Abstract Neisseria meningitidis is a major cause of meningitis and septicemia. Serogroup B (MenB) strains account for most cases of invasive disease in infants and teenagers and nearly all U.S. college outbreaks. The MenB capsule cross-reacts with host antigens, which precluded development of a capsular-based MenB conjugate vaccine. Two manufacturers developed MenB vaccines that target protein antigens. Both contain recombinant meningococcal Factor H binding protein (FHbp) and are licensed in the U.S. for teenagers and young adults but not for infants and young children, the age groups at greatest risk. OMVax, Inc. is developing an improved MenB vaccine for all age groups, including infants and young children. We have shown that binding of host complement Factor H (FH) to FHbp vaccines decreases protective antibody responses and that immunization of healthy young adults with a licensed MenB vaccine can elicit autoantibodies to FH, which may pose safety issues. The OMVax vaccine uses proprietary native outer membrane vesicle (NOMV) technology with genetically attenuated endotoxin that preserves native structures, combined with over-expressed mutant FHbp antigens with low binding to FH. In infant macaques, a prototype NOMV-FHbp vaccine elicited greater protection as reflected by broader and higher serum bactericidal activity (SBA) titers than a licensed MenB vaccine and, unlike the licensed vaccine, did not elicit anti-FH autoantibodies. The OMVax vaccine also protects against non-B strains causing epidemics in Africa. Our hypotheses are that the OMVax vaccine is more effective and better tolerated than currently licensed MenB vaccines and that it will decrease nasopharyngeal colonization and thereby provide community protection, a key limitation of current MenB vaccines. In Aim 1 we will develop production strains (one each with over-expressed FHbp from sub-family A or B) for GMP-compliant process and formulation and development of analytical methods suitable for release of Phase 1 vaccine product. We will characterize research vaccine lots for immunogenicity studies in mice, toxicology in rabbits and stability testing in vitro and with mouse potency assays. The data will allow preparation of SOPs and batch record production to produce a lot of vaccine suitable for Phase 1 human testing. In Aim 2, we will establish human complement SBA methods for demonstrating vaccine efficacy. Strain susceptibility to anti-FHbp SBA can be affected by variations in both FHbp amino acid sequence and level of expression, and we will develop assays using 4 to 8 epidemiologically relevant MenB strains with different FHbp sequence variants and expression levels. The assays will be used to assess immunogenicity of NOMV-FHbp research lots in mice and, subsequently, for GLP-compliant testing of Phase 1 human sera. The proposed studies will help predict coverage of relevant MenB strains and enable NOMV-FHbp to undergo safety and immunogenicity testing in healthy adults a...