Seven-Year Efficacy of RTS,S/AS01 Malaria Vaccine among Young African Children

Abstract

Background: The candidate malaria vaccine RTS,S/AS01 is being evaluated in order to inform a decision regarding its inclusion in routine vaccination schedules.

Methods: We conducted 7 years of follow-up in children who had been randomly assigned, at 5 to 17 months of age, to receive three doses of either the RTS,S/AS01 vaccine or a rabies (control) vaccine. The end point was clinical malaria (temperature of ≥37.5°C and infection with Plasmodium falciparum of >2500 parasites per cubic millimeter). In an analysis that was not prespecified, the malaria exposure of each child was estimated with the use of information on the prevalence of malaria among residents within a 1-km radius of the child's home. Vaccine efficacy was defined as 1 minus the hazard ratio or the incidence-rate ratio, multiplied by 100, in the RTS,S/AS01 group versus the control group.

Results: Over 7 years of follow-up, we identified 1002 episodes of clinical malaria among 223 children randomly assigned to the RTS,S/AS01 group and 992 episodes among 224 children randomly assigned to the control group. The vaccine efficacy, as assessed by negative binomial regression, was 4.4% (95% confidence interval [CI], -17.0 to 21.9; P=0.66) in the intention-to-treat analysis and 7.0% (95% CI, -14.5 to 24.6; P=0.52) in the per-protocol analysis. Vaccine efficacy waned over time (P=0.006 for the interaction between vaccination and time), including negative efficacy during the fifth year among children with higher-than-average exposure to malaria parasites (intention-to-treat analysis: -43.5%; 95% CI, -100.3 to -2.8 [P=0.03]; per-protocol analysis: -56.8%; 95% CI, -118.7 to -12.3 [P=0.008]).

Conclusions: A three-dose vaccination with RTS,S/AS01 was initially protective against clinical malaria, but this result was offset by rebound in later years in areas with higher-than-average exposure to malaria parasites. (Funded by the PATH Malaria Vaccine Initiative and others; ClinicalTrials.gov number, NCT00872963.).

Figure 1 (facing page). Randomization and Follow-up of Trial Participants.

We conducted three extensions: from the end of 12 months of follow-up until November 2008, from then until April 2011, and finally for an additional 3 years. Other reasons for withdrawal included children missing vaccinations because of hospital admission (with contraindications to further vaccination), medical conditions not permitted by the protocol, and incomplete documentation regarding concomitant vaccinations.

Figure 2. Malaria Incidence and Vaccine Efficacy, According to Malaria Exposure and Trial Group in the Intention-to-Treat Cohort.

Panel A shows the incidence of malaria in the cohort with a low exposure index (distance-weighted local prevalence of malaria at or below the cohort mean), and Panel B the incidence in the cohort with a high exposure index (distance-weighted local prevalence of malaria above the cohort mean). The top graphs show the incidence of malaria in the RTS,S/AS01 group and the control group according to year of follow-up. The bottom graphs show the estimates of vaccine efficacy, aggregated in 4-month windows, on the basis of the calculation of 1 minus the incidence-rate ratio times 100, with the incidence-rate ratio calculated as the incidence of malaria in the RTS,S/AS01 group divided by the incidence in the control group. The orange line indicates 0% efficacy, and the blue line indicates smoothed estimates of efficacy over time. The dashed lines indicate 95% confidence intervals, and green dots point estimates of efficacy.

Figure 3. Malaria Cases Averted during Follow-up in the Intention-to-Treat Population.

Shown are the cumulative numbers of malaria cases averted, according to year of follow-up and exposure index of the cohort. We calculated cases averted in each year by subtracting the measured incidence per person-year among participants in the RTS,S/AS01 group from the incidence per person-year among participants in the control group and then multiplying by 1000 to express the result as the number of cases averted per 1000 children vaccinated with RTS,S/AS01. We calculated cumulative cases by summing the cases averted up to and including the year under consideration.