Efficacy of a low-dose candidate malaria vaccine, R21 in adjuvant Matrix-M, with seasonal administration to children in Burkina Faso: a randomised controlled trial

Abstract

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 56% efficacy over 12 months in African children. We therefore assessed a new candidate vaccine for safety and efficacy.

Methods: In this double-blind, randomised, controlled, phase 2b trial, the low-dose circumsporozoite protein-based vaccine R21, with two different doses of adjuvant Matrix-M (MM), was given to children aged 5-17 months in Nanoro, Burkina Faso-a highly seasonal malaria transmission setting. Three vaccinations were administered at 4-week intervals before the malaria season, with a fourth dose 1 year later. All vaccines were administered intramuscularly into the thigh. Group 1 received 5 μg R21 plus 25 μg MM, group 2 received 5 μg R21 plus 50 μg MM, and group 3, the control group, received rabies vaccinations. Children were randomly assigned (1:1:1) to groups 1-3. An independent statistician generated a random allocation list, using block randomisation with variable block sizes, which was used to assign participants. Participants, their families, and the local study team were all masked to group allocation. Only the pharmacists preparing the vaccine were unmasked to group allocation. Vaccine safety, immunogenicity, and efficacy were evaluated over 1 year. The primary objective assessed protective efficacy of R21 plus MM (R21/MM) from 14 days after the third vaccination to 6 months. Primary analyses of vaccine efficacy were based on a modified intention-to-treat population, which included all participants who received three vaccinations, allowing for inclusion of participants who received the wrong vaccine at any timepoint. This trial is registered with ClinicalTrials.gov, NCT03896724.

Findings: From May 7 to June 13, 2019, 498 children aged 5-17 months were screened, and 48 were excluded. 450 children were enrolled and received at least one vaccination. 150 children were allocated to group 1, 150 children were allocated to group 2, and 150 children were allocated to group 3. The final vaccination of the primary series was administered on Aug 7, 2019. R21/MM had a favourable safety profile and was well tolerated. The majority of adverse events were mild, with the most common event being fever. None of the seven serious adverse events were attributed to the vaccine. At the 6-month primary efficacy analysis, 43 (29%) of 146 participants in group 1, 38 (26%) of 146 participants in group 2, and 105 (71%) of 147 participants in group 3 developed clinical malaria. Vaccine efficacy was 74% (95% CI 63-82) in group 1 and 77% (67-84) in group 2 at 6 months. At 1 year, vaccine efficacy remained high, at 77% (67-84) in group 1. Participants vaccinated with R21/MM showed high titres of malaria-specific anti-Asn-Ala-Asn-Pro (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 after the primary series of vaccinations after a fourth dose administered 1 year later.

Interpretation: R21/MM appears safe and very immunogenic in African children, and shows promising high-level efficacy.

Funding: The European & Developing Countries Clinical Trials Partnership, Wellcome Trust, and National Institute for Health Research Oxford Biomedical Research Centre.

Figure 1

Trial profile The main reason for withdrawal or not completing vaccination regimen was relocation outside of the study area. The parent of one participant withdrew consent after the first vaccination and two participants died during the course of the study, unrelated to vaccination. *All participants who received the third vaccination were analysed for the primary outcome, because participants with no event were censored at date of 12-month blood draw or date of withdrawal, except for three participants who withdrew within 14 days of third vaccination.

Figure 2

Kaplan-Meier estimates of the time to first episode of clinical malaria The primary analysis was based on a modified intention-to-treat population. Group 1 received 5 μg R21/25 μg MM, group 2 received 5 μg R21/50 μg MM, and group 3, the control group, received rabies vaccinations (Rabivax-S). (A) Data beginning from 14 days to 6 months after third vaccination. (B) Data beginning from 14 days to 12 months after third vaccination. MM=Matrix-M.

Figure 3

Antibody responses to R21/MM (A) Geometric mean antibody titres (95% CI). Anti-NANP antibodies were measured by ELISA at baseline; 28 days after first vaccination; 28 days, 6 months, and 1 year after the third vaccination; and 28 days after the booster (fourth) dose administered 1 year after the third dose. Group 1 received 5 μg R21/25 μg MM, group 2 received 5 μg R21/50 μg MM, and group 3, the control group, received Rabivax-S. MM=Matrix-M. NANP=Asn-Ala-Asn-Pro.