Randomized controlled trial of RTS,S/AS02D and RTS,S/AS01E malaria candidate vaccines given according to different schedules in Ghanaian children.
BACKGROUND
The target delivery channel of RTS,S candidate malaria vaccines in malaria-endemic countries in Africa is the World Health Organisation Expanded Program on Immunization. As an Adjuvant System, age de-escalation and schedule selection step, this study assessed 3 schedules of RTS,S/AS01(E) and RTS,S/AS02(D) in infants and young children 5-17 months of age in Ghana.


METHODS
A Phase II, partially-blind randomized controlled study (blind to vaccine, not to schedule), of 19 months duration was conducted in two (2) centres in Ghana between August 2006 and May 2008. Subjects were allocated randomly (1:1:1:1:1:1) to one of six study groups at each study site, each defining which vaccine should be given and by which schedule (0,1-, 0,1,2- or 0,1,7-months). For the 0,1,2-month schedule participants received RTS,S/AS01(E) or rabies vaccine at one center and RTS,S/AS01(E) or RTS,S/AS02(D) at the other. For the other schedules at both study sites, they received RTS,S/AS01(E) or RTS,S/AS02(D). The primary outcome measure was the occurrence of serious adverse events until 10 months post dose 1.


RESULTS
The number of serious adverse events reported across groups was balanced. One child had a simple febrile convulsion, which evolved favourably without sequelae, considered to be related to RTS,S/AS01(E) vaccination. Low grade reactions occurred slightly more frequently in recipients of RTS,S/AS than rabies vaccines; grade 3 reactions were infrequent. Less local reactogenicity occurred with RTS,S/AS01(E) than RTS,S/AS02(D). Both candidate vaccines were highly immunogenic for anti-circumsporozoite and anti-Hepatitis B Virus surface antigen antibodies. Recipients of RTS,S/AS01(E) compared to RTS,S/AS02(D) had higher peak anti-circumsporozoite antibody responses for all 3 schedules. Three dose schedules were more immunogenic than 2 dose schedules. Area under the curve analyses for anti-circumsporozoite antibodies were comparable between the 0,1,2- and 0,1,7-month RTS,S/AS01(E) schedules.


CONCLUSIONS
Both candidate malaria vaccines were well tolerated. Anti-circumsporozoite responses were greater with RTS,S/AS01(E) than RTS,S/AS02(D) and when 3 rather than 2 doses were given. This study supports the selection of RTS,S/AS01(E) and a 3 dose schedule for further development in children and infants.


BACKGROUND
ClinicalTrials.gov NCT00360230.
Owusu-Agyei
Seth
S
Kintampo Health Research Centre, Health Research Unit, Kintampo, Ghana. Seth.owusu-agyei@ghana-khrc.org
Ansong
Daniel
D
Asante
Kwaku
K
Kwarteng Owusu
Sandra
S
Owusu
Ruth
R
Wireko Brobby
Naana Ayiwa
NA
Dosoo
David
D
Osei Akoto
Alex
A
Osei-Kwakye
Kingsley
K
Adjei
Emmanuel Asafo
EA
Boahen
Kwadwo Owusu
KO
Sylverken
Justice
J
Adjei
George
G
Sambian
David
D
Apanga
Stephen
S
Kayan
Kingsley
K
Vekemans
Johan
J
Ofori-Anyinam
Opokua
O
Leach
Amanda
A
Lievens
Marc
M
Demoitie
Marie-Ange
MA
Dubois
Marie-Claude
MC
Cohen
Joe
J
Ballou
W Ripley
WR
Savarese
Barbara
B
Chandramohan
Daniel
D
Gyapong
John Owusu
JO
Milligan
Paul
P
Antwi
Sampson
S
Agbenyega
Tsiri
T
Greenwood
Brian
B
Evans
Jennifer
J
D000818:Animals; D019540:Area Under Curve; D002648:Child; D004334:Drug Administration Schedule; D005260:Female; D005869:Ghana; D006801:Humans; D007223:Infant; D017780:Malaria Vaccines / Q000008:administration & dosage / Q000627:therapeutic use*; D016778:Malaria, Falciparum / Q000517:prevention & control*; D008297:Male; D010963:Plasmodium falciparum / Q000276:immunology; D013997:Time Factors; D016896:Treatment Outcome; D014611:Vaccination
D017780:Malaria Vaccines; C533816:RTS,S-AS01E vaccine; C533817:RTS,S-AS02D vaccine