Neisseria meningitidis (Nm) is a Gram-negative bacterium that commonly colonizes the human pharyngeal mucosa, but can also cause invasive meningococcal disease (IMD), a devastating disease that presents as septicemia and meningitis. More than 70,000 cases of IMD are reported annually worldwide with case fatality ratios between 5% and 15%. Bactericidal anti-Nm antibodies may prevent infection and colonization and can be identified by the serum bactericidal assay (SBA), which is the gold standard in vitro surrogate of protection. Vaccination that results in protective bactericidal IgG is, therefore, considered a crucial control measure for IMD. A Reverse Vaccinology approach that starts with in silico prediction of vaccine antigens has led to licensed protein-based vaccines such as the multicomponent 4CMenB (Bexsero®). However, all licensed anti- Nm vaccines have limited breadth of coverage, leaving vaccinees susceptible to IMD caused by non-vaccine type strains. There is an urgent need for continued discovery of vaccine candidates that will provide full coverage, either individually or in synergy with existing vaccines. We hypothesize that the next generation of Reverse Vaccinology (RV 2.0), whereby SBA-active human monoclonal antibodies (hmAbs) are generated from convalescent IMD patients, will provide the platform for discovery of vaccine antigens against Nm. The team of Prof. Paul Langford and Dr. Fadil Bidmos of Imperial College London have generated novel broadly protective bactericidal hmAbs from convalescing patients. The current challenge with RV 2.0 is identifying the cognate antigens of bactericidal hmAbs. Antigen Discovery, Inc. (ADI) of Irvine, CA has established panproteome microarray technology for identification of the protein targets of antibodies associated with protective immunity. A proteome-scale platform for profiling antibody specificity has never before been available to the Nm research community, and this technology has the power to rapidly advance discovery of vaccine candidates. This project aims to identify the antigens targeted by bactericidal antibodies. A Neisseria meningitidis panproteome microarray will be developed for use in an RV 2.0 approach to screen hmAbs and convalescent sera from pediatric IMD patients characterized as having SBA and other in vitro functional antibody activity, such as complement activation, opsonophagocytosis and adhesion inhibition. The most promising antigens will be validated by producing and purifying recombinant proteins, which will be used to develop Luminex assays for confirmation in orthologous immunoassays. At least 5 vaccine candidate antigens that bind antibodies that recognize diverse Nm strains, are broadly immunogenic in the target population and are not currently included in any licensed vaccine will be taken forward for preclinical development in a Phase 2 SBIR application. This grant application addresses the significant problem of IMD in children and adults by laying the foundation for a broad-coverage vaccine through identification of the protein targets of bactericidal antibodies. Public Health Relevance Statement Invasive meningococcal disease caused by the Gram-negative bacterium Neisseria meningitidis is a devastating disease for which effective vaccines are licensed but are limited by a lack of broad strain coverage, reducing their impact due to disease caused by non-vaccine type strains. A new Neisseria meningitidis panproteome microarray being developed at Antigen Discovery, Inc. will provide the opportunity to discover the proteins targeted by IgG antibodies in a unique set of human monoclonal antibodies and pediatric serum samples that have protective bactericidal activity and cross-strain recognition. The most promising antigen candidates for a broadly effective vaccine will be validated and taken forward for further study and the development of a novel or supplementary vaccine to prevent meningococcal disease.
Project Terms: Adhesions ; Adult ; 21+ years old ; Adult Human ; adulthood ; Antibodies ; Antibody Specificity ; Antigens ; immunogen ; Biological Assay ; Assay ; Bioassay ; Biologic Assays ; Blood Circulation ; Bloodstream ; Circulation ; Cells ; Cell Body ; Child ; 0-11 years old ; Child Youth ; Children (0-21) ; youngster ; Cloning ; Communities ; Complement ; Complement Proteins ; Complement Activation ; complement pathway regulation ; Disease ; Disorder ; Escherichia coli ; E coli ; E. coli ; Female ; Foundations ; Future ; Genes ; Goals ; Gold ; Gram-Negative Bacteria ; Hospitals ; Human ; Modern Man ; Immunoglobulin G ; 7S Gamma Globulin ; IgG ; Immune Sera ; Antisera ; immune serum ; Immunity ; Immunoassay ; In Vitro ; Infection ; Libraries ; London ; male ; Meninges ; Meningitis ; Transgenic Mice ; Mucous Membrane ; Mucosa ; Mucosal Tissue ; Neisseria meningitidis ; Meningococcus ; N meningitidis ; N. meningitidis ; Patients ; Printing ; Proteins ; Recombinant Proteins ; Research ; Septicemia ; Blood Poisoning ; septicaemia ; septicemic ; Specificity ; Target Populations ; Technology ; Tissues ; Body Tissues ; Genetic Transcription ; Gene Transcription ; RNA Expression ; Transcription ; Translations ; Vaccines ; Generations ; Measures ; Open Reading Frames ; ORFs ; Protein Coding Region ; Healthcare ; health care ; base ; Blood specimen ; Blood Sample ; Phase ; Plasmablast ; Serum ; Blood Serum ; Childhood ; pediatric ; Individual ; Binding Proteins ; Ligand Binding Protein ; Ligand Binding Protein Gene ; Protein Binding ; bound protein ; Measurement ; Collaborations ; Deposit ; Deposition ; tool ; Slide ; System ; Operative Procedures ; Surgical ; Surgical Interventions ; Surgical Procedure ; surgery ; Operative Surgical Procedures ; interest ; Prevent infection ; Infection prevention ; collegiate ; college ; antigen antibody binding ; synergism ; Animal Models and Related Studies ; model of animal ; model organism ; Animal Model ; novel ; Meningococcal vaccine ; Proteome ; intervention therapy ; Therapeutic Intervention ; Sampling ; cross reactivity ; immunogenic ; Annual Reports ; Manufacturer ; Manufacturer Name ; Protein Array ; antigen bound ; antigen binding ; preventing ; prevent ; Address ; Length ; Microarray-Based Analysis ; microarray analyses ; microarray technology ; Microarray Analysis ; Animal Testing ; Baculovirus Expression System ; Data ; Grant Proposals ; Applications Grants ; Antibody Repertoire ; Antigen Targeting ; Invaded ; Small Business Innovation Research Grant ; SBIR ; Small Business Innovation Research ; Vaccine Antigen ; Validation ; Development ; developmental ; bactericide ; bactericidal ; immunogenicity ; next generation ; vaccinology ; human monoclonal antibodies ; Hu-mABs ; humAbs ; human mAbs ; human monoclonals ; Coupled ; novel vaccines ; new vaccines ; next generation vaccines ; mouse model ; murine model ; commercialization ; vaccine candidate ; safety testing ; pediatric patients ; child patients ; vaccine discovery ; discover vaccines ; clinical development ; preclinical development ; pre-clinical development ; in silico ; vaccination outcome ; outcome following vaccination ; outcome following vaccine ; result following vaccination ; result following vaccine ; vaccination result ; vaccine outcome ; vaccine result ;
