Efficacy of RTS,S/AS01E Vaccine against Malaria in Children 5 to 17 Months of Age

Abstract

BACKGROUND Plasmodium falciparum malaria is a pressing global health problem. A previous study of the malaria vaccine RTS,S (which targets the circumsporozoite protein), given with an adjuvant system (AS02A), showed a 30% rate of protection against clinical malaria in children 1 to 4 years of age. We evaluated the efficacy of RTS,S given with a more immunogenic adjuvant system (AS01E) in children 5 to 17 months of age, a target population for vaccine licensure. METHODS We conducted a double-blind, randomized trial of RTS,S/AS01E vaccine as compared with rabies vaccine in children in Kilifi, Kenya, and Korogwe, Tanzania. The primary end point was fever with a falciparum parasitemia density of more than 2500 parasites per microliter, and the mean duration of follow-up was 7.9 months (range, 4.5 to 10.5). RESULTS A total of 894 children were randomly assigned to receive the RTS,S/AS01E vaccine or the control (rabies) vaccine. Among the 809 children who completed the study procedures according to the protocol, the cumulative number in whom clinical malaria developed was 32 of 402 assigned to receive RTS,S/AS01E and 66 of 407 assigned to receive the rabies vaccine; the adjusted efficacy rate for RTS,S/AS01E was 53% (95% confidence interval [CI], 28 to 69; P<0.001) on the basis of Cox regression. Overall, there were 38 episodes of clinical malaria among recipients of RTS,S/AS01E, as compared with 86 episodes among recipients of the rabies vaccine, with an adjusted rate of efficacy against all malarial episodes of 56% (95% CI, 31 to 72; P<0.001). All 894 children were included in the intention-to-treat analysis, which showed an unadjusted efficacy rate of 49% (95% CI, 26 to 65; P<0.001). There were fewer serious adverse events among recipients of RTS,S/AS01E, and this reduction was not only due to a difference in the number of admissions directly attributable to malaria. CONCLUSIONS RTS,S/AS01E shows promise as a candidate malaria vaccine. (ClinicalTrials.gov number, NCT00380393.)

Preclinical Vaccine Study of Plasmodium vivax Circumsporozoite Protein Derived-Synthetic Polypeptides Formulated in Montanide ISA 720 and Montanide ISA 51 Adjuvants

“…1 Although great efforts have been made to develop an effective malaria vaccine and more than 70 malaria vaccine candidates have been under investigation for the last decade, only the RTS,S a P. falciparum vaccine candidate based on the circumsporozoite (CS) protein is ready to enter phase III clinical trials. [2][3][4][5] In the case of P. vivax, the second most prevalent malaria species, only two parasite antigens, the sexual P. vivax surface protein 25 ( Pv s25) expressed during the sporogonic cycle and the CS protein expressed during the pre-erythrocytic phase of the cycle, have undergone phase I clinical trials. [5][6][7] Further development of these P. vivax vaccine candidates has been difficult mainly because of limited resources and the generalized misconception that P. vivax is a benign malaria species with minor epidemiological importance.…”

Efficacy model for antibody-mediated pre-erythrocytic malaria vaccines

“…Even if a pre-erythrocytic vaccine fails to prevent infection, it can still provide partial protection by reducing the number of exo-erythrocytic forms in the liver [49], thus reducing the number of merozoites emerging from the liver and reducing the severity of blood-stage disease [50]. The increased efficacy against severe as compared with uncomplicated disease in Phase II trials of RTS,S may support this contention [4,5].…”

“…Humans living in malaria endemic areas have a degree of naturally acquired pre-erythrocytic immunity [3], comprising of an antibody response to sporozoites, a cell-mediated response during liver-stage development and an immune response that clears emerging hepatic merozoites before they begin to replicate. The most promising candidate vaccine, RTS,S/ASO1, currently in Phase III trials, boosts this natural pre-erythrocytic immune response [4,5].…”

Highlights of a Symposium, Malaria: Where are we Today, Where are we Going?

“…In phase II field trials in the Gambia [30] and Kenya [31], RTS,S vaccination conferred short-lived protection against malaria infection in approximately 35% of adults. It has recently been shown in phase II field studies in Kenyan, Mozambiquan and Tanzanian children, that 30-50% were protected from malaria after immunization with RTS,S [32][33][34][35].…”