Safety and efficacy of the blood-stage malaria vaccine RH5.1/Matrix-M in Burkina Faso: interim results of a double-blind, randomised, controlled phase 2b trial in children

Background

Two pre-erythrocytic vaccines (R21/Matrix-M and RTS,S/AS01) are now approved forP. falciparummalaria. However, neither induces blood-stage immunity against parasites that breakthrough from the liver. RH5.1/Matrix-M, a blood-stageP. falciparummalaria vaccine candidate, was highly immunogenic in Tanzanian adults and children. We therefore assessed the safety and efficacy of RH5.1/Matrix-M in Burkinabe children.

Methods

In this double-blind, randomised, controlled phase 2b trial, RH5.1/Matrix-M was given to children aged 5-17 months in Nanoro, Burkina Faso – a seasonal malaria transmission setting. Children received either three intramuscular vaccinations with 10 µg RH5.1 protein with 50 µg Matrix-M adjuvant or three doses of rabies control vaccine, Rabivax-S, given either in a delayed third dose (0-1-5-month) regimen (first cohort) or a 0-1-2-month regimen (second cohort). Vaccinations were completed part-way through the malaria season. Children were randomly assigned 2:1 within each cohort to receive RH5.1/Matrix-M or Rabivax-S. Participants were assigned according to a random allocation list generated by an independent statistician using block randomisation with variable block sizes. Participants, their families, and the study teams were masked to group allocation; only pharmacists who prepared the vaccines were unmasked.

Vaccine safety, immunogenicity, and efficacy were evaluated. Co-primary objectives assessed were: i) safety and reactogenicity of RH5.1/Matrix-M, and ii) protective efficacy of RH5.1/Matrix-M against clinical malaria from 14 days to 6 months post-third vaccination in the per-protocol population. This trial is registered with<ext-link xmlns:xlink="http://www.w3.org/1999/xlink" ext-link-type="uri" xlink:href="http://ClinicalTrials.gov">ClinicalTrials.gov</ext-link>(<ext-link xmlns:xlink="http://www.w3.org/1999/xlink" ext-link-type="clintrialgov" xlink:href="NCT05790889">NCT05790889</ext-link>).

Findings

From 6^thto 13^thApril and 3^rdto 7^thJuly 2023, 412 children aged 5-17 months were screened, and 51 were excluded. A total of 361 children were enrolled in this study. In the first cohort, 119 were assigned to the RH5.1/Matrix-M delayed third dose group, and 62 to the equivalent rabies control group. The second cohort included 120 children in the monthly RH5.1/Matrix-M group and 60 in the equivalent rabies control group. The final vaccination was administered to all groups from 4^thto 21^stSeptember 2023. RH5.1/Matrix-M in both cohorts had a favourable safety profile and was well tolerated. Most adverse events were mild, with the most common being local swelling and fever. No serious adverse events were reported. A Cox regression model was used to analyse the primary endpoint of time to first episode of clinical malaria, according to the primary case definition, within 14 days to 6 months post-third vaccination. Comparing the RH5.1/Matrix-M delayed third dose regimen with the pooled control groups resulted in vaccine efficacy of 55% (95% CI 20-75%; p=0·0071). The same analysis showed a vaccine efficacy of 40% (95% CI -3-65%; p=0·066) when comparing the monthly regimen with the pooled control groups. Participants vaccinated with RH5.1/Matrix-M in both cohorts showed high concentrations of anti-RH5.1 serum IgG antibodies 14 days post-third vaccination, and the purified IgG showed high levels ofin vitrogrowth inhibition activity (GIA) againstP. falciparum; these responses were higher in RH5.1/Matrix-M vaccinees who received the delayed third dose, as opposed to monthly, regimen.

Interpretation

RH5.1/Matrix-M appears safe and highly immunogenic in African children and shows promising efficacy against clinical malaria when given in a delayed third dose regimen. This trial remains ongoing to further monitor efficacy over time.

Funding

The European and Developing Countries Clinical Trials Partnership; the UK Medical Research Council; the National Institute for Health and Care Research Oxford Biomedical Research Centre; the Division of Intramural Research, National Institute of Allergy and Infectious Diseases; the US Agency for International Development; and the Wellcome Trust.