The Neisseria gonorrhoeae Vaccine Candidate NHBA Elicits Antibodies That Are Bactericidal, Opsonophagocytic and That Reduce Gonococcal Adherence to Epithelial Cells

Abstract

Due to the continuing emergence of multidrug resistant strains of Neisseria gonorrhoeae there is an urgent need for the development of a gonococcal vaccine. We evaluated the gonococcal Neisseria heparin binding antigen (NHBA) as a potential vaccine candidate, in terms of its sequence conservation and expression in a range of N. gonorrhoeae strains, as well as its immunogenicity and the functional activity of antibodies raised to either the full length NHBA or a C-terminal fragment of NHBA (NHBA-c). The gene encoding NHBA is highly conserved and expressed in all N. gonorrhoeae strains investigated. Recombinant NHBA is immunogenic, and mice immunized with either NHBA or NHBA-c adjuvanted with either Freund’s or aluminium hydroxide (alum) generated a humoral immune response, with predominantly IgG1 antibodies. Antibodies generated by both NHBA and NHBA-c antigens promoted complement activation and mediated bacterial killing via both serum bactericidal activity and opsonophagocytic activity, with slightly higher titers seen for the NHBA-c antigen. Anti-NHBA was also able to block the functional activity of NHBA by reducing binding to heparin and adherence to cervical and urethral epithelial cells. These data suggest that the gonococcal NHBA is a promising vaccine antigen to include in a vaccine to control N. gonorrhoeae.

An open-label randomised controlled trial evaluating the efficacy of a meningococcal serogroup B (4CMenB) vaccine on Neisseria gonorrhoeae infection in gay and bisexual men: the MenGO study Protocol

“…The non-standard of care blood sample for N. gonorrhoeae-speci c antibody assays will be allowed to clot, then centrifuged at 2,000 x g for 10 minutes at the Gold Coast Sexual Health Clinic. Serum will be aliquoted into sterile tubes and stored at −20˚C prior to transport to the Institute for Glycomics, Gri th University for analysis as per standard methods [25,[32][33][34][35]. Antibodies in blood-derived serum will be characterised using enzyme-linked immunosorbent assay (ELISA) to quantify the level of speci c antibody isotypes that cross-react with N. gonorrhoeae whole cell bacteria, and speci c target proteins) [25,[32][33][34][35].…”

“…The ELISA titre is de ned as the reciprocal of highest serum dilution with a positive signal (i.e., a signal greater than the negative sample mean plus three standard deviations). The functional activity of antibodies against N. gonorrhoeae will be tested in serum bactericidal activity (SBA) and neutrophildependent opsonophagocytic activity (OPA) assays [32][33][34][35]. Antibody neutralisation of N. gonorrhoeae may also be tested in functional assays that measure antibody-dependent blocking of bacterial adherence to epithelial cells or of antigen binding to their ligand [33,34].…”

“…Serum will be aliquoted into sterile tubes and stored at −20˚C prior to transport to the Institute for Glycomics, Gri th University for analysis as per standard methods [25,[32][33][34][35]. Antibodies in blood-derived serum will be characterised using enzyme-linked immunosorbent assay (ELISA) to quantify the level of speci c antibody isotypes that cross-react with N. gonorrhoeae whole cell bacteria, and speci c target proteins) [25,[32][33][34][35]. The ELISA titre is de ned as the reciprocal of highest serum dilution with a positive signal (i.e., a signal greater than the negative sample mean plus three standard deviations).…”

Recent Progress Towards a Gonococcal Vaccine

“…Furthermore, this antigen is conserved across Ngo genomes and has a high sequence identity among isolates. It was recently shown that recombinant NHBA is immunogenic and that anti-NHBA antibodies recognize a wide range of Ngo NHBA variants ( Semchenko et al., 2020a ). In addition, these antibodies promote C3 deposition and opsonophagocytosis.…”

Healthy Vaccinee Bias and MenB-FHbp Vaccine Effectiveness Against Gonorrhea

“…12 Meningococcal OMV proteins and NHBA are conserved and surface-exposed in N. gonorrhoeae, suggesting that MenB-4C vaccine-induced antibodies may recognize gonococcal antigenic proteins. 10,13 Murine models have shown that MenB-4C vaccine-induced antibodies cross-reacted with gonococcal antigenic surface proteins and accelerated genital gonococcal clearance. 14 In addition, MenB-4C vaccination produces antibodies in humans that recognize gonococcal antigenic proteins.…”