RTS,S/AS01 and R21/Matrix-M are pre-erythrocytic vaccines that target the central repeat amino acid sequence Asn-Ala-Asn-Pro (NANP) region of the P. falciparum circumsporozoite protein (CSP). Go to footnote 1
Protection extends across diverse P. falciparum strains circulating in Africa. Go to footnote 2, Go to footnote 3
Given the species-specific design of these vaccines and the substantial sequence divergence of CSP across malaria parasites, meaningful protection against non-falciparum species is not expected, although this has not been directly evaluated.
Clinical trials of age-based delivery of RTS,S and R21 vaccines showed more than 50% reduction in malaria cases over the first year of follow up, and prolonged protection with the fourth dose. Go to footnote 1, Go to footnote 4, Go to footnote 5, Go to footnote 6 WHO re-affirmed its recommendation for the 4-dose schedule after a case-control study showed the fourth dose provides 30% incremental effectiveness against severe malaria compared to three doses. Go to footnote 7
An independent evaluation of RTS,S/AS01 pilot implementation in childhood immunization in three African countries during a 46-month period showed a 13% drop in mortality from all causes among children age-eligible for vaccination, and a substantial reduction (22%) in hospitalizations for severe malaria. Go to footnote 8
About 75% reduction of malaria cases was achieved over the first year of follow up when malaria vaccines were given seasonally, just prior to the start of the high transmission season, and prolonged protection with annual seasonal doses. Go to footnote 9
The WHO recommendation for R21/Matrix-M was based on the similar vaccine construct as RTS,S/AS01 and results from an ongoing trial that showed similar high vaccine efficacy across sites using age-based and seasonal vaccination approaches. There is no evidence to date showing that one vaccine performs better than the other. Go to footnote 5
Four doses of RTS,S/AS01 or R21/Matrix-M malaria vaccines provide added protection through early childhood, the period of highest risk of severe malaria in moderate-to-high-transmission settings.
Data show RTS,S/AS01 efficacy against clinical and severe malaria is highest in the first six months after the third dose, then wanes over time until a fourth dose is given 18 months later. Go to footnote 1, Go to footnote 4 The fourth dose extends protection but does not restore to highest efficacy. Protection against clinical malaria persists for up to seven years in children who received three or four doses, whereas sustained protection against severe malaria requires all four doses. Go to footnote 10 There is no evidence of severe malaria rebound in children who received only three doses. Go to footnote 11 When administered seasonally with Seasonal Malaria Chemoprevention (SMC), RTS,S/AS01 (up to seven doses) confers substantial and sustained protection against clinical and severe malaria for over five years. Go to footnote 12
Data show R21/Matrix M demonstrates high efficacy against clinical malaria the first six months after the third dose, with minimal waning observed until the fourth dose was given 12 months later. Long term follow up of Phase-3 study sites using age-based and seasonal approaches is ongoing. Go to footnote 5
- Go back to footnote reference 1aGo back to footnote reference 1bGo back to footnote reference 1c
World Health Organization (2024). Malaria vaccines: WHO position paper, May 2024. Wkly Epidemiol Rec. 99(19):225–248 (https://www.who.int/publications/i/item/who-wer-9919-225-248, accessed 13 May 2026).
- Go back to footnote reference 2
RTS,S Clinical Trials Partnership. Efficacy and safety of RTS,S/AS01 malaria vaccine. N Engl J Med. 2015;372(17):1605–1615. doi:10.1056/NEJMoa1415447.
- Go back to footnote reference 3
Datoo MS, Dicko A, Tinto H, Ouédraogo JB, Hamaluba M et al. Safety and efficacy of malaria vaccine candidate R21/Matrix-M in African children: a multicentre, double-blind, randomised, phase 3 trial. Lancet. 2024;403(10426):533–544. doi:10.1016/S0140-6736(23)02511-4.
- Go back to footnote reference 4aGo back to footnote reference 4b
RTS,S Clinical Trials Partnership. Efficacy and safety of RTS,S/AS01 malaria vaccine with or without a booster dose in infants and children in Africa: final results of a phase 3, individually randomised, controlled trial. Lancet. 2015;386(9988):31–45. doi:10.1016/S0140-6736(15)60721-8.
- Go back to footnote reference 5aGo back to footnote reference 5bGo back to footnote reference 5c
World Health Organization (2024). Full evidence report on the R21/Matrix-M malaria vaccine. Geneva: World Health Organization (https://zenodo.org/records/10908560, accessed 19 January 2026).
- Go back to footnote reference 6
Datoo MS, Dicko A, Tinto H, Ouédraogo JB, Hamaluba M et al. Safety and efficacy of malaria vaccine candidate R21/Matrix-M in African children: a multicentre, double-blind, randomised, phase 3 trial. Lancet. 2024;403(10426):533–544. doi:10.1016/S0140-6736(23)02511-4
- Go back to footnote reference 7
World Health Organization (2025). Meeting of the Strategic Advisory Group of Experts on Immunization, September 2025: conclusions and recommendations, 5 December 2025. Wkly Epidemiol Rec. 100(49):661–700 (https://iris.who.int/handle/10665/384559, accessed 20 May 2026).
- Go back to footnote reference 8
Mwapasa V, Asante KP, Milligan P, Akech S, Oduro A et al. Impact of introducing the RTS,S/AS01E malaria vaccine on mortality in young children in Ghana, Kenya, and Malawi: an observational evaluation of a cluster randomised implementation programme. Lancet. 2026;407(10541):1796–1808. doi:10.1016/S0140-6736(26)00248-5.
- Go back to footnote reference 9
Chandramohan D, Zongo I, Sagara I, Cairns M, Yerbanga RS et al. Seasonal malaria vaccination with or without seasonal malaria chemoprevention. N Engl J Med. 2021;385(11):1005–1017. doi:10.1056/NEJMoa2026330.
- Go back to footnote reference 10
Tinto H, Otieno W, Gesase S, Sorgho H, Otieno L et al. Long-term incidence of severe malaria following RTS,S/AS01 vaccination in children and infants in Africa: an open-label 3-year extension study of a phase 3 randomised controlled trial. Lancet Infect Dis. 2019;19(8):821–832. doi:10.1016/S1473-3099(19)30300-7.
- Go back to footnote reference 11
World Health Organization (2025). Meeting of the Strategic Advisory Group of Experts on Immunization, September 2025: conclusions and recommendations, 5 December 2025. Wkly Epidemiol Rec. 100(49):661–700 (https://iris.who.int/handle/10665/384559, accessed 13 May 2026).
- Go back to footnote reference 12
Dicko A, Ouedraogo J-B, Zongo I, Sagara I, Cairns M et al. Seasonal vaccination with RTS,S/AS01E vaccine with or without seasonal malaria chemoprevention in children up to the age of 5 years in Burkina Faso and Mali: a double-blind, randomised, controlled, phase 3 trial. Lancet Infect Dis. 2024;24(1):75–86. doi:10.1016/S1473-3099(23)00368-7.
