A Meningococcal Native Outer Membrane Vesicle Vaccine With Attenuated Endotoxin and Overexpressed Factor H Binding Protein Elicits Gonococcal Bactericidal Antibodies

Abstract

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.

Genetic Similarity of Gonococcal Homologs to Meningococcal Outer Membrane Proteins of Serogroup B Vaccine

“…It is worth noting that most OMV vaccines were produced by extraction of vesicles using detergents to remove endotoxin from lipopolysaccharides. This extraction method could lower the content of immunogenic proteins released in OMVs compared to detergent-free methods (55)(56)(57). Therefore, the protein composition isolated from OMVs may vary depending on the preparation process.…”

“…Interestingly, the vaccine antigen FHbp was found exclusively in detergent-free OMVs (30,56), which may explain its absence in the detergent-extracted OMVs (24,30,32,34) and underscores the importance of choosing proper laboratory methods in these investigations. In regard to cross-protection, one recent finding shows that a MenB vaccine made of native OMVs elicited gonococcal bactericidal antibodies in a mouse model (57).…”

Integrated Bioinformatic Analyses and Immune Characterization of New Neisseria gonorrhoeae Vaccine Antigens Expressed during Natural Mucosal Infection

“…However, periplasmic proteins may be partially surface-exposed and are present in (either naturally released by bacteria or induced) outer membrane vesicles (OMV). The meningococcal OMV-based vaccine Bexsero contains both OMPs and periplasmic proteins [92][93][94]; this vaccine has been recently shown to be partially protective against N. gonorrhoeae in vaccinated subjects and in animal models, likely attributable to conserved and cross-reactive antigens [36][37][38][39]. For the same reason, proteins predicted to be associated with the inner membrane but facing the periplasm could also be potential candidates.…”

“…Pre-clinical vaccine studies have been carried out in mouse models of immunization and infection [22,23] using classical surface-exposed antigens (for example, the highly conserved LOS epitope 2C7 [24], transferrin binding proteins (TbpA and TbpB) [25,26]), conserved and/or variable proteins (reviewed in Reference [2]) identified by conventional screenings, reverse vaccinology (initially developed for the Neisseria meningitidis serogroup B vaccine 4CMenB [27,28]), "omics" and bioinformatics [29][30][31][32][33][34][35]. Interest in outer membrane vesicles (OMVs) has been recently renewed by evidence of cross-reactive protection against N. gonorrhoeae by a meningococcal OMV-based vaccine [36][37][38][39]. However, evaluation of gonococcal vaccines is complicated by the lack of known correlates of protection against natural mucosal infections in humans [2].…”

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

“…MenA, W, and Y hSBA titers ≥4 were ≥41% (95% [CI]: [34][35][36][37][38][39][40][41][42][43][44][45][46][47][48][49] and ≥37% (95% CI 24-51) in the MenACWY-TT and MenC-CRM 197 groups, respectively. One-month post-booster with the ACWY-TT vaccine, rSBA GMT against the four serogroups increased ≥42-fold.…”