A review of complement sources used in serum bactericidal assays for evaluating immune responses to meningococcal ACWY conjugate vaccines

Abstract

Invasive meningococcal disease is rare and potentially devastating but often vaccine-preventable. Evaluation of meningococcal vaccine effectiveness is impractical owing to relatively low disease incidence; protection is therefore estimated using serum bactericidal antibody (SBA) assays. Original experiments on natural immunity established a titer of ≥4 as the correlate of protection for SBA assays using human complement (hSBA), but human complement is relatively difficult to obtain and standardize. Use of baby rabbit complement (rSBA assays), per standard guidelines for serogroups A and C, generally results in comparatively higher titers. Postlicensure effectiveness data for serogroup C conjugate vaccines support acceptance of rSBA titers ≥8 as the correlate of protection for this serogroup, but no thresholds have been formally established for serogroups A, W, and Y. Studies evaluating MenACWY-TT (Nimenrix®; Pfizer Inc, Sandwich, UK) immunogenicity have used both hSBA and rSBA assays, and ultimately suggest that rSBA may be more appropriate for these measurements.

Immunogenicity and safety of a quadrivalent meningococcal tetanus toxoid-conjugate vaccine (MenACYW-TT) in healthy toddlers: a Phase II randomized study

“…21 Both SBA assays and GMTs were used due to differing preferences globally for licensing data; the first MCV4 was licensed by the US Food and Drug Administration in 2005 based on rSBA assay data, 16,22 however, in Europe, MCV4-CRM was licensed in 2009 on the basis of hSBA assay data, with some rSBA assay data in the assessment report, 16,23 whilst MCV4-TT in 2012 relied primarily on rSBA assay results, with some hSBA assay data. 16,24 All participants in both groups had seroprotective levels of tetanus toxoid antibody concentrations at baseline. Anti-tetanus antibody GMCs increased in both vaccine groups, albeit with numerically higher responses in the MenACYW-TT group, consistent with a higher tetanus toxoid concentration in this vaccine.…”

“…This Phase II study was conducted to evaluate the immunogenicity and safety of MenACYW-TT compared with the licensed vaccine MCV4-TT, in healthy toddlers, using both human complement (hSBA) and baby rabbit complement (rSBA) serum bactericidal antibody assays. hSBA titers ≥4 are an accepted surrogate of protection against serogroups A and C. 15 However, assays using rSBA complement have been used as the basis for licensure of most meningococcal vaccines, with data supporting the acceptance of rSBA titers ≥8 as the correlate of protection against serogroup C. 16…”

Antibody persistence following meningococcal ACWY conjugate vaccine licensed in the European Union by age group and vaccine

“…Meningococcal factor H binding protein may help to explain the difference [21,22]. Factor H binding protein prevents complement-mediated killing [23].…”

“…A series of studies observed that the hSBA but not rSBA titers decreased rapidly post-vaccination, especially serogroup A [24][25][26][27], suggesting that hSBA may underestimate immune response to MenACWY-TT [23]. hSBA assays may also suggest lower initial immune response to serogroup W and Y than rSBA assays, especially for toddlers receiving one dose of vaccine [23,[26][27][28]. However, hSBA titers increased at later time points despite no additional booster doses.…”

“…rSBA titers had the opposite results compared with the result of hSBA titers, as they were high post-primary vaccination and declined over time. Thus, rSBA assays seem to be a more appropriate method to measure antibody persistence and immunogenicity in terms of MenACWY-TT, especially for serogroup A [23,25,26,28,29].…”