Identifying cellular and molecular features of protective anti-malaria B cell response

ended

Malaria is one of the leading life-threatening diseases with a reported 627,000 deaths and 241 million infections in 2020, mostly in low-income countries. Despite the advances gained by control measures, malaria incidence by Plasmodium falciparum (Pf) has plateaued in the last decade. Intervention through vaccines and antibody therapy shows promising results, yet long-lasting protective immunity remains unattainable. Anti-malaria memory B cells comprise transcriptionally distinct sub-populations, but their contribution to protective immunity is unclear. Here, I plan to combine state-of-the-art strategies to identify the cellular and molecular features of protective immunity offered by B cells and encoded antibodies, respectively. To that end, I will use the unique samples from controlled human malaria infection trials to isolate memory B cells reactive to Pf antigens, obtain transcriptome and immunoglobulin (Ig) gene sequences at the single cell level and measure antibody inhibitory properties at the monoclonal level. Transcripts signifying resting, activated or exhausted phenotype will allow memory B cell clustering, whereas Ig gene features will help define clonal expansion and selection strength of antibodies. By cloning and testing antibodies in specialized in vitro and in vivo assays, I aim to discover potent inhibitory antibodies targeting different parasite developmental stages. I will reveal the protective antibody molecular properties defined by Ig gene features, affinity, and epitope specificity. By single-cell level integration of transcriptome and antibody functionality for the first time, this project will not only deliver potent parasite inhibitory antibodies of therapeutic potential but also lay a clear blueprint for attaining protective immunity through future vaccine designs. This fellowship will support me in acquiring interdisciplinary expertise and advancing my career as a leading scientist in B cell immunology and malaria vaccinology.