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Background  RTS,S/AS01  E   is the lead candidate pre-erythrocytic malaria vaccine. In Phase IIb field trials the safety profile was acceptable and the efficacy was 53% (95%CI 31%–72%) for protecting children against clinical malaria caused by  P. falciparum . We studied CS-specific T cell responses in order to identify correlates of protection.    Methods and Findings  We used intracellular cytokine staining (for IL2, IFNγ, and TNFα),  ex-vivo  ELISPOTs (IFNγ and IL2) and IFNγ cultured ELISPOT assays to characterize the CS-specific cellular responses in 407 children (5–17 months of age) in a phase IIb randomized controlled trial of RTS,S/AS01 E  (NCT00380393). RTS,S/ AS01 E  vaccinees had higher frequencies of CS-specific CD4+ T cells producing IFNγ, TNFα or IL2 compared to control vaccinees. In a multivariable analysis TNFα +  CD4 +  T cells were independently associated with a reduced risk for clinical malaria among RTS,S/AS01 E  vaccinees (HR = 0.64, 95%CI 0.49–0.86, p = 0.002). There was a non-significant tendency towards reduced risk among control vaccinees (HR = 0.80, 95%CI 0.62–1.03, p = 0.084), albeit with lower CS-specific T cell frequencies and higher rates of clinical malaria. When data from both RTS,S/AS01  E   vaccinees and control vaccinees were combined (with adjusting for vaccination group), the HR was 0.74 (95%CI 0.62–0.89, p = 0.001). After a Bonferroni correction for multiple comparisons (n-18), the finding was still significant at p = 0.018. There was no significant correlation between cultured or  ex vivo  ELISPOT data and protection from clinical malaria. The combination of TNFα +  CD4 +  T cells and anti-CS antibody statistically accounted for the protective effect of vaccination in a Cox regression model.    Conclusions  RTS,S/AS01  E   induces CS-specific Th1 T cell responses in young children living in a malaria endemic area. The combination of anti-CS antibody concentrations titers and CS-specific TNFα +  CD4 +  T cells could account for the level of protection conferred by RTS,S/AS01  E  . The correlation between CS-specific TNFα +  CD4 +  T cells and protection needs confirmation in other datasets.

Circumsporozoite-Specific T Cell Responses in Children Vaccinated with RTS,S/AS01E and Protection against P falciparum Clinical Malaria