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
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, 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
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.
Copyright © 2011 Elsevier Ltd. All rights reserved.
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References
- Snow RW, Guerra CA, Noor AM, Myint HY, Hay SI. The global distribution of clinical episodes of Plasmodium falciparum malaria. Nature. 2005;434:214–217.
- Bryce J, Boschi-Pinto C, Shibuya K, Black RE, WHO Child Health Epidemiology Reference Group WHO estimates of the causes of death in children. Lancet. 2005;365:1147–1152.
- Okiro EA, Hay SI, Gikandi PW. The decline in paediatric malaria admissions on the coast of Kenya. Malar J. 2007;6:151.
- WHO World malaria report. 2010. (accessed Dec 16, 2010).
- Bhattarai A, Ali AS, Kachur SP. Impact of artemisinin-based combination therapy and insecticide-treated nets on malaria burden in Zanzibar. PLoS Med. 2007;4:e309.
- Bejon P, Lusingu J, Olotu A. Efficacy of RTS,S/AS01E vaccine against malaria in children 5 to 17 months of age. N Engl J Med. 2008;359:2521–2532.
- Alonso PL, Sacarlal J, Aponte JJ. Efficacy of the RTS,S/AS02A vaccine against Plasmodium falciparum infection and disease in young African children: randomised controlled trial. Lancet. 2004;364:1411–1420.
- Alonso PL, Sacarlal J, Aponte JJ. Duration of protection with RTS,S/AS02A malaria vaccine in prevention of Plasmodium falciparum disease in Mozambican children: single-blind extended follow-up of a randomised controlled trial. Lancet. 2005;366:2012–2018.
- Kester KE, Cummings JF, Ofori-Anyinam O. Randomized, double-blind, phase 2a trial of falciparum malaria vaccines RTS,S/AS01B and RTS,S/AS02A in malaria-naive adults: safety, efficacy, and immunologic associates of protection. J Infect Dis. 2009;200:337–346.
- Owusu-Agyei S, Ansong D, Asante K. Randomized controlled trial of RTS,S/AS02D and RTS,S/AS01E malaria candidate vaccines given according to different schedules in Ghanaian children. PLoS One. 2009;4:e7302.
- Lell B, Agnandji S, von Glasenapp I. A randomized trial assessing the safety and immunogenicity of AS01 and AS02 adjuvanted RTS,S malaria vaccine candidates in children in Gabon. PLoS one. 2009;4:e7611.
- Potocnjak P, Yoshida N, Nussenzweig RS, Nussenzweig V. Monovalent fragments (Fab) of monoclonal antibodies to a sporozoite surface antigen (Pb44) protect mice against malarial infection. J Exp Med. 1980;151:1504–1513.
- Aponte JJ, Aide P, Renom M. Safety of the RTS,S/AS02D candidate malaria vaccine in infants living in a highly endemic area of Mozambique: a double blind randomised controlled phase I/IIb trial. Lancet. 2007;370:1543–1551.
- Guinovart C, Aponte JJ, Sacarlal J. Insights into long-lasting protection induced by RTS,S/AS02A malaria vaccine: further results from a phase IIb trial in Mozambican children. PLoS One. 2009;4:e5165.
- Macete EV, Sacarlal J, Aponte JJ. Evaluation of two formulations of adjuvanted RTS, S malaria vaccine in children aged 3 to 5 years living in a malaria-endemic region of Mozambique: a Phase I/IIb randomized double-blind bridging trial. Trials. 2007;8:11.
- Lusingu J, Olotu A, Leach A. Safety of the malaria vaccine candidate, RTS,S/AS01E in 5 to 17 month old Kenyan and Tanzanian children. PLoS One. 2010;5:e14090.
- Reece WH, Pinder M, Gothard PK. A CD4(+) T-cell immune response to a conserved epitope in the circumsporozoite protein correlates with protection from natural Plasmodium falciparum infection and disease. Nat Med. 2004;10:406–410.
- Pombo DJ, Lawrence G, Hirunpetcharat C. Immunity to malaria after administration of ultra-low doses of red cells infected with Plasmodium falciparum. Lancet. 2002;360:610–617.
- Bejon P, Ogada E, Peshu N, Marsh K. Interactions between age and ITN use determine the risk of febrile malaria in children. PLoS One. 2009;4:e8321.
- Amino R, Thiberge S, Martin B. Quantitative imaging of Plasmodium transmission from mosquito to mammal. Nat Med. 2006;12:220–224.
- Yamauchi LM, Coppi A, Snounou G, Sinnis P. Plasmodium sporozoites trickle out of the injection site. Cell Microbiol. 2007;9:1215–1222.
- Vanderberg JP, Frevert U. Intravital microscopy demonstrating antibody-mediated immobilisation of Plasmodium berghei sporozoites injected into skin by mosquitoes. Int J Parasitol. 2004;34:991–996.
Source: PubMed