Background RH5.1 is a soluble protein vaccine candidate for blood-stage Plasmodium falciparum malaria, previously trialed in healthy UK adults in combination with AS01B adjuvant. Here, RH5.1 was formulated with Matrix-M™ adjuvant to assess safety and immunogenicity in a malaria-endemic adult and pediatric population for the first time. Methods We conducted a Phase 1b, single-center, dose-escalation, age de-escalation, first-in-human trial of RH5.1/Matrix-M™ in Bagamoyo, Tanzania. Healthy adults (18-45 years) and infants (5-17 months) were recruited to receive the RH5.1/Matrix-M™ vaccine candidate in a variety of dosing regimens, including monthly dosing (0-1-2 month) or delayed booster dosing (0-1-6 month) using a 10 μg dose of RH5.1, or delayed fractional booster dosing (0-1-6 month) with the first two doses of RH5.1 at 50 μg and the third dose at 10 μg. All RH5.1 protein doses were formulated with 50 μg Matrix-M™ adjuvant. Primary outcomes for vaccine safety included solicited and unsolicited adverse events after each vaccination, along with any serious adverse events (SAEs) during the study period. Secondary outcome measures for immunogenicity included the concentration and avidity of anti-RH5.1 serum IgG antibodies by ELISA and their percentage growth inhibition activity (GIA) in vitro against P. falciparum parasites using purified IgG. All participants receiving at least one dose of vaccine were included in the primary analyses. Findings Between 25th January 2021 and 15th April 2021 a total of 60 adults and infants were enrolled; 57 of these completed the vaccination series, and 55 completed 22 months of follow-up post-third vaccination. Vaccinations were well-tolerated across both age groups. There were five SAEs involving four infant participants during the trial, none of which were deemed related to vaccination. RH5-specific T cell and serum antibody responses were induced by vaccination. The anti-RH5 serum IgG responses were significantly higher in the 5-17 month old infant groups as compared to adults. Serum antibody responses contracted over time post-third vaccination, but a similar hierarchy of responses across the age groups was maintained after 22 months follow-up (674 days post-third vaccination). Vaccine-induced anti-RH5 antibodies showed in vitro GIA with comparable functional quality across all age groups and dosing regimens. The highest anti-RH5 serum IgG responses were observed post-third vaccination in the 5-17 month old infants vaccinated with the 0-1-6 month delayed booster regimen using the 10 μg dose of RH5.1 (median 723 μg/mL ; range: 450-1436 μg/mL), resulting in 100 % (11/11 infants) showing >60 % GIA following dilution of total IgG to 2.5 mg/mL (median 88 %; range: 73-97 %). Interpretation The RH5.1/Matrix-M™ vaccine candidate shows an acceptable safety and reactogenicity profile and highly promising antibody immunogenicity in 5-17 month old infants residing in a malaria-endemic area. The 0-1-6 month delayed booster regimen in 5-17 month old infants induced the highest levels of functional GIA reported to-date following human vaccination, with all infants achieving a level of GIA previously associated with protective outcome against blood-stage P. falciparum challenge in non-human primates. These data support onward efficacy assessment of this vaccine candidate against clinical malaria in young African infants. Funding The European and Developing Countries Clinical Trials Partnership (EDCTP). Trial Registration ClinicalTrials.gov: NCT04318002.

LDWK and SJD are named inventors on patent applications relating to RH5 malaria vaccines. AMM has an immediate family member who is an inventor on patent applications relating to RH5 malaria vaccines. All other authors have declared that no conflict of interest exists.

NCT04318002

This work was funded in part by the European and Developing Countries Clinical Trials Partnership (EDCTP) Multi-Stage Malaria Vaccine Consortium (MMVC) [RIA2016V-1649-MMVC]; an African Research Leader Award to AIO from the UK Medical Research Council (MRC) [MR/P020593/1], this award was jointly funded by the UK MRC and the UK Department for International Development (DFID) under the MRC/DFID Concordat agreement and is also part of the EDCTP2 programme supported by the European Union; the UK MRC [MR/K025554/1]; the National Institute for Health and Care Research (NIHR) Oxford Biomedical Research Centre (BRC), the views expressed are those of the authors and not necessarily those of the NHS, the NIHR, or the Department of Health; the GIA work was supported by the Division of Intramural Research, National Institute of Allergy and Infectious Diseases (NIAID) and by an Interagency Agreement (AID-GH-T-15-00001) between the United States Agency for International Development (USAID) Malaria Vaccine Development Program (MVDP) and NIAID. The findings and conclusions are those of the authors and do not necessarily represent the official position of USAID. CMN held a Wellcome Trust Sir Henry Wellcome Postdoctoral Fellowship [209200/Z/17/Z]. SJD is a Jenner Investigator.

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The VAC080 trial was approved by the Oxford Tropical Research Ethics Committee in the UK (reference 9-20), and the following authorities in Tanzania: the Ifakara Health Institute Institutional Review Board (reference 49-2020), the National Institute for Medical Research, the National Health Research Ethics Sub-Committee and the Tanzania Medicines and Medical Devices Authority (reference TMDA0020/CTR/0006/01).

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