Infectious Disease · 2011
RTS,S/AS01 (Mosquirix) Malaria Vaccine Phase 3 Trial
RTS,S/AS01 stands for the recombinant hepatitis B surface antigen fusion protein (R), the repeat (R) and T-cell epitope (T) regions of the P. falciparum circumsporozoite protein, plus hepatitis B surface antigen (S), with the AS01 adjuvant system; trade name Mosquirix
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. When the RTS,S program advanced to phase 3, it represented more than thirty years of iterative development, starting with early work at Walter Reed Army Institute of Research.
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 more than 15,000 infants and young children at 11 sites in seven sub-Saharan African countries, 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. That figure declined to around 28% over 48 months, and in the youngest age group (6 to 12 weeks at first dose) efficacy was lower throughout. A fourth dose partially restored protection but did not return it to early levels. Brian Greenwood, who had spent decades studying malaria epidemiology across Africa, contributed to site oversight and analysis. Pedro Alonso, then director of the Barcelona Institute for Global Health, coordinated the broader WHO evaluation.
The waning efficacy provoked considerable debate. Some researchers argued that a vaccine protecting little more than a quarter of children over four years was insufficient to recommend widely; others noted that in a disease causing hundreds of thousands of childhood deaths annually, even partial protection at scale could save lives. 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.
Data from the pilot countries showed reductions in childhood hospitalizations and all-cause mortality consistent with the trial efficacy estimates, and WHO issued a formal recommendation for use in African children in October 2021, the first endorsement of a vaccine against any human parasitic disease. Johan Vekemans, who led GSK's clinical development program for RTS,S, had worked on the compound through multiple phase transitions over more than a decade. A newer malaria vaccine, R21/Matrix-M, subsequently showed higher efficacy in early trials, extending the field that the RTS,S program reopened.
Key People
- Pedro Alonso — Led WHO malaria vaccine evaluation; coordinated phase 3 program oversight.
- Johan Vekemans — GSK vaccine scientist; led clinical development of RTS,S across multiple phases.
- Brian Greenwood — Malaria epidemiologist; contributed to African trial site oversight and analysis.
- Joe Cohen — GSK scientist; co-developed the original RTS,S construct.
N Engl J Med. 2011;365(20):1863-1875
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