Circumsporozoite-specific T cell responses in children vaccinated with RTS,S/AS01E and protection against P falciparum clinical malaria

Olotu A, Moris P, Mwacharo J, Vekemans J, Kimani D, Janssens M, Kai O, Jongert E, Lievens M, Leach A, Villafana T, Savarese B, Marsh K, Cohen J, Bejon P
PLoS One. 2011;6

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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, IFNgamma, and TNFalpha), ex-vivo ELISPOTs (IFNgamma and IL2) and IFNgamma 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 IFNgamma, TNFalpha or IL2 compared to control vaccinees. In a multivariable analysis TNFalpha(+) 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 TNFalpha(+) 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 TNFalpha(+) CD4(+) T cells could account for the level of protection conferred by RTS,S/AS01(E). The correlation between CS-specific TNFalpha(+) CD4(+) T cells and protection needs confirmation in other datasets.