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

Kent E. Kester(Walter Reed Army Institute of Research), James F. Cummings(Walter Reed Army Institute of Research), Opokua Ofori‐Anyinam(GlaxoSmithKline (Belgium)), Christian F. Ockenhouse(Walter Reed Army Institute of Research), Urszula Krzych(Walter Reed Army Institute of Research), Philippe Moris(GlaxoSmithKline (Belgium)), Robert Schwenk(Walter Reed Army Institute of Research), Robin A. Nielsen(Walter Reed Army Institute of Research), Zufan Debebe(Walter Reed Army Institute of Research), Evgeny Pinelis(Walter Reed Army Institute of Research), Laure Juompan(Walter Reed Army Institute of Research), Jack Williams(Walter Reed Army Institute of Research), Megan Dowler(Walter Reed Army Institute of Research), V. Ann Stewart(Walter Reed Army Institute of Research), Robert A. Wirtz(Centers for Disease Control and Prevention), Marie‐Claude Dubois(GlaxoSmithKline (Belgium)), Marc Lievens(GlaxoSmithKline (Belgium)), Joe Cohen(GlaxoSmithKline (Belgium)), W. Ripley Ballou(GlaxoSmithKline (Belgium)), D. Gray Heppner(Walter Reed Army Institute of Research), RTS,S Vaccine Evaluation Group
The Journal of Infectious Diseases
July 1, 2009
10.1086/600120
Cited by 538Open Access
Full Text

Abstract

BACKGROUND: To further increase the efficacy of malaria vaccine RTS,S/AS02A, we tested the RTS,S antigen formulated using the AS01B Adjuvant System (GlaxoSmithKline Biologicals). METHODS: In a double-blind, randomized trial, 102 healthy volunteers were evenly allocated to receive RTS,S/AS01B or RTS,S/AS02A vaccine at months 0, 1, and 2 of the study, followed by malaria challenge. Protected vaccine recipients were rechallenged 5 months later. RESULTS: RTS,S/AS01B and RTS,S/AS02A were well tolerated and were safe. The efficacy of RTS,S/AS01B and RTS,S/AS02A was 50% (95% confidence interval [CI], 32.9%-67.1%) and 32% (95% CI, 17.6%-47.6%), respectively. At the time of initial challenge, the RTS,S/AS01B group had greater circumsporozoite protein (CSP)-specific immune responses, including higher immunoglobulin (Ig) G titers, higher numbers of CSP-specific CD4(+) T cells expressing 2 activation markers (interleukin-2, interferon [IFN]-gamma, tumor necrosis factor-alpha, or CD40L), and more ex vivo IFN-gamma enzyme-linked immunospots (ELISPOTs) than did the RTS,S/AS02A group. Protected vaccine recipients had a higher CSP-specific IgG titer (geometric mean titer, 188 vs 73 mug/mL; P < .001), higher numbers of CSP-specific CD4(+) T cells per 10(6) CD4(+) T cells (median, 963 vs 308 CSP-specific CD4(+) T cells/10(6) CD4(+) T cells; P < .001), and higher numbers of ex vivo IFN-gamma ELISPOTs (mean, 212 vs 96 spots/million cells; P < .001). At rechallenge, 4 of 9 vaccine recipients in each group were still completely protected. CONCLUSIONS: The RTS,S/AS01B malaria vaccine warrants comparative field trials with RTS,S/AS02A to determine the best formulation for the protection of children and infants. The association between complete protection and immune responses is a potential tool for further optimization of protection. Trial registration. ClinicalTrials.gov identifier NCT00075049.

Related Papers

No related papers found

Powered by citation graph analysis