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* MRC Human Immunology Unit, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, U.K.;
Beijing You An Hospital, Capital University of Medical Sciences, Beijing, China;
Department of Infectious Diseases, Nan-Fang Hospital, Southern Medical University, Guangzhou, China;
Guangzhou Number 8 Hospital, Guangzhou, China;
¶ Medical Research Council/University College London Centre for Medical Molecular Virology, Division of Infection and Immunity, University College London, U.K.;
|| Human Immunology Section, Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892; and
# Imperial College, Hammersmith Hospital, London, U.K.
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-
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-, TNF-
, and IL-2, and CD8+ T cells producing IFN-, TNF-, 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.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was support by Beijing Municipal Government, National Science Fund for Distinguished Young Scholars, Medical Research Council U.K., and the Euro-Asian SARS-DTV Network (SP22-CT-2004–511064) from the European Commission specific research and technological development Program "Integrating and strengthening the European Research area."
2 C.K.L., H.W., H.Y., and S.M. contributed equally to this work.
3 Address correspondence and reprint requests to: Dr. Xiao-Ning Xu, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, Headington, Oxford, U.K. E-mail address: xiaoning.xu{at}imm.ox.ac.uk or Dr. Jin-Lin Hou, Department of Infectious Diseases, Nan-fan Hospital, Guangzhou, China. E-mail address: jlhou{at}fimmu.com
4 Abbreviations used in this paper: SARS, severe acute respiratory syndrome; CoV, coronavirus; PBMC, peripheral blood mononuclear cell; ICS, intracellular cytokine staining; SFC, spot forming cell; Nab, neutralizing Ab.
5 The online version of this article contains supplemental data.
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