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.
