Defining functional humoral correlates of immunity to guide vaccine design

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Malaria, a mosquito-borne disease caused by Plasmodium spp., was responsible for nearly half a million deaths in 2017, with an additional 3.2 billion people at risk of disease. While aggressive insecticide-treated bed-net distribution, mosquito control, and anti-malarial drug distribution programs have significantly reduced mortality associated with the disease, the disease continues to spread nearly unabated, suggesting that a vaccine against this infection is desperately needed. Despite the slow pace of malaria vaccine design, several vaccines have shown promise in the field demonstrating 30–50% protection in field efficacy or Phase 2 trials. Correlates analyses have suggested that both humoral immune responses and cellular immunity may both play critical parts in protection from infection; however, the precise mechanism by which these immune responses synergize to drive immunity may provide the critical insights to advance the design of next-generation vaccines able to provide higher levels of global protection. Moreover, field studies have highlighted the potentially deleterious influence of pre-existing antibodies in endemic regions on vaccine response. Thus, under this proposal we seek to exploit our Systems Serology antibody profiling approach, across a large array of sporozoite/early liver antigens, to define both the correlates of immunity against malaria infection following PfSPZ immunization as well as to define the specific mechanism(s) by which pre-existing antibodies shape the response to vaccination. Ultimately, the results from this study will provide novel insights for the development of next generation vaccines against malaria.