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A double-blind, phase IIb, randomized controlled trial of the malaria vaccine RTS,S/AS02A showed an efficacy of 45.0% in reducing the force of infection for Plasmodium falciparum and of 29.9% in reducing incidence of clinical malaria in children 1–4 years of age in Manhiça, Mozambique. We simulate this trial using a stochastic model of P. falciparum epidemiology, and the setting-specific seasonal pattern of entomologic inoculations as input. The simulated incidence curve for the control group was comparable with that observed in the trial. To reproduce the observed efficacy in extending time to first infection, the model needed to assume an efficacy of 52% in reducing the force of infection. This bias arises as a result of acquired partial immunity against blood stages, thus suggesting an explanation for the lower efficacy observed in a previous trial in semi-immune adult men in The Gambia. The shape of the incidence of infection curve for the vaccine cohort in Manhiça indicates that the vaccine provides incomplete protection to a large proportion of the vaccinees, rather than offering complete protection to some recipients and none to others. This behavior is compatible with a model of no decay in efficacy over the six-month surveillance period of the trial. The model accurately reproduced the lower efficacy against clinical disease than against infection. In the simulations this finding resulted from loss of acquired clinical immunity as a result of a reduction in the force of infection in the vaccinated cohort. The model also predicted greater efficacy against severe diseases than against clinical disease. The success of the simulation model in reproducing the results of the Manhiça trial encourages us to apply the same model to predict the potential public health and economic impact if RTS,S/AS02A were to be introduced into the existing expanded program on immunization.
Received September 18, 2005. Accepted for publication February 7, 2006.
Acknowledgments: We would like to thank Dan Anderegg for editorial assistance, and the members of the Technical Advisory Group (Michael Alpers, Paul Coleman, David Evans, Brian Greenwood, Carol Levin, Kevin Marsh, F. Ellis McKenzie, Mark Miller, and Brian Sharp), the Project Management Team at The Program for Appropriate Technology in Health (PATH) Malaria Vaccine Initiative, and GlaxoSmithKline Biologicals S.A. for their assistance. We also thank W. Ripley Ballou for his helpful comments on earlier versions of the manuscript.
Financial support: The mathematical modeling study was supported by the PATH Malaria Vaccine Initiative and GlaxoSmithKline Biologicals S.A.
Disclaimer: Publication of this report and the contents hereof do not necessarily reflect the endorsement, opinion, or viewpoints of the PATH Malaria Vaccine Initiative or GlaxoSmithKline Biologicals S.A.
* Address correspondence to Thomas Smith, Swiss Tropical Institute, Socinstrasse 57, PO Box, CH-4002, Basel, Switzerland. E-mail: Thomas-A.Smith{at}unibas.ch
Authors’ addresses: Nicolas Maire, Amanda Ross, Jürg Utzinger, Marcel Tanner, and Thomas Smith, Swiss Tropical Institute, Socinstrasse 57, PO Box, CH-4002, Basel, Switzerland, Telephone: 41-61-284-8274, Fax: 41-61-284-8105. E-mails: nicolas.maire{at}unibas.ch, amanda.ross{at}unibas.ch, juerg.utzinger{at}unibas.ch, marcel.tanner{at}unibas.ch, and Thomas-A.Smith{at}unibas.ch. John J. Aponte and Pedro Alonso, Center for International Health, Hospital Clinic/Institut d’Investigacions Biomèdiques August Pi i Sunyer, University of Barcelona, Spain. Ricardo Thompson, National Insitute of Health, Ministry of Health, Maputo, Mozambique.
Reprint requests: Thomas Smith, Swiss Tropical Institute, Socinstrasse 57, PO Box, CH-4002, Basel, Switzerland.
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