title: A statistical interaction between circumsporozoite protein-specific T cell and antibody responses and risk of clinical malaria episodes following vaccination with RTS,S/AS01E.
abstract: The candidate malaria vaccine RTS,S/AS01(E) provides significant but partial protection from clinical malaria. On in vitro circumsporozoite protein (CSP) peptide stimulation and intra-cellular cytokine staining of whole blood taken from 407 5-17 month-old children in a phase IIb trial of RTS,S/AS01(E), we identified significantly increased frequencies of two CSP-specific CD4+ T cells phenotypes among RTS,S/AS01(E) vaccinees (IFNγ-IL2+TNF- and IFNγ-IL2+TNF+ CD4+ T cells), and increased frequency of IFNγ-IL2-TNF+ CD4+ T cells after natural exposure. All these T cells phenotypes were individually associated with reductions in the risk of clinical malaria, but IFNγ-IL2-TNF+ CD4+ T cells independently predicted reduced risk of clinical malaria on multi-variable analysis (HR = 0.29, 95% confidence intervals 0.15-0.54, p<0.0005). Furthermore, there was a strongly significant synergistic interaction between CSP-specific IFNγ-IL2-TNF+ CD4+ T cells and anti-CSP antibodies in determining protection against clinical malaria (p = 0.002). Vaccination strategies that combine potent cellular and antibody responses may enhance protection against malaria.
authors.affiliation: Kenya Medical Research Institute, Centre for Geographical Medical Research-Coast, Kilifi, Kenya. fndungu@kilifi.kemri-wellcome.org
authors.forename: Francis M
authors.initials: FM
authors.lastname: Ndungu
authors.forename: Jedidah
authors.initials: J
authors.lastname: Mwacharo
authors.forename: Domtila
authors.initials: D
authors.lastname: Kimani
authors.forename: Oscar
authors.initials: O
authors.lastname: Kai
authors.forename: Philippe
authors.initials: P
authors.lastname: Moris
authors.forename: Erik
authors.initials: E
authors.lastname: Jongert
authors.forename: Johan
authors.initials: J
authors.lastname: Vekemans
authors.forename: Ally
authors.initials: A
authors.lastname: Olotu
authors.forename: Philip
authors.initials: P
authors.lastname: Bejon
mesh_terms: D000913:Antibodies, Protozoan / Q000097:blood*; D000917:Antibody Formation; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D017322:Clinical Trials, Phase II as Topic; D016207:Cytokines / Q000097:blood; D006801:Humans; D007223:Infant; D053208:Kaplan-Meier Estimate; D017780:Malaria Vaccines; D016778:Malaria, Falciparum / Q000097:blood / Q000276:immunology / Q000517:prevention & control*; D010963:Plasmodium falciparum / Q000276:immunology*; D016016:Proportional Hazards Models; D015800:Protozoan Proteins / Q000276:immunology / Q000378:metabolism; D016032:Randomized Controlled Trials as Topic; D012306:Risk; D034101:Sporozoites / Q000276:immunology; D014611:Vaccination
chemical_list: D000913:Antibodies, Protozoan; D016207:Cytokines; D017780:Malaria Vaccines; D015800:Protozoan Proteins; C533816:RTS,S-AS01E vaccine; C041595:circumsporozoite protein, Protozoan