Randomized controlled trial of RTS,S/AS02D and RTS,S/AS01E malaria candidate vaccines given according to different schedules in Ghanaian children

Abstract

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.

Methodology: 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.

Trial registration: ClinicalTrials.gov NCT00360230.

Conflict of interest statement

Competing Interests: J Vekemans, O Ofori-Anyinam, A Leach, M Lievens, M Demoitie, M-C Dubois, J Cohen are currently employed by GSK Biologicals. WR Ballou was employed by GSK Biologicals at the time the study was conducted. O Ofori-Anyinam, A Leach, M-C Dubois and J Cohen currently hold shares in GSK Biologicals. J Cohen and WR Ballou are both inventors on patents relating to malaria vaccines.

Figures

Figure 1. CONSORT diagram for study participants.

Figure 2. Percentage of solicited events post dose 1, 2 and 3 (Total Vaccinated Cohort).

Yellow = RTS,S/AS02D; Green = RTS,S/AS01E; Grey = Rabies vaccine; Orange = Grade 3 Bars represent 95% confidence intervals.

Figure 3. Anti-CS GMTs (EU/mL) responses over time (0,1,2- and 0,1,7-month schedules; ATP Cohort for Immunogenicity).

Note : There was no month 2 blood sample in the 0,1,7-month schedule group. Month 2 data from the 0,1-month schedule group was used instead.