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Abstract

Despite the global efforts, malaria is still a serious public health concern with approximately 241 million cases and 627000 deaths globally in 2020 (WHO report 2021) with the majority of deaths occurring in young children living in Sub-Saharan Africa. This underscores the urgent need of highly effective and durable malaria vaccines which are not yet available. The Plasmodium falciparum merozoite surface protein 1 (MSP1) is the most abundant surface antigen of merozoites and has long been considered as a key antigen for naturally acquired immunity (NAI) and a promising blood stage vaccine candidate for malaria; however, sero-epidemiological studies and clinical trials in humans could not confirm protective effects of anti-MSP1 immune responses. Notably, previous studies focussed only on small fragments of the whole protein, particularly the conserved C-terminal subunit and might therefore have missed important B and T cell epitopes that are relevant for a protective immune response. Using samples from a controlled human malaria infection study in semi-immune Kenyan adults (CHMI-SIKA), I showed that pre-challenge antibodies target conserved epitopes distributed across the full-length MSP1 (MSP1FL) protein and induced a range of distinct Fc-mediated effector functions: complement fixation (AbC’), opsonic phagocytosis (OPA), respiratory burst of neutrophils (ADRB), degranulation and IFN expressionof natural killer cells (Ab-NK) that were significantly associated with protection from malaria. Notably, the breadth of effector functions was the strongest correlate of protection. The magnitude of effector functions of antibodies directed against MSP1FL was the strongest compared to other merozoite antigens highlighting MSP1FL as a major driver of anti-merozoite immune responses. Furthermore, I showed that vaccination of malaria-naïve adults from Germany with MSP1FL formulated with the GLA-SE adjuvant (SumayaVac1) elicited highly functional IgG and IgM that exert the same range of Fc-mediated effector functions that were observed for CHMI volunteers. Notably, functions reached similar or even higher levels to that of semi-immune Kenyan adults and remained over baseline levels even 6 months after immunization. Functional antibodies from protected CHMI volunteers as well as vaccinees preferably targeted the C-terminal p42 as well as the N-terminal p83 subunit which has never been included in previous MSP1-based vaccines. My study suggests that full-length MSP1 is an important target of naturally acquired and vaccine-induced functional antibodies which might be strong contributors to protection from malaria. An upcoming phase Ib study with SumayaVac1 is currently under development and expected to be tested in malaria-exposed adults in Tanzania followed by CHMI.