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¹ Emory Vaccine Center and Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, GA 30322
² Department of Pathology, Harvard Medical School and Brigham and Women's Hospital, ³ Department of Medical Oncology, Dana-Farber Cancer Institute, Department of Medicine, Harvard Medical School, Boston, MA 02115

CORRESPONDENCE Rafi Ahmed: ra{at}microbio.emory.edu

Therapeutic vaccination is a potentially promising strategy to enhance T cell immunity and viral control in chronically infected individuals. However, therapeutic vaccination approaches have fallen short of expectations, and effective boosting of antiviral T cell responses has not always been observed. One of the principal reasons for the limited success of therapeutic vaccination is that virus-specific T cells become functionally exhausted during chronic infections. We now provide a novel strategy for enhancing the efficacy of therapeutic vaccines. In this study, we show that blocking programmed death (PD)-1/PD-L1 inhibitory signals on exhausted CD8⁺ T cells, in combination with therapeutic vaccination, synergistically enhances functional CD8⁺ T cell responses and improves viral control in mice chronically infected with lymphocytic choriomeningitis virus. This combinatorial therapeutic vaccination was effective even in the absence of CD4⁺ T cell help. Thus, our study defines a potent new approach to augment the efficacy of therapeutic vaccination by blocking negative signals. Such an approach may have broad applications in developing treatment strategies for chronic infections in general, and perhaps also for tumors.

E.J. Wherry's present address is Immunology Program, The Wistar Institute, Philadelphia, PA 19104.

D.L. Barber's present address is Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious diseases, National Institutes of Health, Bethesda, MD 20892, USA.

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