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.

Naturally Acquired Passive Protective Activity against Neisseria meningitidis Group C in the Absence of Serum Bactericidal Activity

“…Estimates of vaccine efficacy are Ͼ90 percent in all age groups targeted for immunization (1). The high efficacy is particularly striking in infants and toddlers, the age groups at highest risk of acquiring meningococcal disease and in whom peak titers of bactericidal antibodies in serum present 1 month after vaccination decline to low or undetectable levels by 7 to 9 months after vaccination (1).…”

“…However, the interpretation of a bactericidal titer of Ͻ1:4 as an indication of susceptibility is more problematic, and some have questioned whether the proportion of persons with titers below this threshold overestimates the size of the susceptible population (1).…”

“…There is a strong scientific basis for inferring meningococcal vaccine efficacy from immunogenicity data (3,10,11). However, the choice of in vitro assay conditions and serologic endpoints for inferring protection against meningococcal disease are topics of considerable recent debate (1,3,16,32). The reasons are complex but ultimately have to do with the effects of potential disparities between in vitro antibody functional assay conditions and in vivo host defenses.…”

“…The low incidence of meningococcal disease in these populations precludes performing prospective randomized clinical trials to determine the efficacy of these new vaccines. Vaccine efficacy, therefore, will be inferred from immunogenicity data (3), and vaccine effectiveness will be confirmed in subsequent postlicensure studies (1), following a licensure pathway and monitoring strategies adapted in the United Kingdom for the introduction of group C meningococcal conjugate vaccines. There is a strong scientific basis for inferring meningococcal vaccine efficacy from immunogenicity data (3,10,11).…”

Is a single infant priming dose of meningococcal serogroup C conjugate vaccine in the United Kingdom sufficient?

“…At both time points, 98% of subjects achieved an SBA titre of 8, the titer considered to be protective. 7 A rapid decline in antibody levels following the 3 infant doses to the second year of life was observed, however immunological memory was demonstrated with amamnestic responses seen following polysaccharide challenge. 5,8 The observed decline in vaccine effectiveness more than 12 months post-vaccination is consistent with measured declining SBA levels.…”