Background RH5.1 is a soluble protein vaccine candidate for blood-stagePlasmodium falciparummalaria, previously trialed in healthy UK adults in combination with AS01Badjuvant. 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 vitroagainstP. falciparumparasites 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 showedin vitroGIA 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-stageP. falciparumchallenge 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.
