A Phase III Randomised Controlled Trial Evaluating the Malaria Vaccine Candidate R21/Matrix-M™ in African Children

Abstract

Background: Developing malaria vaccines has proved difficult with many challenges, including polymorphic antigens, modest field-trial efficacy, and now limitations on vaccine supply preventing widespread impact. RTS,S/AS01, the most effective malaria vaccine candidate to date, demonstrated 56% efficacy against uncomplicated clinical malaria over 12 months in a licensure trial in African children. Recently, we found that a new R21 nanoparticle in the saponin adjuvant Matrix-M™ showed over 75% efficacy against a similar endpoint with seasonal administration in a phase IIb trial in Burkina Faso. 

Methods: We report the results of a phase III trial of the R21/Matrix-M™ malaria vaccine in 4800 children across five sites in four African countries with differing malaria transmission intensities and seasonality. Children aged 5-36 months were included at all sites. Participants were randomised 2:1 to receive a 5µg dose of R21 in 50µg Matrix-M™ adjuvant or a control vaccine (licensed rabies vaccine). Vaccines were administered as three doses, four weeks apart, with a booster 12 months following the third dose. Half the children recruited were vaccinated at two sites with seasonal malaria transmission and the remainder at “standard” sites with perennial malaria transmission using year-round age-based immunisation. Evaluation of 12-month vaccine efficacy (VE) against clinical malaria was the primary endpoint. VE against multiple malaria episodes and severe malaria as well as safety and immunogenicity were also assessed. We report follow-up to 18 months at seasonal sites and 12 months at standard sites.This trial is registered on ClinicalTrials.gov, NCT04704830    

Findings: The vaccine was well tolerated with injection site pain and fever as the most frequent local and systemic adverse events. A non-significant trend towards more febrile convulsions was observed in those who received R21/Matrix-M™ compared with rabies vaccines. There was no significant difference in the number of Adverse Events of Special Interest (AESIs) and Serious Adverse Events (SAEs) between the vaccine groups. Overall, 12 months VE was 75% (95% CI 71-79; p<0.001) at the seasonal sites and 68% (61-74; p<0.001) at the standard sites for time to first clinical malaria episode. VE against multiple clinical malaria episodes was similar: 75% (71-78; p<0.001) at the seasonal sites and 67% (59-73; p<0.001) at the standard sites. There was similar waning of efficacy over the first year of follow-up at both seasonal and standard sites. At the seasonal sites, a booster dose maintained efficacy to 18 months at the seasonal sites: VE was 74% (70-77; p<0.001) for time to first clinical malaria episode and 72% (68-75; p<0.001) against multiple clinical malaria episodes.  Vaccine-induced antibodies against the conserved central NANP repeat sequence of the circumsporozoite protein correlated strongly with vaccine efficacy. Higher antibody titres were observed in the 5–17-month age group compared with 18–36-month-olds (p<0.0001).  When compared with the older age group, the younger age group, in whom this vaccine is most likely to be deployed first, showed the highest 12-month vaccine efficacy on time to first clinical malaria episode at both seasonal, 79% (73-84, p<0.001), and standard sites, 75% (65-83, p<0.001).

Interpretation: R21/Matrix-M™ has a well-tolerated safety profile and offers high-level efficacy against clinical malaria in African children at sites of both seasonal and perennial transmission. This low-cost vaccine, soon to be available at a scale of over 100 million doses a year, and already licensed in three African countries (Burkina Faso, Ghana & Nigeria), could make a substantial contribution to reducing the burden of malaria disease and deaths in sub-Saharan Africa.

Trial Registration: This trial is registered on ClinicalTrials.gov, NCT04704830.

Funding: The Serum Institute of India Pvt. Ltd, the Wellcome Trust, the UK National Institute for Health Research Oxford Biomedical Research Centre and Open Philanthropy.

Declaration of Interest: AVSH and KJE are named as co-inventors on patent applications related to R21. US, SB, PK, HR and CSP are employees of the Serum Institute of India Private Ltd, co-developer of the R21/Matrix-M™ vaccine. Other authors declare no competing interests.

Ethical Approval: The trial was approved by the following ethics committees: L’Université des Sciences, des Techniques et des Technologies de Bamako, Faculté de Médecine et d’Odonto-Stomatologie, Faculté de Pharmacie/BP 1805, Bamako, Mali; Comité d’Ethique pour la Recherche en Santé (CERS), Ministère de l’Enseignement Superieur, de la Recherche Scientifique et de l’Innovation, Ministère de la Santé, 09 BP 7009 Ouagadougou 09, Burkina Faso; Kenya Medical Research Institute, Scientific and ethics review unit, PO Box 54840 00200, Nairobi, Kenya; National Institute for Medical Research (NIMR), 3 Barack Obama Drive, P. O. Box 9653, 11101 Dar es Salaam, Tanzania; Oxford Tropical Research Ethics Committee, University Offices, Wellington Square, Oxford OX1 2JD, UK; London School of Hygiene and Tropical Medicine Interventions Research Ethics Committee, Keppel Street, London WC1E 7HT, UK. Prior to the screening, parents or guardians of 180 participants provided written or thumb-printed consent, which was verbally re-checked at every study visit.

Keywords: malaria, vaccine, safety, efficacy, licensure trial, public health, low-cost, impact on childhood mortality