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
De autoria de Hamtandi M. Natama,
Jo Salkeld , Athanase Somé, Seyi Soremekun, Salou Diallo, Ousmane Traoré,
Toussaint Rouamba , Florence Ouédraogo, Edouard Ouédraogo, K. Carine Sonia Daboné, Nadine A. Koné, Z. Michael John Compaoré, Miguel Kafando, Massa dit Achille Bonko, Fabé Konaté, Hermann Sorgho, Carolyn M. Nielsen, Dimitra Pipini, Ababacar Diouf, Lloyd D. W. King, Umesh Shaligram, Carole A. Long, Jee-Sun Cho, Alison M. Lawrie, Katherine Skinner, Rachel Roberts, Kazutoyo Miura, John Bradley, Sarah E. Silk,
Simon J. Draper , Halidou Tinto e
Angela M. Minassian
Publicado
16 de outubro de 2024
Servidor
medRxiv
Background Two pre-erythrocytic vaccines (R21/Matrix-M and RTS,S/AS01) are now approved forP. falciparum malaria. However, neither induces blood-stage immunity against parasites that breakthrough from the liver. RH5.1/Matrix-M, a blood-stageP. falciparum malaria 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 withClinicalTrials.gov (NCT05790889 ).
Findings From 6th to 13th April and 3rd to 7th July 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 4th to 21st September 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 vitro growth 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.