MenC Vaccine Research Articles

Gender-specific mortality in DTP-IPV- and MMR±MenC-eligible age groups to determine possible sex-differential effects of vaccination: an observational study.

BackgroundSeveral studies suggested that vaccines could have non-specific effects on mortality depending on the type of vaccine. Non-specific effects seem to be different in boys and girls. In this study we want to investigate whether there are differences in gender-specific mortality among Dutch children according to the last vaccination received. We tested the hypothesis that the mortality rate ratio for girls versus boys is more favourable for girls following MMR ± MenC vaccination (from 14 months of age) compared with the ratio following DTP-IPV vaccination (2–13 months of age). Secondarily, we investigated whether there were gender-specific changes in mortality following booster vaccination at 4 years of age.MethodsThis observational study included all Dutch children aged 0–11 years from 2000 until 2011. Age groups were classified according to the last vaccination offered. The mortality rates for all natural causes of death were calculated by gender and age group. Incidence rate ratios (IRRs) were computed using a multivariable Poisson analysis to compare mortality in boys and girls across different age groups.ResultsThe study population consisted of 6,261,472 children. During the study period, 14,038 children (0.22%) died, 91% of which were attributed to a known natural cause of death. The mortality rate for natural causes was higher among boys than girls in all age groups. Adjusted IRRs for girls compared with boys ranged between 0.81 (95% CI 0.74-0.89) and 0.91 (95% CI 0.77-1.07) over the age groups. The IRR did not significantly differ between all vaccine-related age groups (p = 0.723), between children 2–13 months (following DTP-IPV vaccination) and 14 months - 3 years (following MMR ± MenC vaccination) (p = 0.493) and between children 14 months - 3 years and 4–8 years old (following DTP-IPV vaccination) (p = 0.868).ConclusionsIn the Netherlands, a high income country, no differences in gender-specific mortality related to the type of last vaccination received were observed in DTP-IPV- and MMR ± MenC eligible age groups. The inability to detect this effect indicates that when non-specific effects were present the effects were not reflected in changes in the differences in mortality between boys and girls. The findings in this large population-based study are reassuring for the continued trust in the safety of the national vaccination programme.

Antibody persistence in Australian adolescents following meningococcal C conjugate vaccination.

In Australia, following the introduction of serogroup C meningococcal (MenC) conjugate vaccine for toddlers and catch-up immunization through adolescence, MenC disease incidence plummeted and remains low. However, individual protection following MenC conjugate vaccination, particularly in young children, may be short-lived. We investigated the persistence of MenC serum bactericidal antibody (SBA) titers in adolescents, more than 7 years after a single "catch-up" dose of MenC conjugate vaccine. We also investigated their exposure and susceptibility to meningococcal serogroups A, W and Y. MenC SBA titers and Men A, C, W and Y IgG geometric mean concentration were measured in 240 healthy 11- to 16-year-old adolescents. The correlate of protection was an rSBA titer of ≥8. An rSBA≥8 was observed in 105 [44% (95% confidence interval {CI}, 37-50%)] of 240 adolescents (mean age, 13.2 years, mean interval since MenC immunization, 8.2 years). The proportion with an rSBA≥8, geometric mean rSBA titer and geometric mean IgG concentration increased with age, from 22% to 75%, 3.7 to 33.4 and 0.13 to 0.52 μg/mL, in participants who received MenC vaccine at mean age 2.8 to 7.5 years, respectively. Natural acquired antibody to Men A, W and Y was low with IgG geometric mean concentrations of 1.26, 0.38 and 0.47 μg/mL, respectively. More than half of Australian adolescents have inadequate serological protection against MenC disease and low natural immunity to MenA, W and Y.

Subsets of memory CD4+ T cell and bactericidal antibody response to Neisseria meningitidis serogroup C after immunization of HIV-infected children and adolescents.

Meningococcal disease is endemic in Brazil, with periodic outbreaks and case fatality rates reach as high as 18 to 20% of cases. Conjugate vaccines against meningococci are immunogenic in healthy children. However, we have previously shown a poor bactericidal antibody response to a Men C conjugate vaccine in Brazilian HIV-infected children and adolescents after a single vaccine administration. The goal of the present work was to investigate associations between bactericidal antibody response induced by MenC vaccine and the frequency and activation profile (expression of CD38, HLA-DR and CCR5 molecules) of total CD4+ memory T cell sub-populations in HIV-1-infected children and adolescents. Responders to vaccination against MenC had a predominance (about 44%) of CD4+ TINTERMEDIATE subset followed by TTRANSITIONAL memory subset (23 to 26%). Importantly, CD4+ TINT frequency was positively associated with bactericidal antibody response induced by vaccination. The positive correlation persisted despite the observation that the frequency TINT CD38+HLA-DR+ was higher in responders. In contrast, CD4+ TCENTRAL MEMORY (TCM) subset negatively correlated with bactericidal antibodies. In conclusion, these data indicate that less differentiated CD+ T cells, like TCM may be constantly differentiating into intermediate and later differentiated CD4+ T cell subsets. These include CD4 TINT subset which showed a positive association with bactericidal antibodies.

Investigating the immunodominance of carbohydrate antigens in a bivalent unimolecular glycoconjugate vaccine against serogroup A and C meningococcal disease.

Multicomponent constructs, obtained by coupling different glycans to the carrier protein, have been proposed as a way to co-deliver multiple surface carbohydrates targeting different strains of one pathogen and reduce the number of biomolecules in the formulation of multivalent vaccines. To assess the feasibility of this approach for anti-microbial vaccines and investigate the potential immunodominance of one carbohydrate antigen over the others in these constructs, we designed a bivalent unimolecular vaccine against serogroup A (MenA) and C (MenC) meningococci, with the two different oligomers conjugated to same molecule of carrier protein (CRM197). The immune response elicited in mice by the bivalent MenAC construct was compared with the ones induced by the monovalent MenA and MenC vaccines and their combinations. After the second dose, the bivalent construct induced good levels of anti-MenA and anti-MenC antibodies with respect to the controls. However, the murine sera from the MenAC construct exhibited good anti-MenC bactericidal activity, and very low anti-MenA functionality when compared to the monovalent controls. This result was explained with the diverse relative avidities against MenA and MenC polysaccharides, which were measured in the generated sera. The immunodominant effect of the MenC antigen was fully overcome following the third immunization, when sera endowed with higher avidity and excellent bactericidal activity against both MenA and MenC expressing strains were elicited. Construction of multicomponent glycoconjugate vaccines against microbial pathogens is a feasible approach, but particular attention should be devoted to study and overcome possible occurrence of immune interference among the carbohydrates.

A phase 2 randomized controlled trial of a multicomponent meningococcal serogroup B vaccine (I)

The novel meningococcal serogroup B vaccine (4CMenB, Bexsero®), recently approved in Europe and Australia, may soon be included in routine infant immunization schedules, subject to guidance from national or regional recommending bodies. In the development of 4CMenB and consistent with other newly introduced vaccines, clinical studies have shown concomitant administration with routine infant vaccines induces an incremental increase in some reactions, including fever. As this may hinder acceptability, we examined the impact of prophylactic paracetamol on the occurrence of fever and other solicited reactions, as well as the immune responses to study vaccines, in a prospectively designed study. 4CMenB was administered as a 4-dose series at 2, 3, 4, and 12 months of age concomitantly with routine infant vaccines: DTaP-HBV-IPV/Hib and PCV7, with or without prophylactic paracetamol; a third group received MenC vaccine. Immune responses to 4CMenB were not decreased by the use of paracetamol prophylaxis and there were no clinically relevant effects on immune responses to routine vaccines. Occurrence of fever was higher in infants co-administered with 4CMenB compared with those given MenC vaccine, but was significantly decreased by prophylactic paracetamol, as were other solicited reactions to vaccination, both local and systemic. Co-administration of 4CMenB had an acceptable tolerability profile, with no withdrawals due to vaccination-related adverse events. Inclusion of 4CMenB in routine infant immunization schedules will be a major advance in the control of meningococcal disease, and our study indicates that by using paracetamol prophylaxis, post-vaccination reactions are reduced without clinically relevant negative consequences on vaccine immunogenicity.

Exonic single nucleotide polymorphisms within TLR3 associated with infant responses to serogroup C meningococcal conjugate vaccine

The introduction of the serogroup C meningococcal (MenC) conjugate vaccination has successfully controlled the burden of disease associated with this serogroup in many countries. However, considerable inter-individual variation is observed in immune responses to MenC vaccine, and little is understood of the determinants of this variability. Previously, we reported an association between single nucleotide polymorphisms (SNPs) in TLR3 and CD44 and the persistence of MenC vaccine immunity. Here we further examine polymorphisms within these two candidate genes and immune responses to MenC vaccine. MenC-specific IgG concentrations and serum bactericidal assay (SBA) titres were measured one month after a primary course of MenC vaccination in 318 human infants. Tagging SNPs (TagSNPs) within TLR3 and CD44 were genotyped and regional imputations carried out to screen these genes for variations associated with immunological responses to MenC vaccine. This study reports an association between an exonic variant (rs3775290, P=0.025) in TLR3 and MenC IgG concentrations, as well as an association between three SNPs in CD44 (rs3794109, P=0.021; rs3794110, P=0.022; rs112762, P=0.049) and MenC SBA titres. These data support our previous findings of an association between SNPs in TLR3 and CD44, and present novel findings implicating exonic variants in these genes with MenC vaccine responses.

The link between genetic variation and variability in vaccine responses: Systematic review and meta-analyses

Although immune response to vaccines can be influenced by several parameters, human genetic variations are thought to strongly influence the variability in vaccine responsiveness. Systematic reviews and meta-analyses are needed to clarify the genetic contribution to this variability, which may affect the efficacy of existing vaccines. We performed a systematic literature search to identify all studies describing the associations of allelic variants or single nucleotide polymorphisms in immune response genes with vaccine responses until July 2013. The studies fulfilling inclusion criteria were meta-analyzed.Thirteen studies (11,686 subjects) evaluated the associations of human leukocyte antigen (HLA) and other immunity gene variations with the responses to single vaccines, including MMR-II (measles and rubella virus), HepB (hepatitis virus), influenza virus, and MenC (serogroup C meningococcus) vaccines. Seven HLA genetic variants were included in the meta-analyses. The pooled ORs showed that DRB1*07 (2.46 [95% CI=1.60–3.77]; P for heterogeneity=0.117; I2=49.1%), DQA1*02:01 (2.21 [95% CI=1.22–4.00]; P for heterogeneity=0.995; I2=0.0%), DQB1*02:01 (2.03 [95% CI=1.35–3.07]; P for heterogeneity=0.449; I2=0.0%), and DQB1*03:03 (3.31 [95% CI=1.12–9.78]; P for heterogeneity=0.188; I2=42.4%) were associated with a significant decrease of antibody responses to MMR-II, HepB, and influenza vaccines. The pooled ORs showed that DRB1*13 (0.52 [95% CI=0.32–0.84]; P for heterogeneity=0.001; I2=85.1%) and DRB1*13:01 (0.19 [95% CI=0.06–0.58]; P for heterogeneity=0.367; I2=0.0%) were associated with a significant increase of antibody responses to the above vaccines.While our findings reinforce the concept that individuals with a particular HLA allelic composition are more likely to respond efficiently to vaccines, future studies should be encouraged to further elucidate the link between genetic variation and variability of the human immune response to vaccines.

CD4+ T-cell activation impairs serogroup C Neisseria meningitis vaccine response in HIV-infected children

To investigate the influence of CD4 T-cell activation and regulatory populations in HIV-infected children antibody response to vaccination with a conjugate C polysaccharide vaccine. CD4 T-cell activation was evaluated by expression of CD38, HLA-DR and CCR5 molecules. Regulatory CD4 T cells (TReg) were characterized as FoxP3CD127CD25 and inducer T cells (TInd) as CD4FoxP3CD25CD39. All patients (n = 36) were HIV-vertically infected, aged 2-17 years-old and were vaccinated with one vaccine injection. Blood samples were obtained before and after immunization to determine bactericidal antibody titers (SBA), CD4 T-cell activation and frequency of TReg and TInd subsets (multiparametric flow cytometry). Children not-responding (n = 18) to MenC vaccine expressed higher frequency of activated CD4 T cells (HLA-DRCD38CCR5) than responders (n = 18), both before and after vaccination (P < 0.05). A significant higher frequency of TReg was detected in responders compared with nonresponders (P = 0.0001). We also detected an inverse correlation between CD4DRCD38CCR5 (P = 0.01) or CD4DRCD38 (P = 0.02) T cells and TReg cell frequency after vaccination. CD4 T-cell activation negatively correlated (P = 0.006) with postvaccination SBA titers but a positive correlation (P = 0.0001) was detected between TReg cells and SBA. TReg and TInd subsets were inversely correlated (P = 0.04). Our findings suggest that higher CD4 T-cell activation leads to poor vaccine response in children living with HIV, which may be associated with a TReg/TInd disequilibrium.

Long-term seroprotection after an adolescent booster meningococcal serogroup C vaccination

ObjectivesTo determine long-term seroprotection after serogroup C meningococcal (MenC) vaccination at the age of 9–12 years, with or without booster vaccination at the age of 13–15 years.DesignObservational cohort study; follow-on...

Adolescents need a booster of serogroup C meningococcal vaccine to protect them and maintain population control of the disease

The serogroup C meningococcal immunisation programme was reviewed during 2012 by the Department of Health's Joint Committee on Vaccination and Immunisation (JCVI), and an adolescent booster has been recommended as...

Changes to MenC vaccination schedule announced

Changes to MenC vaccination schedule announced

Impact of vaccination during an epidemic of serogroup C meningococcal disease in Salvador, Brazil

To combat rising incidence of serogroup C meningococcal disease in the city of Salvador, Brazil, the Bahia state immunization program initiated routine childhood immunization with meningococcal C conjugate vaccine (MenC) in February 2010, followed by mass MenC vaccination of city residents 10–24 years of age from May through August 2010. We analyzed trends in incidence of reported cases of meningococcal disease and serogroup distribution among meningococcal isolates identified in hospital-based surveillance in Salvador from January 2000 to December 2011 and estimated vaccine effectiveness using the screening method. Annual incidence of serogroup C meningococcal disease increased from 0.1 cases per 100,000 population during 2000–2006 to 2.3 in 2009 and 4.1 in 2010, before falling to 2.0 per 100,000 in 2011. Estimated coverage of mass vaccination reached 80%, 67% and 41% among 10–14, 15–19 and 20–24 year olds, respectively. Incidence in 2011 was significantly lower than average rates in 2008–2009 among children <5 years, but reductions among 10–24 year olds were not significant. Among 10–24 year olds, a single dose of MenC vaccine was 100% effective (95% confidence interval, 79–100%) against serogroup C meningococcal disease. Low coverage in the population targeted for mass vaccination may have limited impact on ongoing transmission of serogroup C meningococcal disease despite high vaccine effectiveness.

Persistence of the immune response at 5 years of age following infant immunisation with investigational quadrivalent menACWY conjugate vaccine formulations

<h3>Introduction</h3> Meningococcal serogroup C (MenC) conjugate vaccines are used routinely for infant immunisation in Canada and Europe. Quadrivalent serogroup A, C, W−135 and Y meningococcal (MenACWY) conjugate vaccines are licensed in Europe and North America, and recommended for routine immunisation of adolescents in the United States. <h3>Methods</h3> In an open-label, randomised controlled trial in the UK and Canada, we evaluated the persistence of immune response at 40 and 60 months of age after different schedules of two MenACWY-CRM conjugate vaccine formulations administered in infancy with MenC conjugate and MenACWY polysaccharide vaccines at 12 months of age. Two control groups were also recruited at 60 months, who had been immunised as infants or toddlers with MenC vaccines according to country-specific schedules. <h3>Results</h3> 382 children enrolled in 12 groups (22 to 40 per group) were followed up. By age 60 months, 3-11% of children primed and boosted with MenACWY-CRM had serum bactericidal antibody (using human complement [hSBA]) titres ≥1:8 against serogroup A meningococci, 14-45% against serogroup C, 57-84% against serogroup W-135 and 42-69% against serogroup Y. These proportions were similar for children primed with MenC and boosted with MenACWY-CRM except for serogroup C (59%). In age-matched control children at 60 months of age, percentages with hSBA titres ≥1:8 were 0-3%, 29-53%, 33-36% and 10-29% against serogroups A, C, W-135 and Y, respectively. <h3>Conclusions</h3> Immune responses against all serogroups wane following infant immunisation with MenACWY-CRM vaccines, most markedly against serogroup A. Better persistence of serogroup C hSBA titres was observed in schedules with MenC conjugate vaccine priming doses, however use of a booster MenACWY conjugate vaccine could provide broader protection against meningococcal disease.

Maintenance of immune response throughout childhood following serogroup c meningococcal conjugate vaccination in early childhood

<h3>Background</h3> Serogroup C meningococcal (MenC) conjugate vaccines were introduced into the UK routine infant immunisation schedule in 1999, along with a “catch-up” campaign for those aged 1–25 years. Previous cross-sectional studies demonstrated children immunised in early childhood have lower MenC bactericidal antibody 5 years after immunisation than children immunised in late childhood, however the kinetics of antibody decline through childhood have not been evaluated in a longitudinal study. We aimed to evaluate the kinetics of antibody decline through childhood in a longitudinal study of a single cohort following a dose of MenC conjugate vaccine in early childhood, and to calculate the proportion of 11 to 13 year-olds with protective levels of bactericidal antibody 10 years after immunisation. <h3>Method</h3> Stored sera obtained at multiple time-points between 2001 and 2010 from children who had received a single dose of MenC vaccine at age 1 to 3.5 years, were analysed for MenC serum bactericidal antibody using rabbit complement (rSBA). <h3>Results</h3> The MenC rSBA geometric mean titre (GMT) at age 3.5 to 5 years, approximately one year after immunisation, was 8.0 (95% confidence interval [CI] 6.5-9.9, n = 292). Over the subsequent 9 years, rSBA GMT declined to 3.3 (CI 2.5-4.4, n = 98) at age 11.5-13.5 years. The percentage of children with rSBA titres &gt;1:8 (threshold for protection) also declined from 38% (CI 35%-41%) to 15% (CI 12%-19%). <h3>Conclusion</h3> MenC rSBA titres wane rapidly following vaccination in early childhood, without evidence of natural boosting of antibody levels through cross-reactive antigens. In the UK, consideration should be given to a routine adolescent booster of MenC vaccine to protect this cohort of children who are entering the potentially high risk period of adolescence, and to prevent a resurgence in nasopharyngeal carriage and maintain herd immunity.

Phase II study of a three-dose primary vaccination course of DTPa-IPV/Hib-MenC-TT followed by a 12-month Hib-MenC-TT booster in healthy infants

<h3>Aims</h3> Combining the licensed Haemophilus influenzae type b (Hib) and serogroup C meningococcal (MenC) conjugate vaccine (Hib-MenC-TT) and DTaP-IPV vaccine could reduce the number of injections needed to administer the United Kingdom routine infant immunisation schedule. We aimed to demonstrate immunologic non-inferiority for Hib and MenC using a 6-in-1 combination vaccine (DTPa-IPV/Hib-MenC-TT) compared to a schedule using DTPa-IPV-Hib-TT and MenC-CRM197 conjugate vaccines. Secondary objectives included demonstration of non-inferiority of diphtheria, tetanus and polio immunogenicity; persistence of immune response to all antigens at 12 months of age and the response to a 12 month Hib-MenC-TT booster. <h3>Methods</h3> Open-label, randomised, multi-centre, UK study. Combination group received DTPa-IPV/Hib-MenC-TT at 2, 3, 4 months. Control group received DTPa-IPV-Hib-TT at 2, 3, 4 months and MenC-CRM197 at 3, 4 months. Both groups received Hib-MenC-TT booster at 12 months. Concomitant vaccines: pneumococcal conjugate vaccine at 2, 4, 13 months; MMR at 13 months. Blood tests were performed at 4, 5, 12 and 13 months. <h3>Results</h3> 142 children were randomised in each group. 100 children were included in the according-to-protocol cohort for analysis of immunogenicity following the booster vaccine in the combination group; and 112 children in the control group. One month post-primary immunisations 100% of the combination group and 93.3 % of control children had anti-PRP IgG concentration ≥0.15 μg/mL. 96.2% and 100% respectively had rSBA-MenC titres ≥1:8. One month post-booster all children met these thresholds. At 13 months of age, anti-PRP geometric mean concentrations (with 95% confidence intervals) were 66.7 (53.3-83.5) in the combination group and 26.9 (20.9-34.6) in the control group (4.35 [3.51-5.39] and 3.04 [2.21-4.19] respectively at 5 months). rSBA-MenC geometric mean titres (GMTs) were 3062.9 (2421.2-3874.6) and 954.0 (761.3-1195.5) respectively (393.2 [292.5-528.7] and 3110.5 [2612-3704.2] respectively at 5 months). <h3>Conclusion</h3> Non-inferiority of DTPa-IPV/Hib-MenC-TT compared to DTPa-IPV-Hib-TT plus MenC-CRM197 was demonstrated. The lower rSBA-MenC GMTs after primary immunisations and greater booster responses in the combination group suggest that immune priming might be inversely related to post-primary antibody responses. Furthermore, greater immunogenicity of TT conjugates used in primary and booster MenC vaccines in this group may be important.

Persistence of the immune response at 5 years of age following infant immunisation with investigational quadrivalent MenACWY conjugate vaccine formulations

Background and aimsSerogroup A, C, W-135 and Y meningococcal (MenACWY) conjugate vaccines are recommended for routine adolescent immunisation in the United States and Canada. We evaluated the persistence of bactericidal antibodies through early childhood, following infant immunisation with varying schedules of MenACWY-CRM197 vaccine. MethodsUK and Canadian infants were immunised with 2–3 doses of MenACWY-CRM197 or 2 doses of serogroup C meningococcal (MenC) conjugate vaccine, and either MenACWY-CRM197, 1/5 dose of MenACWY polysaccharide vaccine or no booster at 12 months. Control groups recruited at 60 months had received country-specific infant doses of MenC conjugate vaccine. hSBA titres were measured in participants at 40 and 60 months of age. Results382 children were enrolled in 12 groups (22–40 per group). By age 60 months, 3–11% of children primed and boosted with MenACWY-CRM197 had hSBA titres≥1:8 against serogroup A, 14–45% against serogroup C, 57–85% against serogroup W-135 and 42–71% against serogroup Y. Children primed with MenC and boosted with MenACWY-CRM197 had similar results, except for serogroup C (59%). In age-matched controls administered MenC vaccine at 2, 3, and 4 months (UK), 2 and 12 months or 12 months only (Canada), percentages with hSBA titres≥1:8 were 0–3%, 29–53%, 34–36% and 10–29% against serogroups A, C, W-135 and Y respectively. ConclusionsSerogroup-specific bactericidal antibody wane following infant immunisation with MenACWY-CRM197, most markedly against serogroup A. Best persistence against serogroup C is observed with MenC conjugate vaccine priming and MenACWY-CRM197 at 12 months, compared to schedules using only MenACWY-CRM197, with the potential for providing broader protection compared to monovalent MenC vaccines alone.

Is a single dose of meningococcal serogroup C conjugate vaccine sufficient for protection? experience from the Netherlands.

BackgroundThe first meningococcal serogroup C (MenC) conjugate vaccine was licensed in 1999 and introduced in the United Kingdom. Countries that have implemented the MenC vaccine since then in their national immunisation programmes use different schedules. Nevertheless, all involved countries seem to experience substantial declines in the incidence of MenC disease.DiscussionSince 2001, the MenC conjugate vaccine has been implemented in the Netherlands by offering a single dose to all children aged 14 months. Prior to the introduction of the vaccine into the national immunisation programme, a catch-up vaccination campaign was initiated in which a single dose of the MenC conjugate vaccine was offered to all children aged from 14 months up to and including 18 years. Since then, there has been no report of any case of MenC disease among immunocompetent vaccinees. Administration of a single dose of MenC conjugate vaccine after infancy could be beneficial considering the already complex immunisation schedules with large numbers of vaccinations in the first year of life. The present paper deals with the advantages and critical aspects of a single dose of the MenC conjugate vaccine.SummaryA single dose of MenC conjugate vaccine at the age of 14 months in combination with a catch up vaccine campaign appeared to be a successful strategy to prevent MenC disease in the Netherlands, thereby confirming that a single dose of the vaccine could sufficiently protect against disease. Nevertheless, this approach can only be justified in countries with a relatively low incidence of serogroup C meningococcal disease in the first year of life. Furthermore, a good surveillance programme is recommended for timely detection of vaccine breakthroughs and outbreaks among non-vaccinees, since long-term protection after a single dose in the second year of life cannot currently be guaranteed.

Single Nucleotide Polymorphisms in the Toll-Like Receptor 3 and CD44 Genes Are Associated with Persistence of Vaccine-Induced Immunity to the Serogroup C Meningococcal Conjugate Vaccine

The rate of decay of antibody concentration following serogroup C meningococcal (MenC) polysaccharide-protein conjugate vaccination varies between individuals. This depends partly on vaccination age but may be influenced by human genetics. We studied 721 single nucleotide polymorphisms (SNPs) across 131 candidate genes in a first cohort of 905 Caucasians (11 to 21 years old; mean time after vaccination, 4.9 years) and 30 SNPs across 17 genes in a replication study using 155 children, aged 6 to 12 years (mean time after vaccination, 6.7 years), and 196 infants (1 year old; mean time after vaccination, 8 months). Individuals were classified as responders or nonresponders for total MenC IgG concentration and MenC serum bactericidal antibody (SBA) measurements. Associated genes were examined further for quantitative outcome measures. Fifty-nine SNPs in 37 genes were associated with IgG persistence (adjusted for age at measurement), and 56 SNPs in 36 genes were associated with SBA persistence (adjusted for age at measurement and vaccine used). Three SNPs each within the Toll-like receptor 3 (TLR3) (rs3775291, rs3775292, and rs5743312) and CD44 (rs11033013, rs353644, and rs996076) genes were associated with IgG (adjusted for age at measurement) or SBA (adjusted for age at measurement and vaccine used) persistence in the initial genetic study (P, 0.02 to 0.04). Single SNPs within the TLR3 (rs7657186) (P = 0.004 [unadjusted]) and CD44 (rs12419062) (P = 0.01 [unadjusted]) genes were associated with IgG persistence in the replication study. These results suggest that genetic polymorphisms in the TLR3 and CD44 genes are associated with the persistence of the immune response to MenC vaccines 1 to 6 years after vaccination.

Persistence of Serum Bactericidal Antibody One Year After a Booster Dose of Either a Glycoconjugate or a Plain Polysaccharide Vaccine Against Serogroup C Neisseria meningitidis Given to Adolescents Previously Immunized With a Glycoconjugate Vaccine

Bactericidal antibody induced by immunization of infants with serogroup C Neisseria meningitidis (MenC) vaccines wanes rapidly during childhood. Adolescents are at particular risk from meningococcal disease, therefore they might benefit from a booster dose of vaccine. The duration of serologic response to such a booster in adolescents is unknown. In a previous study, English schoolchildren, aged 9 to 12 years, who had received a monovalent MenC glycoconjugate vaccine in 1999-2000, were given either a plain polysaccharide vaccine (MenC-PS group, n = 150) or a glycoconjugate vaccine (MenC-CRM group, n = 95) at 13 to 15 years of age. In this follow-up study, serum bactericidal antibody titers and specific immunoglobulin G concentrations were assessed 1 year later. Results were compared with unboosted controls of similar age (control group, n = 298). Compliance with study protocol was achieved for 146 of the MenC-PS group, 92 of the MenC-CRM group, and 293 of the control group. Compared with the control group, both the MenC-PS and MenC-CRM groups had a significantly higher (P < 0.0001) geometric mean serum bactericidal antibody titers 1 year after the booster dose (geometric mean titers for MenC-PS group 3388 [95% confidence interval {CI}: 2460-4665]; MenC-CRM group 4417 [95% CI: 2951-6609]; control group 316 [95% CI: 252-396]). Specific immunoglobulin G concentration also rose and remained elevated 1 year after the booster. A booster dose of MenC vaccine given to adolescents produced a marked rise in bactericidal antibody, which remained elevated 1 year later. Introduction of an adolescent booster of MenC vaccine might provide enhanced long-term population control of the disease.

Maintenance of Immune Response throughout Childhood following Serogroup C Meningococcal Conjugate Vaccination in Early Childhood

The objectives of this study were to evaluate the kinetics of antibody decline through childhood in a longitudinal study of a single cohort following serogroup C meningococcal (MenC) vaccine immunization in early childhood and to calculate the proportion of 11 to 13 year olds with protective levels of bactericidal antibody 10 years after immunization. United Kingdom children aged 11 to 13 years in 2010 who had previously taken part in a longitudinal study at the Oxford Vaccine Group had blood samples drawn between 2001 and 2010. Sera from each time point were analyzed for the MenC serum bactericidal antibody titer using a baby rabbit complement (rSBA) assay. The median age at MenC immunization was 21 months (range, 1 year 3 months to 3 years 9 months). The MenC rSBA geometric mean titer (GMT) at age 3.5 to 5 years was 8.0 (95% confidence interval, 6.5 to 9.9; n = 287). By age 11.5 to 13.5 years, the rSBA GMT had declined to 3.3 (2.5 to 4.4; n = 98). The percentage of children with rSBA titers of ≥1:8 (the threshold for protection) also declined from 38% (35% to 41%) to 15% (12% to 19%). We concluded that MenC rSBA titers wane rapidly following vaccination in early childhood and continue to decline into the second decade of life. Since nasopharyngeal colonization in adolescents probably provides the major reservoir for MenC in the population, declining immunity in this cohort is of concern. Sustaining high levels of antibody through booster vaccination in this cohort is likely necessary to avoid a resurgence of disease in the decade ahead.