A GMMA vaccine produced from a recombinant African N. meningitidis W strain with deleted capsule locus, lpxL1, gna33 and overexpressed fHbp v.1 has potential as an affordable vaccine with broad coverage against strains from all main serogroups currently causing meningococcal meningitis in sub-Saharan Africa.

Background. Meningococcal outer membrane vesicle (OMV) vaccines are prepared with detergents to remove endotoxin, which also remove desirable antigens such as factor H binding protein (FHbp). Native OMV (NOMV) vaccines with genetically attenuated endotoxin do not require detergent treatment and elicit broader serum bactericidal antibody (SBA) responses than OMV or recombinant FHbp (rFHbp) vaccines.Methods. We measured human complement-mediated SBA responses in mice immunized with NOMV with overexpressed FHbp subfamily B (NOMV-FHbp), NOMV with FHbp genetically inactivated (NOMV-KO), and/or a control rFHbp vaccine against meningococcal and gonococcal strains.Results. Despite having 36-fold less FHbp per dose, the NOMV-FHbp vaccine elicited a ≥3-fold higher serum IgG anti-FHbp geometric mean titer than control vaccines containing rFHbp (P ≤ .003). Against 2 meningococcal outbreak strains with mismatched PorA and heterologous FHbp subfamily B sequence variants, the NOMV-FHbp vaccine produced ≥30-fold higher SBA titers than control vaccines. Mice immunized with NOMV-FHbp and NOMV-KO vaccines also elicited SBA against a gonococcal strain (P < .0001 vs the adjuvant-only control group). In contrast, 2 licensed meningococcal serogroup B vaccines, including one containing detergent-extracted OMV, did not produce gonococcal SBA in humans.Conclusions. A meningococcal NOMV vaccine elicits SBA against gonococci and with overexpressed FHbp elicits SBA against meningococci.

Dysregulation of complement activation causes a number of diseases, including paroxysmal nocturnal hemoglobinuria and atypical hemolytic uremic syndrome. These conditions can be treated with monoclonal antibodies (mAbs) that bind to the complement component C5 and prevent formation of the membrane attack complex (MAC). While MAC is involved in uncontrolled lysis of erythrocytes in these patients, it is also required for serum bactericidal activity (SBA), i.e. clearance of encapsulated bacteria. Therefore, terminal complement blockage in these patients increases the risk of invasive disease by Neisseria meningitidis more than 1000-fold compared to the general population, despite obligatory vaccination. It is assumed that alternative instead of terminal pathway inhibition reduces the risk of meningococcal disease in vaccinated individuals. To address this, we investigated the SBA with alternative pathway inhibitors. Serum was collected from adults before and after vaccination with a meningococcal serogroup A, C, W, Y capsule conjugate vaccine and tested for meningococcal killing in the presence of factor B and D, C3, C5 and MASP-2 inhibitors. B meningococci were not included in this study since the immune response against protein-based vaccines is more complex. Unsurprisingly, inhibition of C5 abrogated killing of meningococci by all sera. In contrast, both factor B and D inhibitors affected meningococcal killing in sera from individuals with low, but not with high bactericidal anti-capsular titers. While the anti-MASP-2 mAb did not impair SBA, inhibition of C3 impeded meningococcal killing in most, but not in all sera. These data provide evidence that vaccination can provide protection against invasive meningococcal disease in patients treated with alternative pathway inhibitors.