OpcA and PorB are novel bactericidal antigens of the 4CMenB vaccine in mice and humans

Abstract

The ability of Neisseria meningitidis Outer Membrane Vesicles (OMV) to induce protective responses in humans is well established and mainly attributed to Porin A (PorA). However, the contribution of additional protein antigens to protection remains to be elucidated. In this study we dissected the immunogenicity of antigens originating from the OMV component of the 4CMenB vaccine in mice and humans. We collected functional data on a panel of strains for which bactericidal responses to 4CMenB in infants was attributable to the OMV component and evaluated the role of 30 OMV-specific protein antigens in cross-coverage. By using tailor-made protein microarrays, the immunosignature of OMV antigens was determined. Three of these proteins, OpcA, NspA, and PorB, triggered mouse antibodies that were bactericidal against several N. meningitidis strains. Finally, by genetic deletion and/or serum depletion studies, we demonstrated the ability of OpcA and PorB to induce functional immune responses in infant sera after vaccination. In conclusion, while confirming the role of PorA in eliciting protective immunity, we identified two OMV antigens playing a key role in protection of infants vaccinated with the 4CMenB vaccine against different N. meningitidis serogroup B strains.

Neisseria gonorrhoeae lipooligosaccharide glycan epitopes recognized by bactericidal IgG antibodies elicited by the meningococcal group B-directed vaccine, MenB-4C

“…Much work has defined the differences and similarities between the N. meningitidis and N. gonorrhoeae outer membranes and has led to successful OMV vaccines for N. meningitidis (MenB-directed vaccines). A recent study has shown that OpcA and PorB are two important OMV protein antigens of MenB-4C, providing broad protection against different group B N. meningitidis ( 62 ). However, the identification of immunologically critical and distinctive gonococcal outer membrane antigens as vaccine candidates has continued to be elusive.…”

Outer membrane vesicles as a platform for the discovery of antibodies to bacterial pathogens

“…While some serum pAb responses have been validated by ELISA using recombinant or purified antigens, many pAb responses have only been documented by western blot or immunoprecipitation; these techniques may be more susceptible to erroneous target attribution due to factors such as antigen abundance bias and low throughput, limiting the number of experimental controls that can be included. However, reproducible detection of the major OM protein classes, membrane-associated polysaccharides, and other associated antigens across independent experiments and in different organisms suggests that OMVs induce Ab responses to these antigens (Dalseg et al 1999 ; Leduc et al 2020 ; Viviani et al 2023 ; Wedege et al 2007 ). Shigella OMVs have also been well studied, and pAb responses to major OM antigens such as LPS, porins, and secretion system components have been observed (Mancini et al 2021 ; Necchi et al 2023 ).…”

Sweet complexity: O-linked protein glycosylation in pathogenic Neisseria

“…Some vaccines against serogroup B meningococcal (MenB) disease have been based on outer membrane vesicles (OMVs) that include a broad range of OMV proteins, and the 4CMenB also contains recombinant protein antigens to increase the protection across diverse MenB strains ( Holst et al., 2009 ; Micoli and Maclennan, 2020 ; Viviani et al., 2022 ). Although not the major antigens in these vaccines, there are numerous antigens that contribute to the protective effect against MenB strains that are known glycoproteins; PorB ( Viviani et al., 2023 ), PilQ ( Haghi et al., 2012 ), Ag473 ( Chu et al., 2012 ), RmpM ( Rosenqvist et al., 1999 ; Williams et al., 2014 ), and Mip ( Humbert and Christodoulides, 2018 ) ( Table 1 ). Given the fact that glycans impact on the immunogenicity, as shown for the PilE protein ( Børud et al., 2010 ), glycan function and diversity may need to be considered when including glycoproteins in future vaccines.…”