MenC Serum Bactericidal Antibody Research Articles

Meningococcal serogroup C immunogenicity, antibody persistence and memory B-cells induced by the monovalent meningococcal serogroup C versus quadrivalent meningococcal serogroup ACWY conjugate booster vaccine: A randomized controlled trial

Adolescents are considered the key transmitters of meningococci in the population. Meningococcal serogroup C (MenC) antibody levels wane rapidly after MenC conjugate vaccination in young children, leaving adolescents with low antibody levels. In this study, we compared MenC immune responses after booster vaccination in adolescence with either tetanus toxoid conjugated MenC (MenC-TT) or MenACWY (MenACWY-TT) vaccine, and aimed to establish an optimal age for this booster. Healthy 10-, 12-, and 15-year-olds, who received a single dose of MenC-TT vaccine in early childhood, were randomized to receive MenC-TT or MenACWY-TT vaccine. MenC serum bactericidal antibody (rSBA) titers, MenC polysaccharide (PS) specific IgG, IgG1 and IgG2 and MenC-specific IgG and IgA memory B-cells were determined before, one month and one year after the booster. Non-inferiority was tested by comparing geometric mean titers (GMTs) between vaccinees at one year. Of 501 participants, 464 (92.6%) were included in the 'according to protocol' cohort analysis. At one month, all participants developed high MenC rSBA titers (>24,000 in all groups) and MenC-PS-specific IgG levels. Non-inferiority was not demonstrated one year after the booster with higher MenC GMTs after the monovalent vaccine, but 462/464 (99.6%) participants maintained protective MenC rSBA titers. IgG levels mainly consisted of IgG1, but similar levels of increase were observed for IgG1 and IgG2. Both vaccines induced a clear increase in the number of circulating MenC-PS specific IgG and IgA memory B-cells. Between one month and one year, the highest antibody decay rate was observed in the 10-year-olds. Both MenC-TT and MenACWY-TT vaccines induced robust protective MenC immune responses after the booster vaccination, although non-inferiority could not be demonstrated for the MenACWY-TT vaccine after one year. Our results underline the importance of optimal timing of a meningococcal booster vaccination to protect against MenC disease in the long-term.

Use of a booster dose of capsular group C meningococcal glycoconjugate vaccine to demonstrate immunologic memory in children primed with one or two vaccine doses in infancy

BackgroundUse of a polysaccharide vaccine challenge to demonstrate immunologic memory after priming with capsular group C meningococcal conjugate vaccines (MenCC) risks induction of immunologic hyporesponsiveness. For this reason, MenCC vaccines are now used as probes of immunologic memory, however, no studies have demonstrated their ability to distinguish primed from unprimed children. MethodsThis study was part of a randomised controlled trial investigating the immunogenicity of a booster dose of the combined Haemophilus influenzae type b and MenC-tetanus toxoid vaccine (Hib-MenC-TT) in infants receiving reduced dose MenCC vaccine priming schedules (one MenC-CRM/MenC-TT or two MenC-CRM vaccine doses) compared with an unprimed group. Antibody kinetics were studied in a subset of 269 children by measuring changes in the MenC serum bactericidal antibody, using rabbit complement, (MenC rSBA) titres and MenC specific IgG memory B-cells before and at 6 and 28days following the 12month booster vaccination. ResultsAt 6days after the 12monthMenCC vaccine, the rise in MenC rSBA titres and MenC specific IgG memory B-cells of the primed groups were significantly higher than the infant MenCC naïve group. Participants primed with one MenC-TT dose had the highest increase in MenC rSBA titres compared with all other groups. The MenC rSBA titres at the 28th compared with the 6th day after boosting was significantly higher in those primed with a single MenC-TT/MenC-CRM vaccine in infancy compared with those who were not primed or who were primed with two doses of the MenC-CRM vaccine. ConclusionImmunologic memory can be demonstrated by a MenCC booster vaccination but is affected by the type and number of MenCC doses used for infant priming. The MenC rSBA responses can be used to demonstrate successful immunologic priming.

Immunogenicity of reduced dose priming schedules of serogroup C meningococcal conjugate vaccine followed by booster at 12 months in infants: open label randomised controlled trial

Objective To determine whether the immunogenicity of a single dose infant priming schedule of serogroup C meningococcal (MenC) conjugate vaccine is non-inferior to a two dose priming schedule when followed...

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.

Interchangeability of meningococcal group C conjugate vaccines with different carrier proteins in the United Kingdom infant immunisation schedule

An open, non-randomised study was undertaken in England during 2011–12 to evaluate vaccine antibody responses in infants after completion of the routine primary infant immunisation schedule, which included two doses of meningococcal group C (MenC) conjugate (MCC) vaccine at 3 and 4 months. Any of the three licensed MCC vaccines could be used for either dose, depending on local availability. Healthy term infants registered at participating general practices (GPs) in Hertfordshire and Gloucestershire, UK, were recruited prospectively to provide a single blood sample four weeks after primary immunisation, which was administered by the GP surgery. Vaccination history was obtained at blood sampling. MenC serum bactericidal antibody (SBA) and IgG antibodies against Haemophilus influenzae b (Hib), pertussis toxin (PT), diphtheria toxoid (DT), tetanus toxoid (TT) and thirteen pneumococcal serotypes were analysed according to MCC vaccines received. MenC SBA responses differed significantly (P<0.001) according to MCC vaccine schedule as follows: MenC SBA geometric mean titres (GMTs) were significantly lower in infants receiving a diphtheria cross-reacting material-conjugated MCC (MCC-CRM) vaccine followed by TT-conjugated MCC (MCC-TT) vaccine (82.0; 95% CI, 39–173; n=14) compared to those receiving two MCC-CRM (418; 95% CI, 325–537; n=82), two MCC-TT (277; 95% CI, 223–344; n=79) or MCC-TT followed by MCC-CRM (553; 95% CI, 322–949; n=18). The same group also had the lowest Hib geometric mean concentrations (0.60μg/mL, 0.27–1.34) compared to 1.85μg/mL (1.23–2.78), 2.86μg/mL (2.02–4.05) and 4.26μg/mL (1.94–9.36), respectively. Our results indicate that MCC vaccines with different carrier proteins are not interchangeable. When several MCC vaccines are available, children requiring more than one dose should receive MCC vaccines with the same carrier protein or, alternatively, receive MCC-TT first wherever possible.

Evaluation of the safety and immunogenicity in United Kingdom laboratory workers of a combined Haemophilus influenzae type b and meningococcal capsular group C conjugate vaccine.

BackgroundAlthough a combined Haemophilus influenzae type b (Hib)/meningococcal capsular group C (MenC) conjugate vaccine with a tetanus toxoid carrier protein (Hib/MenC-TT) is not licensed for use in those above 2 years of age due to lack of data on safety and efficacy, certain patient groups at high risk of MenC and/or Hib disease are recommended to receive it. Laboratory workers working with Hib and/or MenC cultures may be at a potentially increased risk of acquiring infectious diseases and vaccination is therefore an important safety consideration. We undertook a clinical trial to investigate the safety and immunogenicity of Hib/MenC-TT vaccine in this cohort.MethodsA total of 33 subjects were recruited to the trial, all of whom were vaccinated. Serology was completed on samples taken at baseline and four weeks following vaccination to determine MenC specific IgG, MenC serum bactericidal antibody (SBA), anti-Hib polyribosylribitol phosphate (PRP) IgG and anti-tetanus toxoid IgG responses.ResultsAt baseline, high proportions of subjects had protective antibody concentrations against MenC, Hib and tetanus due to previous vaccination and/or natural exposure. Vaccination induced > 3, 10 and 220 fold increases in geometric mean concentrations for MenC SBA, anti-tetanus toxoid IgG and anti-Hib PRP IgG, respectively. Following vaccination, 97% of subjects had putative protective SBA titres ≥ 8, 100% had short term protective anti-Hib PRP IgG concentrations ≥ 0.15 μg/mL and 97% had protective anti-tetanus toxoid concentrations ≥ 0.1 IU/mL. No safety concerns were reported with minor local reactions being reported by 21% of subjects.ConclusionsImmunological responses determined in this trial are likely a combination of primary and secondary responses due to previous vaccination and natural exposure. Subjects were a representative cross-section of laboratory workers, enabling us to conclude that a single dose of Hib/MenC-TT was safe and immunogenic in healthy adults providing the evidence that this vaccine may be used for providing protection in an occupational setting.

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...

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.

Effect of Increased CRM197Carrier Protein Dose on Meningococcal C Bactericidal Antibody Response

New multivalent CRM(197)-based conjugate vaccines are available for childhood immunization. Clinical studies were reviewed to assess meningococcal group C (MenC) antibody responses following MenC-CRM(197) coadministration with CRM(197)-based pneumococcal or Haemophilus influenzae type b conjugate vaccines. Infants receiving a total CRM(197) carrier protein dose of ∼50 μg and concomitant diphtheria-tetanus-acellular pertussis (DTaP)-containing vaccine tended to have lower MenC geometric mean antibody titers and continued to have low titers after the toddler dose. Nevertheless, at least 95% of children in the reported studies achieved a MenC serum bactericidal antibody (SBA) titer of ≥ 1:8 after the last infant or toddler dose. SBA was measured using an assay with a baby rabbit or human complement source. Additional studies are needed to assess long-term antibody persistence and MenC CRM(197) conjugate vaccine immunogenicity using alternative dosing schedules.

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.

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.

Serum Antibody Kinetics following Nasal or Parenteral Challenge with Meningococcal Polysaccharide in Healthy Adults

Limited data are available on the kinetics of meningococcal serogroup C (MenC)-specific antibody responses following parenteral or nasal challenge in those who have received prior MenC vaccination (polysaccharide or conjugate). Young adults who had previously received either meningococcal A/C polysaccharide (MACP) or MenC conjugate (MCC) vaccine or naïve subjects were challenged with MACP via one of two routes, nasal or parenteral. Blood samples were taken prevaccination and on days 1 to 4 and day 10 postvaccination. MenC serum bactericidal antibody (SBA) and MenC-specific IgG were measured. Following parenteral challenge, MenC SBA and IgG responses were seen to occur between 4 and 7 days postchallenge. A lower proportion of subjects responded following nasal challenge, with naïve subjects showing little change in SBA geometric mean titer (GMT) and IgG geometric mean concentration (GMC) over the 10 days following challenge. Increases in SBA GMTs were seen between 4 and 7 days after nasal challenge in those who had received prior MCC and between 7 and 10 days in those who had received prior MACP, and the responses in the prior-MACP group were of lower magnitude than the responses of the prior-MCC group. The data presented here indicate that, following MCC vaccination, memory has been induced at the mucosal level, and these subjects were able to respond with increases in SBA levels. These results demonstrate that the speed of response (primary or secondary) to challenge with MenC polysaccharide via the nasal or parenteral route does not differ and support concerns that immunological memory alone is too slow to provide protection.