Meningococcal Outer Membrane Vesicle Vaccines Derived from Mutant Strains Engineered To Express Factor H Binding Proteins from Antigenic Variant Groups 1 and 2

Abstract

Meningococcal outer membrane vesicle (OMV) vaccines, which are treated with detergents to decrease endotoxin activity, are safe and effective in humans. However, the vaccines elicit serum bactericidal antibody responses largely directed against PorA, which is antigenically variable. We previously prepared a native (non-detergent-treated) OMV vaccine from a mutant of group B strain H44/76 in which the lpxL1 gene was inactivated, which resulted in penta-acylated lipid A with attenuated endotoxin activity. To enhance protection, we overexpressed factor H binding protein (fHbp) from the antigenic variant 1 group. The vaccine elicited broad serum bactericidal antibody responses in mice against strains with fHbp variant 1 (ϳ70% of group B isolates) but not against strains with variant 2 or 3. In the present study, we constructed a mutant of group B strain NZ98/254 with attenuated endotoxin that expressed both endogenous variant 1 and heterologous fHbp variant 2. A mixture of the two native OMV vaccines from the H44/76 and NZ98/254 mutants stimulated proinflammatory cytokine responses by human peripheral blood mononuclear cells similar to those stimulated by control, detergent-treated OMV vaccines from the wild-type strains. In mice, the mixture of the two native OMV vaccines elicited broad serum bactericidal antibody responses against strains with heterologous PorA and fHbp in the variant 1, 2, or 3 group. By adsorption studies, the principal bactericidal antibody target was determined to be fHbp. Thus, native OMV vaccines from mutants expressing fHbp variants have the potential to be safe for humans and to confer broad protection against meningococcal disease from strains expressing fHbp from each of the antigenic variant groups.

Expression of Factor H Binding Protein of Meningococcus Responds to Oxygen Limitation through a Dedicated FNR-Regulated Promoter

“…Recombinant fHBP (rLP2086) is the principal antigen of another MenB vaccine containing recombinant proteins from two different variant subfamilies (16,56). More recent studies also support the strategy to prepare native OMV vaccines from mutant strains engineered to express different fHBP alleles that would confer broad protection against meningococcal strains expressing fHBP from each of the antigenic variant groups (22,25).…”

Characterization of fHbp , nhba ( gna2132 ), nadA , porA , Sequence Type (ST), and Genomic Presence of IS 1301 in Group B Meningococcal ST269 Clonal Complex Isolates from England and Wales

“…An equivalent vaccine for group B meningococci (menB), however, has remained elusive due its poorly immunogenic (␣2-8)-linked capsular polysaccharide, which is also found in fetal neural tissue (38). Outer membrane vesicle (OMV) vaccines, in which PorA constitutes the major immunodominant antigen, have proven highly effective against menB clonal epidemics (2,4,16,30), and efforts to broaden their coverage are ongoing (17,37,39). In an alternative approach, genome mining was used to search the menB strain MC58 genome for genes for putative surface proteins, which were then characterized for their global distribution and diversity, surface expression, and immunogenicity in a process termed "reverse vaccinology" (25).…”

Meningococcal Factor H Binding Protein Vaccine Antigens with Increased Thermal Stability and Decreased Binding of Human Factor H

“…Several preclinical studies have been conducted using FHbp variant group 2 antigens (27,34,35). Since FHbp variant group 2 is more prevalent than variant group 3 (1, 21) and there is a high degree of cross-protection between them (26,36), these antigens have the potential to provide greater coverage against the majority of prevalent disease-producing strains.…”