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