Safety and efficacy of the RTS,S/AS01E candidate malaria vaccine given with expanded-programme-on-immunisation vaccines: 19 month follow-up of a randomised, open-label, phase 2 trial

Kwaku Poku Asante, Salim Abdulla, Selidji Agnandji, John Lyimo, Johan Vekemans, Solange Soulanoudjingar, Ruth Owusu, Mwanajaa Shomari, Amanda Leach, Erik Jongert, Nahya Salim, Jose F. Fernandes, David Dosoo, Maria Chikawe, Saadou Issifou, Kingsley Osei-Kwakye, Marc Lievens, Maria Paricek, Tina Möller, Stephen ApangaGrace Mwangoka, Marie Claude Dubois, Tigani Madi, Evans Kwara, Rose Minja, Aurore B. Hounkpatin, Owusu Boahen, Kingsley Kayan, George Adjei, Daniel Chandramohan, Terrell Carter, Preeti Vansadia, Marla Sillman, Barbara Savarese, Christian Loucq, Didier Lapierre, Brian Greenwood, Joe Cohen, Peter Kremsner, Seth Owusu-Agyei, Marcel Tanner, Bertrand Lell

    Research output: Contribution to journalArticle

    Abstract

    Background: RTS,S/AS01E is the lead candidate malaria vaccine. We recently showed efficacy against clinical falciparum malaria in 5–17 month old children, during an average of 8 months follow-up. We aimed to assess the efficacy of RTS,S/AS01E during 15 months of follow-up.

    Methods: Between March, 2007, and October, 2008, we enrolled healthy children aged 5–17 months in Kilifi, Kenya, and Korogwe, Tanzania. Computer-generated block randomisation was used to randomly assign participants (1:1) to receive three doses (at month 0, 1, and 2) of either RTS,S/AS01E or human diploid-cell rabies vaccine. The primary endpoint was time to first clinical malaria episode, defined as the presence of fever (temperature ≥37·5°C) and a Plasmodium falciparum density of 2500/μL or more. Follow-up was 12 months for children from Korogwe and 15 months for children from Kilifi. Primary analysis was per protocol. In a post-hoc modelling analysis we characterised the associations between anti-circumsporozoite antibodies and protection against clinical malaria episodes. This study is registered with ClinicalTrials.gov, number NCT00380393.

    Findings: 894 children were assigned, 447 in each treatment group. In the per-protocol analysis, 82 of 415 children in the RTS,S/AS01E group and 125 of 420 in the rabies vaccine group had first or only clinical malaria episode by 12 months, vaccine efficacy 39·2% (95% CI 19·5–54·1, p=0·0005). At 15 months follow-up, 58 of 209 children in the RTS,S/AS01E group and 85 of 206 in the rabies vaccine group had first or only clinical malaria episode, vaccine efficacy 45·8% (24·1–61·3, p=0·0004). At 12 months after the third dose, anti-circumsporozoite antibody titre data were available for 390 children in the RTS,S/AS01E group and 391 in the rabies group. A mean of 15 months (range 12–18 months) data were available for 172 children in the RTS,S/AS01E group and 155 in the rabies group. These titres at 1 month after the third dose were not associated with protection, but titres at 6·5 months were. The level of protection increased abruptly over a narrow range of antibody concentrations. The most common adverse events were pneumonia, febrile convulsion, gastroenteritis, and P falciparum malaria.

    Interpretation: RTS,S/AS01E confers sustained efficacy for at least 15 months and shows promise as a potential public health intervention against childhood malaria in malaria endemic countries.

    Original languageEnglish
    Pages (from-to)741-749
    Number of pages9
    JournalLancet Infectious Diseases
    Volume11
    Issue number10
    DOIs
    Publication statusPublished - Oct 2011

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  • Cite this

    Asante, K. P., Abdulla, S., Agnandji, S., Lyimo, J., Vekemans, J., Soulanoudjingar, S., Owusu, R., Shomari, M., Leach, A., Jongert, E., Salim, N., Fernandes, J. F., Dosoo, D., Chikawe, M., Issifou, S., Osei-Kwakye, K., Lievens, M., Paricek, M., Möller, T., ... Lell, B. (2011). Safety and efficacy of the RTS,S/AS01E candidate malaria vaccine given with expanded-programme-on-immunisation vaccines: 19 month follow-up of a randomised, open-label, phase 2 trial. Lancet Infectious Diseases, 11(10), 741-749. https://doi.org/10.1016/S1473-3099(11)70100-1