Journal Article

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

Cohen, Joe, Ockenhouse, Christian F., Dowler, Megan, Kester, Kent E., Stewart, V. Ann, Juompan, Laure, Cummings, James F., Krzych, Urszula, Heppner, D. Gray, Wirtz, Robert A., Ballou, W. Ripley, Dubois, Marie-Claude, Ofori-Anyinam, Opokua, Schwenk, Robert, Nielsen, Robin A., Lievens, Marc, Debebe, Zufan, Pinelis, Evgeny, Moris, Philippe, Williams, Jack

2009

Overview

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]-γ, tumor necrosis factor-α, or CD40L), and more ex vivo IFN-γ 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 µg/mL; P <.001), higher numbers of CSP-specific CD4+ T cells per 106 CD4+ T cells (median, 963 vs 308 CSP-specific CD4+ T cells/106 CD4+ T cells; P <.001), and higher numbers of ex vivo IFN-γ 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 deter-mine 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.

• Publisher: The University of Chicago Press,Oxford University Press
• Subject: Adult / Animals / Antibodies, Protozoan - blood / Applied microbiology / Biological and medical sciences / Cross-Sectional Studies / Double-Blind Method / Follow-Up Studies / Fundamental and applied biological sciences. Psychology / Human protozoal diseases / Humans / Infectious diseases / Malaria / Malaria Vaccines - adverse effects / Malaria Vaccines - immunology / Malaria Vaccines - standards / Malaria, Falciparum - immunology / Malaria, Falciparum - prevention & control / Medical sciences / Microbiology / Mozambique - epidemiology / Parasitemia / Parasitic diseases / Plasmodium falciparum - immunology / Protozoal diseases / Time Factors / Vaccines, antisera, therapeutical immunoglobulins and monoclonal antibodies (general aspects)