title: Circumsporozoite-specific T cell responses in children vaccinated with RTS,S/AS01E and protection against P falciparum clinical malaria.
abstract: 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.
  
  
  RESULTS
  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.
authors: Kenya Medical Research Institute/ Wellcome Trust Programme, Centre for Geographic Medicine Research, Coast, Kilifi, Kenya.
authors: Ally
authors: A
authors: Olotu
authors: Philippe
authors: P
authors: Moris
authors: Jedidah
authors: J
authors: Mwacharo
authors: Johan
authors: J
authors: Vekemans
authors: Domtila
authors: D
authors: Kimani
authors: Michel
authors: M
authors: Janssens
authors: Oscar
authors: O
authors: Kai
authors: Erik
authors: E
authors: Jongert
authors: Marc
authors: M
authors: Lievens
authors: Amanda
authors: A
authors: Leach
authors: Tonya
authors: T
authors: Villafana
authors: Barbara
authors: B
authors: Savarese
authors: Kevin
authors: K
authors: Marsh
authors: Joe
authors: J
authors: Cohen
authors: Philip
authors: P
authors: Bejon
mesh_terms: D000595:Amino Acid Sequence; D000918:Antibody Specificity / Q000276:immunology*; D002675:Child, Preschool; D006801:Humans; D007223:Infant; D007371:Interferon-gamma / Q000096:biosynthesis / Q000378:metabolism; D007376:Interleukin-2 / Q000096:biosynthesis / Q000378:metabolism; D042541:Intracellular Space / Q000378:metabolism; D008288:Malaria / Q000517:prevention & control*; D017780:Malaria Vaccines / Q000009:adverse effects / Q000737:chemistry / Q000276:immunology*; D008969:Molecular Sequence Data; D010963:Plasmodium falciparum / Q000276:immunology*; D015800:Protozoan Proteins / Q000276:immunology*; D013601:T-Lymphocytes / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D013997:Time Factors; D014611:Vaccination / Q000009:adverse effects / Q000379:methods*; D022223:Vaccines, Subunit / Q000009:adverse effects / Q000737:chemistry / Q000276:immunology
chemical_list: D007376:Interleukin-2; D017780:Malaria Vaccines; D015800:Protozoan Proteins; D022223:Vaccines, Subunit; C041595:circumsporozoite protein, Protozoan; D007371:Interferon-gamma