Efficacy of RTS,S/AS01E malaria vaccine and exploratory analysis on anti-circumsporozoite antibody titres and protection in children aged 5-17 months in Kenya and Tanzania: a randomised controlled trial.
BACKGROUND
RTS,S/AS01E is the lead candidate malaria vaccine. We recently showed efficacy against clinical falciparum malaria in 5-17 month old children, during an average of 8 months follow-up. We aimed to assess the efficacy of RTS,S/AS01E during 15 months of follow-up.


METHODS
Between March, 2007, and October, 2008, we enrolled healthy children aged 5-17 months in Kilifi, Kenya, and Korogwe, Tanzania. Computer-generated block randomisation was used to randomly assign participants (1:1) to receive three doses (at month 0, 1, and 2) of either RTS,S/AS01E or human diploid-cell rabies vaccine. The primary endpoint was time to first clinical malaria episode, defined as the presence of fever (temperature ≥37·5°C) and a Plasmodium falciparum density of 2500/μL or more. Follow-up was 12 months for children from Korogwe and 15 months for children from Kilifi. Primary analysis was per protocol. In a post-hoc modelling analysis we characterised the associations between anti-circumsporozoite antibodies and protection against clinical malaria episodes. This study is registered with ClinicalTrials.gov, number NCT00380393.


RESULTS
894 children were assigned, 447 in each treatment group. In the per-protocol analysis, 82 of 415 children in the RTS,S/AS01E group and 125 of 420 in the rabies vaccine group had first or only clinical malaria episode by 12 months, vaccine efficacy 39·2% (95% CI 19·5-54·1, p=0·0005). At 15 months follow-up, 58 of 209 children in the RTS,S/AS01E group and 85 of 206 in the rabies vaccine group had first or only clinical malaria episode, vaccine efficacy 45·8% (24·1-61·3, p=0·0004). At 12 months after the third dose, anti-circumsporozoite antibody titre data were available for 390 children in the RTS,S/AS01E group and 391 in the rabies group. A mean of 15 months (range 12-18 months) data were available for 172 children in the RTS,S/AS01E group and 155 in the rabies group. These titres at 1 month after the third dose were not associated with protection, but titres at 6·5 months were. The level of protection increased abruptly over a narrow range of antibody concentrations. The most common adverse events were pneumonia, febrile convulsion, gastroenteritis, and P falciparum malaria.


CONCLUSIONS
RTS,S/AS01E confers sustained efficacy for at least 15 months and shows promise as a potential public health intervention against childhood malaria in malaria endemic countries.


BACKGROUND
PATH Malaria Vaccine Initiative (MVI), GlaxoSmithKline.
Kenya Medical Research Institute-Wellcome Trust Programme, Centre for Geographic Medicine Research, Kenya Medical Research Institute, Kilifi, Kenya. aolotu@kilifi.kemri-wellcome.org
Ally
A
Olotu
John
J
Lusingu
Amanda
A
Leach
Marc
M
Lievens
Johan
J
Vekemans
Salum
S
Msham
Trudie
T
Lang
Jayne
J
Gould
Marie-Claude
MC
Dubois
Erik
E
Jongert
Preeti
P
Vansadia
Terrell
T
Carter
Patricia
P
Njuguna
Ken O
KO
Awuondo
Anangisye
A
Malabeja
Omar
O
Abdul
Samwel
S
Gesase
Neema
N
Mturi
Chris J
CJ
Drakeley
Barbara
B
Savarese
Tonya
T
Villafana
Didier
D
Lapierre
W Ripley
WR
Ballou
Joe
J
Cohen
Martha M
MM
Lemnge
Norbert
N
Peshu
Kevin
K
Marsh
Eleanor M
EM
Riley
Lorenz
L
von Seidlein
Philip
P
Bejon
D000913:Antibodies, Protozoan / Q000097:blood*; D001769:Blood / Q000469:parasitology; D005334:Fever / Q000175:diagnosis; D005500:Follow-Up Studies; D006801:Humans; D007223:Infant; D007630:Kenya; D017780:Malaria Vaccines / Q000276:immunology*; D016778:Malaria, Falciparum / Q000276:immunology / Q000517:prevention & control*; D015800:Protozoan Proteins / Q000276:immunology*; D013636:Tanzania
D000913:Antibodies, Protozoan; D017780:Malaria Vaccines; D015800:Protozoan Proteins; C533816:RTS,S-AS01E vaccine; C041595:circumsporozoite protein, Protozoan
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