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.

Keywords: MenACWY-TT; Meningococcal vaccine; complement; immunogenicity; serum bactericidal antibody assay.

Figure 1.

Schematic illustrating serum bactericidal antibody assay using either human or baby rabbit complement. For serogroups A and C, the World Health Organization guidelines stipulate that complement sourced from baby rabbits should be used.²⁴ For the subject shown, the SBA titer would be 8. SBA = serum bactericidal antibody. Figure has been adapted with permission from Gandhi A, Balmer P, York LJ. Characteristics of a new meningococcal serogroup B vaccine, bivalent rLP2086 (MenB-FHbp; Trumenba®). Postgrad Med. 2016;128(6):548–556.

Figure 2.

Percentages of infants/toddlers with rSBA titers ≥8 or hSBA titers ≥4 for serogroups A, C, W, and Y at various time points after vaccination with either 3 primary doses of MenACWY-TT (at 2, 4, and 6 months of age) followed by a booster dose at 15–18 months of age (3 + 1 schedule) or 1 primary dose of MenACWY-TT at 6 months of age followed by a booster dose at 15–18 months of age (1 + 1 schedule). Data are plotted as percentages along with 95% CIs. hSBA = serum bactericidal antibody assay using human complement; MenACWY-TT = meningococcal serogroups A, C, W, and Y conjugate vaccine using tetanus toxoid as a carrier protein; rSBA = serum bactericidal antibody assay using rabbit complement. Data are from Dbaibo G, Tinoco Favila JC, Traskine M, Jastorff A, Van der Wielen M. Immunogenicity and safety of MenACWY-TT, a meningococcal conjugate vaccine, co-administered with routine childhood vaccine in healthy infants: a phase III, randomized study. Vaccine. 2018;36(28):4102–4111.

Figure 3.

Percentages of toddlers with rSBA titers ≥8 or hSBA titers ≥4 for serogroups A, C, W, and Y at various time points before or after vaccination with 1 dose of MenACWY-TT at 12 to 23 months of age. Data are plotted as percentages along with 95% CIs. hSBA = serum bactericidal antibody assay using human complement; MenACWY-TT = meningococcal serogroups A, C, W, and Y conjugate vaccine using tetanus toxoid as a carrier protein; pre = prevaccination; rSBA = serum bactericidal antibody assay using rabbit complement. Data are from Vesikari T, Forsten A, Boutriau D, Bianco V, Van der Wielen M, Miller JM. Randomized trial to assess the immunogenicity, safety and antibody persistence up to three years after a single dose of a tetravalent meningococcal serogroups A, C, W-135 and Y tetanus toxoid conjugate vaccine in toddlers. Hum Vaccin Immunother. 2012;8(12):1892–1903.