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SAFETY AND IMMUNOGENICITY OF RTS,S+TRAP MALARIA VACCINE, FORMULATED IN THE AS02A ADJUVANT SYSTEM, IN INFANT RHESUS MONKEYS

Malaria vaccine RTS,S combined with thrombospondin-related anonymous protein (TRAP) and formulated with AS02A (RTS,S+TRAP/AS02A) is safe and immunogenic in adult humans and rhesus monkeys (Macaca mulatta). Here, RTS,S+TRAP/AS02A was administered on a 0-, 1-, and 3-month schedule to three cohorts of infant monkeys, along with adult comparators. Cohort 1 evaluated 1/5, 1/2, and full adult doses, with the first dose administration at one month of age; cohort 2 monkeys received full adult doses, with the first dose administration at one versus three months of age; and, cohort 3 compared infants gestated in mothers with or without previous RTS,S/AS02A immunization. Immunization site reactogenicity was mild. Some infants, including the phosphate-buffered saline only recipient, developed transient iron-deficiency anemia, which is considered a result of repeated phlebotomies. All RTS,S+TRAP/AS02A regimens induced vigorous antibody responses that persisted through 12 weeks after the last vaccine dose. Modest lymphoproliferative and ELISPOT (interferon- and interleukin-5) responses, particularly to TRAP, approximated adult comparators. RTS,S+TRAP/AS02A was safe and well tolerated. Vigorous antibody production and modest, selective cell-mediated immune responses suggest that RTS,S+TRAP/AS02A may be immunogenic in human infants.

Received November 17, 2003. Accepted for publication January 19, 2004.

Acknowledgments: We thank Howard Engers, John Parrish, David Ruble, Urszula Krzych, and Kip Hartman for scientific support, and Prapatsorn Ngaowichit for administrative support.

Financial support: This study was supported by a grant from the Special Program for Research and Training in Tropical Diseases (TDR) from the World Health Organization (Geneva, Switzerland) and by the U.S. Army Medical Research and Materiel Command (Fort Detrick, Frederick, MD).

Disclaimer: The opinions or assertions presented herein are the private views of the authors and are not to be construed as official or as reflecting the views of the U.S. Departments of the Army or Defense.

Disclosures: Gerald Voss, Joe Cohen, and W. Ripley Ballou are employees of GlaxoSmithKline. The RTS,S malaria vaccine is being co-developed by Walter Reed Army Institute of Research and Glaxo-SmithKline. The study used GlaxoSmithKline vaccine.

Authors’ addresses: Douglas S. Walsh, Dermatology Service, Eisenhower Army Medical Center, Fort Gordon, GA 30905, Telephone: 706-787-1472, Fax: 706-787-1354, E-mail: douglas. walsh{at}se.amedd.army.mil. Sathit Pichyangkul, Montip Gettayacamin, Pongsri Tongtawe, Pranee Hansukjariya, and R. Scott Miller, U.S. Army Medical Component, Armed Forces Research Institute of Medical Sciences, 315/6 Rajvithi Road, Bangkok 10400, Thailand. Claire-Anne Siegrist, World Health Organization Collaborating Center for Vaccinology and Neonatal Immunology, Department of Pathology and Pediatrics, University of Geneva Medical School, Geneva, Switzerland. Kent E. Kester, Department of Clinical Trials, Walter Reed Army Institute of Research, Silver Spring, MD 20910. Carolyn A. Holland, Ann V. Stewart, and D. Gary Heppner, Jr., Department of Immunology, Walter Reed Army Institute of Research, Silver Spring, MD 20910. Gerald Voss, Joe Cohen, and W. Ripley Ballou, GlaxoSmithKline Biologicals, Rixensart, Belgium.

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