicle vaccine; Wedege E et al.; Antibody specificities of pre- and postvaccination serum samples from 40 (53%) teenagers who received three doses of the Norwegian Neisseria meningitidis serogroup B vaccine (B:15:P1.7,16) during a previous trial in Iceland (Perkins et al., J . Infect . Dis . 177:683-691, 1998) were analyzed with serum bactericidal activity (SBA) and immunoblotting assays with reference and isogenic meningococcal H44/76 vaccine strains . The H44/76 variants demonstrated significant vaccine-induced SBA to P1.7,16 PorA and Opc but not to PorB, Opa5.5, and a heterologous PorA protein . On blots, immunoglobulin G levels to all these proteins increased significantly after vaccination . Measurement of SBA to the two main variable regions (P1.7 and P1.16) on the P1.7,16 PorA with PorA deletion mutants revealed significantly higher activity to the P1.7,- and P1.-,16 mutants compared to the P1.7,16 strain, indicating exposure of new accessible epitopes . Only 12 (30%) serum samples showed distinct decreases with these or the P1.-,- mutant, with most samples containing SBA to the P1.7 and P1.16 combination . In contrast, P1.16-specific antibodies were mainly found on blots . Thirteen of the vaccinees (32.5%) were carriers of meningococci at the time of the third dose, of whom four (30.8%) harbored strains of the ET-5 complex . Carriage of P1.15 strains was generally reflected in > or =4-fold increases in SBA and distinct immunoglobulin G binding to the P1.19,15 PorA on blots . Although vaccination did not elicit bactericidal activity to the serotype 15 PorB, most carriers of serotype 15 strains showed > or =4-fold increases in SBA to this antigen.

Arch Dis Child, 2003 Jul, 88(7), 608 - 14
Treatment of meningococcal infection; Welch SB et al.; Aggressive early treatment of meningococcal disease can reduce mortality . This relies on prompt recognition and treatment of the complications of septicaemia and meningitis, appropriate ongoing intensive care where necessary, and adequate management of multiple organ failure . Most children with meningococcal disease survive intact, but long term sequelae are increasingly recognised and make follow up essential . New treatments continue to be evaluated, but none has so far proven to be effective in further reducing morbidity or mortality . Simple, timely therapeutic manoeuvres may greatly improve the prospects for survival.

Arch Dis Child, 2003 Jul, 88(7), 601 - 7
Pathophysiology of meningococcal meningitis and septicaemia; Pathan N et al.; Neisseria meningitidis is remarkable for the diversity of interactions that the bacterium has with the human host, ranging from asymptomatic nasopharyngeal colonisation affecting virtually all members of the population; through focal infections of the meninges, joints, or eye; to the devastating and often fatal syndrome of meningococcal septic shock and purpura fulminans.

Health Bull (Edinb), 2000 Mar, 58(2), 148 - 51
Presenting features of paediatric meningococcal disease--a five year experience from a paediatric accident and emergency department; Leonard PA et al.; OBJECTIVES: To determine the clinical features, initial management and outcome of meningococcal disease presenting to a paediatric accident and emergency (A&E) department . DESIGN: A retrospective study of all cases of meningococcal disease seen in the department over a five year period . SETTING: A paediatric A&E department which treats approximately 30,000 patients a year . SUBJECTS: All children under the age of 13 years with a discharge diagnosis of meningococcal disease RESULTS: Fifty patients, forty-six with microbiological confirmation of their diagnosis were identified . Sixty six percent of patients were seen first by their general practitioner . However only 28% had received prehospital parenteral antibiotics . Twenty six percent of children had neither meningism nor a classical purpuric rash, 60% showed signs of shock and 66% had an altered conscious level . The case fatality rate was 4%, with 78% making a full recovery . CONCLUSION: Classical features of meningococcal disease are often absent . Assessing simple clinical parameters such as capillary refill, respiratory rate and conscious level adds to the detection of the disease . If meningococcal disease is suspected parental benzylpenicillin should be given and the child transferred to hospital.

Pediatr Crit Care Med, 2000 Jul, 1(1), 84 - 7
Antithrombin concentrate with plasma exchange in purpura fulminans; Munteanu C et al.; OBJECTIVE: To report successful treatment of three patients admitted with purpura fulminans . DESIGN: Three cases with purpura fulminans: clinical presentation, laboratory findings, treatment, and outcome . SETTING: A seven-bed medical and general surgical Intensive therapy unit in a district general hospital . PATIENTS: Three young patients with clinical and laboratory findings of severe meningococcal sepsis and purpura . INTERVENTIONS: Early replacement therapy with antithrombin concentrate after a single initial plasma exchange, together with conventional antibiotic and supportive treatment . MEASUREMENTS AND MAIN RESULTS: All three cases had abnormal coagulation profile consistent with disseminated intravascular coagulation, adult respiratory distress syndrome, impaired renal function, and severe hemodynamic instability requiring inotropic support . Plasma antithrombin levels were measured in all cases . All patients survived and made a good recovery . CONCLUSIONS: We consider that correction of antithrombin to supranormal levels may have a beneficial effect on survival and outcome in purpura fulminans despite sustained low levels of protein C.

J Endotoxin Res, 2003, 9(2), 124 - 8
Lessons from an LPS-deficient Neisseria meningitidis mutant; van der Ley P et al.; In the pathogen Neisseria meningitidis, a completely LPS-deficient but viable mutant can be obtained by insertional inactivation of the lpxA gene, encoding UDP-GlcNAc acyltransferase required for the first step of lipid A biosynthesis . The expression and assembly of integral outer membrane proteins in the absence of LPS is largely unaffected . However, the expression of iron limitation-inducible, cell surface-exposed lipoproteins is greatly reduced . Major changes were seen in the phospholipid composition, with a shift towards PE and PG species containing mostly shorter chain, saturated fatty acids . The presence of the capsular polysaccharide turned out to be essential for viability without LPS . The immunogenicity of outer membrane proteins in mice was greatly reduced for the LPS-deficient mutant, showing the importance of LPS as an internal adjuvant in such vaccines . Stimulation of MM6 cells and peripheral blood mononuclear cells showed that induction of TNF-alpha by whole meningococci was greatly reduced for the LPS-deficient mutant . However, even without LPS the mutant strain could still induce a significant inflammatory response.

Drug Discov Today, 2003 May 15, 8(10), 459 - 64
Reverse vaccinology; Mora M et al.; Whole-genome sequencing of bacteria and advances in bioinformatics have revolutionized the vaccinology field, leading to the identification of potential vaccine candidates without the need for cultivating the pathogen . This approach, termed "reverse vaccinology", reduces the time and cost required for the identification of candidate vaccines and provides new solutions for those diseases for which conventional approaches have failed . The first example of the potential of reverse vaccinology has been the identification of novel antigens of meningococcus B as potential candidates for a novel and effective vaccine . The same approach has been successfully applied to other important human pathogens, demonstrating the feasibility to develop vaccines against any infectious disease . This review focuses on some recent advances in the identification of vaccine candidates by mining the genomic sequences of pathogenic bacteria.

Pediatr Infect Dis J, 2003 Jun, 22(6), 532 - 40
Effect of a nonavalent conjugate vaccine on carriage of antibiotic-resistant Streptococcus pneumoniae in day-care centers; Dagan R et al.; BACKGROUND: In the developed societies, day-care centers (DCCs) play an important role in the spread of antibiotic-resistant pneumococci both within the facility and from the facility to the community . This study was conducted to determine the effect of a nonavalent pneumococcal conjugate vaccine (PCV-9) on the carriage of antibiotic-resistant pneumococci in the DCC . SUBJECTS AND METHODS: Healthy DCC attendees ages 12 to 35 months were randomized to receive either PCV-9 or a control vaccine (conjugate meningococcus C vaccine) in a double blinded manner . Nasopharyngeal Streptococcus pneumoniae cultures were obtained from each subject before vaccination, monthly during the first year of follow-up and every 2 to 3 months during the second year of follow-up . For each isolate the serotype and antibiotic susceptibility were determined . RESULTS: A total of 132 and 130 evaluable toddlers received either PCV-9 or the control vaccine, respectively . In total 3748 cultures were obtained, of which 2450 (65%) were positive for S . pneumoniae . The resistance rates to penicillin, trimethoprim-sulfamethoxazole and erythromycin were 36, 35 and 16%, respectively . Resistance rates to > or =1 and > or =3 antibiotic categories were 52 and 9%, respectively . Antibiotic resistance was found mainly in the 5 serotypes included in the pneumococcal conjugate vaccines (6B, 9V, 14, 19F and 23F) and in 2 related serotypes (6A and 19A) . In the vaccinated group a clear and significant reduction of the carriage rate of the serotypes included in the vaccine and the related serotype 6A as well as an increase in the carriage rate of the serotypes not included in the vaccine were observed . In parallel a significant decrease in carriage rate of antibiotic-resistant pneumococci was observed . The reduction of carriage of antibiotic-resistant pneumococci was seen in all age windows but was greater in the age window <36 months . CONCLUSIONS: The carriage rate of antibiotic-resistant S . pneumoniae, including multiply resistant S . pneumoniae, in DCC attendees is high . Pneumococcal conjugate vaccines seem to be an important tool for reducing the carriage rate of antibiotic-resistant pneumonia in DCCs.

Pediatr Infect Dis J, 2003 Jun, 22(6), 524 - 32
Vaccination of day-care center attendees reduces carriage of Streptococcus pneumoniae among their younger siblings; Givon-Lavi N et al.; AIM: We conducted a study to determine whether administration of a pneumococcal conjugate vaccine to toddlers attending day-care centers (DCCs) could prevent acquisition of Streptococcus pneumoniae of the vaccine serotypes (VT) by their younger siblings . METHODS: In a double blind study, 262 DCC attendees ages 12 to 35 months were randomized to receive a 9-valent pneumococcal conjugate vaccine (PnCRM9; n = 132), or a control vaccine (meningococcus C vaccine; n = 130) . It was planned to follow the groups for 2 years with monthly nasopharyngeal pneumococcal cultures during the first follow-up year and every 2 months during the second year . Forty-six younger siblings of the above described children, age <18 months (23 siblings of the PnCRM9 recipients and 23 of the controls), were also enrolled, and nasopharyngeal cultures were obtained monthly until the children reached the age of 18 months or started to attend DCC, if before the age of 18 months . Pneumococcal isolates were serotyped and tested for antibiotic susceptibility . RESULTS: Of the 3748 cultures obtained from the DCC attendees, 2450 (65%) were positive for S . pneumoniae . Of 306 cultures obtained from the younger siblings, 151 (49%) were positive . Among the PnCRM9 recipients, cultures were significantly less frequently positive for the VT S . pneumoniae than among the controls (13% vs . 21%, respectively; P < 0.001) . The same pattern was seen in the younger siblings of PnCRM9 recipients vs . the siblings of controls (21% vs . 34%, respectively; P = 0.017) . The reverse trend was seen for non-VT strains in both the DCC attendees (44% vs . 34%, respectively; P < 0.001) and their younger siblings (19% vs . 13%, respectively; P = 0.15) . There was a significant decrease in the carriage rate of antibiotic-resistant S . pneumoniae in both the PnCRM9 recipients and their younger siblings . The relative risks (and 95% confidence intervals) to carry S . pneumoniae penicillin-nonsusceptible, resistant to > or =1, > or =2 and > or =3 antibiotic categories among younger siblings of PnCRM9 recipients vs . siblings of controls were 0.47 (0.31 to 0.70), 0.49 (0.33 to 0.71), 0.46 (0.30 to 0.73) and 0.49 (0.21 to 1.17), respectively . When acquired, VT and antibiotic-resistant S . pneumoniae were carried for a significantly shorter period of time among siblings of PnCRM9 recipients than in siblings of controls . CONCLUSION: The marked effect of PnCRM9 administration to DCC attendees on carriage of VT and antibiotic-resistant S . pneumoniae among their younger household close contacts demonstrates a herd effect of the vaccine.

J Biol Chem, 2003 Aug 22, 278(34), 31521 - 8 Epub 2003 Jun 10.
Detailed structural analysis of the peptidoglycan of the human pathogen Neisseria meningitidis; Antignac A et al.; We used reverse-phase high pressure liquid chromatography (HPLC), matrix-assisted laser desorption ionization mass spectrometry (MALDI-MS) and post source decay analysis (MALDI-PSD) to determine the muropeptide composition of the human pathogen Neisseria meningitidis . Structural assignment was determined for 28 muropeptide species isolated after HPLC separation and purification . Fourteen of these muropeptides were O-acetylated to different degrees . We identified the entire O-acetylation spectrum of dimers and trimers both in muropeptides and 1,6-anhydromuropeptides . On average, one of three disaccharides was O-acetylated . Furthermore, the degree of cross-linking of the N . meningitidis peptidoglycan was around 39% in all the strains analyzed . MALDI-PSD analysis of several muropeptide species indicated that meningococci only synthesize D-alanyl-meso-diaminopimelate cross-bridges . No muropeptides representative of covalent linkages of lipoproteins to the peptidoglycan could be identified, unlike in Escherichia coli . Finally, comparison of the muropeptide composition of penicillin-susceptible and penicillin-intermediate clinical strains of meningococci showed a positive correlation between the minimum inhibitory concentration (MIC) of penicillin G and the amount of muropeptides carrying an intact pentapeptide chain in the peptidoglycan . This suggests that reduced susceptibility to penicillin G in N . meningitidis is associated with a decrease in d,d-carboxypeptidase activity and/or D,D-transpeptidase activity.

J Biol Chem, 2003 Aug 22, 278(34), 31529 - 35 Epub 2003 Jun 10.
Correlation between alterations of the penicillin-binding protein 2 and modifications of the peptidoglycan structure in Neisseria meningitidis with reduced susceptibility to penicillin G; Antignac A et al.; Reduced susceptibility to penicillin G in Neisseria meningitidis is directly correlated with alterations in the penA gene, which encodes the penicillin-binding protein 2 (PBP2) . Using purified PBP2s from different backgrounds, we confirmed that the reduced susceptibility to penicillin G is associated with a decreased affinity of altered PBP2s for penicillin G . Infrared spectroscopy analysis using isogenic penicillin-susceptible strains and strains with reduced susceptibility to penicillin G suggested that the meningococcal cell wall is also modified in a penA-dependent manner . Moreover, reverse-phase high pressure liquid chromatography and mass spectrometry analysis of these meningococcal strains confirmed the modifications of peptidoglycan components and showed an increase in the peaks corresponding to pentapeptide-containing muropeptides . These results suggest that the D,D-transpeptidase and/or D,D-carboxypeptidase activities of PBP2 are modified by the changes in penA gene.

Vaccine, 2003 Jun 20, 21(21-22), 2877 - 81
Reflections on the meningococcal group C infection immunisation campaign: views from the sharp end; Lansley M et al.; In July 1999, the Department of Health launched a campaign to immunise all children aged from 0-17 years with a new vaccine giving protection against meningococcal group C infection . Following the campaign, a survey of Immunisation Co-ordinators in England was conducted to identify strengths and weaknesses of the campaign . This paper summarises the main findings.

Vaccine, 2003 Jun 20, 21(21-22), 2871 - 6
Comparison of PorA VR types and porA promoter sequence from Neisseria meningitidis B isolated from non-immunised children and vaccine failures immunised with a serogroup B outer membrane protein vaccine; Gorla MC et al.; PorA protein is an important component of group B meningococcal protein-based vaccines . The goals of this study were: (i) to classify the non-serosubtypable strains recovered from vaccine failures and controls by porA variable region (VR) type; (ii) to investigate if point mutations of VRs of the porA gene are present in P1.19,15 strains recovered from vaccine failures and controls; (iii) to investigate if nucleotide sequence variation in the promoter region of porA gene is related to low expression of PorA protein . VR type P1.19,15 predominated in younger vaccine failures (3-47 months) compared to older failures (48-83 months) . No changes in VRs of porA were observed in 46 P1.19,15 strains studied . A promoter spacer of 16bp and 10 guanidine residues in the polymeric G tract was detected in five of six strains with weak PorA expression . Overall, this study indicated that lack of antibody response was probably the major cause of low vaccine efficacy in young children.

Infect Genet Evol, 2001 Dec, 1(2), 117 - 22
The population structure of Neisseria meningitidis serogroup A fits the predictions for clonality; Bart A et al.; The population structure of Neisseria meningitidis is supposedly epidemic according to . The model predicts that linkage disequilibrium in N . meningitidis populations is only temporary and arises due to the outgrowth of highly successful clonal genotypes from an essentially sexual population . These clones should disappear after a few years because of frequent recombination . In contrast, multilocus enzyme electrophoresis (MLEE) data had previously been interpreted as showing that serogroup A meningococci are truly clonal and possess only limited genetic variability (Wang et al., 1992) . The two interpretations are contradictory . In order to elucidate the true population structure of serogroup A meningococci, we analyzed data for a representative group of 84 serogroup A isolates obtained by MLEE, random amplified polymorphic DNA (RAPD) and multilocus sequence typing (MLST) . Analysis of linkage disequilibrium and bootstrap analyses of cluster analysis showed a strongly structured population with highly significant linkage disequilibrium . This was not due to the overrepresentation of certain genotypes, in contrast to the expectations for an epidemic population . The analyses identify two main clades, within each of which linkage disequilibrium was also highly significant, thus, excluding a cryptic speciation model . These observations support a population structure based on clonal evolution, in which clones are much more stable than expected for epidemic clonality . We propose that serogroup A meningococci may possess a different population structure from other serogroups of Neisseria meningitidis.

Pediatr Crit Care Med, 2001 Jan, 2(1), 51 - 6
Abdominal compartment syndrome in children; Beck R et al.; OBJECTIVE: To investigate the frequency, predisposing factors, clinical presentation, and outcome of abdominal compartment syndrome (ACS) in critically ill pediatric patients . DESIGN: A prospective study over a 5-yr period . SETTING: Pediatric intensive care unit of a tertiary care, university hospital . PATIENTS: All patients admitted to the pediatric intensive care unit were screened for the presence of ACS and were treated with a uniform protocol . ACS was defined as abdominal distention with intra-abdominal pressure (IAP) > 15 mm Hg, accompanied by at least two of the following: oliguria or anuria; respiratory decompensation; hypotension or shock; metabolic acidosis . MEASUREMENTS AND MAIN RESULTS: Of 1762 patients admitted over 5 yrs, ten patients (0.6%) had a total of 15 episodes of ACS . Of 406 trauma cases, three had ACS (0.7%) . Three of the ten patients had primary abdominal conditions (mesenteric vein thrombosis, intussusception, enterocolitis), three had abdominal surgery (trauma, Kasai operation, esophageal perforation and peritonitis), three had primary central nervous system involvement, and one had meningococcemia . At laparotomy, bowel ischemia or necrosis was found in four episodes of ACS (27%) . Mean IAP at diagnosis of ACS was 23.9 +/- 3.8 (range 17-31) mm Hg . Physiologic parameters were compared during 4 hrs before the development of ACS, during ACS, and after abdominal decompression . Mean arterial pressure, Pao(2), Pao(2)/Fio(2) ratio, and urinary output decreased significantly, whereas Paco(2), peak inspiratory pressures, positive end-expiratory pressures, and base deficit increased significantly after the development of ACS . After decompressive laparotomy, the condition of the patients improved promptly and these variables returned to pre-ACS values . Overall mortality rate in this group was 60% . CONCLUSIONS: Although relatively infrequent compared with adults, ACS occurs in critically ill children . Timely decompression of the abdomen results in uniform improvement, but overall mortality is still high . In contrast with adults, children with ACS have diverse primary diagnoses, with a significant number of primary extra-abdominal-mainly central nervous system-conditions . Ischemia and reperfusion injury appear to be the major mechanisms for development of ACS in children . Clinical presentation is similar to adults, but children may develop ACS at a lower IAP (as low as 16 mm Hg).

Crit Care Med, 2003 Jun, 31(6), 1839 - 47
Activation of protein C following infusion of protein C concentrate in children with severe meningococcal sepsis and purpura fulminans: a randomized, double-blinded, placebo-controlled, dose-finding study; de Kleijn ED et al.; BACKGROUND: Meningococcal septic shock in children results in high mortality and morbidity, and decreased protein C levels in these patients are associated with a poor outcome . We carried out a randomized, double-blinded, placebo-controlled study by supplying protein C concentrate . This phase 2 study was designed to assess the activation process of protein C and to study the dosing regimen of protein C concentrate in children with purpura fulminans and meningococcal septic shock in the perspective of a possible phase 3 trial . METHODS: Forty children were randomized to receive placebo or protein C concentrate (200 IU/kg, 400 IU/kg, or 600 IU/kg), for a maximum of 7 days . Clinical and laboratory data, including plasma levels of protein C and activated protein C (APC), were collected at various time points . All patients received standard therapy for septic shock, including antibiotics, inotropic/vasoactive drugs, and blood products . RESULTS: Increased APC levels relative to baseline were observed for the 27 of 28 patients treated with protein C concentrate, and the areas under the curve of protein C and APC were correlated with the dosage of protein C concentrate administered . Activation of coagulation, as evidenced by d-dimer levels, as well as the ratio of thrombin vs . APC normalized significantly faster with increasing dosages of protein C concentrate . No adverse reactions related to protein C concentrate were observed . Nine of the 40 (23%) patients died, and five survivors required amputations, with no differences in these rates among the randomized groups . Baseline APC levels were positively correlated with sequential organ failure assessment and pediatric risk of mortality scores and with d-dimers, tumor necrosis factor-alpha, interleukin-1, interleukin-6, interleukin-8, plasminogen activator inhibitor-1, TAT complexes, and PAP complexes . CONCLUSIONS: Treatment with protein C concentrate is safe in children with purpura fulminans and meningococcal septic shock and leads to dose-related increases of plasma APC and resolution of coagulation imbalances.

Pediatr Crit Care Med, 2001 Jul, 2(3), 225 - 231
Early severe neutropenia and thrombocytopenia identifies the highest risk cases of severe meningococcal disease; Peters MJ et al.; OBJECTIVE: To determine the performance of established predictors of mortality in pediatric acute meningococcal disease (MD) in a contemporary population and to develop a simple predictive score that will not vary with observer . DESIGN: Prospective study for development set and mixed retrospective and prospective study for validation set . Setting and PATIENTS: A total of 227 patients with clinical meningococcal disease who were referred to three multidisciplinary pediatric intensive care units from 1993 to 1999 . Early deaths before transfer to pediatric intensive care unit and deaths from cerebral herniation were included in the analysis . MEASUREMENTS AND MAIN RESULTS: The product of platelet and neutrophil counts at presentation (PN product) predicts mortality from meningococcal disease better than either count alone and at least as well as established severity scores . The Glasgow Meningococcal Septicaemia Prognostic Score and Malley scores performed poorly in these populations . The positive predictive value (PPV) for a Glasgow meningococcal septicemia prognostic score of >/=8/15 was 17.5% (16 of 91; 95% CI = 9%-25%), significantly lower than published estimates of 30%-74%, (p <.01) . The PPV for death (or amputation) with a Malley score of 3/3 was 50% (12 of 24; 29%-71%), significantly lower than the published value of 100% (p <.001) . The PN product appears to be a useful predictor . For a PN product of <40, PPV = 82% (9 of 11), specificity = 99% (195 of 197), and sensitivity = 73% (23 of 30) . The performance of this score was greatest in younger children <5 yrs of age in whom clinical cerebral herniation was not seen as a cause of death (0 of 21 deaths at <5 yrs of age; 4 of 9 deaths at >/=5 yrs of age) . CONCLUSION: Established scores significantly overestimate the occurrence of adverse outcomes in meningococcal disease . This may reflect improved resuscitation and outcome or variability in the application of these scores . The PN product achieves similar prediction to the scores currently in use and is independent of the observer . Factors that reflect the extent of the inflammatory response rather than the care before presentation are becoming increasingly important.

Pediatr Infect Dis J, 2003 May, 22(5), 418 - 22
Neonatal meningococcal disease in the United States, 1990 to 1999; Shepard CW et al.; BACKGROUND: Although neonatal bacterial meningitis is common, the rate of invasive meningococcal disease in the United States among children < or =30 days old has not been defined . Most relevant literature consists of case reports or case series, which note high case-fatality ratios but do not describe the overall burden of disease . METHODS: We used active, population-based surveillance data from the Active Bacterial Core Surveillance program to estimate the incidence of neonatal meningococcal disease in the United States from 1990 to 1999 . A case of neonatal meningococcal disease was defined as isolation of Neisseria meningitidis from a normally sterile site in a resident of the surveillance area < or =30 days of age . RESULTS: The median annual number of neonates under surveillance was 25 900 . Between 1990 and 1999, 22 cases of neonatal meningococcal disease were identified . Three (14%) patients died . The average annual incidence was 9 per 100 000 . CONCLUSIONS: The rate of neonatal meningococcal disease in the United States is higher than previous estimates . Meningococcal disease is uncommon in neonates, but its rate is similar to that of meningococcal disease in 6- to 23-month-old children.

J Clin Microbiol, 2003 Jun, 41(6), 2697 - 9
Identification of Neisseria meningitidis serogroups Y and W135 by siaD nucleotide sequence analysis; Lewis C et al.; Rapid serogrouping of meningococci is essential for the effective public health management of cases of the disease and the contacts of infected patients . Here we describe an accurate nucleotide-sequencing method for the confirmation of serogroup Y and W135 meningococci by siaD gene analysis from cultures of Neisseria meningitidis.

J Clin Microbiol, 2003 Jun, 41(6), 2440 - 3
Comparison of commercial DNA extraction kits for extraction of bacterial genomic DNA from whole-blood samples; Smith K et al.; The demand for molecular diagnostic tests in medical microbiology has highlighted the need for efficient methods of DNA extraction . In addition, it is preferable for these methods to be automated . An example of such a requirement is for the confirmation of meningococcal disease where rapid, sensitive, and specific procedures are required for public health management purposes . Previous studies have shown that whole blood is the preferred method for the isolation of bacterial DNA in meningococcal disease, and in this study, we compare five commercially available kits for the extraction of bacterial genomic DNA from whole-blood samples . These include kits in a 96-well binding plate, 96-well filter plate, and metallic bead formats . The method for all five kits is described, and the sensitivity, specificity, ease of automation, and overall efficiency are determined.

Indian J Pediatr, 2003 Mar, 70(3), 227 - 31
Cefpodoxime: pharmacokinetics and therapeutic uses; Chugh K et al.; Cefpodoxime is a semi-synthetic, third generation cephalosporin . The drug is available for use as a prodrug-Cefpodoxime proxetil, which is absorbed readily from the gut . It reaches adequate levels exceeding the MIC in most of the body fluids . It is excreted by kidneys, unchanged . Dose needs adjustment in compromised renal function . The drug is active against common gram-positive cocci like staphylococci including penicillinase producing strains, streptococci and gram negative bacteria like Hemophilus, E . coli, Klebsiella, Moraxella, Meningococci, Gonococci etc . The drug is useful in common upper and lower respiratory tract infections, sinusitis, and otitis media . The drug is also used in skin and soft tissue infections, urinary tract infection and respiratory tract infection . Cefpodoxime is being used as a step down from parenteral cephalosporin . The recommended dose is 8-10 mg/kg/d in a single or two doses . Different schedules have been given for different infections . The drug is safe, effective as a short course (5 vs . 10 days) . With a low incidence of side effects, and twice a day dosing, it proves to be a useful drug.

J Clin Pathol, 2003 Jun, 56(6), 417 - 22
The immunopathogenesis of meningococcal disease; Kvalsvig AJ et al.; This review describes the mechanisms of the immune response to meningococcal disease, examining the extent to which individual variation of the immune response can determine susceptibility . It concludes by summarising the difficulties encountered by recent efforts to develop new immunomodulatory treatments.

Int J Parasitol, 2003 May, 33(5-6), 615 - 20
Rational antibacterial vaccine design through genomic technologies; Grandi G; After 200 years of practice, vaccinology has proved to be very effective in preventing infectious diseases . However, several human and animal pathogens exist for which vaccines have not yet been discovered . As for other fields of medical sciences, it is expected that vaccinology will greatly benefit from the emerging genomics technologies such as bioinformatics, proteomics and DNA microarrays . In this review, the potential of these technologies will be illustrated taking into account part of the research activities currently in progress in our laboratories . In particular, I will describe the identification of new vaccine candidates against Meningococcus B through high-throughput cloning and expression of meningococcal antigens selected by: (i) in silico analysis of genome sequence; and (ii) transcriptome analysis of bacteria adherent to epithelial cells . In addition, I will show how the combination of high-throughput cloning and expression technology with two-dimensional gel/mass spectrometry led us to the elucidation of Chlamydia pneumoniae surface protein subproteome and to the identification of potential vaccine candidates.

Virology, 2003 Jun 5, 310(2), 267 - 79
Probing the ability of the coat and vertex protein of the membrane-containing bacteriophage PRD1 to display a meningococcal epitope; Huiskonen JT et al.; Bacteriophage PRD1 is an icosahedral dsDNA virus with a diameter of 740 A and an outer protein shell composed of 720 copies of major coat protein P3 . Spike complexes at the vertices are composed of a pentameric base (protein P31) and a spike structure (proteins P5 and P2) where the N-terminal region of the trimeric P5 is associated with the base and the C-terminal region of P5 is associated with receptor-binding protein P2 . The functionality of proteins P3 and P5 was investigated using insertions and deletions . It was observed that P3 did not tolerate changes whereas P5 tolerated changes much more freely . These properties support the hypothesis that viruses have core structures and functions, which remain stable over time, as well as other elements, responsible for host interactions, which are evolutionally more fluid . The insertional probe used was the apex of exposed loop 4 of group B meningococcal outer membrane protein PorA, a medically important subunit vaccine candidate . It was demonstrated that the epitope could be displayed on the virus surface as part of spike protein P5.

Med Clin (Barc), 2003 May 24, 120(19), 721 - 4
{Diagnosis of meningococcal disease by polymerase chain reaction}; Munoz-Almagro C et al.; BACKGROUND AND OBJECTIVE: The objective of the present study was to evaluate the application of a rapid and simple PCR technique to diagnose meningococcal disease . PATIENTS AND METHOD: A retrospective study was undertaken from January 1999 to June 2002, comprising 110 samples of cerebrospinal fluid (CSF) or plasma from 110 different pediatric patients attending the Hospital Sant Joan de Deu of Barcelona . The selection of patients was based on their diagnosis at discharge: Forty three patients had a discharge diagnose of meningococcal disease (13 meningitis, 12 sepsis and 18 sepsis with meningitis) while 67 had clinical conditions other than meningococcal disease . The samples were processed following standard bacteriological methods (Gram smear and culture) and a PCR technique designed to amplify a segment of the meningococcal insertion sequence IS1106 was performed . RESULTS: Sensitivity of PCR in the group of patients with a clinical diagnosis of meningococcal disease was 93% while sensitivity of the culture was 55.8% . Samples from 19 patients were processed once treatment with -lactam antibiotics had begun (range 8-144 hours), and positive PCR results were seen in 17 cases (sensitivity: 89.4%); a positive culture was observed in two cases of pre-treated patients (sensitivity 10.5%) . A false positive result was detected in the group of patients with non-meningococcal disease (specificity 98.5%) . CONCLUSIONS: The application of this PCR permits a rapid (roughly 5 hours), specific and sensitive method that increases the microbiologic confirmation of meningococcal disease, mainly in patients who have received previous antibiotic treatment.

Emerg Infect Dis, 2003 Jun, 9(6), 734 - 7
Absence of Neisseria meningitidis W-135 electrophoretic Type 37 during the Hajj, 2002; Wilder-Smith A et al.; We document the absence of carriage of Neisseria meningitidis W-135 of the sequence type 11 in returning pilgrims after the Hajj 2002 . This finding contrasts with the 15% carriage rate we previously reported in pilgrims returning from the Hajj 2001 . The epidemiology of carriage may be changing or may have been controlled by vaccination and a policy of administering antibiotics to pilgrims from countries with a high incidence of meningococcal disease.

Emerg Infect Dis, 2003 Jun, 9(6), 665 - 71
Serogroup W-135 meningococcal disease during the Hajj, 2000; Lingappa JR et al.; An outbreak of serogroup W-135 meningococcal disease occurred during the 2000 Hajj in Saudi Arabia . Disease was reported worldwide in Hajj pilgrims and their close contacts; however, most cases were identified in Saudi Arabia . Trends in Saudi meningococcal disease were evaluated and the epidemiology of Saudi cases from this outbreak described . Saudi national meningococcal disease incidence data for 1990 to 2000 were reviewed; cases from January 24 to June 5, 2000, were retrospectively reviewed . The 2000 Hajj outbreak consisted of distinct serogroup A and serogroup W-135 outbreaks . Of 253 identified cases in Saudi Arabia, 161 (64%) had serogroup identification; serogroups W-135 and A caused 93 (37%) and 60 (24%) cases with attack rates of 9 and 6 cases per 100,000 population, respectively . The 2000 Hajj outbreak was the first large serogroup W-135 meningococcal disease outbreak identified worldwide . Enhanced surveillance for serogroup W-135, especially in Africa, is essential to control this emerging epidemic disease.

Mol Biotechnol, 2003 Jul, 24(3), 303 - 8
Automated pneumococcal MLST using liquid-handling robotics and a capillary DNA sequencer; Jefferies J et al.; Multilocus sequence typing (MLST) is used by the Scottish Meningococcus and Pneumococcus Reference Laboratory (SMPRL) as a routine method for the characterization of certain bacterial pathogens . The SMPRL recently started performing MLST on strains of Streptococcus pneumoniae, and here we describe a fully automated method for MLST using a 96-well-format liquid-handling robot and a 96-capillary automated DNA sequencer.

J Leukoc Biol, 2003 Jun, 73(6), 722 - 30
Severe meningococcal disease is characterized by early neutrophil but not platelet activation and increased formation and consumption of platelet-neutrophil complexes; Peters MJ et al.; Approximately 25% of polymorphonuclear leukocytes (PMNL) circulate in heterotypic complexes with one or more activated platelets . These platelet-neutrophil complexes (PNC) require platelet CD62P expression for their formation and represent activated subpopulations of both cell types . In this study, we have investigated the presence, time course, and mechanisms of PNC formation in 32 cases of severe pediatric meningococcal disease (MD) requiring intensive care . There were marked early increases in PMNL CD11b/CD18 expression and activation, and reduced CD62L expression compared with intensive care unit control cases . Minimal platelet expression of the active form of alphaIIbbeta3 (GpIIb/IIIa) was seen . PNC were reduced on presentation and fell to very low levels after 24 h . Immunostaining of skin biopsies demonstrated that PNC appear outside the circulation in MD . In vitro studies of anticoagulated whole blood inoculated with Neisseria meningitidis supported these clinical findings with marked increases in PMNL CD11b/CD18 expression and activation but no detectable changes in platelet-activated alphaIIbbeta3 or CD62P expression . In vitro PMNL activation with N . meningitidis (or other agonists) potentiated the formation of PNC in response to platelet activation with adenine diphosphate . Therefore, in severe MD, PMNL activation is likely to promote PNC formation, and we suggest that the reduced levels of PNC seen in established MD reflect rapid loss of PNC from the circulation rather than reduced formation.

Intensive Care Med, 2003 Jul, 29(7), 1081 - 7 Epub 2003 May 22.
Combined antithrombin and protein C supplementation in meningococcal purpura fulminans: a pharmacokinetic study; Fourrier F et al.; PURPOSE: To document in patients with meningococcal purpura fulminans (PF), the effects of a combined supplementation with antithrombin (AT) and protein C (PC) plasma concentrates and to estimate the pharmacokinetics and dose requirements of each inhibitor . DESIGN: Retrospective study of 15 patients . SETTING . One paediatric and one adult ICU in a university hospital . INTERVENTIONS: In addition to standard intensive care, all patients received a 100 IU/kg loading dose of AT and PC concentrates, followed by a continuous infusion (AT: 100-150 IU.kg.day; PC: 100 IU.kg.day in adults, and 400 IU/kg in infants) . MEASUREMENTS: Clinical data, coagulation, and fibrinolysis parameters, AT and PC activities, and free protein S (PS) levels were sequentially measured . Restitution ratio, median increment after supplementation, and half-life of clearance from plasma were calculated for the two plasma substitutes . RESULTS . At admission, all patients had a severe decrease in AT, PC, and PS levels . The supplementation regimen induced a substantial increase in AT and PC activities, peaking at H18 and H48, respectively . The supplementation procedure did not modify free PS levels . The median values of AT and PC restitution ratio, increment in plasma activity observed after 100 IU/kg concentrate, and apparent half-life of clearance from plasma were 0.85 U.ml.U.kg and 0.59 U.ml.U.kg, 23% and 21%, 16 h and 6 h, respectively . CONCLUSION: If AT and PC concentrates are to be given in fulminant meningococcemia, the doses of supplementation should be at least 150 IU/kg AT and 250 IU/kg PC as loading dose and 150 IU/kg AT and 200 IU/kg PC as daily maintenance therapy . Taking into account the individual variability in inhibitor deficiency and restitution ratio, repeated measurements of plasma levels are mandatory to obtain a patient-based adjustment of the supplementation.

Infect Immun, 2003 Jun, 71(6), 3402 - 8
Disparity in functional activity between serum anticapsular antibodies induced in adults by immunization with an investigational group A and C Neisseria meningitidis-diphtheria toxoid conjugate vaccine and by a polysaccharide vaccine; Harris SL et al.; Polysaccharide-protein conjugate vaccines elicit higher concentrations of serum anticapsular antibody in infants and children than do unconjugated polysaccharide vaccines . The conjugate-induced antibodies also have higher avidity and complement-mediated bactericidal activity . Similar vaccine-related differences in the magnitude or functional activity of antibody are observed infrequently in immunized adults . We compared the antibody responses of adults immunized with an investigational group A and C meningococcal conjugate vaccine to those elicited by an unconjugated meningococcal polysaccharide vaccine . Although there were no significant differences between the respective geometric mean bactericidal titers of the two vaccine groups, it took, on average, three- to fourfold higher concentrations of polysaccharide-induced serum anticapsular antibody to achieve 50% complement-mediated bacteriolysis than conjugate-induced antibody (P < 0.001 for groups A and C) . At limiting doses, the polysaccharide-induced anticapsular antibodies also were less effective in conferring passive protection against meningococcal bacteremia in infant rats challenged with a group C strain (P < 0.04) . The avidity index of the group C antibodies was higher in the conjugate vaccine group than in the polysaccharide vaccine group (P < 0.005) . The disparities in the functional activity of the anticapsular antibodies elicited in adults by the two vaccines imply fundamental differences in the respective B-cell populations stimulated.

Curr Infect Dis Rep, 2003 Jun, 5(3), 238 - 245
Gram-negative Diplococcal Respiratory Infections; Naheed N et al.; Human respiratory tract infections caused by gram- negative diplococci continue to remain significant issues in health care . Although not addressed as frequently as the classical diplococcal pneumonia, the gram-positive Streptococcus pneumoniae (the pneumococcus), infections due to Neisseria meningitidis (the meningococcus), and Moraxella catarrhalis (formerly called both Neisseria catarrhalis and Branhamella catarrhalis) are addressed here including their microbiology, respiratory tract manifestations, antimicrobial treatment, and potential prevention with immunization.

An Sist Sanit Navar, 2003 Jan-Apr, 26(1), 99 - 108
{Diseases of Compulsory Notification (DCN) in Navarra . 2002}; Urtiaga M et al.; Since 1998, the Epidemiological Survelliance System of Navarra has included the notification of 34 transmissible infectious diseases, to which are added epidemic outbreaks of any aetiology and cause . Reporting to the system is carried out on a weekly basis by every doctor who suspects, or diagnoses, any of these processes . In our autonomous community, Diseases of Compulsory Notification (DCN) are reported using standardised forms on a weekly basis to the Section of Infectious Diseases and Control of Outbreaks of the Public Health Institute . Notification is made by the doctors and/or paediatricians of Primary Care and by certain services of Specialised Care . Subsequently, the information is sent to the National Epidemiology Centre where data from the Autonomous Communities is centralised and diffused . The year 2002 marks the fifth year of the new Epidemiological Vigilance System . In these five years there have been 74,814 notifications of disease, 17,184 in the year 2002, which provides a balance of notification of 74.07% for this year . In 2002, under the heading of respiratory transmitted diseases, 24,870 cases of Inluenza were reported, Epidemic Index (EI: 0.80) . 58% of total annual cases were reported in the first nine weeks of the year, with a maximum in week 4 when 3,277 cases were reported . 16 cases of Meningococcal Disease were reported to the system (EI: 1.07) . All the cases were confirmed microbiologically and all appeared in a sporadic way . With respect to the causative serogroup, on 12 occasions Neisseria meningitidis serogroup B was isolated and in the 4 remaining cases serogroup C was isolated . One case was notified in infants of less than 2 years of age (Rate: 10.52 cases per 100,000), another case in children between 2 and 5 years (5.52 cases per 100,000), 5 cases in the age group of 6 to 19 years (Rate: 5.86 cases per 100,000) and the remaining nine cases in the age group of persons aged 20 years or over (2.2 per 100,000) . 70 cases of Legionellosis were declared in 2002 (EI: 4.67), all but one under the clinical form of pneumonia . Twenty-two of the cases were presented in the context of two outbreaks with a community origin, which affected 17 and 5 persons respectively . Similarly, there was a notable increase in the declaration of cases of bacillary dysentery, with 6 cases (EI: 2.00), brucellosis, with 10 cases (EI: 1.67) and chickenpox, with 4,346 notified cases (EI: 1.61).

FEMS Microbiol Lett, 2003 May 16, 222(1), 99 - 106
A model of meningococcal bacteremia after respiratory superinfection in influenza A virus-infected mice; Alonso JM et al.; We developed a model of sequential influenza A virus (IAV)-Neisseria meningitidis serogroup C (Nm) infection in BALB/c mice . Mice infected intranasally with a sublethal IAV dose (260 pfu) were superinfected intranasally with Nm . Fatal meningococcal pneumonia and bacteremia were observed in IAV-infected mice superinfected with Nm on day 7, but not in those superinfected on day 10 . The susceptibility of mice to Nm superinfection was correlated with the peak interferon-gamma production in the lungs and decrease in IAV load . After Nm challenge, both IAV-infected and uninfected control mice produced the inflammatory cytokines interleukin (IL)-1 and IL-6 . However, IL-10 was detected in susceptible mice superinfected on day 7 after IAV infection, but not in resistant mice . This model of dual IAV-Nm infection was also used to evaluate the role of bacterial virulence factors in the synthesis of the capsule . A capsule-defective mutant was cleared from the lungs, whereas a mutant inactivated for the crgA gene, negatively regulating expression of the pili and capsule, upon contact with host cells, retained invasiveness . Therefore, this model of meningococcal disease in adult mice reproduces the pathogenesis of human meningococcemia with fatal sepsis, and is useful for analyzing known or new genes identified in genomic studies.

J Travel Med, 2003 May-Jun, 10(3), 147 - 9
Meningococcal carriage in Umra pilgrims returning from Saudi Arabia; Wilder-Smith A et al.; BACKGROUND: Moslems from all over the world go to Mecca and Medina in Saudi Arabia for two types of pilgrimage: the major pilgrimage (hajj) and the minor (umra) . An international outbreak of meningococcal disease with serogroup W-135 occurred in association with hajj pilgrimage in the years 2000 and 2001, and it has been shown that pharyngeal carriage of a single W-135 strain was high in returning hajj pilgrims . We investigated the meningococcal carriage in umra pilgrims to determine the extent of circulation of this strain, during the minor pilgrimage . METHOD: Tonsillopharyngeal swabs were taken from umra returnees . Serogrouping and pulsed field gel electrophoresis were performed on all meningococcal isolates . Subjects were questioned about the occurrence of symptoms of upper respiratory tract infection and use of antibiotics during the pilgrimage . RESULTS: were compared with those previously reported in hajj pilgrims . Results: We enrolled 160 pilgrims returning from the umra pilgrimage in 2001 . The meningococcal carriage rate was 1.3%, which is significantly lower compared with the hajj pilgrimage (17%; p<0.001) . None of the umra pilgrims carried serogroup W-135, whereas 90% of the isolates in returning hajj pilgrims were Neisseria meningitidis W-135 . CONCLUSIONS: Meningococcal carriage during the umra pilgrimage was significantly lower compared with the hajj pilgrimage in the year 2001 . No carriage of N . meningitidis W-135 was documented in umra pilgrims, whereas this was the predominant serogroup in hajj pilgrims . Public health measures to reduce the potential introduction of N . meningitidis W-135 into the countries of origin of returning pilgrims need to be prioritized for the hajj pilgrimage.

Int J Urol, 2003 Jun, 10(6), 346 - 7
Acute urethritis caused by Neisseria meningitidis; Kanemitsu N et al.; A 48-year-old heterosexual Japanese man visited the outpatient clinic of Nagoya Urology Hospital, complaining of burning pain at voiding and pus discharge from the urethral orifice . These symptoms appeared the day following oral-genital contact (fellatio) with a commercial sex worker . On the basis of the presumptive clinical diagnosis of gonorrhea because of the microscopic detection of diplococci in the urethral discharge, he was treated with levofloxacin (300 mg per day) for 7 days . His symptoms responded quickly and urinalysis taken 7 days later was normal . Microbiological examinations isolated Neisseria meningitidis in the urethral discharge by culture with the use of enzymatic profiles . Further prevalence of sexually transmitted diseases (STD) through oral-genital contact would lead to an increase in meningococcal urethritis.

Pediatr Surg Int, 2003 Jul, 19(5), 376 - 9 Epub 2003 May 17.
Early full blood count and severity of disease in neonates with necrotizing enterocolitis; Ragazzi S et al.; Thrombocytopaenia occurs during necrotizing enterocolitis (NEC), and nadir platelet count is associated with extent of disease . In paediatric meningococcal disease, the product of neutrophil and platelet count at admission is prognostically useful . We therefore aimed to determine whether the first full blood count (FBC) after diagnosis of NEC is useful as a score for poor outcome and severity of disease . Between 1987 to 2001, neutrophils (N), platelets (P) and their product (PN) was available in 187 neonates treated for NEC at our institution . Neonates with NEC were grouped according to the extent of disease (no gangrene, focal, multifocal and pan-intestinal) . Data were not normally distributed so Mann-Whitney U test or analysis of variance (ANOVA) on logged data were used ( p<0.05 was considered significant) . Receiver operating characteristics (ROC) curves were used to examine the relationship between specificity and sensitivity . A perfect test would have an ROC curve area of 1 . Initial P count and PN product of non-survivors were both significantly lower than in survivors ( p<0.0001), whereas N was not different ( p<0.08) . Low Log(10)PN was significantly associated with greater extent of disease (ANOVA; no gangrene vs multifocal, p<0.01, vs panintestinal, p<0.0005), suggesting that the initial FBC could be prognostically useful . Area under the ROC survival curve for neutrophils was 0.58, for platelets 0.75 and for PN product 0.71; thus, although no test performed extremely well, initial platelet count and NP product could be useful in evaluating disease severity in neonates with NEC and for further monitoring.

J Bacteriol, 2003 Jun, 185(11), 3270 - 7
Phosphorylation of the lipid A region of meningococcal lipopolysaccharide: identification of a family of transferases that add phosphoethanolamine to lipopolysaccharide; Cox AD et al.; A gene, NMB1638, with homology to the recently characterized gene encoding a phosphoethanolamine transferase, lpt-3, has been identified from the Neisseria meningitidis genome sequence and was found to be present in all meningococcal strains examined . Homology comparison with other database sequences would suggest that NMB1638 and lpt-3 represent genes coding for members of a family of proteins of related function identified in a wide range of gram-negative species of bacteria . When grown and isolated under appropriate conditions, N . meningitidis elaborated lipopolysaccharide (LPS) containing a lipid A that was characteristically phosphorylated with multiple phosphate and phosphoethanolamine residues . In all meningococcal strains examined, each lipid A species contained the basal diphosphorylated species, wherein a phosphate group is attached to each glucosamine residue . Also elaborated within the population of LPS molecules are a variety of "phosphoforms" that contain either an additional phosphate residue, an additional phosphoethanolamine residue, additional phosphate and phosphoethanolamine residues, or an additional phosphate and two phosphoethanolamine residues in the lipid A . Mass spectroscopic analyses of LPS from three strains in which NMB1638 had been inactivated by a specific mutation indicated that there were no phosphoethanolamine residues included in the lipid A region of the LPS and that there was no further phosphorylation of lipid A beyond one additional phosphate species . We propose that NMB1638 encodes a phosphoethanolamine transferase specific for lipid A and propose naming the gene "lptA," for "LPS phosphoethenolamine transferase for lipid A."

Scand J Immunol, 2003 May, 57(5), 453 - 62
Cloning, sequencing and expression of immunoglobulin variable regions of murine monoclonal antibodies specific for the P1.7 and P1.16 PorA protein loops of Neisseria meningitidis; Ihle O et al.; The P1.7 and P1.16 epitopes on the PorA protein on the outer membrane of Neisseria meningitidis can induce protective antibodies upon vaccination . Structural analysis of antibodies to these targets can give information on the immune response induced by these epitopes and can reveal any structural similarities among the antibodies . To do so, we have isolated the immunoglobulin (Ig) variable genes from four mouse hybridomas expressing antibodies against the P1.7 and P1.16 epitopes . These V genes were successfully expressed as functional chimeric (ch) mouse/human IgG1 antibodies by subcloning them into expression vectors containing the constant genes of human heavy and light chains . Sequencing the two sets of V genes against P1.16 revealed a high degree of homology, similar to that previously published for P1.7 V genes . The close homology allowed us to interchange heavy and light chains between antibodies in some instances to construct new antibodies that bind the original antigen . This study demonstrates that the immune response in mice against the meningococcal PorA protein epitopes P1.7 as well as P1.16 is limited to few and very similar germline genes, and therefore the P1.7- and P1.16-specific antibodies share high degree of similarities amongst each other . These V genes were used to construct chimeric antibodies with conserved antigen-binding activity.

J Med Microbiol, 2003 Jun, 52(Pt 6), 505 - 8
Nucleotide sequence-based typing of meningococci directly from clinical samples; Diggle MA et al.; The unpredictable characteristics of meningococcal disease (MD) make outbreaks complicated to monitor and consequently lead to high levels of public anxiety . Traditional molecular techniques have been utilized in order to understand better the epidemiology of MD, but some have disadvantages such as being highly specialized and labour-intensive, with low reproducibility . Some of these problems have been overcome by using multilocus sequence typing (MLST) . This technique exploits the unambiguous nature and electronic portability of nucleotide sequencing data for the characterization of micro-organisms . The need for enhanced surveillance of MD after the introduction of serogroup C conjugate vaccines means that it is important to gain typing information from the infecting organism in the absence of a culture isolate . Here, the application of MLST for the laboratory confirmation and characterization of Neisseria meningitidis directly from clinical samples is described . This involved using a newly designed set of primers that were complementary to nucleotide sequences external to the existing MLST primers already in use for culture-based MLST of meningococci . This combination has produced a highly sensitive procedure to allow the efficient genotypic characterization of meningococci directly from clinical samples.

Vaccine, 2003 Jun 2, 21(19-20), 2573 - 9
Effect of infant immunisation with meningococcus serogroup C-CRM(197) conjugate vaccine on diphtheria immunity and reactogenicity in pre-school aged children; McVernon J et al.; The majority of Men C conjugate vaccines given in the UK use CRM(197), a mutant diphtheria toxoid, as their protein carrier . We studied the effects of prior immunisation with Men C-CRM(197) conjugate vaccine on immunity to diphtheria in 193 children before and after a booster dose of Men C at 4 years . Baseline diphtheria antibodies were higher in children given four previous doses of Men C (P<0.0001) and tended to be higher following boosting in those who had received three or four doses . This enhanced immunity was not associated with increased reactogenicity.

Vaccine, 2003 Jun 2, 21(19-20), 2468 - 73
Analysis of PorA variable region 3 in meningococci: implications for vaccine policy?
Clarke SC, Diggle MA, Molling P, Unemo M, Olcen P.
Outer membrane protein (OMP) vaccines are being developed against Neisseria meningitidis serogroup B which may provide protection against common circulating serotypes and serosubtypes in some countries . However, limited data is available in Europe from genosubtyping meningococci . We therefore undertook a retrospective analysis of the three main variable regions, VR1, VR2 as well as VR3, of the porA gene from N . meningitidis isolated from different countries, mainly from Scotland and Sweden . Analysis of this gene showed that, amongst 226 strains studied, there were a total of 78 different strains . No new VR1 or VR2 alleles were found but five new VR3 alleles are described . Our data indicates the importance of analysing the VR3 region of PorA in addition to VR1 and VR2 and also highlights, in general terms, the need for genosubtyping meningococci . Such analyses have major implications for the design of new meningococcal vaccines.

Int Arch Allergy Immunol, 2003 Apr, 130(4), 314 - 21
Antibody-dependent killing of meningococci by human neutrophils in serum of late complement component-deficient patients; Platonov AE et al.; BACKGROUND: Thirty-one Russian patients with late complement component deficiency (LCCD) who had experienced one to five meningococcal infections were immunized with meningococcal polysaccharide vaccine (A + C + W135 + Y) and were followed for 3-8 years . We investigated the potentially protective killing effect of human neutrophils (PMNL) on serogroup A and W135 meningococci . METHODS: Meningococci were incubated in LCCD vaccine sera in the absence or presence of PMNL, and the number of live bacteria (CFU) was determined by plating onto chocolate agar . RESULTS: When meningococci were incubated in the LCCD sera alone, exponential growth of meningococci occurred despite the presence of meningococcal antibodies . After the addition of PMNL, meningococci were inhibited in their growth or even eliminated . Group A or W135 meningococci were killed effectively by PMNL in 80% of the sera which were collected 1 month to 1 year after vaccination compared to only 40% in the prevaccination LCCD sera (p < 0.05) . Three years after vaccination 67% of the LCCD sera were still capable of promoting killing (and even 90% after revaccination) . The rate of killing correlated with the concentration of serogroup-specific immunoglobulins . In 83% of the 72 LCCD sera with more than 5 microg/ml anti-group A immunoglobulins the killing of group A meningococci was promoted . By contrast, only 21% of 19 samples with lower specific antibody levels showed a PMNL-mediated meningococcal killing (p < 0.05) . The same effect was observed for group W135 meningococci . CONCLUSION: PMNL kill meningococci during incubation in LCCD serum; this effect increases after vaccination and depends on both specific antibody and complement . Protection by vaccination may therefore be caused by an increased killing capacity of PMNL .

J Mol Microbiol Biotechnol, 2003, 5(2), 82 - 6
Nucleotide sequence analysis of the sialyltransferase genes of meningococcal serogroups B, C, Y and W135; Lewis C et al.; A rapid method for serogrouping meningococci is essential for the characterization of phenotypically non-groupable meningococcal isolates and clinical samples, particularly for public health management purposes . The Scottish Meningococcus and Pneumococcus Reference Laboratory (SMPRL) provides serogrouping results of meningococcal isolates and clinical samples using a PCR assay which detects restriction fragment length polymorphisms in meningococcal serogroups B, C, Y and W135 . Although this PCR system was invaluable when first introduced, it has several drawbacks and lacks the required sensitivity for detecting DNA in clinical samples . Due to the recent introduction of the meningococcal group C conjugate vaccine and an impending group B vaccine, a more robust and informative method for serogroup determination is required . A protocol was devised allowing PCR amplification of the siaD gene of serogroup B, C, Y and W135 meningococci . This system was multiplexed and allowed serogroup differentiation between serogroups B and C and also between B/C and Y/W135 by product size analysis . A nested stage was incorporated into the system for enhanced detection of meningococci in clinical samples, and finally a sequencing protocol was designed allowing detection of any nucleotide changes within the siaD gene . This system allows rapid serogrouping results for use within an agarose gel system as well as more informative results when used for sequencing within the siaD gene .

J Theor Biol, 2003 Jun 7, 222(3), 347 - 59
Meningitis, pathogenicity near criticality: the epidemiology of meningococcal disease as a model for accidental pathogens; Stollenwerk N et al.; We formulate and analyse a model for infectious diseases transmitted by asymptomatic carriers finding, that if harmless and pathogenic strains of the infected agent compete, frequent outbreaks of the pathogenic strains can occur . A counterintuitively high number of clustered outbreaks at low pathogenicity in our model compares well with observations in diseases with severe and often fatal results for the host, as for example in meningitis . These clustered outbreaks can be described by the typical scaling behaviour around criticality . The epidemic model is a susceptible-infected-recovered system (SIR) for the harmless infective agent, acting as a background to a mutant strain Y which occasionally creates severely affected hosts X . The full system of SIRYX is described in the master equation framework, confirming limiting assumptions about a reduced YX-system with the SIR-system in stationarity . In this limiting case we can analytically show convergence to power law scaling typical for critical states, as well as the divergence of the variance of outbreaks near criticality . These large fluctuations of outbreaks of accidental pathogens as mutants of otherwise harmless commensal organisms is the challenging new feature of our model for future epidemiology of diseases like meningococcal disease.

Proc Natl Acad Sci U S A, 2003 May 13, 100(10), 6075 - 80 Epub 2003 May 02.
Assay of locus-specific genetic load implicates rare Toll-like receptor 4 mutations in meningococcal susceptibility; Smirnova I et al.; As the central component of the human endotoxin sensor, Toll-like receptor 4 (TLR4) functions in the early detection and response to Gram-negative infection . We therefore examined a large collection of patients with meningococcal sepsis, comparing the frequency of rare TLR4 coding changes to those in an ethnically matched control population . TLR2 sequences were also acquired and compared . Total nucleotide variation at TLR4 and TLR2 loci was assayed by using a novel computational method . A total of 3.01 megabases of coding sequence was captured at these loci from white subjects with or without meningococcal disease . Authentic mutations were found and high-quality, bidirectional coverage was measured across the coding region by using mutationseeker, a program specifically designed to assay locus-specific genetic load . Using a method that obviates the confounding effect of linkage disequilibrium, we observed that rare heterozygous missense mutations of TLR4 contribute to the development of systemic meningococcal disease among white populations of the southern United Kingdom (P = 0.02; odds ratio 8.2) . When results from all white populations were pooled, an overwhelmingly significant excess of such mutations was observed among individuals with disease (P = 2 x 10(-6); odds ratio 27.0) . The common white TLR4 variant (TLR4B), synonymous TLR4 substitutions, and variant TLR2 alleles were not significantly over-represented among patients with systemic meningococcal infections . No single variant of TLR4 was significantly over-represented in the meningococcal population . Collectively, however, rare TLR4 coding variants were markedly over-represented . Sensing via TLR4 probably contributes to the early containment of meningococcal infection, and sensing defects create increased risk of disease.

Epidemiol Infect, 2003 Apr, 130(2), 193 - 9
FcgammaRIIa and FcgammaRIIIb polymorphisms were not associated with meningococcal disease in Western Norway; Smith I et al.; Fcgamma-receptor (FcyR) polymorphisms have been associated with acquisition and severity of invasive meningococcal disease . We studied FcgammaR polymorphisms in a population with a high incidence of meningococcal disease . Fifty meningococcal disease patients aged 14-60 years, with bacteriologically confirmed disease and without detected complement deficiency, together with 100 healthy adult controls were included in the study . Clinical and bacteriological data were collected prior to FcgammaRIIa and FcgammaRIIb genotyping, which was performed by polymerase chain reaction . The distribution of the FcgammaRIIa and FcgammaRIIIb allotypes and their allele frequencies were not significantly different amongst the patients and the controls . The combination FcgammaRIIa-R/R and FcgammaRIIb-Na2/Na2 was less common among patients than controls (OR = 0.11, Fisher's exact P = 0.05) . No significant association was found between the two FcgammaRs and severity of disease, meningococcal serogroup, age groups or gender . In contrast to previous findings, our study indicates that in Norwegian teenagers and adults, the FcgammaRIIa and FcgammaRIIIb allotypes are not decisive for the acquisition or for the severity of meningococcal disease.

FEMS Immunol Med Microbiol, 2003 May 15, 36(1-2), 87 - 94
The evolving epidemiology of invasive meningococcal disease: a two-year prospective, population-based study in children in the area of Athens; Tsolia MN et al.; In response to an increase in the incidence in invasive meningococcal disease (IMD) due to Neisseria meningitidis, a system of hospital- and laboratory-based surveillance was used in a prospective epidemiological and clinical assessment of IMD in children 0-13 years of age hospitalized in the Athens area between 1 January 1999 and 31 December 2000 . The annual incidence of laboratory-confirmed disease was 10.2/100,000 . Serogroup B strains were predominant . There was a sharp decrease in serogroup C from 19% of cases in 1999 to 3% in 2000 (P=0.013) . Of note was the emergence of serogroup A responsible for 7% of the cases . The overall case fatality rate was 4.5%, but 2.8% for microbiologically confirmed cases . A remarkable decrease in disease severity assessed by admissions to intensive care units was noted during the second study year . Polymerase chain reaction-based methods for detection of meningococcal DNA were the sole positive laboratory test in 45% of the cases and the only test on which serogroup determination was based in 52% of groupable cases . The epidemiological and clinical profile of meningococcal disease appears to be rapidly evolving and close monitoring is required particularly for input into decisions regarding use of meningococcal vaccines.

Acta Clin Belg, 2002 Nov-Dec, 57(6), 345 - 8
Primary meningococcal arthritis of the hip in an immunocompetent adolescent; De Laere E et al.; The clinical spectrum of meningococcal infection ranges from asymptomatic carriage to fulminant sepsis, with meningitis and septicemia being well-recognized clinical presentations . Meningococcal arthritis as a complication of Neisseria meningitidis infection occurs in about 2-10% of cases, whereas primary meningococcal arthritis (PMA) is a relatively rare phenomenon, even in children . We report here a case of meningococcal infection in an immunocompetent adolescent suffering from acute pain of the right hip as the only symptom upon presentation at the hospital . In such a situation, meningococci are not usually considered as a possible causative agent.

J Infect Dis, 2003 May 15, 187(10), 1616 - 28 Epub 2003 Apr 30.
Genetic basis for nongroupable Neisseria meningitidis; Dolan-Livengood JM et al.; Nongroupable Neisseria meningitidis may constitute one-third or more of meningococcal isolates recovered from the nasopharynx of human carriers . The genetic basis for nongroupability was determined in isolates obtained from a population-based study in which 60 (30.9%) of 194 meningococcal isolates from asymptomatic carriers were not groupable . Forty-two percent of nongroupable isolates were related to serogroup Y ET-508/ST-23 clonal complex strains, the most common groupable carrier isolate from the study population . Nongroupable isolates were all rapidly killed by 10% normal human serum . The capsule loci of 6 of the ET-508/ST-23 complex strains and of 25 other genetically diverse nongroupable meningococci were studied in detail . Serogroup A or novel capsule biosynthesis genes were not found . Nongroupable isolates were genetically serogroup Y, B, or C isolates that did not express capsule but were related to groupable isolates found in the population (class I); capsule deficient because of insertion element-associated deletions of capsule biosynthesis genes (class II); or isolates that lacked all capsule genes and formed a distinct genetic cluster not associated with meningococcal disease (class III).

Pediatr Surg Int, 2003 Apr, 19(1-2), 91 - 5 Epub 2003 Mar 28.
Mutilations due to medical disorders in children; Palacios J et al.; Soft-tissue and bone necrosis, although rare in childhood, occasionally occur in the course of infectious diseases, either viral or bacterial, and seem to be the result of hypoperfusion on a background of disseminated intravascular coagulation . Treatment consists in correction of septic shock and control of necrosis . Necrosis, once started, shows extraordinarily rapid evolution, leading to soft-tissue and bone destruction and resulting in anatomic, functional, psychological, and social handicaps . Ten mutilated children were treated from January 1986 to January 1999 in Hospital de Dona Estefania, Lisbon, Portugal . One was recovering from hemolytic-uremic syndrome with a severe combined immunodeficiency, another malnourished, anemic child had malaria, and three had chicken pox (in one case complicated by meningococcal septicemia) . There were three cases of meningococcal and two of pyocyanic septicemia (one in a burned child and one in a patient with infectious mononucleosis) . The lower limbs (knee, leg, foot) were involved in five cases, the face (ear, nose, lip) in four, the perineum in three, the pelvis (inguinal region, iliac crest) in two, the axilla in one, and the upper limb (radius, hand) in two . Primary prevention is based on early recognition of risk factors and timely correction . Secondary prevention consists of immediate etiologic and thrombolytic treatment to restrict the area of necrosis . Tertiary prevention relies on adequate rehabilitation with physiotherapy and secondary operations to obtain the best possible functional and esthetic result.

J Infect Dis, 2003 May 1, 187(9), 1433 - 41 Epub 2003 Apr 15.
Serological correlates of protection against meningococci in a cohort of university students, before and during an outbreak of serogroup C infection; Williams JN et al.; The association between individual meningococcal antigens and the development of protective immunity to both serogroup C and B meningococci was studied before and during an outbreak of serogroup C infection among university students . Persons who became infected showed, in serum taken either before infection or on admission to the hospital, low levels of bactericidal activity against the outbreak strain; patients who survived infection developed bactericidal activity that correlated with production of antibodies to serogroup C capsular polysaccharide but not to either lipopolysaccharide or major outer-membrane proteins . Uninfected classmates also showed a strong correlation between bactericidal activity and the presence of anti-capsular antibodies . In contrast, bactericidal activity against serogroup B did not correlate with the presence of antibodies to capsular polysaccharide but did correlate with antibodies reacting with the porin proteins PorA and PorB . These studies support the introduction of conjugate MenC vaccines, validate strategies for prevention of serogroup B infection that are based on vaccines containing PorA, and suggest that PorB may also be an important component of such vaccines.

J Biol Chem, 2003 Jul 4, 278(27), 24825 - 30 Epub 2003 Apr 26.
Crystal structure of Neisserial surface protein A (NspA), a conserved outer membrane protein with vaccine potential; Vandeputte-Rutten L et al.; The neisserial surface protein A (NspA) from Neisseria meningitidis is a promising vaccine candidate because it is highly conserved among meningococcal strains and induces bactericidal antibodies . NspA is a homolog of the Opa proteins, which mediate adhesion to host cells . Here, we present the crystal structure of NspA, determined to 2.55-A resolution . NspA forms an eight-stranded antiparallel beta-barrel . The four loops at the extracellular side of the NspA molecule form a long cleft, which contains mainly hydrophobic residues and harbors a detergent molecule, suggesting that the protein might function in the binding of hydrophobic ligands, such as lipids . In addition, the structure provides a starting point for structure-based vaccine design.

Zh Mikrobiol Epidemiol Immunobiol, 2000 Jul-Aug, (4 Suppl), 17 - 22
{Molecular and biological mechanisms of the meningococcal carrier state}; Kostiukova NN; A review of the results of the latest molecular biological investigations on the problem of the formation of meningococcal carrier state, the colonization of human nasopharynx . The process of the adhesion of meningococci to epithelial cells by means of fimbrial and nonfimbrial adhesins, the transmission of signals between bacterial and epithelial cells, as well as the role phasic changes in the structure of meningococci in the process of adhesion are considered . The data on the penetration of meningococci into the epithelium and their fate within the cell are discussed . The biomolecular mechanisms of iron uptake by meningococci at the stage of their colonization of the nasopharyngoal mucosa are considered . The aspects of the prophylaxis of meningococcal carrier state are analyzed.

Vaccine, 2003 May 16, 21(17-18), 2042 - 51
Comparison of functional immune responses in humans after intranasal and intramuscular immunisations with outer membrane vesicle vaccines against group B meningococcal disease; Aase A et al.; A serogroup B meningococcal outer membrane vesicle (OMV) vaccine was delivered either intranasally or intramuscularly to 12 and 10 volunteers, respectively . The mucosal vaccine was given as four weekly doses followed by a fifth dose after 5 months; each dose consisted of OMVs equivalent to 250 microg of protein . The intramuscular (i.m.) vaccine, consisting of the same OMVs but adsorbed to Al(OH)(3), was administered as three doses each of 25 microg of protein, with 6 weeks interval between first and second doses and the third dose after 10 months . Both groups of vaccinees demonstrated significant immune responses when measured as specific IgG antibodies against live meningococci, as serum bactericidal activity (SBA) and as opsonophagocytic activity . Two weeks after the last dose, the anti-meningococcal IgG concentrations were significantly higher in the i.m . group (median IgG concentration: 43.1 microg/ml) than in the intranasal group (10.6 microg/ml) (P=0.001) . The corresponding opsonophagocytic activity was 7.0 and 3.0 (median log(2) titre) (P=0.001), and the SBA was 5.0 and 2.0 (median log(2) titre) (P=0.005), for the i.m . and intranasal groups, respectively . The last immunisation induced an enhanced immune response in the i.m . group, whereas the intranasal group showed no significant booster response . Accordingly, affinity maturation of anti-OMV-specific IgG antibodies was seen only after i.m . vaccination . The IgG1 subclass dominated the responses in both groups, whereas the significant IgG3 responses observed in the i.m . group were absent in the intranasal group . Although the intranasal OMV vaccination schedule used here induced functional immune responses relevant to protection, an improved vaccine formulation and/or a modified mucosal immunisation regimen may be needed to achieve a systemic effect comparable to that seen after three doses of intramuscular vaccination.

Br J Plast Surg, 2003 Jan, 56(1), 55 - 7
Mandatory bone scans for the assessment of extremity loss in meningococcal septicaemia?
Treharne LJ, Banwell P, Cadier M.
Meningococcal septicaemia can cause progressive necrosis of skin, soft tissue and bone . Successful limb reconstruction following the disease depends on an accurate assessment of the viability of these tissues and on a multidisciplinary team approach to ensure optimal care . However, bone scanning is not commonly performed in these patients . We present a case of meningococcal septicaemia where bone scanning significantly altered the management by demonstrating an extensive area of bone necrosis proximal to the soft-tissue necrosis . In view of this finding, we propose that bone scanning should be considered in all cases of meningococcal septicaemia where there is tissue necrosis affecting a limb, and that the radiologist should be considered a vital member of the multidisciplinary team.

Infect Immun, 2003 May, 71(5), 2897 - 901
Differential expression of genes that harbor a common regulatory element in Neisseria meningitidis upon contact with target cells; Deghmane AE et al.; The expression of several genes in Neisseria meningitidis upon contact with epithelial cells was associated with the presence of the contact regulatory elements of NEISSERIA: These genes are involved in various aspects of meningococcal biology and could be coordinately regulated upon contact with target cells.

Infect Immun, 2003 May, 71(5), 2331 - 40
Functional activity of antibodies against the recombinant OpaJ protein from Neisseria meningitidis; de Jonge MI et al.; The opacity proteins belong to the major outer membrane proteins of the pathogenic Neisseria and are involved in adhesion and invasion . We studied the functional activity of antibodies raised against the OpaJ protein from strain H44/76 . Recombinant OpaJ protein was obtained from Escherichia coli in two different ways: cytoplasmic expression in the form of inclusion bodies followed by purification and refolding and cell surface expression followed by isolation of outer membrane complexes (OMCs) . Immunization with purified protein and Quillaja saponin A (QuilA) induced high levels of Opa-specific antibodies, whereas the E . coli OMC preparations generally induced lower levels of antibodies . Two chimeric Opa proteins, hybrids between OpaB and OpaJ, were generated to demonstrate that the hypervariable region 2 is immunodominant . Denatured OpaJ with QuilA induced high levels of immunoglobulin G2a (IgG2a) in addition to IgG1, whereas refolded OpaJ with QuilA induced IgG1 exclusively . These sera did not induce significant complement-mediated killing . However, all sera blocked the interaction of OpaJ-expressing bacteria to CEACAM1-transfected cells . In addition, cross-reactive blocking of OpaB-expressing bacteria to both CEACAM1- and CEA-transfected cells was found for all sera . Sera raised against purified OpaJ and against OpaJ-containing meningococcal OMCs also blocked the nonopsonic interaction of Opa-expressing meningococci with human polymorphonuclear leukocytes.

Emerg Infect Dis, 2003 Apr, 9(4), 411 - 7
Bacterial resistance to penicillin G by decreased affinity of penicillin-binding proteins: a mathematical model; Temime L et al.; Streptococcus pneumoniae and Neisseria meningitidis have very similar mechanisms of resistance to penicillin G . Although penicillin resistance is now common in S . pneumoniae, it is still rare in N . meningitidis . Using a mathematical model, we studied determinants of this difference and attempted to anticipate trends in meningococcal resistance to penicillin G . The model predicted that pneumococcal resistance in a population similar to that of France might emerge after 20 years of widespread use of beta-lactam antibiotics; this period may vary from 10 to 30 years . The distribution of resistance levels became bimodal with time, a pattern that has been observed worldwide . The model suggests that simple differences in the natural history of colonization, interhuman contact, and exposure to beta-lactam antibiotics explain major differences in the epidemiology of resistance of S . pneumoniae and N . meningitidis.

Pathology, 2003 Feb, 35(1), 61 - 4
Ultrasound-enhanced latex immunoagglutination test (USELAT) for detection of capsular polysaccharide antigen of Neisseria meningitidis from CSF and plasma; Porritt RJ et al.; AIMS: An ultrasonic instrument, the Immunosonic, was used to evaluate ultrasound-enhanced latex immunoagglutination testing (USELAT) for detection and serogroup determination of Neisseria meningitidis in clinical specimens . METHODS: Eighty-two CSF and EDTA blood specimens from patients with suspected meningococcal disease (MD) were tested by USELAT . Results were compared with routine laboratory tests for confirmation of MD and discrepant results were resolved by analysis of further laboratory and clinical data . RESULTS: Using the Wellcogen Bacterial Antigen Kit, USELAT was positive in 20 (24%) specimens . The resolved sensitivity of USELAT was 49% compared with 67% for PCR . There were no discrepancies between serogroups indicated by USELAT and serogroups confirmed by PCR or culture grouping . CONCLUSIONS: Although USELAT could be performed in laboratories without facilities for PCR testing, a specific ultrasonic instrument is necessary and some experience is required in interpreting results . The lower resolved sensitivity makes USELAT unsuitable as a stand-alone rapid test, and it added little value to standard laboratory culture with PCR testing.

EMBO J, 2003 Apr 15, 22(8), 1780 - 9
The Omp85 protein of Neisseria meningitidis is required for lipid export to the outer membrane; Genevrois S et al.; In Gram-negative bacteria, lipopolysaccharide and phospholipid biosynthesis takes place at the inner membrane . How the completed lipid molecules are subsequently transported to the outer membrane remains unknown . Omp85 of Neisseria meningitidis is representative for a family of outer membrane proteins conserved among Gram-negative bacteria . We first demonstrated that the omp85 gene is co-transcribed with genes involved in lipid biosynthesis, suggesting an involvement in lipid assembly . A meningococcal strain was constructed in which Omp85 expression could be switched on or off through a tac promoter-controlled omp85 gene . We demonstrated that the presence of Omp85 is essential for viability . Depletion of Omp85 leads to accumulation of electron-dense amorphous material and vesicular structures in the periplasm . We demonstrated, by fractionation of inner and outer membranes, that lipopolysaccharide and phospholipids mostly disappeared from the outer membrane and instead accumulated in the inner membrane, upon depletion of Omp85 . Omp85 depletion did not affect localization of integral outer membrane proteins PorA and Opa . These results provide compelling evidence for a role for Omp85 in lipid transport to the outer membrane.

Rev Esp Salud Publica, 2003 Jan-Feb, 77(1), 125 - 42
{Evolution of meningococcal infection among infant population in the autonomous community of Valencia (1996-2000) . Effectiveness of A+C meningococcal vaccination}; Goicoechea Saez M et al.; BACKGROUND: The increase in meningococcal disease caused by serogroup C in the Autonomous Community of Valencia during the 1996-1997 period gave rise to an A + C meningococcal vaccination campaign having been conducted targeting the population ranging from 18 months to 19 years of age . The purpose of this study is that of analyzing the impact of this campaign regarding the epidemiology, clinical aspects and evolution of meningococcal disease and the vaccination status of the youth population for the purpose of evaluating the efficacy of this vaccination . METHODS: The data was taken from the clinical records of the children under 15 years of age who showed clinical signs and symptoms suggesting an invasive disease with isolation of Neisseria meningitidis and/or which meet the established case definition criteria which had been treated at all of the public hospital in the Autonomous Community of Valencia within the 1996-2000 period . The trend of incidence was evaluated by means of incidence rates . The clinical aspects and their progress (sequelae and lethality) by frequency and distribution by serogroup and age . The vaccination efficacy was calculated using the Orestein equation . RESULTS: A total of 302 cases of invasive disease caused by N . Meningitidis were recorded . The rate of incidence by serogroup C in children under age 15 dropped following the vaccination campaign from 5.82/10(5) habitants in 1997 to 1.68/10(5) habitants in 1998 . Rates similar to those prior to the time prior to the vaccination recorded three years subsequent to the campaign, showing an increase in the disease caused by serogroup B over the last 2 years . Sixty-one percent of the sequelae were among children under 5 years of age . Lethality was higher for serogroup C . Vaccination efficacy three years subsequent to the campaign was 83.7% for the 5-14 age range and 69.1% for the 19 month-4 year age range . CONCLUSION: The polysaccharide vaccine was shown to be effective for halting the outbreak . The drop in the incidence of serogroup C can be attributed to the vaccination efficacy achieved.

Bull Soc Pathol Exot, 2002 Dec, 95(5), 326 - 30
{Which vaccination strategies for African meningococcal meningitis?}; Saliou P et al.; In 1963, Lapeyssonnie published a masterful description of the epidemiology of cerebrospinal meningococcal meningitis in the Sahel region of Africa (essentially due to the Neisseria meningitidis sero-group A): geographic spread (meningitis belt), seasonal cycle (dry and cool season) . When a combined polyosidic AC vaccine became available in the early 1970s, a disease control strategy was defined along the lines of epidemiological surveillance, prophylaxis of lethality by early treatment of cases and reactive vaccination, since the polyosidic vaccine could not be included in the Expanded Programme on Immunization (EPI) . Despite some success, this strategy has not led to the control of cerebrospinal meningococcal meningitis in Africa . Amongst the obstacles encountered are the difficulty to define at what point an out-break becomes an epidemic, gaps in epidemiological surveillance, unavailable vaccine doses, delayed and complex vaccination campaigns . At the end of the 1990s, controversy ensued: since reactive vaccination was fraught with so many problems, why not consider a strategy of preventive AC vaccination for high risk areas? But this controversy may well die out with the emergence of the present-day W 135 serogroup responsible for the first large scale epidemic in Burkina Faso in 2002 . If this is confirmed, a polyosidic vaCcine containing the W 135 antigen would be required, pending the availability for Africa of a conjugate tetravalent ACYW135 vaccine which could be included in the EPI.

Bull Soc Pathol Exot, 2002 Dec, 95(5), 323 - 4; discussion 324-5
{Clonal expansion of Neisseria meningitidis W135 . Epidemiological implications for the African meningitis belt}; du Chatelet IP et al.; Meningococcal meningitis occur as large epidemics in the "African meningitis belt" described by L . Lapeyssonnie . Neisseria meningitidis serogroup A, clone III-I, was involved in recent epidemics and immunization with A and C vaccine was therefore adequate . However, we report here the emergence of a new clone of N . meningitidis of serogroup W135 during the 2001 epidemics in Niger and in Burkina Faso and discuss the implications of this new epidemiological feature for future surveillance and vaccine strategies.

Bull Soc Pathol Exot, 2002 Dec, 95(5), 319 - 22
{Molecular epidemiology of meningococci}; Caugant DA; By using the techniques of molecular biology, such as multilocus enzyme electrophoresis and multilocus sequence typing, it has been possible to identify the clones of meningococci that have been responsible for major epidemics in the world and to elucidate the routes of spread of these bacteria . Although meningococci can rearrange very rapidly their genome through the process of transformation, some clones or some groups of closely related clones have been stable and have been associated with increases of incidence of disease during decades . A clone with an epidemic potential can be disseminated globally within a few years, but the reasons for the development of an epidemic in a particular population are still not fully understood.

J Infect Dis, 2003 Apr 15, 187(8), 1223 - 34 Epub 2003 Apr 02.
Highly conserved Neisseria meningitidis inner-core lipopolysaccharide epitope confers protection against experimental meningococcal bacteremia; Plested JS et al.; Inner-core lipopolysaccharide (LPS) from Neisseria meningitidis is under investigation as a vaccine for prevention of meningococcal disease caused by N . meningitidis serogroup B (NmB) . We investigated the functional activity of murine monoclonal antibody (MAb) B5 that recognizes a highly conserved (galE) LPS epitope . Three patterns of MAb reactivity were observed in N . meningitidis by Western blot, depending on the relative prevalence of sialylated, nonsialylated, and/or truncated LPS glycoforms . Three representative N . meningitidis strains (8047, M986, and 2996) were investigated with MAb B5 in functional assays in vitro and in vivo . MAb B5 completely protected infant rats against bacteremia caused by 8047, partially protected against 2996, and had no protective activity against M986 . Thus, an inner-core LPS epitope can be a target for protective immunity, but the affinity of MAb B5 may only be sufficient to mediate protection against NmB strains possessing at least some truncated glycoforms.

Eur J Biochem, 2003 Apr, 270(8), 1759 - 66
Identification of a novel inner-core oligosaccharide structure in Neisseria meningitidis lipopolysaccharide; Cox AD et al.; The structure of the lipopolysaccharide (LPS) from three Neisseria meningitidis strains was elucidated . These strains were nonreactive with mAbs that recognize common inner-core epitopes from meningococcal LPS . It is well established that the inner core of meningococcal LPS consists of a diheptosyl-N-acetylglucosamine unit, in which the distal heptose unit (Hep II) can carry PEtn at the 3 or 6 position or not at all, and the proximal heptose residue (Hep I) is substituted at the 4 position by a glucose residue . Additional substitution at the 3 position of Hep II with a glucose residue is also a common structural feature in some strains . The structures of the O-deacylated LPSs and core oligosaccharides of the three chosen strains were deduced by a combination of monosaccharide analysis, NMR spectroscopy and MS . These analyses revealed the presence of a structure not previously identified in meningococcal LPS, in which an additional beta-configured glucose residue was found to substitute Hep I at the 2 position . This provided the structural basis for the nonreactivity of LPS with these mAbs . The determination of this novel structural feature identified a further degree of variability within the inner-core oligosaccharide of meningococcal LPS which may contribute to the interaction of meningococcal strains with their host.

J Korean Med Sci, 2003 Apr, 18(2), 163 - 6
Meningococcal disease in the republic of Korea army: incidence and serogroups determined by PCR; Lee SO et al.; This study was performed to determine the incidence and serogroups of meningococcal disease in the Korean Army . From August 2000 to July 2001, we identified prospective cases in the Korean Army . Meningococcal disease was confirmed by isolation of Neisseria meningitidis or detection of its antigen by latex agglutination from cerebrospinal fluid (CSF) or blood . Polymerase chain reactions (PCRs) were performed in the crgA gene to identify N . meningitidis regardless of its serogroup, and then in orf-2 (serogroup A) and siaD (serogroups B, C, Y, and W135) respectively for serogroup prediction . During the study period, twelve patients (four meningitis and eight septicaemia) were identified . The annual incidence was 2.2 per 100,000 (95% confidence interval, 1.3-3.8) among 550,000 private soldiers . Latex agglutinations were positive to A/C/Y/W135 polyvalent latex, but not to B latex in all patients . PCRs of crgA gene were positive in ten patients, whose samples (2 isolates from CSF, 2 CSFs, and 6 sera) were stored . In PCRs for serogroup prediction, one isolate was serogroup A, and one isolate and two sera were serogroup C . The need for meningococcal vaccination would be considered in the Korean Army through the cost-benefit analysis based on the result of this study.

Cent Eur J Public Health, 2003 Mar, 11(1), 14 - 8
Administration of antibiotics before admission in patients with meningococcal disease; Roznovsky L et al.; PURPOSE: To determine whether parenteral or oral antibiotics given before admission to a regional hospital with a special intensive care unit (ICU) reduce the case fatality rate in patients with meningococcal disease . DESIGN: Prospective analysis of 164 consecutive patients with meningococcal disease admitted to 5 regional hospitals in the Czech Republic between August 1996 and October 2001 . Main outcome measure was number of deaths from meningococcal disease . Fisher's exact test was used for statistical analysis . MAIN FINDINGS: Nine out of 116 patients (8%) given antibiotics before admission died, compared with five deaths in 48 patients (10%) admitted without such a treatment (p = 0.55) . None of 19 patients given oral or combined oral and parenteral pre-admission antibiotics died . CONCLUSION: Parenteral and probably also oral antibiotics given before admission to a regional hospital and an adequate treatment of shock can reduce the case fatality rate from meningococcal disease.

J Clin Microbiol, 2003 Apr, 41(4), 1766 - 8
Evaluation of a fluorescence-based PCR method for identification of serogroup a meningococci; Diggle MA et al.; Standard and fluorescence-based PCR assays were developed for the identification of serogroup A meningococci by detection of the mynA gene . This assay was evaluated using bacterial cultures but provides the sensitivity required for the detection of the mynA gene from bodily fluids during meningococcal disease.

Pharmacoeconomics, 2003, 21(6), 429 - 42
Cost-benefit model comparing two alternative immunisation programmes against serogroup C meningococcal disease: for Quebec residents aged 2 months to 20 years; Rancourt C et al.; OBJECTIVE: To evaluate the most efficient approach to managing an outbreak of serogroup C meningococcal disease . An early planned mass immunisation programme (MIP) was compared with a delayed programme implemented at the peak of a meningococcal outbreak . DESIGN AND SETTING: A cost-benefit model was constructed of meningococcal cases reported in Quebec, Canada, from 1990-1993, before and after the MIP, during the winter of 1992-1993, when 84% of residents aged 6 months to 20 years were vaccinated . Epidemiological data from 1990-1993 were transposed to 2002-2003 under the assumption that Quebec is on the brink of an identical outbreak cycle . All Quebec residents aged 2 months to 20 years were assumed to be vaccinated, which required a total of 1.7 million doses of conjugated vaccine . Clinical and economic outcomes of both vaccination scenarios were compared . All costs were transformed to 2001 Canadian dollars ($Can), at an annual inflation rate of 3% . Future earnings due to premature death were discounted at 5% per year with a 3% increase in wages per year and a 9% unemployment rate . PERSPECTIVE: Ministry of Health and society . MAIN OUTCOME MEASURES: The number of new cases avoided and the prevention of hospital and societal costs due to meningococcal disease-attributed premature mortality and morbidity, and direct costs associated with implementation of a MIP . RESULTS: When compared with a delayed MIP over a 14-month period, an early planned MIP would have prevented 112 new cases of meningococcal disease (16 deaths, 21 major complications) while saving $ Can 37.1 million in total direct costs to the Ministry of Health and an additional $ Can 17.4 million in societal costs in the province of Quebec . CONCLUSION: An early planned MIP implemented in Quebec in September 2001, should be cost beneficial compared with delaying mass immunisation until a meningococcal outbreak is underway . Although this conclusion is limited by the assumption that epidemiological trends in 2001 in absence of a MIP would have been similar to that observed in the early 1990s prior to the MIP, the analysis still indicates that an early MIP in the 1990s would have been cost beneficial compared with a delayed MIP.

J Pediatr Surg, 2003 Apr, 38(4), 597 - 603
Surgical interventions in children with meningococcal purpura fulminans--a review of 117 procedures in 21 children; Wheeler JS et al.; BACKGROUND/PURPOSE: There are few reports describing the surgical management and outcome of children suffering purpura fulminans secondary to meningococcal sepsis . New Zealand is in the grips of a meningococcal epidemic, and, with the attendant sequalae of the disease process, the authors sought to formally review the children who have required surgical involvement . METHODS: A retrospective case review of children with the sequalae of meningococcal disease presenting to the Orthopedic and Plastic Surgical Units in a university teaching hospital was undertaken . RESULTS: There were 117 procedures in 21 children performed over a 12-year period . Surgical management was separated into 2 phases-early and late . The mean delay from admission with acute sepsis to the first surgical procedure (ie, early intervention) was 15.9 days . Debridement and autologous skin grafting was the mainstay of managing the necrotic defects; however, allograft skin proved a useful adjunct as a physiologic dressing . Local flaps were used with deep defects down to bone, but in the extremities amputation to viable tissue was required once gangrene was demarcated . Amputations were carried out in 9 of 21 children . Late interventions were related to relief of contractures or fibula overgrowth causing stump ulceration . Clinical follow-up showed that all children interviewed over 5 years of age (9 children) attend ordinary regular school classes and were physically active within the context of their physical disabilities . CONCLUSIONS: The data would suggest that children requiring surgery for purpura fulminans achieve age-appropriate milestones and are primarily limited by their physical disability related to amputations, scarring, and abnormal bone growth .

Prescrire Int, 2003 Apr, 12(64), 43 - 6
Serogroup C meningococcal conjugate vaccines: new preparations . Effective from age two months; The REP2 repeats of the genome of Neisseria meningitidis are associated with genes coordinately regulated during bacterial cell interaction; INSERM U570, Faculte de Medecine Necker-Enfants Malades, Universite Rene Descartes, Paris, FranceInteraction with host cells is essential in meningococcal pathogenesis especially at the blood-brain barrier . This step is likely to involve a common regulatory pathway allowing coordinate regulation of genes necessary for the interaction with endothelial cells . The analysis of the genomic sequence of Neisseria meningitidis Z2491 revealed the presence of many repeats . One of these, designated REP2, contains a -24/-12 type promoter and a ribosome binding site 5 to 13 bp before an ATG . In addition most of these REP2 sequences are located immediately upstream of an ORF . Among these REP2-associated genes are pilC1 and crgA, described as being involved in steps essential for the interaction of N . meningitidis with host cells . Furthermore, the REP2 sequences located upstream of pilC1 and crgA correspond to the previously identified promoters known to be induced during the initial localized adhesion of N . meningitidis with human cells . This characteristic led us to hypothesize that at least some of the REP2-associated genes were upregulated under the same circumstances as pilC1 and crgA . Quantitative PCR in real time demonstrated that the expression of 14 out of 16 REP2-associated genes were upregulated during the initial localized adhesion of N . meningitidis . Taken together, these data suggest that these repeats control a set of genes necessary for the efficient interaction of this pathogen with host cells . Subsequent mutational analysis was performed to address the role of these genes during meningococcus-cell interaction.

Curr Opin Mol Ther, 2003 Feb, 5(1), 33 - 8
Recent developments in vaccines to prevent meningococcal serogroup B infections; Vermont CL et al.; Meningococcal disease in most western countries is mainly caused by serogroup B . Despite the availability of successful meningococcal serogroup C conjugate vaccines, there is no effective vaccine against serogroup B . Efficacy trials with outer membrane vesicle (OMV) vaccines were ineffective and are complicated by the high variability of its main component, porin A . Several new approaches to either optimizing these OMV vaccines or searching for new, highly conserved antigens are therefore being investigated . The completion of the meningococcal genome sequence has provided new challenges . This review summarizes recent developments in the search for a broadly protective meningococcal serogroup B vaccine.

Ann Intern Med, 2003 Apr 1, 138(7), 534 - 41
Variation within genes encoding interleukin-1 and the interleukin-1 receptor antagonist influence the severity of meningococcal disease; Read RC et al.; BACKGROUND: Genetically determined variation in proinflammatory cytokine release influences severity of meningococcal disease and other serious infections . OBJECTIVE: To ascertain the relative frequencies of single nucleotide polymorphisms within the interleukin-1 gene locus among patients who survived and those who died of meningococcal disease and a control population of blood donors . DESIGN: Association study . SETTING: England and Wales . PATIENTS: 1106 consecutively received blood samples from persons with microbiologically confirmed meningococcal disease and 839 samples from blood donors . MEASUREMENTS: Patient demographic and outcome data, infecting meningococcal serogroups, and genotype at the IL1B(-511) and IL1RN(+2018) loci of patients and blood donor controls . RESULTS: Genotype frequency did not differ between patients with meningococcal disease and blood donor controls . Logistic regression analysis revealed that the likelihood of death was significantly influenced by age but not socioeconomic status and was higher in patients who were infected with serogroup C (odds ratio for survival, 0.50 {95% CI, 0.33 to 0.78}) . Patients carrying the common allele at IL1B(-511) were more likely to survive (odds ratio, 2.01 {CI, 1.11 to 3.79}) . Patients with this allele were less likely to survive if they also carried the rare allele at IL1RN(+2018) (odds ratio, 0.61 {CI, 0.38 to 0.993}) . CONCLUSION: Genotype at the interleukin-1 gene locus influences likelihood of survival of meningococcal disease but has no effect on susceptibility to the infection . Increasing age and infection with serogroup C also influence the likelihood of death.

J Pak Med Assoc, 2003 Jan, 53(1), 3 - 7
Clinical and microbiological spectrum of meningococcal disease in adults during Hajj 2000: an implication of quadrivalent vaccination policy; Karima TM et al.; OBJECTIVE: To describe the epidemiological, clinical and laboratory features of meningococcal disease and explore the factors responsible for its morbidity and mortality among the pilgrims during Hajj 2000 . SETTING: This study was conducted at King Faisal Hospital, Makkah, Saudi Arabia . METHOD: Any patient suspected of meningococcal disease during the period of pilgrimage presenting with fever, head ache, signs of meningeal irritation and turbid CSF, confirmed on gram stain smears . Latex agglutination test and culture was included in this study . Their clinical features, management and outcome was recorded and analysed . RESULTS: Of 105 confirmed cases of meningococcal disease, 64% had predominantly meningitis, 36% meningococcaemia and meningitis . Meningococcal rash was found in 2% and co-morbidity in 18% of cases . Antibiotics used empirically were benzylpenicillin or ceftriaxone along or in combination . Overall case fatility rate was 34% . Delay in diagnosis, delay of antibiotic administration, older patients and patients with serious concurrent medical problems, were the factors leading to higher than expected mortality rate . Maximum number of patients were Pakistanis (18%) followed by Indians (15%) and Indonesians (12%) . Overall serogrouping was as follows: group A (44), W135 (19), B (1) and untypable (1) . Serogroup W135 appeared more invasive and more fatal . CONCLUSION: Quadrivalent vaccine ACYW135 is recommended for pilgrims to enter Saudi Arabia and for mass vaccination in local population.

Ned Tijdschr Geneeskd, 2003 Feb 22, 147(8), 321 - 3
{Nuchal rigidity in children: meningitis or not?}; van Eeuwijk JS et al.; Three children, two girls aged 4 and 2.5 years and one boy aged 8 years, presented with nuchal rigidity and symptoms such as fever, headache and nausea . Upon investigation they had: torticollis on the bases of an upper respiratory tract infection, viral meningitis and bacterial meningitis (meningococcus type C) respectively . They all recovered well after treatment . Nuchal rigidity can be caused by many illnesses other than bacterial meningitis . Lumbar puncture should be performed when meningeal irritation is suspected . In children this can be identified using the Vincent test as well as the Kernig and Brudzinski tests.

J Infect Dis, 2003 Mar 15, 187(6), 1010 - 4 Epub 2003 Feb 27.
Dynamics of the penA gene in serogroup C meningococcal strains; Arreaza L et al.; The transpeptidase encoding region of the penA gene was sequenced in 44 meningococcal strains (41 serogroup C {23 characterized as serotype 2b and 18 as serotype 2a} and 3 serogroup B {B:2b:P1.2,5}) . All strains were characterized by multilocus sequence typing and were determined to be susceptible or intermediate resistant to penicillin (Pen(s) or Pen(i), respectively) . A high degree of homology was found among the penA alleles identified in the Pen(s) strains . All the Pen(i) C:2b strains, which belonged to 2 different clonal complexes, showed the same penA gene allele . This fact suggests that 1 of the clonal complexes acquired that allele, spreading it to the other by horizontal transfer . The same allele also was found in the B:2b strains studied, indicating that 1 of the Pen(i) C:2b strains underwent a capsular switching event . A different mosaic penA allele was identified in the Pen(i) C:2a strains, which belonged to the ET37 cluster.

J Infect Dis, 2003 Apr 1, 187(7), 1142 - 6 Epub 2003 Mar 13.
Immunogenicity and immunological priming of the serogroup a portion of a bivalent meningococcal A/C conjugate vaccine in 2-year-old children; Joseph H et al.; Two-year-old children were vaccinated with 1 dose of meningococcal A/C conjugate (MACC) or meningococcal A/C polysaccharide (MACP) vaccine . Meningococcal serogroup A (MenA)-specific IgG geometric mean avidity indices (GMAIs) increased 1 month after vaccination with MACC (GMAI, 210; 95% confidence interval {CI}, 140-300) and MACP (GMAI, 190; 95% CI, 120-310) . One year after vaccination, the GMAI of the MACP-vaccinated cohort decreased to 130 (95%, CI 100-170), but a constant GMAI was maintained in the MACC-vaccinated cohort (210; 95% CI, 140-300), despite declining MenA-specific IgG antibody levels.

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