CSU 32/2011: EFFICACY OF RTS,S/AS01E MALARIA VACCINE

Tuesday, 25th of January 2011

Original Text

Dr Ally Olotu MD a , John Lusingu PhD b e f, Amanda Leach MRCPCH c, Marc Lievens MSc c, Johan Vekemans PhD c, Salum Msham MD b e, Trudie Lang PhD a, Jayne Gould PhD b e, Marie-Claude Dubois MSc c, Erik Jongert PhD c, Preeti Vansadia MHS h, Terrell Carter MHS h, Patricia Njuguna MMeD a, Ken O Awuondo HND a, Anangisye Malabeja MD b e, Omar Abdul MD b e, Samwel Gesase MD b e, Neema Mturi MRCPaed a, Chris J Drakeley PhD b g, Barbara Savarese RN h, Tonya Villafana PhD j, Didier Lapierre PhD c, W Ripley Ballou MD c, Joe Cohen PhD c, Martha M Lemnge PhD b e, Norbert Peshu MBChB a, Kevin Marsh FRCP a d, Eleanor M Riley PhD b g, Lorenz von Seidlein PhD b g i k, Philip Bejon PhD a d

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.

Funding

PATH Malaria Vaccine Initiative (MVI), GlaxoSmithKline.