SBIR-STTR Award

For more than 100 years, sub-Saharan Africa has suffered with high rates of endemic meningococcal disease and periodic epidemic epidemics involving over 100,000 cases. In 2010, a low cost serogroup A polysaccharide-protein conjugate vaccine (MenAfriVac) was introduced in the region. The vaccine confers protection against serogroup A (MenA) disease as well as asymptomatic nasopharyngeal MenA carriage, but has no effect on strains with other serogroups that also cause epidemics in the region. Multivalent serogroup A,C,Y and W conjugate vaccines are available in industrialized countries but are not affordable in Sub-Sahara, which is one of the poorest regions of the world. These vaccines also do not prevent disease from MenX strains, which also can cause epidemics in the region. Recently, two MenB vaccines based on Neisserial factor H binding protein (FHbp) have been licensed in the US and Europe. FHbp specifically binds human or non- human primate complement FH. We are developing a novel native outer membrane vesicle (NOMV) vaccine with genetically attenuated endotoxin and over-expressed mutant FHbp with low FH binding (NOMV-FHbp). In a non-human infant primate model, a mutant recombinant FHbp antigen with two amino acid substitutions elicited broader serum bactericidal antibody responses than the control FHbp vaccine that bound FH. In human FH transgenic mice, our NOMV-FHbp vaccine provided broader protection than a licensed multivalent A,C,Y and W conjugate vaccine or the MenB vaccine developed by Novartis that contains FHbp that binds FH. However, FHbp is variable with protein sequences falling into two sub-families, A and B. Our prototype NOMV- FHbp vaccine only contained sub-family B FHbp. Our hypothesis is that including a second sub-family A FHbp in NOMV-FHbp will result in a “universal” vaccine for Africa against strains with FHbp sub-family A or B, while at the same time expanding coverage against MenB strains worldwide. The goal of this Phase I proposal is to produce a safe, broadly protective, affordable vaccine for use in preventing meningococcal disease generally and in Africa specifically. To accomplish this goal, in Aim 1, we will produce NOMV with over- expressed FHbp from both A and B sub-families. Immunogenicity will be evaluated in established transgenic (Tg) mouse models expressing human FH and functional activity of elicited antibodies in complement-mediated serum bactericidal assays (SBA), which is an established correlate of protection against disease in humans. In Aim 2, we will build upon the success of MenAfriVac by combining it with the new NOMV-FHbp A+B vaccine. The combined vaccine has the potential to ensure coverage against all of the predominant MenA strains while at the same time suppressing the emergence of new pathogenic strains from other serogroups.

Public Health Relevance Statement:
Project Narrative/Relevance Meningococcal disease is a major global health concern, particularly in sub-Saharan Africa, which has periodic epidemics involving hundreds of thousands of cases and tens of thousands of deaths. Attempts to prevent meningococcal disease in Sub-Sahara have been confounded by emergence of strains not covered by the existing serogroup A conjugate vaccine, and high cost of multivalent capsular polysaccharide-protein conjugate vaccines which do not include serogroup X. The goal of this project is to produce a novel safe, effective and affordable vaccine to prevent disease caused by all strains causing epidemics in Africa.

Project Terms:
Africa; Africa South of the Sahara; African; Aluminum; Amino Acid Sequence; Amino Acid Substitution; Antibodies; Antibody Response; Antigens; Attenuated; bactericide; base; Binding; Binding Proteins; Biological Assay; Businesses; Carrier Proteins; Cessation of life; Clinical Trials; Combined Vaccines; commercialization; Complement; Complement Factor H; Conjugate Vaccines; cost; Country; Developed Countries; Disease; Dose; Endemic Diseases; Endotoxins; Engineering; Ensure; Epidemic; Epitopes; Europe; falls; Familial Mediterranean Fever; Family; Future; global health; Goals; Human; immunogenicity; India; Infant; Institutes; Lead; Length; Licensing; Licensure; Measures; Mediating; Membrane; Meningococcal meningitis; Meningococcal vaccine; Modeling; mouse model; Mus; mutant; Nigeria; nonhuman primate; novel; Peptide Sequence Determination; Phase; Polysaccharides; prevent; Prevention; Primates; Production; Proteins; prototype; Recombinants; reconstitution; Sahara; Salts; Serum; Small Business Technology Transfer Research; Source; success; Testing; Time; Transgenic Mice; Vaccine Antigen; vaccine evaluation; Vaccines; Variant; Vesicle

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 and, subsequently, in adolescents and younger age groups, including infants, necessary for licensure of what OMVax anticipates to be a more effective and safer MenB vaccine for all age groups.

Public Health Relevance Statement:
Project Narrative Currently, there is no licensed vaccine in the US to prevent disease caused by Neisseria meningitidis serogroup B (MenB) strains in those less than 10 years old, the age group at greatest risk of developing meningococcal meningitis and sepsis. OMVax is developing a MenB vaccine for use in all age groups including infants and young children. The new vaccine also covers epidemic non-B strains from Africa, and uses proprietary technology based on native outer membrane vesicles prepared from mutant MenB strains with genetically attenuated endotoxin and over-expressed antigens to elicit broadly protective antibodies.

Project Terms:
10 year old; Address; Adolescent; Adult; Affect; Africa; age group; Amino Acid Sequence; analytical method; Antibodies; Antibody Response; Antigens; Attenuated; Autoantibodies; bactericide; base; Binding; Binding Proteins; Biological Assay; capsule; Child; Childhood Acute Lymphocytic Leukemia; clinical lot; college; Communities; Complement; Complement Factor H; Conjugate Vaccines; Data; Development; Disease; Disease Outbreaks; Effectiveness; Endotoxins; Epidemic; Epidemiology; Europe; Family; Formulation; Goals; Human; human tissue; Immunization; immunogenicity; improved; in vitro testing; Infant; Integration Host Factors; Licensure; Macaca; Manufacturer Name; Measures; Mediating; Membrane; Meningitis; Meningococcal meningitis; Meningococcal vaccine; Methods; Mus; mutant; Mutation; Neisseria meningitidis; next generation; novel vaccines; Oryctolagus cuniculus; overexpression; Phase; phase 1 testing; Phase I Clinical Trials; Polysaccharides; Predisposition; Preparation; preservation; prevent; Process; Production; Proteins; prototype; Recombinants; Research; response; Risk; Safety; Sepsis; Septicemia; Serogroup B Neisseria meningitidis; Serum; stability testing; Structure; Technology; Teenagers; Testing; Toxicology; Vaccination; vaccine efficacy; Vaccine Research; vaccine safety; Vaccines; Variant; Vesicle; young adult