Full-length merozoite surface protein 1 of Plasmodium falciparum is a major target of protective immunity following controlled human malaria infections

The merozoite surface protein 1 (MSP1) is the most abundant protein on the surface of the invasive merozoite stages of Plasmodium falciparum and has long been considered a key target of protective immunity. However, previous studies focused on small C-terminal fragments and potentially missed the opportunity to identify important epitopes that are relevant for protection. We used samples from a controlled human malaria challenge (CHMI) study in semi-immune volunteers to show that levels of pre-challenge antibodies directed against the full-length MSP1 (MSP1FL) are significantly correlated with protection from malaria. Furthermore, we showed that anti-MSP1FL antibodies induced five distinct Fc-mediated effector mechanisms: complement fixation, phagocytosis, respiratory burst, degranulation and IFNγ production, each of which was strongly associated with protection. The breadth of Fc-mediated effector functions was the strongest correlate of protection. Our findings suggest that MSP1FL is an important target of functional antibodies that contribute to a protective immune response against malaria and support the development of MSP1FL-based vaccines. ### Competing Interest Statement In the CHMI-SIKA team, Y. A., P. F. B., S. L. H., E.R.J., B. K. L. S., and T. R. are salaried, full- time employees of Sanaria Inc., the manufacturer of Sanaria PfSPZ Challenge. Thus, all authors associated with Sanaria Inc. have potential conflicts of interest. All other authors declare no competing interests. ### Clinical Trial NCT02739763 ### Funding Statement The CHMI-SIKA study was supported by a Wellcome Trust grant (107499) and sponsored by the University of Oxford. This work was supported by a Sofja Kovalevskaja Award from the Alexander von Humboldt Foundation (3.2 − 1184811 -KEN - SKP) and an EDCTP Senior Fellowship (TMA 2015 SF1001) which is part of the EDCTP2 programme supported by the European Union awarded to F.H.A.O. K.M was supported by an NIHR Global Health Research Unit grant number 16/136/33; Tackling Infections to Benefit Africa (TIBA). K.M was also supported through the DELTAS Africa Initiative Grant No.107754/Z/15/Z-DELTAS Africa SSACAB and from DELTAS Africa Initiative [DEL-15-003]. The DELTAS Africa Initiative is an independent funding scheme of the African Academy of Sciences (AAS) s Alliance for Accelerating Excellence in Science in Africa (AESA) and supported by the New Partnership for Africa s Development Planning and Coordinating Agency (NEPAD Agency) with funding from the Wellcome Trust [107769/Z/10/Z] and the UK government. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The CHMI study was conducted at the KEMRI Wellcome Trust Research Programme in Kilifi, Kenya with ethical approval from the KEMRI Scientific and Ethics Review Unit and the University of Oxford Tropical Research Ethics Committee. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable. Yes Further information and requests for resources and reagents should be directed to and will be fulfilled by Prof. Faith Osier (f.osier{at}imperial.ac.uk)