PvDBPII-Matrix M elicits polyfunctional antibodies that limit parasite growth in a challenge trial

The receptor-binding domain, region II, of Plasmodium vivax Duffy binding protein (PvDBPII) binds the Duffy antigen on reticulocytes to mediate invasion. A heterologous vaccine challenge trial recently showed that a delayed dosing regimen with recombinant PvDBPII SalI formulated with adjuvant Matrix-MTM reduced the in vivo parasite multiplication rate (PMR) challenged with the P. vivax Thai isolate PvW1. We describe extensive analysis of the polyfunctional antibody responses elicited by PvDBPII immunization and identify immune correlates for PMR reduction. A classification algorithm identified antibody features that contribute significantly to PMR reduction. These included antibody titre, receptor-binding inhibitory titre, dissociation constant for PvDBPII-antibody interaction, complement C1q and Fc gamma receptor binding and specific IgG subclasses. These data suggest that multiple immune mechanisms elicited by PvDBPII immunization are associated with protection. The identified immune correlates could guide the development of an effective vaccine for P. vivax malaria. Importantly, all the polyfunctional antibody features that correlated with protection cross-reacted with both PvDBPII SalI and PvW1 variants, suggesting that immunization with PvDBPII should protect against diverse P. vivax isolates. ### Competing Interest Statement SJD has provided consultation services to GSK on malaria vaccines, is an inventor on patent applications relating to adenovirus-based vaccines and is an inventor on intellectual property licensed by Oxford University Innovation to AstraZeneca. AMM has provided consultation services to GSK on malaria vaccines and has an immediate family member who is an inventor on patents relating to adenovirus-based vaccines, and is an inventor on intellectual property licensed by Oxford University Innovation to AstraZeneca. CEC is an inventor on patents that relate to binding domains of erythrocyte-binding proteins of Plasmodium parasites including PvDBP. JMR is an employee of Novavax, developer of the Matrix-MTM adjuvant. ### Clinical Trial The trials are registered under the following ClinicalTrials.gov numbers: VAC069 [NCT03797989][1], VAC071 [NCT04009096][2], VAC079 [NCT04201431][3]. The research conducted at the Institut Pasteur received approval from the Institutional Review Board (IRB) of the Institut Pasteur (Research Ref IRB2022-03). ### Funding Statement Development of PvDBPII as a vaccine candidate was supported by grants from the Biotechnology Industry Research Assistance Council (BIRAC), New Delhi and PATH Malaria Vaccine Initiative. MVDP was supported by grants from the Bill and Melinda Gates Foundation and Department of Biotechnology (DBT), Government of India. This work was also supported in part by grants from Agence Nationale de Recherche to CEC [ANR-18-CE15-0026 and ANR-21-CE15-0013-01]. CEC is supported by the French Government's Laboratoire d'Excellence "PARAFRAP" [ANR-11-LABX-0024-PARAFRAP] in addition to core funding from Institut Pasteur. FJM was supported by a Fellowship from Ecole Doctorale BioSPC (ED562), F-75006, Université Paris Cité. The VAC069 and VAC071 trials were funded by the European Union's Horizon 2020 research and innovation program under grant agreement 733073 for MultiViVax. The VAC079 trial was funded by the Wellcome Trust Malaria Infection Study in Thailand (MIST) program [212336/Z/18/Z]. This work was also supported in part by the UK Medical Research Council (MRC) [G1100086] and the National Institute for Health Research (NIHR) Oxford Biomedical Research Centre (BRC). CMN held a Wellcome Trust Sir Henry Wellcome Postdoctoral Fellowship [209200/Z/17/Z]. SJD is a Jenner Investigator and held a Wellcome Trust Senior Fellowship [106917/Z/15/Z]. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Not Applicable The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The clinical trial studies had received ethical approval from UK National Health Service Research Ethics Services, (VAC069: Hampshire A Research Ethics Committee, Ref 18/SC/0577; VAC071: Oxford A Research Ethics Committee, Ref 19/SC/0193; VAC079: Oxford A Research Ethics Committee, Ref 19/SC/0330). The vaccine trials were approved by the UK Medicines and Healthcare products Regulatory Agency (VAC071: EudraCT 2019-000643-27; VAC079: EudraCT 2019-002872-14). The trials are registered under the following ClinicalTrials.gov numbers: VAC069 [NCT03797989][1], VAC071 [NCT04009096][2], VAC079 [NCT04201431][3]. The research conducted at the Institut Pasteur received approval from the Institutional Review Board (IRB) of the Institut Pasteur (Research Ref IRB2022-03). 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. Not Applicable 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). Not Applicable I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Not Applicable All data that support the findings of this study will be made available online with the manuscript. [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT03797989&atom=%2Fmedrxiv%2Fearly%2F2023%2F08%2F02%2F2023.08.01.23293515.atom [2]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT04009096&atom=%2Fmedrxiv%2Fearly%2F2023%2F08%2F02%2F2023.08.01.23293515.atom [3]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT04201431&atom=%2Fmedrxiv%2Fearly%2F2023%2F08%2F02%2F2023.08.01.23293515.atom