Thursday, May 8, 2025
5/8/2025
Systems Antibody Immunology of the Malaria Sporozoite Vaccine - Project Summary Over 200 million people are infected with malaria every year. An effective and long-lasting vaccine will be essential for the elimination and eradication of malaria in Sub-Sharan Africa and worldwide. Though WHO- approved circumsporozoite protein (CSP) protein vaccine RTS,S is the only vaccine in current use, it provides <50% protection that is also short lived. The proposed research will delve into the humoral immunity of the whole sporozoite vaccine (PfSPZ), a model system to identify protective immune responses beyond the immunodominant epitope CSP - essential insights needed to create new, highly effective malaria vaccines. This proposal describes a five-year career development plan to study humoral immunity to the malaria- causing pathogen Plasmodium falciparum. Though antibodies are important for PfSPZ-mediated protection, the protective antibody targets and functions remains unknown. Further, PfSPZ's efficacy drops in malaria- exposed individuals and how pre-existing anti-malarial antibodies affect PfSPZ vaccination remains unanswered. Our preliminary systems serology analysis of malaria naïve PfSPZ vaccinees has suggested a new protective role for IgM antibodies to SSP2/TRAP, a malaria host cell recognition and invasion protein, and validated our approach. The studies proposed here are to 1) define the functional antibody correlates of protection in malaria-exposed individuals and the effect of pre-existing immunity 2) identify new correlates of protection with a whole-proteome approach, and 3) define mechanisms of anti-sporozoite immunity of SSP2/TRAP IgM antibodies. These aims will be carried out with human serum from PfSPZ vaccination and controlled human malaria infection (CHMI) challenge trials in malaria-naïve and exposed individuals. The candidate is currently an Associate Physician at Brigham and Women's Hospital, Instructor in Medicine at Harvard Medical School (HMS), and Research Fellow at the Ragon Institute with an ongoing commitment of 80% time to research. The proposal is supported by an expert mentor in humoral immunology, HMS Professor Facundo Batista, and co-Mentored by expert in systems biology MIT Professor Douglas Lauffenburger. The candidate is supported by a SAC containing an expert in phage display serological assays, HMS Professor Stephen Elledge, an expert in malaria vaccinology, NIAID Chief of Cellular Immunology Dr. Robert Seder, and expert in malaria host-pathogen interactions and pre-erythrocytic immunity University of Washington Associate Professor Noah Sather. Building on the candidate's doctoral training in malaria pathogenesis and genomics, this proposal will further his training in humoral immunology, systems biology, and bioinformatics as well as research scientist-focused professional development and responsible conduct of research coursework. Completion of this comprehensive training plan will enable the candidate to create a successful and unique research program, obtain independent funding, and transition to running an independent laboratory focused on malaria antibody immunology, phage display serologic assay tool development, and vaccinology.
HHS’ Tracking Accountability in Government Grants System (TAGGS) website provides access to detailed descriptions of grants, loans, aggregated direct payments and other types of financial assistance awarded by the HHS Operating Divisions (OPDIVs) and the Office of the Secretary Staff Divisions (STAFFDIVs).