RTS,S/AS01 (Mosquirix) Malaria Vaccine Phase 3 Trial

Malaria has resisted vaccine development for reasons that reflect the complexity of the Plasmodium parasite itself. Unlike viruses, which present relatively few antigens, Plasmodium falciparum expresses thousands of proteins and shifts its antigenic profile as it passes through mosquito, liver, and red-cell stages. Decades of attempts to raise protective immunity had produced no licensed vaccine. By the time WHO recommended RTS,S in 2021, the vaccine reflected about 30 years of research and development by GSK, much of it later in partnership with PATH.

The vaccine targets the circumsporozoite protein on the surface of P. falciparum sporozoites, the parasite form inoculated during a mosquito bite, before it reaches the liver. The construct links repeat and T-cell epitope regions of the circumsporozoite protein to hepatitis B surface antigen, and is formulated with the AS01 adjuvant system to boost cellular and humoral immunity. The phase 3 trial enrolled 15,460 infants and young children in seven African countries between March 2009 and January 2011, comparing three or four doses of the vaccine against control.

In children aged 5 to 17 months given three doses, vaccine efficacy against clinical malaria was approximately 56% over the first 12 months of follow-up (50.4% by intention to treat), and efficacy against severe malaria was 47%. Over a median of 48 months, efficacy fell to 28%, and in the youngest age group (6 to 12 weeks at first dose) it was lower throughout. A fourth dose raised efficacy over the same period to 36% but did not return it to early levels. Pedro Alonso of ISGlobal in Barcelona had worked on earlier RTS,S trials in Mozambican children, and the malaria epidemiologist Brian Greenwood was an author on many RTS,S studies.

The waning efficacy provoked debate over whether a vaccine that protected little more than a quarter of children over four years should be used widely, when a disease causing hundreds of thousands of childhood deaths a year might still be cut substantially by partial protection at scale. Ghana, Kenya, and Malawi conducted a WHO-coordinated pilot rollout starting in 2019, administering the vaccine through routine immunization programs to children aged 5 to 9 months.

By October 2021 the pilots had reached more than 900,000 children and showed a 30% reduction in deadly severe malaria, and on 6 October WHO recommended the vaccine for children in sub-Saharan Africa and other regions with moderate to high transmission. Johan Vekemans, a GSK vaccine scientist, worked on RTS,S trials over more than a decade. On 2 October 2023 WHO recommended a second malaria vaccine, R21/Matrix-M.