Circumsporozoite-specific T cell responses in children vaccinated with RTS,S/AS01 E and protection against P falciparum clinical malaria

Ally Olotu, Philippe Moris, Jedidah Mwacharo, Johan Vekemans, Domtila Kimani, Michel Janssens, Oscar Kai, Erik Jongert, Marc Lievens, Amanda Leach, Tonya Villafana, Barbara Savarese, Kevin Marsh, Joe Cohen, Philip Bejon

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    Abstract

    Background: RTS,S/AS01E 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/AS01E (NCT00380393). RTS,S/ AS01E 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/AS01E 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/AS01E 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/AS01E 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/AS01E. The correlation between CS-specific TNFα+ CD4+ T cells and protection needs confirmation in other datasets.
    Original languageEnglish
    Article numbere25786
    Pages (from-to)1-11
    Number of pages11
    JournalPLoS One
    Volume6
    Issue number10
    DOIs
    Publication statusPublished - 2011

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  • Cite this

    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. (2011). Circumsporozoite-specific T cell responses in children vaccinated with RTS,S/AS01 E and protection against P falciparum clinical malaria. PLoS One, 6(10), 1-11. [e25786]. https://doi.org/10.1371/journal.pone.0025786