Multi-component meningococcal serogroup B (MenB)-4C vaccine induces effective opsonophagocytic killing in children with a complement deficiency

Abstract

Vaccination against meningococcal serogroup B is recommended for patients with a complement deficiency; however, although immunogenicity in this patient group has been shown, efficacy has not yet been established. In this study, we collected serum from children with a complement deficiency in the alternative pathway or in late terminal pathway before and after vaccination with multi-component meningococcal serogroup B (MenB)-4C. MenB-4C is a multi-component, protein-based vaccine against MenB consisting of factor H-binding protein, Neisserial heparin-binding protein, Neisserial adhesion A and outer membrane vesicles containing Porin A. We assessed the vaccine immunogenicity and vaccine-mediated protection by a whole cell enzyme-linked immunosorbent assay with Neisseria meningitidis serogroup B strains H44/76, 5/99 and NZ98/254, which shows that vaccination induced antibody titers against meningococcus. We show that the classical serum bactericidal activity assay with exogenous serum indicates the presence of vaccine-induced antibodies and capacity to activate complement-mediated pathogen lysis. However, in children with a late terminal pathway deficiency, no complement-mediated pathogen lysis was observed when autologous serum was applied in the serum bactericidal activity assay, demonstrating a lack of serum bactericidal activity in children with complement deficiencies. However, MenB-4C vaccination still induced effective complement-dependent opsonophagocytic killing against N. meningitidis serogroup B in reconstituted whole blood with autologous serum from children with an alternative pathway or late terminal pathway deficiency. These findings support the recommendation to vaccinate all complement-deficient children against MenB.

Keywords: Neisseria meningitidis; MenB-4C; children; complement-deficient; vaccine.

Figure 1

Multi‐component meningococcal serogroup B (MenB)‐4C vaccine responses of sera from complement‐deficient patients or controls assessed by whole cell total immunoglobulin (Ig)G enzyme‐linked immunosorbent assay (ELISA). Sera were collected from three patients with a late terminal complement pathway (LTP def.); C6 deficiency (○) or C8 deficiency (Δ and □) or two patients with alternative pathway deficiency (AP def.); factor I deficiency (○) or factor D deficiency (□) before (filled symbols) and after (open symbols) vaccination with MenB‐4C. The sera were assessed for the presence of antibodies against Neisseria meningitides serotype B strain H44/76, 5/99 and NZ98/254 by whole cell total IgG ELISA. Each of these strains express at least one of the antigens in the MenB‐4C vaccine. Results with a P‐value of < 0·05 were considered significant and are marked with an asterisk. Pre‐vaccination titers were compared between groups. The same was performed for post‐vaccination titers.

Figure 2

Exogenous human complement source serum bactericidal activity assay with sera from complement‐deficient patients or controls. Sera were collected from three patients with a late terminal complement pathway (LTP def.); C6 deficiency (○) or C8 deficiency (Δ and □) or two patients with alternative pathway deficiency (AP def.); factor I deficiency (○) or factor D deficiency (□) before (filled symbols) and after (open symbols) vaccination with multi‐component meningococcal serogroup B (MenB)‐4C. Classical serum bactericidal activity assay with exogenous human serum was determined (a). Serum bactericidal activity assay with autologous human serum was determined (b). Titers were based on the initial serum dilution that showed 90% or more killing. Results with a P‐value of < 0·05 were considered significant and are marked with an asterisk. Pre‐vaccination titers were compared between groups. The same was performed for post‐vaccination titers.

Figure 3

Bacterial survival in reconstituted whole blood with sera from complement‐deficient patients or controls. Sera were collected from three patients with a late terminal complement pathway (LTP def.); C6 deficiency (○) or C8 deficiency (Δ and □) or two patients with alternative pathway deficiency (AP def.); factor I deficiency (○) or factor D deficiency (□) before (filled symbols) and after (open symbols) vaccination with multi‐component meningococcal serogroup B (MenB)‐4C. Clearance of the bacterium in whole blood reconstituted with patient sera (a) or heat‐inactivated patient sera (b) was determined. Results with a P‐value of < 0·05 were considered significant and are marked with an asterisk. Pre‐vaccination titers were compared between groups. The same was performed for post‐vaccination titers.

Figure 4

Schematic presentation of the differences between the assays used.