TY - JOUR
T1 - Four-year efficacy of RTS,S/AS01E and its interaction with malaria exposure
AU - Olotu, Ally
AU - Fegan, Greg
AU - Wambua, Juliana
AU - Nyangweso, George
AU - Awuondo, Ken
AU - Leach, Amanda
AU - Lievens, Marc
AU - Leboulleux, Didier
AU - Njuguna, Patricia
AU - Peshu, Norbert
AU - Marsh, Kevin
AU - Bejon, Philip
PY - 2013
Y1 - 2013
N2 - 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.)
AB - 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.)
U2 - 10.1056/NEJMoa1207564
DO - 10.1056/NEJMoa1207564
M3 - Article
SN - 0028-4793
VL - 368
SP - 1111
EP - 1120
JO - New England Journal of Medicine
JF - New England Journal of Medicine
IS - 12
ER -
