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 withNeisseria 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.

Neisseria meningitidis Serogroup Z Meningitis in a Child With Complement C8 Deficiency and Potential Cross Protection of the MenB-4C Vaccine

“…Increased whole blood killing of N. meningitidis serogroup Z was observed after MenB-4C vaccination, which is consistent with previous results with N. meningitidis serogroup B. 8 This indicates that there is cross protection that results in increased clearance of the bacterium (Fig. 1E).…”

Alternative Complement Pathway Inhibition Abrogates Pneumococcal Opsonophagocytosis in Vaccine-Naïve, but Not in Vaccinated Individuals

“…To address this, we compared two physiologic opsonophagocytosis assays adapted from recently published methods. A hirudin-anticoagulated whole blood assay ( 49 ) was directly compared to an assay based on cells from EDTA-anticoagulated blood, where plasma was removed, cells were washed and supplemented with active serum ( 50 ). The two assays yielded highly comparable results, with both assays demonstrating the relative importance of antibodies and of AP and CP activation for opsonophagocytic killing of pneumococci.…”

“…Focusing on isolated cell types, however, reduces the complexity found within whole blood and affects the biological properties of the investigated cell types ( 48 ). Recently, more physiological methods to study complement-mediated opsonophagocytosis of bacteria have been reported that circumvent these limitations ( 49 , 50 ). Hirudin-anticoagulated whole blood – by irreversible direct thrombin inhibition ( 51 ) – can be directly deployed for opsonophagocytosis assays after venous puncture.…”

“…Hirudin is used to replace lepirudin ( 52 , 53 ), which has been withdrawn from the market. Another physiological assay makes use of cells from ethylenediamine tetraacetic acid (EDTA)-anticoagulated whole blood, which are washed and reconstituted with active serum and Ca 2+ and Mg 2+ to override the effect of chelating bivalent cations by EDTA ( 50 ), which interferes with complement activation ( Figure 1B ) ( 49 ). Here we compared results obtained with these two physiological opsonophagocytosis assays and investigated the relative contribution of opsonisation by antibodies, classical, lectin, alternative and terminal complement pathways to pneumococcal opsonophagocytosis.…”

Evaluating Functional Immunity Following Encapsulated Bacterial Infection and Vaccination

“…Since SBA relies exclusively on complement-mediated killing, studies in children and adults with primary terminal complement deficiencies found no serum bactericidal activity against MenB. However, complement-dependent opsonophagocytic killing was still detectable in these individuals, suggesting that they might still be protected following vaccination [38,42]. Measurement of this immune mechanism in this immunocompromised cohort may also be relevant to vaccines against other bacterial pathogens.…”