Enhancing therapeutic vaccination by blocking PD-1-mediated inhibitory signals during chronic infection

Sang Jun Ha, Scott N. Mueller, E. John Wherry, Daniel L. Barber, Rachael D. Aubert, Arlene H. Sharpe, Gordon J. Freeman, Rafi Ahmed

Research output: Contribution to journalArticlepeer-review

73 Citations (Scopus)


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. JEM

Original languageEnglish
Pages (from-to)543-555
Number of pages13
JournalJournal of Experimental Medicine
Issue number3
Publication statusPublished - 2008 Mar 17

All Science Journal Classification (ASJC) codes

  • Immunology and Allergy
  • Immunology


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