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Structural basis for inhibition of Plasmodium vivax invasion by a broadly neutralizing vaccine-induced human antibody

Nature Microbiology volume 4, pages 1497–1507 (2019)Cite this article

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Abstract

The most widespread form of malaria is caused by Plasmodium vivax. To replicate, this parasite must invade immature red blood cells through a process requiring interaction of the P. vivax Duffy binding protein (PvDBP) with its human receptor, the Duffy antigen receptor for chemokines. Naturally acquired antibodies that inhibit this interaction associate with clinical immunity, suggesting PvDBP as a leading candidate for inclusion in a vaccine to prevent malaria due to P. vivax. Here, we isolated a panel of monoclonal antibodies from human volunteers immunized in a clinical vaccine trial of PvDBP. We screened their ability to prevent PvDBP from binding to the Duffy antigen receptor for chemokines, and their capacity to block red blood cell invasion by a transgenic Plasmodium knowlesi parasite genetically modified to express PvDBP and to prevent reticulocyte invasion by multiple clinical isolates of P. vivax. This identified a broadly neutralizing human monoclonal antibody that inhibited invasion of all tested strains of P. vivax. Finally, we determined the structure of a complex of this antibody bound to PvDBP, indicating the molecular basis for inhibition. These findings will guide future vaccine design strategies and open up possibilities for testing the prophylactic use of such an antibody.

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Fig. 1: Binding kinetics and epitope bins for the human anti-PvDBPII mAb panel.
Fig. 2: Inhibition of the binding of recombinant PvDBPII to the DARC ectodomain.
Fig. 3: Growth inhibition of transgenic P. knowlesi lines expressing PvDBP.
Fig. 4: Inhibition of invasion of reticulocytes by Thai P. vivax clinical isolates.
Fig. 5: Assessment of synergy, additivity and antagonism by anti-PvDBPII human mAb combinations.
Fig. 6: Structural basis for inhibition of PvDBPII by the antibody DB9.

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Data availability

Crystallographic data are deposited in the Protein Data Bank with accession number 6R2S. DNA sequences are deposited in GenBank with accession numbers MK752505–24. The remaining data that support the findings of this study are available from the corresponding author on request.

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Acknowledgements

The authors are grateful for the assistance of J. Furze, D. Llewellyn, D. Worth, K. Johnson, J. Barrett and S. Biswas (Jenner Institute, University of Oxford), P. C. Wilson (University of Chicago) for the expression plasmids, O. Fedorov (Structural Genomics Consortium, University of Oxford) for use of the Octet RED384, A. Duckett and C. Banner (University of Oxford) for arranging contracts, Y. Durocher for the HEK293E cells (CNRC-NRC, Canada), A. Rushdi Shakri (ICGEB, India) and C. E. Chitnis (Institute Pasteur, France) for the PvDBPII variant proteins, J. McCarthy (QIMR, Australia) for the HMP013 P. vivax strain PvDBPII sequence, O. Bertrand (INSERM, Paris) for the VHH camelid anti-DARC nanobody, and the VAC051 PvDBPII vaccine clinical trial study volunteers and staff and patients associated with the Shoklo Malaria Research Unit for the P. vivax sample donation (SMRU, Thailand). This work was supported in part by funding from the European Union’s Horizon 2020 Research and Innovation programme under a grant agreement for MultiViVax (number 733073). T.A.R. held a Wellcome Trust Research Training Fellowship (108734/Z/15/Z), N.M.B. is funded by the Wellcome Trust DPhil programme in structural cell biology, J.S.C. held a Singapore International Graduate Award (SINGA), D.G.W.A. held a UK Medical Research Council (MRC) iCASE PhD Studentship (MR/K017632/1), M.K.H. is a Wellcome Trust investigator (101020/Z/13/Z), and S.J.D. is a Jenner investigator, a Lister Institute Research Prize fellow and a Wellcome Trust senior fellow (106917/Z/15/Z). SMRU is part of the Mahidol Oxford Tropical Medicine Research Unit supported by the Wellcome Trust. R.W.M. and F.M. are supported by a UK MRC Career Development Award (MR/M021157/1) jointly funded by the UK MRC and Department for International Development.

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  1. These authors contributed equally: Thomas. A. Rawlinson, Natalie M. Barber.

Authors and Affiliations

  1. Jenner Institute, University of Oxford, Oxford, UK

    Thomas. A. Rawlinson, Jee Sun Cho, Daniel G. W. Alanine, Geneviève M. Labbé, Sean C. Elias, Sarah E. Silk, Doris Quinkert, Jing Jin, Jennifer M. Marshall, Ruth O. Payne, Angela M. Minassian & Simon J. Draper

  2. Department of Biochemistry, University of Oxford, Oxford, UK

    Natalie M. Barber, Samuel F. Gérard & Matthew K. Higgins

  3. Department of Immunology and Infection, Faculty of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, London, UK

    Franziska Mohring & Robert W. Moon

  4. Faculty of Public Health, Mahidol University, Bangkok, Thailand

    Varakorn Kosaisavee

  5. Department of Microbiology and Immunology, School of Biomedical Sciences, University of Otago, Dunedin, New Zealand

    Bruce Russell

  6. Singapore Immunology Network, A*STAR, Singapore, Singapore

    Laurent Rénia

  7. Centre for Tropical Medicine and Global Health, Nuffield Department of Medicine, University of Oxford, Oxford, UK

    François H. Nosten

  8. Shoklo Malaria Research Unit, Mahidol Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand

    François H. Nosten

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  1. Thomas. A. Rawlinson
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Contributions

T.A.R., N.M.B., M.K.H. and S.J.D. conceived the study and wrote the manuscript. T.A.R., N.M.B., F.M., J.S.C., V.K., S.F.G., D.G.W.A., G.M.L., S.C.E., S.E.S., D.Q., J.J., J.M.M., R.W.M. and M.K.H. performed the experiments. T.A.R., N.M.B., F.M., J.S.C., D.G.W.A., M.K.H. and S.J.D. performed the data analysis and interpretation. R.O.P., A.M.M., J.J., R.W.M., B.R., L.R. and F.H.N. contributed reagents or materials and facilities.

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Correspondence to Matthew K. Higgins or Simon J. Draper.

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D.G.W.A., M.K.H. and S.J.D. are named inventors on patent applications relating to malaria vaccines, mAbs and/or immunization regimens.

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Rawlinson, T.A., Barber, N.M., Mohring, F. et al. Structural basis for inhibition of Plasmodium vivax invasion by a broadly neutralizing vaccine-induced human antibody. Nat Microbiol 4, 1497–1507 (2019). https://doi.org/10.1038/s41564-019-0462-1

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