A 4-dose RTS,S malaria vaccine schedule provides higher protection against severe malaria than a 3-dose schedule.

The MVPE-CC consortium contributed key evidence reviewed in a joint session of the WHO’s Strategic Advisory Group of Experts on Immunisation (SAGE) and Malaria Policy Advisory Group (MPAG) held in September 2025 for considerations of malaria vaccination schedules in perennial settings. The conclusions and recommendations of the SAGE and MPAG were published in the latest issue of the Weekly Epidemiological Record (No 49, 5 December 2025).

December 2025

WHO has recommended two malaria vaccines, RTS,S/AS01 (RTS,S) and R21/Matrix-M (R21) to prevent P. falciparum malaria in children. Pilot implementation of malaria vaccination in Ghana, Kenya and Malawi between 2019 and 2023 showed high community demand and acceptance for malaria vaccination. During the 4 years of the RTS,S pilots, malaria vaccine introduction resulted in a 13% drop in deaths from all causes among children age-eligible for vaccination and a substantial reduction in hospitalisations for severe malaria.

Following completion of the pilots, other countries across Africa have introduced the vaccines into their routine immunisation systems. As of November 2025, 24 countries, including the three pilot countries, are providing malaria vaccines through their routine immunization systems.  In September 2025, a joint session of the WHO’s Strategic Advisory Group of Experts on Immunisation (SAGE) and Malaria Policy Advisory Group (MPAG) was held to assess whether a 3-dose malaria vaccine schedule may be considered an alternative to the currently recommended 4-dose schedule in certain contexts. SAGE and MPAG reviewed all available evidence, including findings of the Malaria Vaccine Programme Evaluation case control studies (MVPE-CC).

RTS,S/AS01 malaria vaccine, also known as Mosquirix. Credit: Kintampo Health Research Center (KHRC)

The case-control studies were recommended by the WHO’s SAGE and MPAG Working Group as part of the broad evaluation of the pilot introduction of RTS,S to provide additional information on safety and effectiveness of the vaccine, in vaccinated children compared to unvaccinated children. In 2021, the MVPE-CC consortium received a grant from the European and Developing Countries Clinical Trial Partnership (EDCTP) to implement the case-control studies in Ghana, Kenya and Malawi. The studies were designed to ascertain the added health benefit of the fourth dose of RTS,S, compared to a three-dose regimen; provide additional estimates of the vaccine’s effectiveness; and consolidate information about safety in children who received the malaria vaccine through the national immunisation programmes.  

Following the review of all available evidence, SAGE and MPAG reiterated the WHO recommendation for a four-dose schedule for malaria vaccines. The case-control studies confirmed the safety of the malaria vaccine and its impact on severe malaria. The evidence showed that the four-dose schedule provides higher protection against clinical and severe malaria than a three-dose schedule in moderate to high transmission settings and that a four-dose schedule should be retained. Additionally, there was no evidence of a rebound or increase in malaria among children who received only three doses of the malaria vaccine. The recommendation further states that children living in fragile areas where the delivery of vaccines in the second year of life is not operationally feasible can benefit from a three-dose schedule until obstacles to the delivery of the fourth dose are resolved. Additionally, the WHO recommends that countries align the timing of the fourth dose with the timing of other vaccines already administered in the second year of a child’s life to reduce delivery burden.

The conclusions and recommendations of the SAGE and MPAG session were published in the December 2025 issue of the Weekly Epidemiological Record.

The MVPE-CC consortium, its partners and collaborators are happy to have contributed key evidence that has informed malaria vaccine dose schedule recommendations. The consortium is preparing a manuscript detailing the results of the case-control studies, as well as a methodology manuscript and a case-control toolkit to disseminate the methodology to the larger scientific community.

If you wish to learn more about how the case-control studies were conducted, check out our video.

About MVPE-CC:

The MVPE-CC project, part of the Malaria Vaccine Pilot Evaluation, uses case-control studies to assess the safety and effectiveness of the RTS,S malaria vaccine, including the added benefit of the fourth dose. By supporting national immunisation and malaria programs, MVPE-CC helps strengthen their capacity to monitor vaccine safety and impact. Funded by the European and Developing Countries Clinical Trials Partnership (EDCTP), MVPE-CC is a collaborative project that brings together a multidisciplinary consortium led by Kintampo Health Research Centre (Ghana), alongside European Vaccine Initiative (Germany), African Research Collaboration for Health Limited (Kenya), Kenya Medical Research Institute (Kenya), London School of Hygiene and Tropical Medicine (UK), PATH (USA), and Kamuzu University of Health Sciences (Malawi). Learn more: https://mvpecc.kintampo-hrc.org/

This project is part of the EDCTP2 programme supported by the European Union (RIA2020S-3310-MVPE-CC). With special thanks to the World Health Organization and National Ministries of Health from Malawi, Kenya and Ghana for their valuable contributions.