T Cell Responses to the RTS,S/AS01E and RTS,S/AS02D Malaria Candidate Vaccines Administered According to Different Schedules to Ghanaian Children

Abstract

BackgroundThe Plasmodium falciparum pre-erythrocytic stage candidate vaccine RTS,S is being developed for protection of young children against malaria in sub-Saharan Africa. RTS,S formulated with the liposome based adjuvant AS01E or the oil-in-water based adjuvant AS02D induces P. falciparum circumsporozoite (CSP) antigen-specific antibody and T cell responses which have been associated with protection in the experimental malaria challenge model in adults.MethodsThis study was designed to evaluate the safety and immunogenicity induced over a 19 month period by three vaccination schedules (0,1-, 0,1,2- and 0,1,7-month) of RTS,S/AS01E and RTS,S/AS02D in children aged 5–17 months in two research centers in Ghana. Control Rabies vaccine using the 0,1,2-month schedule was used in one of two study sites.ResultsWhole blood antigen stimulation followed by intra-cellular cytokine staining showed RTS,S/AS01E induced CSP specific CD4 T cells producing IL-2, TNF-α, and IFN-γ. Higher T cell responses were induced by a 0,1,7-month immunization schedule as compared with a 0,1- or 0,1,2-month schedule. RTS,S/AS01E induced higher CD4 T cell responses as compared to RTS,S/AS02D when given on a 0,1,7-month schedule.ConclusionsThese findings support further Phase III evaluation of RTS,S/AS01E. The role of immune effectors and immunization schedules on vaccine protection are currently under evaluation.Trial RegistrationClinicalTrials.gov NCT00360230

Evaluation of the immune response to RTS,S/AS01 and RTS,S/AS02 adjuvanted vaccines

“…Induction of CD4 + T cells directed against P. falciparum CS protein by RTS,S adjuvanted formulations has been shown in clinical field trials in adults and children. 6,8,9,[21][22][23] No systematic vaccine-induced CD8 + T cell response was detected in PBMCs in our study, which was consistent with other studies that showed RTS,S/AS induces little or no detectable CD8 + T cell response. 6,11,21,24,25 The anti-CS humoral immune responses in this study tended to be lower than those observed following administration of 3 doses of RTS,S/AS01 or RTS,S/AS02 to malaria-experienced children in Africa 13,14 but higher than those in African adults in a high malaria transmission area.…”

“…[5][6][7] CS-specific CD4 + T cells induced by RTS,S produce a mixture of cytokines, such as interleukin (IL)-2, tumor necrosis factor (TNF)-α, and interferon (IFN)-γ. [7][8][9][10][11] In phase 2 clinical trials of adults and children, the RTS,S/AS01 formulation had an improved immunogenicity profile, in terms of humoral and cell-mediated immune (CMI) responses, and an equally favorable safety profile as compared with RTS,S/AS02. [11][12][13][14] The RTS,S/AS01 formulation was…”

Adjuvant system AS01: helping to overcome the challenges of modern vaccines

“…The choice of adjuvant was reconsidered following evidence in larger studies conducted in adult volunteers, and subsequently in children, of improved CD4 + T-cell responses and improved efficacy when AS01 was used instead of AS02 [41][42][43][44][45]. In a large Phase-3 study, efficacy against any malaria due to P. falciparum over 12 months of follow-up after dose 3 was 31.3% in infants 6-12 weeks of age with coadministration of EPI (Expanded Program on Immunization) vaccines and 55.8% in children 5-17 months of age at the time of the first dose [46].…”

The RTS,S/AS01 malaria vaccine in children 5 to 17 months of age at first vaccination

“…It should however be noted that the fourth dose-enhanced VE compared to RTS,S/AS01 vaccinees who didn't receive a fourth dose. The potential of the RTS,S/ AS01 vaccine to predispose to humoral hypo-responsiveness to CS by a mechanism similar to that observed for non-conjugated polysaccharides seems unlikely in view of the characteristics of the CS immune response, mainly the induction of CD4 + T cell [16,21,49] and CS-specific memory B-cell responses [49]. In addition, similar anti-CS antibody kinetics were previously observed with a delayed third vaccine dose when RTS, S/AS01 was given according to a 0,1,7-month schedule in a phase II study [19].…”