Abstract
A malaria vaccine could be an important addition to current control strategies. We report the safety and vaccine efficacy (VE) of the RTS,S/AS01 vaccine during 18 mo following vaccination at 11 African sites with varying malaria transmission. 6,537 infants aged 6-12 wk and 8,923 children aged 5-17 mo were randomized to receive three doses of RTS,S/AS01 or comparator vaccine. VE against clinical malaria in children during the 18 mo after vaccine dose 3 (per protocol) was 46% (95% CI 42% to 50%) (range 40% to 77%; VE, p<0.01 across all sites). VE during the 20 mo after vaccine dose 1 (intention to treat [ITT]) was 45% (95% CI 41% to 49%). VE against severe malaria, malaria hospitalization, and all-cause hospitalization was 34% (95% CI 15% to 48%), 41% (95% CI 30% to 50%), and 19% (95% CI 11% to 27%), respectively (ITT). VE against clinical malaria in infants was 27% (95% CI 20% to 32%, per protocol; 27% [95% CI 21% to 33%], ITT), with no significant protection against severe malaria, malaria hospitalization, or all-cause hospitalization. Post-vaccination anti-circumsporozoite antibody geometric mean titer varied from 348 to 787 EU/ml across sites in children and from 117 to 335 EU/ml in infants (per protocol). VE waned over time in both age categories (Schoenfeld residuals p<0.001). The number of clinical and severe malaria cases averted per 1,000 children vaccinated ranged across sites from 37 to 2,365 and from -1 to 49, respectively; corresponding ranges among infants were -10 to 1,402 and -13 to 37, respectively (ITT). Meningitis was reported as a serious adverse event in 16/5,949 and 1/2,974 children and in 9/4,358 and 3/2,179 infants in the RTS,S/AS01 and control groups, respectively. RTS,S/AS01 prevented many cases of clinical and severe malaria over the 18 mo after vaccine dose 3, with the highest impact in areas with the greatest malaria incidence. VE was higher in children than in infants, but even at modest levels of VE, the number of malaria cases averted was substantial. RTS,S/AS01 could be an important addition to current malaria control in Africa. www.ClinicalTrials.gov NCT00866619 Please see later in the article for the Editors' Summary.
Highlights
Considerable gains have been made in the control of malaria during the past decade as a result of improved diagnosis, introduction of effective treatment with artemisinin combination therapy (ACT), and widespread deployment of insecticide-treated nets (ITNs) [1,2]
RTS,S/AS01 could be an important addition to current malaria control in Africa
vaccine efficacy (VE) was lower in young infants vaccinated at the age of 6–12 wk when RTS,S/AS01 was given at the same time as routine Expanded Program on Immunization (EPI) vaccines; VE against first or only clinical malaria episode in the per-protocol population was 31% (97.5% CI 24% to 38%) against clinical malaria and 37% against severe malaria
Summary
Considerable gains have been made in the control of malaria during the past decade as a result of improved diagnosis, introduction of effective treatment with artemisinin combination therapy (ACT), and widespread deployment of insecticide-treated nets (ITNs) [1,2]. The AS01 adjuvant was shown to be more immunogenic than the AS02 adjuvant used in initial studies [11], and RTS,S/AS01 was well tolerated and efficacious [12,13,14] These encouraging phase 2 trial results led to the decision to conduct a large-scale phase 3 clinical trial involving 15,460 children recruited at 11 sites in seven countries across Africa. Malaria transmission can be prevented by using long-lasting insecticides sprayed on the indoor walls of homes to kill the mosquitoes that spread the malaria parasite or by sleeping under insecticide-treated nets to avoid mosquito bites and further reduce mosquito numbers Widespread use of these preventative measures, together with the introduction of artemisinin combination therapy (an effective antimalarial treatment), has reduced the global burden of malaria by 45% in all age groups, and by 51% among young children, since 2000. Vaccine efficacy (VE) is the reduction in the incidence of a disease (the number of new cases that occur in a population in a given period) among trial participants who receive the vaccine compared to the incidence among participants who do not receive the vaccine
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