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Monoclonal antibodies to the circumsporozoite proteins as an emerging tool for malaria prevention

Nature Immunology volume 25, pages 1530–1545 (2024)Cite this article

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Abstract

Despite various public health strategies, malaria caused by Plasmodium falciparum parasites remains a major global health challenge that requires development of new interventions. Extended half-life human monoclonal antibodies targeting the P. falciparum circumsporozoite protein on sporozoites, the infective form of malaria parasites, prevent malaria in rodents and humans and have been advanced into clinical development. The protective epitopes on the circumsporozoite protein targeted by monoclonal antibodies have been defined. Cryogenic electron and multiphoton microscopy have enabled mechanistic structural and functional investigations of how antibodies bind to the circumsporozoite protein and neutralize sporozoites. Moreover, innovations in bioinformatics and antibody engineering have facilitated enhancement of antibody potency and durability. Here, we summarize the latest scientific advances in understanding how monoclonal antibodies to the circumsporozoite protein prevent malaria and highlight existing clinical data and future plans for how this emerging intervention can be used alone or alongside existing antimalarial interventions to control malaria across at-risk populations.

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Fig. 1: The multistage life cycle of Pf malaria in humans.
Fig. 2: Epitope specificities and binding properties of PfCSP-specific mAbs.
Fig. 3: Mechanisms by which PfCSP-specific antibodies inhibit SPZs.
Fig. 4: Experimental approaches to optimize the clinical utility of PfCSP-specific mAbs.

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Acknowledgements

We thank L. S. Pereira and P. Tripathi for helpful comments during the writing process. We thank A. Hoofring, E. Tyler, and J.N. Allen for invaluable assistance in designing the figures. This work was supported by the Vaccine Research Center and Division of Intramural Research of the National Institute of Allergy and Infectious Diseases. The funders had no role in the study design, data collection and interpretation or the decision to submit the work for publication.

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  1. These authors contributed equally: Lawrence T. Wang, Azza H. Idris.

Authors and Affiliations

  1. Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA

    Lawrence T. Wang, Azza H. Idris, Neville K. Kisalu & Robert A. Seder

  2. Department of Medicine, Weill Cornell Medicine, New York, NY, USA

    Lawrence T. Wang

  3. The Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology and Harvard University, Cambridge, MA, USA

    Azza H. Idris

  4. PATH’s Center for Vaccine Innovation and Access, Washington, DC, USA

    Neville K. Kisalu

  5. Malaria Infection Biology and Immunity Section, Laboratory of Immunogenetics, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, MD, USA

    Peter D. Crompton

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Contributions

L.T.W., A.H.I., N.K.K., P.D.C. and R.A.S. wrote the article. All authors contributed to researching the article and to the review and editing of the manuscript.

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Correspondence to Azza H. Idris or Robert A. Seder.

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Competing interests

R.A.S., A.H.I. and N.K.K. have filed patent PCT/US2018/017826 describing the CIS43 antibody. R.A.S. and L.T.W. have filed patent PCT/US2020/031345 describing the L9 antibody. All other authors declare no competing interests.

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Nature Immunology thanks Rafick Sekaly and the other, anonymous, reviewer(s) for their contribution to the peer review of this work. Primary Handling Editor: Jamie D. K. Wilson, in collaboration with the Nature Immunology team.

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Wang, L.T., Idris, A.H., Kisalu, N.K. et al. Monoclonal antibodies to the circumsporozoite proteins as an emerging tool for malaria prevention. Nat Immunol 25, 1530–1545 (2024). https://doi.org/10.1038/s41590-024-01938-2

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