Endogenous complement human serum bactericidal assay (enc-hSBA) for vaccine effectiveness assessments against meningococcal serogroup B.

Immunogenicity of vaccines against meningococcal serogroup B (MenB) has been assessed pre-licensure with a human serum bactericidal activity assay (hSBA), tested against small numbers of strains. We report the qualification/validation of an alternative qualitative hSBA which uses endogenous complement (enc-hSBA) present in the vaccinee's serum. Serum samples were collected from adults pre-vaccination and post-vaccination with the 4-component MenB vaccine (4CMenB). A representative panel of invasive isolates and 4 antigen-specific indicator strains were used in qualification experiments. Each strain was tested in ≥3 experiments with pre/post-vaccination sera to evaluate intermediate precision. A 110-strain panel and the 4 indicator strains met qualification criteria, demonstrating assay precision. Assay robustness, specificity and sensitivity were demonstrated using the 4 indicator strains. Enc-hSBA is highly standardized, allows testing across large panels of epidemiologically-relevant MenB strains, and accounts for complement activity differences between vaccinees. Therefore, enc-hSBA enables a more accurate estimation of effectiveness for vaccines against MenB.

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.

BACKGROUND: University 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. METHODS: Immunogenicity 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. RESULTS: All 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. CONCLUSIONS: 4CMenB and MenACWY-CRM were both highly immunogenic. There was no correlation between carriage and post-vaccination hSBA titers.

Pooled-sera hSBA titres predict individual seroprotection in infants and toddlers vaccinated with 4CMenB.

UNLABELLED: The Serum Bactericidal Antibody assay with human complement (hSBA) using individual immune sera is a surrogate of protection for meningococcal vaccines. Strain coverage of 4CMenB, a licensed vaccine against serogroup B meningococcal (MenB) disease, has been extensively assessed in hSBA using pooled sera, directly or through the Meningococcal Antigen Typing System (MATS). The extent to which pooled-sera hSBA titres reflect individual protection is not yet fully understood. We analysed more than 17000 individual hSBA titres from infants and toddlers vaccinated with 4CMenB, pooled-serum hSBA titres from subsets therein and MATS data from a 40 strain panel representative of invasive MenB disease in England and Wales. Individual hSBA titres segregated in two normal distributions, respectively from responding and non-responding subjects (fit_model-data: r=0.996, p-values <0.05). No individual subject showed abnormally high titres compared to the distributions. Also, when sera from the same subjects were tested individually and in pool, pooled-sera titre and average of individual titres from the same group were substantially indistinguishable (r=0.97, p-value <<0.001). We identified a robust mathematical relationship between the mean of individual hSBA titres and the proportion of subjects achieving a protective titre (seroprotection rate, r=0.95, p-value <<0.001). Using this relation, the seroprotection rate in 15 groups of vaccinees tested against 11 diverse meningococcal isolates was accurately predicted by the hSBA titre of the respective pooled sera (average prediction error 9%). Finally, strains defined covered by MATS had on average 77% predicted seroprotection rate (interquartile range, IQR: 66-100%) and 39% for non-covered strains (IQR: 19-46%). We conclude that seroprotection rates in infants and toddlers vaccinated with 4CMenB can be accurately predicted by pooled-serum hSBA, and that strain coverage defined by MATS is associated with high seroprotection rates. SUMMARY: The Serum Bactericidal Antibody assay (SBA) from individual sera is a surrogate of protection for meningococcal vaccines. We show that SBA performed on pooled sera predicts individual protection.

Immunogenicity and safety of a multicomponent meningococcal serogroup B vaccine and a quadrivalent meningococcal CRM197 conjugate vaccine against serogroups A, C, W-135, and Y in adults who are at increased risk for occupational exposure to meningococcal isolates.

Laboratory staff who work with meningococcal isolates are at increased risk for developing invasive disease relative to the general population. This was the first study of laboratory workers who received both a conjugate vaccine against meningococcal serogroups A, C, W-135, and Y (Men ACWY-CRM, Menveo) and an investigational multicomponent vaccine against serogroup B containing factor H binding protein, neisserial adhesin A, Neisseria heparin binding antigen, and New Zealand strain outer membrane vesicles (4CMenB). Healthy adults (18 to 50 years of age) received three doses of 4CMenB at baseline, 2 months, and 6 months followed by a single dose of MenACWY-CRM 1 month later. Immunogenicity was assessed via serum bactericidal assay using human complement (hSBA) at 1 month postvaccination; solicited reactogenicity and adverse events were monitored. Fifty-four participants enrolled. Bactericidal immune responses were evident after each dose of 4CMenB, as assessed by hSBA geometric mean titers and percentages of subjects with hSBA titers of ≥4 against the test strains or a 4-fold rise in titer over baseline. At 1 month postvaccination, most MenACWY-CRM recipients had hSBA titers of ≥8 against serogroups A, C, W-135, and Y. Few participants discontinued due to an adverse event or vaccine reaction. Rates of solicited reactions were lower after MenACWY-CRM than after 4CMenB administration. Sequential administration of 4CMenB and MenACWY-CRM provided robust evidence of an immune response against serogroups A, B, C, W-135, and Y in laboratory workers routinely exposed to meningococcal isolates.