Efficacy and safety of RTS,S/AS01 malaria vaccine with or
without a booster dose in infants and children in Africa: final
results of a phase 3, individually randomised, controlled trial
- Publication date
- Publisher
- 'Elsevier BV'
Abstract
BACKGROUND: The efficacy and safety of the RTS,S/AS01 candidate
malaria vaccine during 18 months of follow-up have been
published previously. Herein, we report the final results from
the same trial, including the efficacy of a booster dose.
METHODS: From March 27, 2009, until Jan 31, 2011, children (age
5-17 months) and young infants (age 6-12 weeks) were enrolled at
11 centres in seven countries in sub-Saharan Africa.
Participants were randomly assigned (1:1:1) at first vaccination
by block randomisation with minimisation by centre to receive
three doses of RTS,S/AS01 at months 0, 1, and 2 and a booster
dose at month 20 (R3R group); three doses of RTS,S/AS01 and a
dose of comparator vaccine at month 20 (R3C group); or a
comparator vaccine at months 0, 1, 2, and 20 (C3C [control
group]). Participants were followed up until Jan 31, 2014. Cases
of clinical and severe malaria were captured through passive
case detection. Serious adverse events (SAEs) were recorded.
Analyses were by modified intention to treat and per protocol.
The coprimary endpoints were the occurrence of malaria over 12
months after dose 3 in each age category. In this final
analysis, we present data for the efficacy of the booster on the
occurrence of malaria. Vaccine efficacy (VE) against clinical
malaria was analysed by negative binomial regression and against
severe malaria by relative risk reduction. This trial is
registered with ClinicalTrials.gov, number NCT00866619.
FINDINGS: 8922 children and 6537 young infants were included in
the modified intention-to-treat analyses. Children were followed
up for a median of 48 months (IQR 39-50) and young infants for
38 months (34-41) after dose 1. From month 0 until study end,
compared with 9585 episodes of clinical malaria that met the
primary case definition in children in the C3C group, 6616
episodes occurred in the R3R group (VE 36.3%, 95% CI 31.8-40.5)
and 7396 occurred in the R3C group (28.3%, 23.3-32.9); compared
with 171 children who experienced at least one episode of severe
malaria in the C3C group, 116 children experienced at least one
episode of severe malaria in the R3R group (32.2%, 13.7 to 46.9)
and 169 in the R3C group (1.1%, -23.0 to 20.5). In young
infants, compared with 6170 episodes of clinical malaria that
met the primary case definition in the C3C group, 4993 episodes
occurred in the R3R group (VE 25.9%, 95% CI 19.9-31.5) and 5444
occurred in the R3C group (18.3%, 11.7-24.4); and compared with
116 infants who experienced at least one episode of severe
malaria in the C3C group, 96 infants experienced at least one
episode of severe malaria in the R3R group (17.3%, 95% CI -9.4
to 37.5) and 104 in the R3C group (10.3%, -17.9 to 31.8). In
children, 1774 cases of clinical malaria were averted per 1000
children (95% CI 1387-2186) in the R3R group and 1363 per 1000
children (995-1797) in the R3C group. The numbers of cases
averted per 1000 young infants were 983 (95% CI 592-1337) in the
R3R group and 558 (158-926) in the R3C group. The frequency of
SAEs overall was balanced between groups. However, meningitis
was reported as a SAE in 22 children: 11 in the R3R group, ten
in the R3C group, and one in the C3C group. The incidence of
generalised convulsive seizures within 7 days of RTS,S/AS01
booster was 2.2 per 1000 doses in young infants and 2.5 per 1000
doses in children. INTERPRETATION: RTS,S/AS01 prevented a
substantial number of cases of clinical malaria over a 3-4 year
period in young infants and children when administered with or
without a booster dose. Efficacy was enhanced by the
administration of a booster dose in both age categories. Thus,
the vaccine has the potential to make a substantial contribution
to malaria control when used in combination with other effective
control measures, especially in areas of high transmission.
FUNDING: GlaxoSmithKline Biologicals SA and the PATH Malaria
Vaccine Initiative