Efficacy of RTS,S/ASO2 malaria vaccine against Plasmodium falciparum infection in semi-immune adult men in The Gambia: a randomised trial

Background RTS,S/AS02 is a pre-erythrocytic malaria vaccine based on the ci rcumsporozoite surface protein of Plasmodium falciparum fused to HBsAg, inc orporating a new adjuvant (AS02). We did a randomised trial of the efficacy of RTS,S/AS02 against natural P falciparum infection in semi-immune adult men in The Gambia. Methods 306 men aged 18-45 years were randomly assigned three doses of eith er RTS,S/AS02 or rabies vaccine (control). Volunteers were given sulfadoxin e/pyrimethamine 2 weeks before dose 3, and kept under surveillance througho ut the malaria transmission season. Blood smears were collected once a week and whenever a volunteer developed symptoms compatible with malaria. The p rimary endpoint was time to first infection with P falciparum. Analysis was per protocol. Findings 250 men (131 in the RTS,S/AS02 group and 119 in the control group) received three doses of vaccine and were followed up for 15 weeks. RTS,S/A S02 was safe and well tolerated. P falciparum infections occurred significa ntly earlier in the control group than the RTS,S/AS02 group (Wilcoxon's tes t p=0.018). Vaccine efficacy, adjusted for confounders, was 34% (95% CI 8.0 -53, p=0.014). Protection seemed to wane: estimated efficacy during the fir st 9 weeks of follow-up was 71% (46-85), but decreased to 0% (-52 to 34) in the last 6 weeks. Vaccination induced strong antibody responses to circums porozoite protein and strong T-cell responses. Protection was not limited t o the NF54 parasite genotype from which the vaccine was derived. 158 men re ceived a fourth dose the next year and were followed up for 9 weeks; during this time, vaccine efficacy was 47% (4-71, p=0.037). Interpretation RTS,S/AS02 is safe, immunogenic, and is the first pre-erythr ocytic vaccine to show significant protection against natural P falciparum infection.