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.)

Figure 1. Screening, Randomization, and Follow-up of Study Participants

The 177 children who were deemed ineligible at screening had an age outside the acceptable range (67 children), an acute disease at enrollment (23), a serious illness on clinical screening (42), a laboratory result outside the acceptable limit (28), or another reason for ineligibility: a parent or guardian who was judged by the investigator to be unable to give consent, an inability to follow the protocol, a planned administration of another vaccination, or the use of blood products in the previous 3 months (17). The other reasons for ineligibility or withdrawal from the study were enrollment in other clinical trials (for the eight children excluded at screening only), missed vaccinations because of hospital admission, contraindications to further vaccination, medical conditions not permitted according to the protocol, and unavailability of documentation about concomitant vaccination.

Figure 2. Kaplan–Meier Estimates of the Time to the First or Only Episode of Clinical Malaria

Clinical malaria was defined as fever with a parasite count of more than 2500 per microliter. Panel A shows data for the according-to-protocol analysis, beginning 2 weeks after the last vaccination; Panel B shows data for the intention-to-treat analysis, beginning at the time of the first vaccination. P values were calculated with the use of the log-rank test.

Figure 3. Time Course of Anticircumsporozoite Antibody Titers for the According-to-Protocol Cohort, According to Vaccination Group

The box-and-whisker plots show the distribution of anticircumsporozoite antibodies according to time point and according to vaccination group. When only a horizontal line is shown, it represents the 25th, 50th, and 75th percentiles (all of which were identical). Otherwise, the horizontal line within each box represents the median, the top and bottom of each box represent the 25th and 75th percentiles, respectively, and the I bars represent the highest and lowest values within 1.5 times the interquartile range. The circles denote outliers. EU denotes enzyme-linked immunosorbent assay units.