Serum bactericidal antibody assays – The role of complement in infection and immunity

Complement is an essential component of the immune system and human pathogenic organisms have developed various mechanisms for evading complement mediated serum killing. The “gold standard” for measuring the ability of vaccine-induced antibody to kill Neisseria meningitidis is the serum bactericidal antibody (SBA) assay which measures complement mediated killing via antibody. This assay requires active complement, either intrinsic from the serum being tested or the addition of exogenous complement, either from a human or from another species such as rabbit. For serogroup C, an SBA titre of ≥4 was established as the correlate of protection when using human complement and ≥8 as the threshold when using rabbit complement, based on comparative assay results. Licensure of meningococcal vaccines, including polysaccharide protein conjugate vaccines and serogroup B vaccines has been based on the immune responses measured with the SBA assay, thus on a surrogate of vaccine efficacy. This review examines the use of complement and the SBA assay to assess immunity to meningococcal infection, and provides examples of vaccine trials in different age groups where various assays have been used.     

A phase III observer-blind randomized,controlled study to evaluate the immune response and the correlation with nasopharyngeal carriage after immunization of university students with a quadrivalent meningococcal ACWY glycoconjugate or serogroup B meningococcal vaccine

BackgroundUniversity students have high rates of pharyngeal carriage of Neisseria meningitidis. Interruption of carriage acquisition is an important mechanism of vaccines for inducing herd protection. 4CMenB and MenACWY-CRM vaccines have been shown to be immunogenic against meningococcal serogroups B and ACWY respectively in younger age groups, and also to elicit a modest impact on meningococcal carriage in vaccinated students. However, vaccine responses in university students and the impact of serum bactericidal antibody (SBA) titers on meningococcal carriage are undetermined.MethodsImmunogenicity of two 4CMenB doses or one MenACWY-CRM dose was measured in university students at Months 2, 4, 6 and 12 post-first vaccination. Immunogenicity of one MenACWY-CRM dose in students with previous meningococcal serogroup C conjugate vaccination was also assessed. Immune responses were measured with an SBA assay using human complement (hSBA) against three reference strains for serogroup B and against one strain for each for serogroups C and Y. Correlations between hSBA titers and meningococcal carriage were analyzed.ResultsAll subjects demonstrated robust functional antibody responses to both vaccines at Month 2 and a high proportion maintained protective hSBA titers up to Month 12. At baseline, carriage of disease-associated serogroup B strains and serogroups C and Y were higher in subjects with already-protective hSBA titers. Post-vaccination, while both 4CMenB and MenACWY-CRM elicited robust immunogenicity in students, significant correlations between post-vaccination hSBA titers and carriage of disease-associated serogroups were not observed.Conclusions4CMenB and MenACWY-CRM were both highly immunogenic. There was no correlation between carriage and post-vaccination hSBA titers.     

Age-specific seroprevalence of serogroup C meningococcal serum bactericidal antibody activity and serogroup A, C, W135 and Y-specific IgG concentrations in the Turkish population during 2005

Like many other developing countries; there is no accurate information about the antibody levels against Neisseria meningitidis in Turkey. We collected serum samples from four health centers located in different geographic regions and stratified according to age in order to obtain a baseline seroprevalence of protective antibodies to meningococcal serogroup C and provide data on seroprevalence of IgG antibodies to serogroups A, C, W135 and Y. Sera were tested for serum bactericidal antibodies (SBA) to serogroup C meningococci using rabbit serum as the complement source and by a bead based assay for serogroup A, C, W135 and Y-specific IgG. It was observed that 30% and 12% of individuals within the study population had SBA titers of > or =8 and > or =128, respectively. Overall; at least 70% of the population are susceptible (SBA titer <8) to meningococcal serogroup C disease. The rate of susceptibility was highest in infants aged 7-12 months and young children (1-4 years). Regardless of age, for serogroup A, C, W135 and Y, 60.5%, 27.2%, 12.3% and 19.2% of subjects, respectively, had serogroup-specific IgG concentrations > or =2 microg/mL. These data highlight that a large proportion of the Turkish population are susceptible to serogroups C, W135 and Y and should be considered, along with serogroup-specific disease incidence data, in future decisions on possible meningococcal vaccination programmes.     

Effect of sequence variation in meningococcal PorA outer membrane protein on the effectiveness of a hexavalent PorA outer membrane vesicle vaccine in toddlers and school children

Though meningococcal conjugate vaccines are effective against serogroup C, there is currently no vaccine solution for serogroup B disease. PorA outer membrane protein (OMP) is a potential serogroup B vaccine candidate. A hexavalent PorA outer membrane vesicle (OMV) vaccine has been evaluated in phase I and II trials with promising results. However, considerable sequence variation occurs in the variable regions (VRs) encoding these serosubtypes. By using five wild type P1.19,15 variant strains we examined the serum bactericidal antibody (SBA) titres from sera collected from toddlers and school children pre- and post-vaccination. The numbers of subjects with SBA titres of <4, 4 and > or = 8 varied greatly between the different strains. This was also reflected when > or = 4-fold rises in SBA titres were examined. This finding in sera from toddlers and school children may have implications for PorA based vaccines.     

Correlation between serum bactericidal activity against Neisseria meningitidis serogroups A, C, W-135 and Y measured using human versus rabbit serum as the complement source

The surrogate of protection against invasive meningococcal disease is the presence of serum bactericidal activity (SBA) at a titer ≥4 in an assay using human serum as the complement source (hSBA). However, for various practical and logistical reasons, many meningococcal vaccines in use today were licensed based on a modified SBA assay that used baby rabbit serum as the complement source (rSBA). To assess the strength of correlation between the two assay systems for serogroups A, C, W-135 and Y, we analyzed a subset of samples from adolescent subjects enrolled in a Phase II study of Novartis’ MenACWY-CRM conjugate vaccine vs. an ACWY polysaccharide vaccine; samples were analyzed in parallel using hSBA and rSBA. We compared geometric mean titers (GMTs), calculated Pearson correlation coefficients between paired hSBA and rSBA results, and calculated sensitivity/specificity and likelihood ratios for an rSBA ≥8 or ≥128 for classifying hSBA ≥4, taking hSBA as the ‘gold standard’. Correlations between hSBA and rSBA ranged from 0.46 to 0.78 for serogroup C, but were weaker for serogroups A, W-135 and Y (range −0.15 to 0.57). In post vaccination samples, nearly all subjects had rSBA titers ≥8, though up to 15% remained seronegative by hSBA. In post vaccination settings, rSBA titers at ≥8 or ≥128 was highly sensitive for an hSBA titer ≥4, but non-specific. In conclusion, results generated by rSBA did not accurately classify serostatus according to hSBA for serogroups A, W-135 and Y.     

The bivalent factor H binding protein meningococcal serogroup B vaccine elicits bactericidal antibodies against representative non-serogroup B meningococci

MenB-FHbp (Trumenba®; bivalent rLP2086) is a meningococcal serogroup B vaccine containing 2 variants of the recombinant lipidated factor H binding protein (FHbp) antigen. The expression of FHbp, an outer membrane protein, is not restricted to serogroup B strains of Neisseria meningitidis (MenB). This study investigated whether antibodies elicited by MenB-FHbp vaccination also protect against non-MenB strains. Immunological responses were assessed in serum bactericidal assays using human complement (hSBAs) with non-MenB disease-causing test strains from Europe, Africa, and the United States. Importantly, FHbp variant distribution varies among meningococcal serogroups; therefore, strains that code for serogroup-specific prevalent variants (ie, representative of the 2 antigenically distinct FHbp subfamilies, designated subfamily A and subfamily B) and with moderate levels of FHbp surface expression were selected for testing by hSBA. After 2 or 3 doses of MenB-FHbp, 53% to 100% of individuals had bactericidal responses (hSBA titers ≥ 1:8) against meningococcal serogroup C, W, Y, and X strains, and 20% to 28% had bactericidal responses against serogroup A strains; in fact, these bactericidal responses elicited by MenB-FHbp antibodies against non-MenB strains, including strains associated with emerging disease, were greater than the serological correlate of protection for meningococcal disease (ie, hSBA titers ≥ 1:4). This is in comparison to a quadrivalent polysaccharide conjugate vaccine, MCV4 (Menactra®, targeting meningococcal serogroups A, C, W, and Y), which elicited bactericidal responses of 90% to 97% against the serogroup A, C, W, and Y strains and had no activity against serogroup X. Together, these results provide clinical evidence that MenB-FHbp may protect against meningococcal disease regardless of serogroup.     

Serogroup B meningococcal disease in persons previously vaccinated with a serogroup B meningococcal vaccine – United States, 2014–2019

Since serogroup B meningococcal (MenB) vaccines became available in the United States, six serogroup B meningococcal disease cases have been reported in MenB-4C (n = 4) or MenB-FHbp (n = 2) recipients. Cases were identified and characterized through surveillance and health record review. All five available isolates were characterized using whole genome sequencing; four isolates (from MenB-4C recipients) were further characterized using flow cytometry, MenB-4C-induced serum bactericidal activity (SBA), and genetic Meningococcal Antigen Typing System (gMATS). Three patients were at increased meningococcal disease risk because of an outbreak or underlying medical conditions, and only four of the six patients had completed a full 2-dose MenB series. Isolates were available from 5 patients, and all contained sub-family A FHbp. The four isolates from MenB-4C recipients expressed NhbA but were mismatched for the other MenB-4C vaccine antigens. These four isolates were relatively resistant to MenB-4C-induced SBA, but predicted by gMATS to be covered. Overall, patient risk factors, incomplete vaccine series completion, waning immunity, and strain resistance to SBA likely contributed to disease in these six patients.     

Safety and immunogenicity of a CRM or TT conjugated meningococcal vaccine in healthy toddlers

BackgroundMenACWY-CRM (Menveo^®; GlaxoSmithKline) and MenACWY-TT (Nimenrix^®; Pfizer) are two meningococcal vaccines licensed in the European Union for use in both children and adults. While both vaccines target meningococcal serogroups A, C, W and Y, immunogenicity and reactogenicity of these quadrivalent meningococcal conjugate vaccines may differ due to differences in formulation processes and chemical structure. Yet data on the comparability of these two vaccines are limited.MethodsThe reactogenicity and immunogenicity of one dose of either MenACWY-CRM or MenACWY-TT were evaluated in healthy toddlers aged 12–15 months. Immunogenicity was assessed using serum bactericidal antibody assays (SBA) with human (hSBA) and rabbit (rSBA) complement.ResultsA total of 202 children aged 12–15 months were enrolled to receive one dose of MenACWY-CRM or MenACWY-TT. Similar numbers of subjects reported solicited reactions within 7 days following either vaccination. Tenderness at the injection site was the most common local reaction. Systemic reactions reported were similar for both vaccines and mostly mild to moderate in severity: irritability, sleepiness and change in eating habits were most commonly reported. Immunogenicity at 1 month post-vaccination was generally comparable for both vaccines across serogroups. At 6 months post-vaccination antibody persistence against serogroups C, W, and Y was substantial for both vaccines, as measured by both assay methodologies. For serogroup A, hSBA titers declined in both groups, while rSBA titers remained high.ConclusionDespite differences in composition, the MenACWY-CRM and MenACWY-TT vaccines have comparable reactogenicity and immunogenicity profiles. Immediate immune responses and short-term antibody persistence were largely similar between groups. Both vaccines were well-tolerated and no safety concerns were identified.     

Considerations for controlling invasive meningococcal disease in high income countries

The development of conjugate vaccines has enabled the prevention and control of Neisseria meningitidis caused by serogroups A, C, W-135 and Y. Vaccines that provide protection against a broad number of serogroup B strains likely will be available soon to enable greater control of meningococcal disease in high income countries. We present an argument for adequate post-marketing surveillance to monitor epidemiological shifts and to provide a context for the safety and reactogenicity of serogroup B vaccines, including the newer recombinant vaccines. We also offer a series of recommendations to address possible concerns about vaccine safety.     

Vaccine prevention of meningococcal disease, coming soon?

The past century has seen the use of a number of vaccines for prevention and control of meningococcal disease with varied success. The use of polysaccharide vaccines for the control of outbreaks of serogroup C infections in teenagers and young adults and epidemic serogroup A disease has been established for 30 years and an effective protein-polysaccharide conjugate vaccine against serogroup C was introduced into the UK infant immunisation schedule in 2000. The next generation of these glycoconjugate vaccines will be on the shelf soon, eventually offering the prospect of eradication of serogroups A, C, Y and W135 through routine infant immunisation. Despite these exciting prospects, serogroup B meningococci still account for a majority of infections in industrialised nations but development of safe, immunogenic and effective serogroup B meningococcal vaccines has been an elusive goal. Outer membrane vesicle vaccines for B disease are already used in some countries, and will likely be used more widely in the next few years, but efficacy for endemic disease in children has so far been disappointing. However, the innovations arising from the availability of the meningococcal genome sequence, public and scientific interest in the disease and recent pharmaceutical company investment in development of serogroup B vaccines may have started the countdown to the end of meningococcal infection in children.     

Time-series analysis of meningococcal disease in Catalonia

PURPOSE: In Catalonia, a region in the northeast of Spain, a rate of five cases of meningococcal disease per 100,000 inhabitants was reported during the period of 1996-1997, which was higher than in previous years. The objective of this study was to analyze the temporal behavior of serogroup B and C meningococcal disease cases in Catalonia. METHODS: The study included confirmed cases of meningococcal disease from the 4-week period 11 of 1996 to the 4-week period 10 of 2004. A Poisson regression model (GLM) was fit for time series of serogroup B cases, whereas a zero-inflated Poisson model (ZIP) was necessary to adjust time series of serogroup C cases. RESULTS: The evolution of cases in both serogroups was correlated over time. For serogroup B, there was also an association with the influenza epidemics reported in four of the seasons analyzed. For serogroup C, a positive association with three influenza epidemics and a negative association with vaccination campaigns were found. Time series analysis of meningococcal disease shows that serogroups B and C behave in a different way. CONCLUSIONS: The study of the evolution of each serogroup may be useful in evaluating vaccination strategies.     

Induction of immunological memory in UK infants by a meningococcal A/C conjugate vaccine

The induction of immunological memory to serogroup A and C polysaccharides in UK infants immunized with three doses of a meningococcal A/C oligosaccharide CRM197 conjugate vaccine was investigated. Forty UK infants vaccinated previously with three doses of a meningococcal A/C oligosaccharide-CRM197 conjugate vaccine at 2, 3 and 4 months of age, were revaccinated at a mean age of 145.6 weeks with either a 10 or 50 microg dose of licensed meningococcal A/C polysaccharide vaccine. Serogroup-specific antibody and serum bactericidal antibody (SBA) responses were measured by enzyme-linked immunosorbent assay and serum bactericidal assays, respectively. Following challenge, anti-serogroup A and C polysaccharide antibody levels rose from pre-booster geometric mean concentrations (GMC) of 3.1 and 2.1 microg/ml respectively to 19.6 and 21.0 microg/ml 1 month post-booster. Serum bactericidal antibody geometric mean titres (GMTs) for serogroups A and C increased 156- and 113-fold from 2.1 and 7.1 pre-booster respectively to 327.4 and 800.7 post-booster. A serogroup A control group of 45 children received a 10 microg dose of licensed meningococcal A/C polysaccharide vaccine (with no prior history of serogroup A vaccination) had serogroup A SBA GMTs of 2.3 pre-vaccination rising to 8 post-vaccination with corresponding GMCs of 0.8 and 10.8 microg/ml. These rises in SBA following serogroup A/C conjugate vaccination are indicative of immunological priming.     

Broad vaccine protection against Neisseria meningitidis using factor H binding protein

Neisseria meningitidis, the causative agent of invasive meningococcal disease (IMD), is classified into different serogroups defined by their polysaccharide capsules. Meningococcal serogroups A, B, C, W, and Y are responsible for most IMD cases, with serogroup B (MenB) causing a substantial percentage of IMD cases in many regions. Vaccines using capsular polysaccharides conjugated to carrier proteins have been successfully developed for serogroups A, C, W, and Y. However, because the MenB capsular polysaccharide is poorly immunogenic, MenB vaccine development has focused on alternative antigens. The 2 currently available MenB vaccines (MenB-4C and MenB-FHbp) both include factor H binding protein (FHbp), a surface-exposed protein harboured by nearly all meningococcal isolates that is important for survival of the bacteria in human blood. MenB-4C contains a nonlipidated FHbp from subfamily B in addition to other antigens, including Neisserial Heparin Binding Antigen, Neisserial adhesin A, and outer membrane vesicles, whereas MenB-FHbp contains a lipidated FHbp from each subfamily (A and B). FHbp is highly immunogenic and a main target of bactericidal activity of antibodies elicited by both licensed MenB vaccines. FHbp is also an important vaccine component, in contrast to some other meningococcal antigens that may have limited cross-protection across strains, as FHbp-specific antibodies can provide broad cross-protection within each subfamily. Limited cross-protection between subfamilies necessitates the inclusion of FHbp variants from both subfamilies to achieve broad FHbp-based vaccine coverage. Additionally, immune responses to the lipidated form of FHbp have a superior cross-reactive profile to those elicited by the nonlipidated form. Taken together, the inclusion of lipidated FHbp variants from both FHbp subfamilies is expected to provide broad protection against the diverse disease-causing meningococcal strains expressing a wide range of FHbp sequence variants. This review describes the development of vaccines for MenB disease prevention, with a focus on the FHbp antigen.     

A comparative evaluation of two investigational meningococcal ABCWY vaccine formulations: Results of a phase 2 randomized,controlled trial

BackgroundA meningococcal vaccine protective against all major disease-associated serogroups (A, B, C, W and Y) is an unmet public health need. In this phase 2 observer-blinded, randomized, controlled study, two investigational meningococcal ABCWY vaccine formulations were evaluated to assess their immunological noninferiority to a licensed quadrivalent meningococcal ACWY glycoconjugate vaccine (MenACWY-CRM) for serogroups ACWY and immunogenicity against serogroup B test strains, as well as for formulation selection based on a desirability index (DI). Each investigational MenABCWY formulation contained recombinant protein and outer membrane vesicle (OMV) components of a licensed serogroup B vaccine (4CMenB) combined with components of MenACWY-CRM.MethodsA total of 484 healthy 10–25 year-old participants were randomized to receive two doses, two months apart, of an investigational MenABCWY formulation that contained either a full or one-quarter dose of OMV, 4CMenB alone, or a Placebo followed by MenACWY-CRM. Immunogenicity against each of serogroups ACWY and four serogroup B test strains was assessed by serum bactericidal assay with human complement (hSBA). MenABCWY formulations were compared by a DI based on key immunogenicity and reactogenicity parameters.ResultsSeroresponse rates for serogroups ACWY were significantly higher after two doses of either MenABCWY formulation than after one dose of MenACWY-CRM: respectively, A: 90–92% vs. 73%; C: 93–95% vs. 63%; W: 80–84% vs. 65%; and Y: 90–92% vs. 75%. Prespecified noninferiority criteria were met. Both MenABCWY formulations induced substantial immune responses against serogroup B test strains, although 4CMenB responses were higher. Overall DIs for both MenABCWY formulations were similar. Reactogenicity profiles of the MenABCWY formulations were similar to each other and to that of 4CMenB. No vaccine-related serious adverse events were reported.ConclusionsBoth investigational MenABCWY formulations elicited robust immune responses against serogroups ACWY and serogroup B test strains, and had acceptable reactogenicity profiles, with no safety concerns identified.     

Neisseria meningitidis serogroup B outer membrane vesicle vaccine in adults with occupational risk for meningococcal disease.

Vaccination provides a safe and effective means of reducing the risk of laboratory-acquired infection due to some Neisseria meningitidis serogroups. However, there is currently no serogroup B meningococcal vaccine licensed for use in the US. We used an investigational N. meningitidis serogroup B outer membrane vesicle (B:15:P1.7,16) vaccine produced by the National Institute of Public Health (NIPH) in Norway to immunize 20 researchers with occupational risk for disease. Three doses of vaccine were administered via intramuscular injection at 8-week intervals. The vaccine produced moderate or severe pain with 19 (33%) of the 58 doses administered. Reactions were similar following first, second and third doses. The number and severity of reactions peaked at 24 h postvaccination and then gradually waned. Of 16 vaccinees with results available from all blood draws, 12 (75%) showed a fourfold or greater rise in serum bactericidal activity (SBA) against the vaccine type-strain following two doses of vaccine, and 15 (94%) responded after three doses. Geometric mean titers increased by more than sixfold following two doses of vaccine when compared with prevaccination levels, and by more than 11-fold following a third dose. There was no significant difference between SBA measured using the vaccinee's own complement versus a donor complement source. The NIPH vaccine elicited an excellent bactericidal response against the vaccine type-strain in researchers with an occupational risk for disease. It may be useful for other laboratory personnel who routinely work with meningococcal strains containing similar outer membrane antigens. These findings reconfirm that the NIPH vaccine is immunogenic in adults and support the validity of using properly screened human donor complement in serum bactericidal assays against serogroup B meningococci.     

Antibody responses to meningococcal (groups A, C, Y and W135) polysaccharide diphtheria toxoid conjugate vaccine in children who previously received meningococcal C conjugate vaccine

A randomised, modified, double-blind trial was conducted in children 2 to < 5 years of age to evaluate immunogenicity and reactogenicity of a meningococcal (serogroups A, C, Y, W135) diphtheria toxoid conjugate vaccine (MCV-4) in healthy children previously vaccinated with a monovalent meningococcal C conjugate vaccine. Participants received one dose of either MCV-4 or Haemophilus influenzae type b vaccine (Hib vaccine, control group). Serum bactericidal antibodies (SBA) were determined in sera obtained before and approximately 28 days following vaccination. MCV-4 was highly immunogenic for serogroups A, C, Y and W135, the response to serogroup C being consistent with a booster response in participants primed with monovalent C conjugate vaccine. No major between-group differences in solicited local and systemic reactions or adverse events (AEs).     

Breadth of coverage against a panel of 110 invasive disease isolates,immunogenicity and safety for 2 and 3 doses of an investigational MenABCWY vaccine in US adolescents – Results from a randomized,controlled, observer-blind phase II study

BackgroundNeisseria meningitidis serogroups A, B, C, W and Y cause most meningococcal disease worldwide. An investigational MenABCWY vaccine combining serogroup B antigens and a meningococcal ACWY CRM₁₉₇-glycoconjugate vaccine (MenACWY-CRM) could provide protection against all 5 serogroups. Complement mediated bactericidal activity induced by MenABCWY was tested against a panel of 110 randomly-selected serogroup B strains causing invasive disease in the US to evaluate the vaccine’s breadth of coverage (BoC).MethodsWe conducted this observer-blind study (NCT02140762) and its extension (NCT02285777) in 8 centers in the US. Adolescents aged 10–18 years were randomized (1:1) to receive either 3 MenABCWY doses (MenABCWY group), on a 0, 2, 6-month (M) schedule or a single MenACWY-CRM dose at M2 and placebo at 0,6-M (Control group). MenABCWY BoC was calculated as (1 − relative risk) × 100 (relative risk = ratio between the percentage of samples seronegative at 1:4 dilution against the selected strains in the MenABCWY vs Control group). BoC was determined at 1 M and 4 M after 2 and 3 doses, using an endogenous complement serum bactericidal assay. Immunogenicity and safety were assessed.Results301 and 189 adolescents were vaccinated in the parent and extension study, respectively. At 1 M post-vaccination, the BoC of MenABCWY across the 110 serogroup B strains was 67% (95%CI: 65–69) after 2 doses and 71% (95%CI: 69–73) after 3 doses. BoC decreased to 44% (95%CI: 41–47) and 51% (95%CI: 48–55) at 4 M after 2 and 3 MenABCWY doses, respectively. Robust immune responses to antigen-specific test strains for each serogroup were observed at all timepoints in the MenABCWY group. No reactogenicity or safety concerns arose during the study.ConclusionTwo or 3 doses of MenABCWY showed similar BoC against the panel of invasive US serogroup B isolates and comparable immunogenicity against the antigen-specific test strains, with no safety concerns identified.     

Comparison of antibody kinetics following meningococcal serogroup C conjugate vaccine between healthy adults previously vaccinated with meningococcal A/C polysaccharide vaccine and vaccine-naïve controls

Few data are available on the kinetics of meningococcal serogroup C-specific antibody production following meningococcal serogroup C conjugate (MCC) vaccination, particularly in those who have received prior meningococcal A/C polysaccharide (MACP) vaccination(s). Laboratory staff who had previously received either one dose (n = 35), two doses (n = 18) of MACP vaccine or who were na?ve to previous meningococcal vaccination (n = 42) were vaccinated with MCC. Bloods were taken pre-vaccination, on the subsequent 4 days and on days 10 and 28. Serogroup C serum bactericidal antibody (SBA), and anti-serogroup C-specific IgG, IgM and IgA were measured. There were no significant differences between the groups who had received either 2 or 1 prior dose(s) of MACP, therefore, these results were combined. Up to day 4 there was no evidence of a significant increase or decrease in the median levels of SBA, IgG, IgM or IgA in either the na?ve or MACP groups, although about 20% of individuals did have 4-fold SBA rises by day 4. By day 10 there were large significant increases in the levels of SBA, IgG, IgM and IgA with respective fold increases from pre-vaccination levels of 4.6, 1.9, 1.2 and 2.1 in the MACP group and 270, 13.4, 4.8 and 33.8 in the na?ve group. Further significant increases were seen between day 10 and 28 for SBA, IgG and IgM (na?ve group only). By day 28, 4-fold SBA rises had occurred in 63.5% of the MACP group and 97.6% of the na?ve group. The SBA GMT on day 28 significantly differed between the na?ve and MACP groups with GMTs 2.8-fold higher in the na?ve group (P = 0.021). In conclusion, no decline in serogroup C-specific antibody levels was demonstrated immediately post-MCC vaccination whilst these levels had risen significantly by day 10. Putative protective SBA titres (> or =8, 32 or 128) were observed by day 10 following MCC vaccination regardless of MACP history.     

Long-term antibody persistence after a booster dose of quadrivalent meningococcal ACWY-tetanus toxoid conjugate vaccine in healthy 5-year-old children

BackgroundTo provide continuing protection, available meningococcal vaccines must provide long-term persistence of circulating functional antibodies against prevalent serogroups causing invasive meningococcal disease (IMD). This study assessed antibody persistence and safety of the quadrivalent meningococcal vaccine conjugated to tetanus toxoid (MenACWY-TT) and the meningococcal serogroup C vaccine conjugated to Corynebacterium diphtheriae CRM₁₉₇ protein (MenC-CRM) for up to 6 years after booster dosing in children.MethodsIn the primary vaccination study, children were vaccinated at age 12 to 23 months. In the first extension study, children who completed the primary study received a booster dose 4 years later with the same primary vaccine. The current study assessed antibody persistence at 2 to 6 years postbooster against each of the 4 meningococcal serogroups using serum bactericidal assays using rabbit (rSBA) or human (hSBA) complement with antibody titer thresholds of ≥1:8 or ≥1:4, respectively, and geometric mean titers (GMTs). Safety evaluations during this period included serious adverse events (SAEs) related to vaccination and any event related to lack of vaccine efficacy.ResultsA total of 184 subjects were enrolled (MenACWY-TT = 159; MenC-CRM = 25). For MenACWY-TT, the percentages of subjects with rSBA titers ≥1:8 ranged from 96.7% to 100% across serogroups at 2 years postbooster and 71.6% to 94.0% at 6 years postbooster; rSBA GMTs decreased from Year 2 to 4 and generally remained stable thereafter. The percentages of subjects in the MenACWY-TT group with hSBA titers ≥1:4 were 70.0% to 100% across serogroups at 2 years postbooster and 58.5% to 98.5% at 6 years postbooster. No lack of efficacy, SAEs, or vaccine-related adverse events were reported.ConclusionsThe persistence of rSBA and hSBA antibodies was shown up to 6 years postbooster (10 years postprimary vaccination) with either MenACWY-TT or MenC-CRM, suggesting that this schedule may provide long-term protection against IMD. Clinicaltrials.gov: NCT01900899.     

The changing and dynamic epidemiology of meningococcal disease

The epidemiology of invasive meningococcal disease continues to change rapidly, even in the three years since the first Meningococcal Exchange Meeting in 2008. Control of disease caused by serogroup C has been achieved in countries that have implemented meningococcal C or quadrivalent meningococcal ACWY conjugate vaccines. Initiation of mass immunization programs with meningococcal A conjugate vaccines across the meningitis belt of Africa may lead to the interruption of cyclical meningococcal epidemics. A meningococcal B vaccination program in New Zealand has led to a decreased incidence of high rates of endemic serogroup B disease. Increases in serogroup Y disease have been observed in certain Nordic countries which, if they persist, may require consideration of use of a multiple serogroup vaccine. The imminent availability of recombinant broadly protective serogroup B vaccines may provide the tools for further control of invasive meningococcal disease in areas where serogroup B disease predominates. Continued surveillance of meningococcal disease is essential; ongoing global efforts to improve the completeness of reporting are required.