Circumsporozoite-specific T cell responses in children vaccinated with RTS,S/AS01E and protection against P falciparum clinical malaria.
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...
| Main Authors: | , , , , , , , , , , , , , , |
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| Format: | Journal article |
| Language: | English |
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2011
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| _version_ | 1797068236460654592 |
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| author | 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 |
| author_facet | 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 |
| author_sort | Olotu, A |
| collection | OXFORD |
| description | 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. |
| first_indexed | 2024-03-06T22:07:48Z |
| format | Journal article |
| id | oxford-uuid:50c1638d-601d-4b5c-ab29-6d9d3f9b86d0 |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-06T22:07:48Z |
| publishDate | 2011 |
| record_format | dspace |
| spelling | oxford-uuid:50c1638d-601d-4b5c-ab29-6d9d3f9b86d02022-03-26T16:15:24ZCircumsporozoite-specific T cell responses in children vaccinated with RTS,S/AS01E and protection against P falciparum clinical malaria.Journal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:50c1638d-601d-4b5c-ab29-6d9d3f9b86d0EnglishSymplectic Elements at Oxford2011Olotu, AMoris, PMwacharo, JVekemans, JKimani, DJanssens, MKai, OJongert, ELievens, MLeach, AVillafana, TSavarese, BMarsh, KCohen, JBejon, P 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. |
| spellingShingle | 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 Circumsporozoite-specific T cell responses in children vaccinated with RTS,S/AS01E and protection against P falciparum clinical malaria. |
| title | Circumsporozoite-specific T cell responses in children vaccinated with RTS,S/AS01E and protection against P falciparum clinical malaria. |
| title_full | Circumsporozoite-specific T cell responses in children vaccinated with RTS,S/AS01E and protection against P falciparum clinical malaria. |
| title_fullStr | Circumsporozoite-specific T cell responses in children vaccinated with RTS,S/AS01E and protection against P falciparum clinical malaria. |
| title_full_unstemmed | Circumsporozoite-specific T cell responses in children vaccinated with RTS,S/AS01E and protection against P falciparum clinical malaria. |
| title_short | Circumsporozoite-specific T cell responses in children vaccinated with RTS,S/AS01E and protection against P falciparum clinical malaria. |
| title_sort | circumsporozoite specific t cell responses in children vaccinated with rts s as01e and protection against p falciparum clinical malaria |
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