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Randomized, controlled trial of the long term safety, immunogenicity and efficacy of RTS,S/AS02D malaria vaccine in infants living in a malaria-endemic region

Salim Abdulla19*, Nahya Salim1, Francisca Machera1, Richard Kamata1, Omar Juma1, Mwanajaa Shomari1, Sulende Kubhoja2, Ali Mohammed1, Grace Mwangoka1, Thomas Aebi13, Hassan Mshinda4, David Schellenberg5, Terrell Carter6, Tonya Villafana6, Marie-Claude Dubois7, Amanda Leach7, Marc Lievens7, Johan Vekemans7, Joe Cohen7, W Ripley Ballou7 and Marcel Tanner38

Author Affiliations

1 Bagamoyo Research and Training Centre of Ifakara Health Institute, Pwani, Tanzania

2 Muhimbili University of Health and Allied Sciences, Dar es Salaam, Tanzania

3 Swiss Tropical and Public Health Institute, Basel, Switzerland

4 Tanzania Commission for Science and Technology, Dar es Salaam, Tanzania

5 London School of Hygiene and Tropical Medicine, London, UK

6 PATH Malaria Vaccine Initiative, Washington, DC, USA

7 GlaxoSmithKline Biologicals, Rue De L'Institut 89, Rixensart, Belgium

8 University of Basel, Basel, Switzerland

9 Ifakara Health Institute, 360 Kiko Avenue, Mikocheni, PO Box 78373, Dar es Salaam, Tanzania

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Malaria Journal 2013, 12:11  doi:10.1186/1475-2875-12-11

Published: 8 January 2013

Abstract

Background

The RTS,S/AS malaria candidate vaccine is being developed with the intent to be delivered, if approved, through the Expanded Programme on Immunization (EPI) of the World Health Organization. Safety, immunogenicity and efficacy of the RTS,S/AS02D vaccine candidate when integrated into a standard EPI schedule for infants have been reported over a nine-month surveillance period. This paper describes results following 20 months of follow up.

Methods

This Phase IIb, single-centre, randomized controlled trial enrolled 340 infants in Tanzania to receive three doses of RTS,S/AS02D or hepatitis B vaccine at 8, 12, and 16 weeks of age. All infants also received DTPw/Hib (diphtheria and tetanus toxoids, whole-cell pertussis vaccine, conjugated Haemophilus influenzae type b vaccine) at the same timepoints. The study was double-blinded to month 9 and single-blinded from months 9 to 20.

Results

From month 0 to 20, at least one SAE was reported in 57/170 infants who received RTS,S/AS02D (33.5%; 95% confidence interval [CI]: 26.5, 41.2) and 62/170 infants who received hepatitis B vaccine (36.5%; 95% CI: 29.2, 44.2). The SAE profile was similar in both vaccine groups; none were considered to be related to vaccination. At month 20, 18 months after completion of vaccination, 71.8% of recipients of RTS,S/AS02D and 3.8% of recipients of hepatitis B vaccine had seropositive titres for anti-CS antibodies; seroprotective levels of anti-HBs antibodies remained in 100% of recipients of RTS,S/AS02D and 97.7% recipients of hepatitis B vaccine. Anti-HBs antibody GMTs were higher in the RTS,S/AS02D group at all post-vaccination time points compared to control. According to protocol population, vaccine efficacy against multiple episodes of malaria disease was 50.7% (95% CI: -6.5 to 77.1, p = 0.072) and 26.7% (95% CI: -33.1 to 59.6, p = 0.307) over 12 and 18 months post vaccination, respectively. In the Intention to Treat population, over the 20-month follow up, vaccine efficacy against multiple episodes of malaria disease was 14.4% (95% CI: -41.9 to 48.4, p = 0.545).

Conclusions

The acceptable safety profile and good tolerability of RTS,S/AS02D in combination with EPI vaccines previously reported from month 0 to 9 was confirmed over a 20 month surveillance period in this infant population. Antibodies against both CS and HBsAg in the RTS,S/AS02D group remained significantly higher compared to control for the study duration. Over 18 months follow up, RTS,S/AS02D prevented approximately a quarter of malaria cases in the study population.

Clinical trials

Gov identifier: NCT00289185

Keywords:
RTS,S/AS02; Falciparum; Malaria; Infants; Immunogenicity; Safety; Efficacy; EPI