Breadth of IgG Fc antibody-mediated protective immunity against Plasmodium falciparum malaria in humans (BigFc)

The global burden of malaria remains unacceptable with >200 million cases and >600,000 deaths annually. Vaccines are the most effective and cost-effective public health interventions against infectious diseases, but the only one licensed for malaria has limited efficacy that wanes rapidly. The fact immunity can be acquired and passively transferred through immunoglobulins strongly motivates research to understand the immune responses that underpin protection. New data from the Osier laboratory challenge the long-held view that the inhibition of erythrocyte invasion is the main correlate of protection. We found that IgG Fc-dependent mechanisms targeting merozoites and involving complement, monocytes, neutrophils, and natural killer cells strongly predicted clinical outcome following intravenous challenge with Plasmodium falciparum parasites in humans. Invasion-inhibition did not. We will now partner with a renown structural biologist, B-cell immunologist, and experts in glycobiology and Fc- receptor pathways to map out the precise structural and fine molecular characteristics that lead to the successful control of malaria. We will use this knowledge to design and test new vaccine constructs and monoclonal antibody therapies. These data will transform our understanding of acquired immunity, provide urgently needed candidates for new vaccines and immuno-therapeutics, and create new benchmarks against which these can be assessed.