Malaria Vaccines: Introduction, Use, and Potential Impact

In October 2021, WHO recommended widespread use of the RTS,S/AS01 (RTS,S) malaria vaccine among children in sub-Saharan Africa and other regions with moderate to high P. falciparum transmission [3]. The RTS,S vaccine was the first malaria vaccine to be tested in phase 3 clinical trials and the first to be assessed in routine immunization programs in malaria-endemic areas [4]. The WHO recommendation came following a successful pilot program in Ghana, Kenya, and Malawi that reached more than 900,000 children and demonstrated that malaria vaccines could be administered through routine immunization programs despite their unique dosing schedule.

The RTS,S vaccine has been found to be safe and effective, with vaccine efficacy varying with differing vaccination strategies. Post-introduction studies from clinical trials and the pilot program provide evidence of a significant reduction in malaria burden following vaccination. A randomized controlled trial found that RTS,S provided substantial protection against clinical malaria: Across 11 study sites in seven countries, four doses of RTS,S provided 36% vaccine efficacy against clinical malaria in children aged 15–17 months [5]. Additional yearly doses have been shown to maintain vaccine efficacy for up to 50 months [6]. When the vaccine was administered just prior to the transmission season, areas with lower transmission often saw higher vaccine efficacy, while high transmission areas—where disease burden is higher—saw a greater reduction in malaria cases, indicating where the vaccine may have the most public health impact [7]. Results from the pilot program countries showed that 24 months after vaccination, there was a 9% reduction in all-cause mortality and 32% reduction in severe malaria hospitalizations among children under 5 years [8]. 

In October 2023, WHO recommended the R21/Matrix-M (R21) vaccine for the prevention of malaria among children [9]. Like the RTS,S vaccine, the R21 vaccine protects against P. falciparum malaria. Studies have found the R21 vaccine to be safe and effective, particularly when given just before the high transmission season. In a randomized phase 3 clinical trial, vaccine efficacy of three doses of R21 in children aged 5–36 months against multiple episodes of clinical malaria was 72% across seasonal sites and standard sites (where malaria transmission occurs throughout the year) [10]. In areas with highly seasonal malaria transmission, the vaccine was found to reduce symptomatic cases of malaria by 75% for 12 months following a three-dose series, compared to 67% at standard sites, with a fourth dose given a year later found to maintain high efficacy [10]. 

Both the RTS,S and R21 vaccines have been prequalified by WHO. WHO recommends countries choose a vaccine product based on programmatic characteristics, vaccine supply, and vaccine affordability considerations.  

These two vaccines use the same mechanism to protect against malaria [11]. These pre-erythrocytic vaccines are based on the circumsporozoite protein and trigger the production of antibodies that target sporozoites (highly mobile forms of P. falciparum parasites that are injected by female anopheline mosquitoes) before they infect liver cells, preventing them from going on to invade red blood cells [4]. There are more than a dozen additional malaria vaccines in clinical development, many of which target different stages of the parasite. Blood stage vaccines target the parasite stage that infects red blood cells, while transmission-blocking vaccines aim to interrupt human-to-mosquito-to-human transmission by targeting the sexual stage of the parasite [12]. 

Of the 25 countries that have introduced malaria vaccines to date, 10 countries use the RTS,S vaccine, 14 countries use the R21 vaccine, and one country (Ghana) uses both vaccines.