Vaccination to treat persistent viral infection

Therapeutic vaccination is a potentially powerful strategy to establish immune control and eradicate persistent viral infections. Yet, despite numerous different approaches and for reasons that are unclear, vaccines administered during an established persistent viral infection fail to substantially elicit immunity or to control viral replication. Our hypothesis to explain this failure is that although vaccines are designed to stimulate T cells, they do not alleviate the immunosuppressive environment. As a result, vaccine‐activated T cells rapidly succumb to the same constraints that previously limited T cell responses during persistent infection. Using the lymphocytic choriomeningitis virus (LCMV) model of infection we found that the immunosuppressive environment (and not the vaccinating agent, level of virus replication or an inherent inability of exhausted T cells to respond to stimulation) is indeed responsible for the failure of therapeutic vaccines. Antibody blockade of the key suppressive factor interleukin‐10 rendered otherwise ineffective therapeutic vaccines highly efficient at restoring T cell immunity leading to immune‐mediated control of an established persistent viral infection. Thus, our findings help solve one of the great enigmas in infectious disease and vaccine design by demonstrating why therapeutic administration of a vaccine agent is unsuccessful whereas prophylactic administration of the same vaccine to pathogen naïve individuals (in which no immunosuppressive environment exists) is highly effective.