High Efficacy of a Low Dose Candidate Malaria Vaccine, R21 in 1 Adjuvant Matrix-M™, with Seasonal Administration to Children in Burkina Faso

Background: Stalled progress in controlling Plasmodium falciparum malaria highlights the need for an effective and deployable vaccine. RTS,S/AS01, the most effective malaria vaccine candidate to date, demonstrated 55·8% (97·5% confidence interval [CI], 51-60) efficacy over 12 months in African children. Methods: We conducted a double-blind, randomised, controlled trial of a low-dose circumsporozoite protein-based vaccine, R21, with two different doses of adjuvant, Matrix-M™ (MM), in children aged 5-17 months in Nanoro, Burkina Faso, a highly seasonal malaria transmission setting. Three vaccinations were administered at 4-week intervals prior to the malaria season with a fourth dose one year later. Vaccine safety, immunogenicity and efficacy were evaluated over one year. Findings: 450 children were randomised to receive the R21/MM vaccine or a control rabies vaccine. R21/MM had a 43 favourable safety profile and was well-tolerated. At 6 months, 43/146 (29·5%) who received R21/MM with low44 dose adjuvant, 38/146 (26%) who received R21/MM with high-dose adjuvant, and 105/147 (71·4%) who received the rabies vaccine developed clinical malaria. Vaccine efficacy (VE) was 74% (95% CI, 63-82) and 77% (95% CI, 67-84) in the low- and high-dose adjuvant groups, respectively. At 1 year, VE remained high at 77% (95% CI, 67-84) in the high-dose adjuvant group. Participants vaccinated with R21/MM showed high titres of malaria-specific anti-NANP antibodies 28 days after the third vaccination, which were almost doubled with the higher adjuvant dose. Titres waned but were boosted to levels similar to peak titres following the primary series of vaccinations after a fourth dose administered one year later. Interpretation: R21/Matrix-M appears safe and very immunogenic in African children, and demonstrates promising high-level efficacy. Trial Registration: ClinicalTrials.gov number: NCT03896724. Funding: The European & Developing Countries Clinical Trials Partnership (EDCTP), The Wellcome Trust and the NIHR Oxford Biomedical Research Centre. Declaration of Interest: AVSH and KJE are named as co-inventors on patent applications related to R21. GG, LF, JR and PP-A are employees of Novavax, developers of the Matrix-M adjuvant, and US is an employee of the Serum Institute of India Private Ltd, co-developer of the R21/MM vaccine. Other authors declare no competing interests. Ethical Approval: The trial was approved by the Comite d’Ethique pour la Recherche en Sante, Burkina Faso (CERS, reference number 2019-01-012), and by the national regulatory authority, Agence National de Regulation Pharmaceutique, Burkina Faso (ANRP, reference number 5005420193EC0000). Ethical approval was also granted in the United Kingdom by the Oxford Tropical Research Ethics Committee (OxTREC reference number 19-19).