Journal of Infectious Diseases
1 August 2009 Volume 200, Number 3
Major Articles and Brief Reports
Long-Term Safety and Efficacy of the RTS,S/AS02A Malaria Vaccine in Mozambican Children
Jahit Sacarlal, Pedro Aide, John J. Aponte, Montse Renom, Amanda Leach, Inácio Mandomando, Marc Lievens, Quique Bassat, Sarah Lafuente, Eusébio Macete, Johan Vekemans, Caterina Guinovart, Betuel Sigaúque, Marla Sillman, Jessica Milman, Marie-Claude Dubois, Marie-Ange Demoitié, Joelle Thonnard, Clara Menéndez, W. Ripley Ballou, Joe Cohen, and Pedro L. Alonso
Background.We previously reported that the RTS,S/AS02A vaccine had an acceptable safety profile, was immunogenic, and demonstrated efficacy against Plasmodium falciparum malaria disease for 21 months.
Methods.We conducted a randomized, controlled, phase 2b trial of RTS,S/AS02A in 2022 Mozambican children aged 1–4 years. We now report safety results for all randomized subjects and vaccine efficacy (VE) findings for children in the Manhiça area over the 45-month surveillance period.
Results.During the surveillance period, the VE(2.5–45) (VE over months 2.5–45 of surveillance) against a first or only episode of clinical malaria disease was 30.5% (95% confidence interval [CI], 18.9%–40.4%; ), and the VE(2.5–45) against all episodes was 25.6% (95% CI, 11.9%–37.1%; ). When the same period was considered, the VE(2.5–45) for subjects protected against severe malaria was 38.3% (95% CI, 3.4%–61.3%; ). At study month 45, the prevalence of P. falciparum was 34% lower in the RTS,S/AS02A group than in the control group (66 [12.2%] of 541 patients vs 101 [18.5%] of 547 patients) ( ).
Conclusion.These results show evidence that RTS,S/AS02A maintained protection during the 45‐month surveillance period, and they highlight the feasibility of developing an effective vaccine against malaria. In combination with other malaria‐control measures, such a vaccine could greatly contribute to reducing the intolerable global burden of this disease.
Trial registration.ClinicalTrials.gov identifiers NCT00197041 and NCT00323622.
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, James F. Cummings, Opokua Ofori-Anyinam, Christian F. Ockenhouse, Urszula Krzych, Philippe Moris, Robert Schwenk, Robin A. Nielsen, Zufan Debebe, Evgeny Pinelis, Laure Juompan, Jack Williams, Megan Dowler, V. Ann Stewart, Robert A. Wirtz, Marie‐Claude Dubois, Marc Lievens, Joe Cohen, W. Ripley Ballou, D. Gray Heppner, Jr., and the RTS,S Vaccine Evaluation Group
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; ), higher numbers of CSP‐specific CD4+ T cells per CD4+ T cells (median, 963 vs 308 CSP‐specific CD4+ T cells/ CD4+ T cells; ), and higher numbers of ex vivo IFN‐γ ELISPOTs (mean, 212 vs 96 spots/million cells; ). 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.