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

  1. Hamtandi M. Natama
  2. Jo Salkeld
  3. Athanase Somé
  4. Seyi Soremekun
  5. Salou Diallo
  6. Ousmane Traoré
  7. Toussaint Rouamba
  8. Florence Ouédraogo
  9. Edouard Ouédraogo
  10. K. Carine Sonia Daboné
  11. Nadine A. Koné
  12. Z. Michael John Compaoré
  13. Miguel Kafando
  14. Massa dit Achille Bonko
  15. Fabé Konaté
  16. Hermann Sorgho
  17. Carolyn M. Nielsen
  18. Dimitra Pipini
  19. Ababacar Diouf
  20. Lloyd D. W. King
  21. Umesh Shaligram
  22. Carole A. Long
  23. Jee-Sun Cho
  24. Alison M. Lawrie
  25. Katherine Skinner
  26. Rachel Roberts
  27. Kazutoyo Miura
  28. John Bradley
  29. Sarah E. Silk
  30. Simon J. Draper
  31. Halidou Tinto
  32. Angela M. Minassian

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Abstract

Background

Two pre-erythrocytic vaccines (R21/Matrix-M and RTS,S/AS01) are now approved for P. falciparum malaria. However, neither induces blood-stage immunity against parasites that breakthrough from the liver. RH5.1/Matrix-M, a blood-stage P. 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 with ClinicalTrials.gov ( NCT05790889 ).

Findings

From 6 th to 13 th April and 3 rd to 7 th 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 4 th to 21 st 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 of in vitro growth inhibition activity (GIA) against P. 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.

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  1. PREreview

    This Zenodo record is a permanently preserved version of a Structured PREreview. You can view the complete PREreview at https://prereview.org/reviews/14159663.

    Does the introduction explain the objective of the research presented in the preprint? Yes The introduction clearly states the objective of assessing the safety and efficacy of the RH5.1/Matrix-M blood-stage malaria vaccine candidate in children aged 5-17 months in Burkina Faso. It provides context on existing pre-erythrocytic vaccines and explains the potential benefits of a blood-stage vaccine.
    Are the methods well-suited for this research? Highly appropriate The study uses a double-blind, randomized, controlled design, which is the gold standard for vaccine efficacy trials. The methods include appropriate control groups, blinding procedures, and statistical analyses. The trial design, including the use of two different dosing regimens, allows for comprehensive evaluation of the vaccine's safety and efficacy.
    Are the conclusions supported by the data? Somewhat supported The conclusions are largely supported by the data presented. The authors accurately report the efficacy results and safety profile. However, some conclusions about the potential for combining this vaccine with pre-erythrocytic vaccines are somewhat speculative and would require further study to confirm these claims. Additionally, longer-term follow-up studies are necessary to confirm the durability and efficacy of the vaccine.
    Are the data presentations, including visualizations, well-suited to represent the data? Somewhat appropriate and clear The current figures and tables effectively communicate the key results, but additional visualizations could further enhance clarity and interpretation. Specifically, adding forest plots for efficacy comparisons between dosing regimens and subgroups would provide a more detailed view of the effect sizes and confidence intervals. Furthermore, the Kaplan-Meier curves for efficacy could benefit from additional annotations or breakpoints, highlighting when and where differences in efficacy become evident between groups. These enhancements would make it easier for readers to grasp the nuances of vaccine performance across different conditions and over time.
    How clearly do the authors discuss, explain, and interpret their findings and potential next steps for the research? Somewhat clearly The authors mention ongoing trials but could improve the discussion by specifying how these studies will address the limitations of the current trial, such as testing in areas with varying malaria transmission intensities. Highlighting potential combination strategies with pre-erythrocytic vaccines in future work could also provide a roadmap for their next experiments.
    Is the preprint likely to advance academic knowledge? Highly likely This study represents the first demonstration of significant efficacy for a blood-stage malaria vaccine in young children. It provides important proof-of-concept data that could lead to new approaches in malaria vaccine development and potentially improve overall vaccine efficacy when combined with existing strategies.
    Would it benefit from language editing? No The preprint is well-written and clear. Any minor language issues do not significantly impact the understanding of the research, however simplifying some of the technical jargon or adding parenthetical explanations for key terms.
    Would you recommend this preprint to others? Yes, it's of high quality This preprint reports on a well-designed and executed clinical trial with important implications for malaria vaccine development. The methods are rigorous, the results are clearly presented, and the discussion provides valuable context and future directions.
    Is it ready for attention from an editor, publisher or broader audience? Yes, as it is The preprint is well-structured, comprehensive, and reports on important findings from a rigorously conducted clinical trial. While the peer review may suggest some minor revisions or additional analyses, the core content and conclusions are likely to remain unchanged and are of immediate interest to the scientific community.

    Competing interests

    The authors declare that they have no competing interests.

  2. Version published to 10.1101/2024.10.15.24315473v1 on medRxiv