Safety, immunogenicity and duration of protection of the RTS,S/AS02(D) malaria vaccine: one year follow-up of a randomized controlled phase I/IIb trial

Pedro Aide, John J Aponte, Montse Renom, Tacilta Nhampossa, Jahit Sacarlal, Inacio Mandomando, Quique Bassat, Maria Nélia Manaca, Amanda Leach, Marc Lievens, Johan Vekemans, Marie-Claude Dubois, Christian Loucq, W Ripley Ballou, Joe Cohen, Pedro L Alonso, Pedro Aide, John J Aponte, Montse Renom, Tacilta Nhampossa, Jahit Sacarlal, Inacio Mandomando, Quique Bassat, Maria Nélia Manaca, Amanda Leach, Marc Lievens, Johan Vekemans, Marie-Claude Dubois, Christian Loucq, W Ripley Ballou, Joe Cohen, Pedro L Alonso

Abstract

Background: The RTS,S/AS02(D) vaccine has been shown to have a promising safety profile, to be immunogenic and to confer protection against malaria in children and infants.

Methods and findings: We did a randomized, controlled, phase I/IIb trial of RTS,S/AS02(D) given at 10, 14 and 18 weeks of age staggered with routine immunization vaccines in 214 Mozambican infants. The study was double-blind until the young child completed 6 months of follow-up over which period vaccine efficacy against new Plasmodium falciparum infections was estimated at 65.9% (95% CI 42.6-79.8, p<0.0001). We now report safety, immunogenicity and estimated efficacy against clinical malaria up to 14 months after study start. Vaccine efficacy was assessed using Cox regression models. The frequency of serious adverse events was 32.7% in the RTS,S/AS02(D) and 31.8% in the control group. The geometric mean titers of anti-circumsporozoite antibodies declined from 199.9 to 7.3 EU/mL from one to 12 months post dose three of RTS,S/AS02(D), remaining 15-fold higher than in the control group. Vaccine efficacy against clinical malaria was 33% (95% CI: -4.3-56.9, p = 0.076) over 14 months of follow-up. The hazard rate of disease per 2-fold increase in anti-CS titters was reduced by 84% (95% CI 35.1-88.2, p = 0.003).

Conclusion: The RTS,S/AS02(D) malaria vaccine administered to young infants has a good safety profile and remains efficacious over 14 months. A strong association between anti-CS antibodies and risk of clinical malaria has been described for the first time. The results also suggest a decrease of both anti-CS antibodies and vaccine efficacy over time.

Trial registration: ClinicalTrials.gov NCT00197028.

Conflict of interest statement

Competing Interests: MVI supports the development and testing of a number of malaria vaccines that can be seen as competitors. Amanda Leach, Marc Lievens, Johan Vekemans, Marie-Claude Dubois, W. Ripley Ballou, and Joe Cohen are current or previous employees of GlaxoSmithKline Biologicals. Amanda Leach, W. Ripley Ballou, Marie-Claude Dubois and Joe Cohen own shares in GlaxoSmithKline. Both Joe Cohen and W. Ripley Ballou are listed as the ‘Inventors’ of patented malaria vaccines. However, neither individual holds a patent for a malaria vaccine. This does not alter the authors' adherence to all the PLoS ONE policies on sharing data and materials. None of the other authors in this paper have declared a conflict of interest.

Figures

Figure 1. Trial Profile.
Figure 1. Trial Profile.
Figure 2. Kaplan-Meier curves for the cumulative…
Figure 2. Kaplan-Meier curves for the cumulative proportion of children with at least one episode of clinical malaria between study months 3 to14 (ATP 3–14).

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