title: T cell responses to whole SARS coronavirus in humans.
abstract: Effective vaccines should confer long-term protection against future outbreaks of severe acute respiratory syndrome (SARS) caused by a novel zoonotic coronavirus (SARS-CoV) with unknown animal reservoirs. We conducted a cohort study examining multiple parameters of immune responses to SARS-CoV infection, aiming to identify the immune correlates of protection. We used a matrix of overlapping peptides spanning whole SARS-CoV proteome to determine T cell responses from 128 SARS convalescent samples by ex vivo IFN-gamma ELISPOT assays. Approximately 50% of convalescent SARS patients were positive for T cell responses, and 90% possessed strongly neutralizing Abs. Fifty-five novel T cell epitopes were identified, with spike protein dominating total T cell responses. CD8(+) T cell responses were more frequent and of a greater magnitude than CD4(+) T cell responses (p < 0.001). Polychromatic cytometry analysis indicated that the virus-specific T cells from the severe group tended to be a central memory phenotype (CD27(+)/CD45RO(+)) with a significantly higher frequency of polyfunctional CD4(+) T cells producing IFN-gamma, TNF-alpha, and IL-2, and CD8(+) T cells producing IFN-gamma, TNF-alpha, and CD107a (degranulation), as compared with the mild-moderate group. Strong T cell responses correlated significantly (p < 0.05) with higher neutralizing Ab. The serum cytokine profile during acute infection indicated a significant elevation of innate immune responses. Increased Th2 cytokines were observed in patients with fatal infection. Our study provides a roadmap for the immunogenicity of SARS-CoV and types of immune responses that may be responsible for the virus clearance, and should serve as a benchmark for SARS-CoV vaccine design and evaluation.
authors.affiliation: MRC Human Immunology Unit, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, UK.
authors.forename: Chris Ka-fai
authors.initials: CK
authors.lastname: Li
authors.forename: Hao
authors.initials: H
authors.lastname: Wu
authors.forename: Huiping
authors.initials: H
authors.lastname: Yan
authors.forename: Shiwu
authors.initials: S
authors.lastname: Ma
authors.forename: Lili
authors.initials: L
authors.lastname: Wang
authors.forename: Mingxia
authors.initials: M
authors.lastname: Zhang
authors.forename: Xiaoping
authors.initials: X
authors.lastname: Tang
authors.forename: Nigel J
authors.initials: NJ
authors.lastname: Temperton
authors.forename: Robin A
authors.initials: RA
authors.lastname: Weiss
authors.forename: Jason M
authors.initials: JM
authors.lastname: Brenchley
authors.forename: Daniel C
authors.initials: DC
authors.lastname: Douek
authors.forename: Juthathip
authors.initials: J
authors.lastname: Mongkolsapaya
authors.forename: Bac-Hai
authors.initials: BH
authors.lastname: Tran
authors.forename: Chen-lung Steve
authors.initials: CL
authors.lastname: Lin
authors.forename: Gavin R
authors.initials: GR
authors.lastname: Screaton
authors.forename: Jin-lin
authors.initials: JL
authors.lastname: Hou
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: McMichael
authors.forename: Xiao-Ning
authors.initials: XN
authors.lastname: Xu
mesh_terms: D000328:Adult; D000914:Antibodies, Viral / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D015331:Cohort Studies; D016207:Cytokines / Q000276:immunology; D005260:Female; D006801:Humans; D007156:Immunologic Memory; D017493:Leukocyte Common Antigens / Q000276:immunology; D052118:Lysosomal-Associated Membrane Protein 1 / Q000276:immunology; D008297:Male; D008875:Middle Aged; D020543:Proteome / Q000276:immunology; D045473:Severe acute respiratory syndrome-related coronavirus / Q000276:immunology*; D045169:Severe Acute Respiratory Syndrome / Q000276:immunology* / Q000401:mortality; D018418:Th2 Cells / Q000276:immunology*; D018127:Tumor Necrosis Factor Receptor Superfamily, Member 7 / Q000276:immunology; D014765:Viral Vaccines / Q000276:immunology
chemical_list: D000914:Antibodies, Viral; D016207:Cytokines; D052118:Lysosomal-Associated Membrane Protein 1; D020543:Proteome; D018127:Tumor Necrosis Factor Receptor Superfamily, Member 7; D014765:Viral Vaccines; D017493:Leukocyte Common Antigens