Immunogenicity and safety of a quadrivalent meningococcal tetanus toxoid-conjugate vaccine (MenACYW-TT) vs. a licensed quadrivalent meningococcal tetanus toxoid-conjugate vaccine in meningococcal vaccine-naïve and meningococcal C conjugate vaccine-primed toddlers: a phase III randomised study

Vaccination remains the best strategy to reduce invasive meningococcal disease. This study evaluated an investigational tetanus toxoid-conjugate quadrivalent meningococcal vaccine (MenACYW-TT) vs. a licensed tetanus toxoid-conjugate quadrivalent meningococcal vaccine (MCV4-TT) (NCT02955797). Healthy toddlers aged 12–23 months were included if they were either meningococcal vaccine-naïve or MenC conjugate (MCC) vaccine-primed (≥1 dose of MCC prior to 12 months of age). Vaccine-naïve participants were randomised 1:1 to either MenACYW-TT (n = 306) or MCV4-TT (n = 306). MCC-primed participants were randomised 2:1 to MenACYW-TT (n = 203) or MCV4-TT (n = 103). Antibody titres against each of the four meningococcal serogroups were measured by serum bactericidal antibody assay using the human complement. The co-primary objectives of this study were to demonstrate the non-inferiority of MenACYW-TT to MCV4-TT in terms of seroprotection (titres ≥1:8) at Day 30 in both vaccine-naïve and all participants (vaccine-naïve and MCC-primed groups pooled). The immune response for all four serogroups to MenACYW-TT was non-inferior to MCV4-TT in vaccine-naïve participants (seroprotection: range 83.6–99.3% and 81.4–91.6%, respectively) and all participants (seroprotection: range 83.6–99.3% and 81.4–98.0%, respectively). The safety profiles of both vaccines were comparable. MenACYW-TT was well-tolerated and demonstrated non-inferior immunogenicity when administered to MCC vaccine-primed and vaccine-naïve toddlers.

Immune Responses in U.S. Military Personnel Who Received Meningococcal Conjugate Vaccine (MenACWY) Concomitantly with Other Vaccines Were Higher than in Personnel Who Received MenACWY Alone

ABSTRACTImmunological responses to vaccination can differ depending on whether the vaccine is given alone or with other vaccines. This study was a retrospective evaluation of the immunogenicity of a tetravalent meningococcal conjugate vaccine for serogroups A, C, W, and Y (MenACWY) administered alone (n= 41) or concomitantly with other vaccines (n= 279) to U.S. military personnel (mean age, 21.6 years) entering the military between 2006 and 2008. Concomitant vaccines included tetanus/diphtheria (Td), inactivated polio vaccine (IPV), hepatitis vaccines, and various influenza vaccines, among others; two vaccine groups excluded Tdap and IPV. Immune responses were evaluated in baseline and postvaccination sera forNeisseria meningitidisserogroups C and Y 1 to 12 months (mean, 4.96 months) following vaccination. Functional antibodies were measured by using a serum bactericidal antibody assay with rabbit complement (rSBA) and by measurement of serogroup-specific immunoglobulin G (IgG) antibodies. The percentage of vaccinees reaching threshold levels (IgG concentration in serum, ≥2 μg/ml; rSBA titer, ≥8) corresponding to an immunologic response was higher postvaccination than at baseline (P< 0.001). Administration of MenACWY along with other vaccines was associated with higher geometric means of IgG concentrations and rSBA titers than those measured 4.60 months after a single dose of MenACWY. In addition, higher percentages of vaccinees reached the immunological threshold (range of odds ratios [ORs], 1.5 to 21.7) and more of them seroconverted (OR range, 1.8 to 4.8) when MenACWY was administered with any other vaccine than when administered alone. Additional prospective randomized clinical trials are needed to confirm the observed differences among groups in the immune response to MenACWY when given concomitantly with other vaccines to U.S. military personnel.

Comparison of Phenotypically Indistinguishable but Geographically Distinct Neisseria meningitidis Group B Isolates in a Serum Bactericidal Antibody Assay

ABSTRACT The “gold standard” assay for measuring serologic protection against Neisseria meningitidis group B (MenB) is the serum bactericidal antibody (SBA) assay. Of vital importance to the outcome of the SBA assay is the choice of the target strain(s), which is often chosen on the basis of phenotype or genotype. We therefore investigated the effect on the results produced by the SBA assay of using phenotypically indistinguishable but geographically distinct MenB isolates. Nine PorA P1.19,15 and 11 PorA P1.7-2,4 MenB isolates were incorporated into the SBA assay using human complement and were assayed against sera obtained either before or after outer membrane vesicle vaccination. Large differences in the results produced by the isolates in the SBA assay were demonstrated. These included differences as great as 5.8-fold in SBA geometric mean titers and in the proportions of subjects with SBA titers of ≥4. Ranges of as many as 9 SBA titers were achieved by individual sera across the panels of isolates. To determine the reasons for the differences observed, investigations into the expression of capsular polysaccharide, PorA, PorB, Opc, and lipooligosaccharide (LOS) and into LOS sialylation were completed. However, minor differences were found between strains, indicating similar expression and no antigen masking. These results have implications for the choice of MenB target strains for inclusion in future studies of MenB vaccines and highlight the requirement for standardization of target strains between laboratories.

Inadequacy of Colominic Acid as an Absorbent Intended To Facilitate Use of Complement-Preserved Baby Rabbit Serum in the Neisseria meningitidis Serogroup B Serum Bactericidal Antibody Assay

ABSTRACT The surrogate of protection against Neisseria meningitidis serogroup B (MenB) is the serum bactericidal antibody (SBA) assay, which measures the functional activity of antibody by using an exogenous complement source. Despite baby rabbit complement having been used in meningococcal serogroup A, C, Y, and W135 SBA assays, it is not recommended for use in the MenB SBA assay due to elevated SBA titers caused by low-avidity anti-MenB capsular antibody in test sera. Therefore, the possibility of absorbing anti-MenB capsular antibody from test sera to enable the use of baby rabbit complement in the MenB SBA assay was investigated by comparing the results with those gained using human complement. Colominic acid from Escherichia coli K1, which shares the same linkage residue as MenB polysaccharide, was used as an absorbent due to the commercial unavailability of purified MenB polysaccharide. Inclusion of soluble colominic acid as an absorbent with baby rabbit complement resulted in a general reduction in SBA titers compared with those obtained using baby rabbit complement alone. However, these were not comparable to human SBA titers for all samples. Further optimization and investigations demonstrated that for some samples, colominic acid reduced titers to less than those achieved with human complement, and for others, it was not possible to inhibit titers by using colominic acid. The results suggested that the use of colominic acid will not result in the ability to use baby rabbit complement in the MenB SBA assay, thus not alleviating the difficulties in procuring human complement. However, alternative absorbents, such as purified MenB polysaccharide, may warrant further evaluation.

Immunoglobulin G Subclass Response to a Meningococcal Quadrivalent Polysaccharide-Diphtheria Toxoid Conjugate Vaccine

ABSTRACT Changes in the immunoglobulin G1 (IgG1)/IgG2 ratio following vaccination can indicate the activation of cellular control mechanisms typical of a T-cell-dependent response. We examined IgG subclass ratios in 17 healthy adults (26 to 55 years of age) before and 4 to 6 weeks following immunization with a quadrivalent meningococcal-polysaccharide diphtheria toxoid conjugate vaccine against serogroups A, C, Y, and W135. Serologic responses were determined by serum bactericidal antibody assay and serogroup-specific IgG, IgG1, and IgG2 enzyme-linked immunosorbent assay. Prevaccination serogroup A-specific IgG1/IgG2 ratios were <1 for all subjects and differed by subject for C, Y, and W-135. Postvaccination, significant increases in IgG, IgG1, and IgG2, were observed for all serogroups. Serogroup-specific IgG1/IgG2 ratios increased for group A (14/17 subjects, 88%), decreased in more than half of subjects for groups C (9/17, 53%) and W135 (12/17, 71%) and decreased for serogroup Y (16/17, 94%). IgG1/IgG2 ratios differed between individual vaccinees and were similar to the responses of adults who received pneumococcal conjugate vaccines or a monovalent C conjugate vaccine. Further studies on IgG subclasses following meningococcal polysaccharide and conjugate vaccination are needed.

Validation of Serological Correlate of Protection for Meningococcal C Conjugate Vaccine by Using Efficacy Estimates from Postlicensure Surveillance in England

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