Safety of the RTS,S/AS02D candidate malaria vaccine in infants living in a highly endemic area of Mozambique: a double blind randomised controlled phase I/IIb trial.
BACKGROUND
Malaria remains a leading global health problem that requires the improved use of existing interventions and the accelerated development of new control methods. We aimed to assess the safety, immunogenicity, and initial efficacy of the malaria vaccine RTS,S/AS02D in infants in Africa.


METHODS
We did a phase I/IIb double-blind randomised trial of 214 infants in Mozambique. Infants were randomly assigned to receive three doses either of RTS,S/AS02D or the hepatitis B vaccine Engerix-B at ages 10 weeks, 14 weeks, and 18 weeks of age, as well as routine immunisation vaccines given at 8, 12, and 16 weeks of age. The primary endpoint was safety of the RTS,S/AS02D during the first 6 months of the study, and analysis was by intention to treat. Secondary endpoints included immunogenicity and analysis of new Plasmodium falciparum infections during a 3-month follow up after the third dose. Time to new infections in the per-protocol cohort were compared between groups using Cox regression models. This study is registered with ClinicalTrials.gov, number NCT00197028.


RESULTS
There were 17 children (15.9%; 95% CI 9.5-24.2) with serious adverse events in each group. In the follow-up which ended on March 6, 2007, there were 31 serious adverse events in the RTS,S/AS02D group and 30 serious adverse events in the Engerix-B group, none of which were reported as related to vaccination. There were four deaths during this same follow-up period; all of them after the active detection of infection period had finished at study month 6 (two in RTSS/AS02D group and two in the Engerix-B group). RTS,S/AS02D induced high titres of anti-circumsporozoite antibodies. 68 first or only P falciparum infections were documented: 22 in the RTS,S/AS02D group and 46 in the control group. The adjusted vaccine efficacy was 65.9% (95% CI 42.6-79.8%, p<0.0001).


CONCLUSIONS
The RTS,S/AS02D malaria vaccine was safe, well tolerated, and immunogenic in young infants. These findings set the stage for expanded phase III efficacy studies to confirm vaccine efficacy against clinical malaria disease.
Aponte
John J
JJ
Barcelona Centre for International Health Research (CRESIB), Hospital Clínic/Institut d'Investigacions Biomediques August Pi i Sunyer, Universitat de Barcelona, Barcelona, Spain.
Aide
Pedro
P
Renom
Montse
M
Mandomando
Inacio
I
Bassat
Quique
Q
Sacarlal
Jahit
J
Manaca
M Nelia
MN
Lafuente
Sarah
S
Barbosa
Arnoldo
A
Leach
Amanda
A
Lievens
Marc
M
Vekemans
Johan
J
Sigauque
Betuel
B
Dubois
Marie-Claude
MC
Demoitié
Marie-Ange
MA
Sillman
Marla
M
Savarese
Barbara
B
McNeil
John G
JG
Macete
Eusebio
E
Ballou
W Ripley
WR
Cohen
Joe
J
Alonso
Pedro L
PL
D000818:Animals; D000913:Antibodies, Protozoan / Q000097:blood; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D007115:Immunization Schedule; D007223:Infant; D008288:Malaria / Q000517:prevention & control*; D017780:Malaria Vaccines / Q000008:administration & dosage / Q000009:adverse effects*; D008297:Male; D009073:Mozambique; D010963:Plasmodium falciparum / Q000276:immunology*
D000913:Antibodies, Protozoan; D017780:Malaria Vaccines