Efficacy of RTS,S/AS01E malaria vaccine and exploratory analysis on anti-circumsporozoite antibody titres and protection in children aged 5-17 months in Kenya and Tanzania: a randomised controlled trial.

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.

FUNDING:

PATH Malaria Vaccine Initiative (MVI), GlaxoSmithKline.

• Authors: Ally Olotu, John Lusingu, Amanda Leach, Marc Lievens, Johan Vekemans, Salum Msham, Trudie Lang, Jayne Gould, Marie-Claude Dubois, Erik Jongert, Preeti Vansadia, Terrell Carter, Patricia Njuguna, Ken O Awuondo, Anangisye Malabeja, Omar Abdul, Samwel Gesase, Neema Mturi, Chris J Drakeley, Barbara Savarese, Tonya Villafana, Didier Lapierre, W Ripley Ballou, Joe Cohen, Martha M Lemnge, Norbert Peshu, Kevin Marsh, Eleanor M Riley, Lorenz von Seidlein, Philip Bejon
• Journal: The Lancet. Infectious diseases (Lancet Infect Dis) Vol. 11 Issue 2 Pg. 102-9 (Feb 2011) ISSN: 1474-4457 [Electronic] United States
• PMID: 21237715 (Publication Type: Journal Article, Randomized Controlled Trial, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2011 Elsevier Ltd. All rights reserved.

Chemical References

• Antibodies, Protozoan
• Malaria Vaccines
• Protozoan Proteins
• RTS,S-AS01E vaccine
• circumsporozoite protein, Protozoan

Topics

• Antibodies, Protozoan (blood)
• Blood (parasitology)
• Fever (diagnosis)
• Follow-Up Studies
• Humans
• Infant
• Kenya
• Malaria Vaccines (immunology)
• Malaria, Falciparum (immunology, prevention & control)
• Protozoan Proteins (immunology)
• Tanzania