Four-year efficacy of RTS,S/AS01E and its interaction with malaria exposure

Abstract

Background: The candidate malaria vaccine RTS,S/AS01E has entered phase 3 trials, but data on long-term outcomes are limited.

Methods: For 4 years, we followed children who had been randomly assigned, at 5 to 17 months of age, to receive three doses of RTS,S/AS01E vaccine (223 children) or rabies vaccine (224 controls). The end point was clinical malaria (temperature of ≥37.5°C and Plasmodium falciparum parasitemia density of >2500 parasites per cubic millimeter). Each child's exposure to malaria was estimated with the use of the distance-weighted local prevalence of malaria.

Results: Over a period of 4 years, 118 of 223 children who received the RTS,S/AS01E vaccine and 138 of 224 of the controls had at least 1 episode of clinical malaria. Vaccine efficacies in the intention-to-treat and per-protocol analyses were 29.9% (95% confidence interval [CI], 10.3 to 45.3; P=0.005) and 32.1% (95% CI, 11.6 to 47.8; P=0.004), respectively, calculated by Cox regression. Multiple episodes were common, with 551 and 618 malarial episodes in the RTS,S/AS01E and control groups, respectively; vaccine efficacies in the intention-to-treat and per-protocol analyses were 16.8% (95% CI, -8.6 to 36.3; P=0.18) and 24.3% (95% CI, 1.9 to 41.6; P=0.04), respectively, calculated by the Andersen-Gill extension of the Cox model. For every 100 vaccinated children, 65 cases of clinical malaria were averted. Vaccine efficacy declined over time (P=0.004) and with increasing exposure to malaria (P=0.001) in the per-protocol analysis. Vaccine efficacy was 43.6% (95% CI, 15.5 to 62.3) in the first year but was -0.4% (95% CI, -32.1 to 45.3) in the fourth year. Among children with a malaria-exposure index that was average or lower than average, the vaccine efficacy was 45.1% (95% CI, 11.3 to 66.0), but among children with a malaria-exposure index that was higher than average it was 15.9% (95% CI, -11.0 to 36.4).

Conclusions: The efficacy of RTS,S/AS01E vaccine over the 4-year period was 16.8%. Efficacy declined over time and with increasing malaria exposure. (Funded by the PATH Malaria Vaccine Initiative and Wellcome Trust; ClinicalTrials.gov number, NCT00872963.).

Figure 1. Kaplan–Meier Curves and Vaccine Efficacy over Time in the Per-Protocol Cohort.

Kaplan–Meier plots of the cumulative incidence of malaria and corresponding vaccine efficacy over time are shown for the entire cohort (Panel A) and for the cohorts with low and high malaria exposure indexes (Panels B and C, respectively). Clinical falciparum malaria was defined as the presence of fever (temperature ≥37.5°C) and a Plasmodium falciparum density of more than 2500 parasites per cubic millimeter. A log (time) interaction model was used to produce the fit for the vaccine-efficacy plots. In these plots, the solid line indicates the point estimates of efficacy and the dotted lines indicate 95% confidence intervals. Vaccine efficacy was truncated at 0% as the lower limit; hence, the lower limit of the confidence interval is visible only at the start of monitoring. The lower limit of the 95% confidence interval for vaccine efficacy against the first or only episode in the cohort with a low exposure index is not visible because it is below 0 and has been truncated.

Figure 2. Incidence of Malaria in the Entire Cohort and According to Exposure Level, and Vaccine-Attributable Reduction in Cases of Malaria in the Intention-to-Treat Cohort.

Panel A shows the incidence of malaria according to year of follow-up in the entire cohort, Panel B shows the incidence in the cohort with a high exposure index, and Panel C shows the incidence in the cohort with a low exposure index. Panel D shows the cumulative number of malaria cases averted in the entire cohort and in the high-exposure and low-exposure cohorts.

Figure 3. Anti-circumsporozoite Antibody Titers in the RTS,S/AS01E Group in the Per-Protocol Cohort.

Panel A shows anti-circumsporozoite antibody titers during follow-up in children who received the RTS,S/AS01E vaccine. Anti-circumsporozoite antibody titers in the control group were consistently low or undetectable throughout follow-up and are not shown. 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. The horizontal line under the baseline values indicates that the values for the median and interquartile range were identical. Panel B shows the association between imputed anti-circumsporozoite antibody titers and the hazard ratio for clinical malaria episodes among children who received the RTS,S/AS01E vaccine, according to a Cox regression model with cubic splines and with a baseline titer of 1.0 enzyme-linked immunosorbent assay unit (EU) per milliliter as the reference. The dotted lines indicate the 95% confidence interval. There was no significant variation in risk between 1 EU per milliliter and 100 EU per milliliter (i.e., the confidence intervals include a hazard ratio of 1.0); at values above 100 EU per milliliter, however, there was a reduced risk of clinical malaria with increasing antibody titers.