Research Project
10256250
ABSTRACT 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.
