Abstract
Background 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. Methods and Findings 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. Conclusions 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.
RTS, S/AS zero one Malaria Vaccine Trial: eighteen Months Follow-up
RTS, S/AS zero one Malaria Vaccine Trial: eighteen Months Follow-up
Efficacy and Safety of the RTS,S/AS01 Malaria Vaccine during 18 Months after Vaccination: A Phase 3 Randomized, Controlled Trial in Children and Young Infants at Eleven African Sites
Abstract
Abstract
Background: A malaria vaccine could be an important addition to current control strategies. We report the safety and vaccine efficacy of the RTS,S/AS01 vaccine during eighteen months following vaccination at eleven African sites with varying malaria transmission.
Methods and Findings: Six thousand five hundred thirty-seven infants aged six to twelve weeks and eight thousand nine hundred twenty-three children aged five to seventeen months were randomized to receive three doses of RTS,S/AS01 or comparator vaccine. Vaccine efficacy against clinical malaria in children during the eighteen months after vaccine dose three (per protocol) was forty-six percent (ninety-five percent confidence interval forty-two to fifty percent) (range forty to seventy-seven percent; vaccine efficacy, P less than 0.01 across all sites). Vaccine efficacy during the twenty months after vaccine dose one (intention to treat) was forty-five percent (ninety-five percent confidence interval forty-one to forty-nine percent). Vaccine efficacy against severe malaria, malaria hospitalization, and all-cause hospitalization was thirty-four percent (fifteen to forty-eight percent), forty-one percent (thirty to fifty percent), and nineteen percent (eleven to twenty-seven percent), respectively (intention to treat). Vaccine efficacy against clinical malaria in infants was twenty-seven percent (twenty to thirty-two percent, per protocol; twenty-seven percent, intention to treat), with no significant protection against severe malaria, malaria hospitalization, or all-cause hospitalization. Post-vaccination anti-circumsporozoite antibody geometric mean titer varied from three hundred forty-eight to seven hundred eighty-seven EU per milliliter across sites in children and from one hundred seventeen to three hundred thirty-five EU per milliliter in infants (per protocol). Vaccine efficacy waned over time in both age categories (Schoenfeld residuals P less than 0.001). The number of clinical and severe malaria cases averted per one thousand children vaccinated ranged across sites from thirty-seven to two thousand three hundred sixty-five and from negative one to forty-nine, respectively; corresponding ranges among infants were negative ten to one thousand four hundred two and negative thirteen to thirty-seven, respectively (intention to treat). Meningitis was reported as a serious adverse event in sixteen out of five thousand nine hundred forty-nine and one out of two thousand nine hundred seventy-four children and in nine out of four thousand three hundred fifty-eight and three out of two thousand one hundred seventy-nine infants in the RTS,S/AS01 and control groups, respectively.
Conclusions: RTS,S/AS01 prevented many cases of clinical and severe malaria over the eighteen months after vaccine dose three, with the highest impact in areas with the greatest malaria incidence. Vaccine efficacy was higher in children than in infants, but even at modest levels of vaccine efficacy, the number of malaria cases averted was substantial. RTS,S/AS01 could be an important addition to current malaria control in Africa.
options in the GlaxoSmithKline group of companies. JC and WRB declare that they are named inventors on patents for which the rights have been assigned to GlaxoSmithKline group of companies. DK, DLe, and BS are employees at PATH-MVI. DSc is employed by the London School of Hygiene and Tropical Medicine, and his consultancy activities for MVI are funded as a grant to the LSHTM by MVI. DK holds stock or stock options from Merck, Sharpe and Dome.