Host Factors Appear To Affect Impact of Therapeutic Vaccines

Administering a “therapeutic” vaccine only modestly enhances T cell responses to control lymphocytic choriomeningitis virus (LCMV) in mice chronically infected with this virus, according to E. John Wherry, formerly of Emory University School of Medicine in Atlanta, Ga., and now at the Wistar Institute, Philadelphia, Penn. “This was in striking contrast to the strong response to the vaccine. . . in healthy . . . mice,” he says, referring to findings that he and his collaborators published in the July issue of the Journal of Virology. The main reason for the feeble response appears to be that host T cells, which the vaccine was designed to boost, fail to proliferate vigorously and respond only weakly, Wherry says. “T cells can become dysfunctional during chronic infections, losing antiviral functions. Importantly, mice with lower viral loads at the time of vaccination responded better, suggesting that the more severe the state of chronic infection, the more dysfunctional the responding T cells and the more poorly they will respond to therapeutic vaccination.” “Therapeutic vaccination, in principle an appealing approach to enhance immune control in infectious and neoplastic disease, has been troubled by only minimal to moderate. . . benefits in a wide variety of experimental systems,” says Dirk Homann of the University of Colorado at Denver. Even so, Wherry’s studies “validate” an approach in which “the antigenic burden”—in this case, viral load—is lowered before administering the therapeutic vaccine to infected hosts, Homann points out. Thus, this combined approach in which other steps are taken to counteract the virus and boost the host immune response could “improve the quantity and quality of specific T cells induced by this therapeutic regimen,” he says. “One observation in particular caught my attention,” Homann continues. “While the number of virusspecific T cells induced by the vaccine was variable and at best moderately increased, the T cells responsive to the vaccine appeared to demonstrate improved functionality. This . . . may result from the preferential expansion of a ‘more functional’ T cell subset. . .” “Our future studies will focus on understanding the molecular mechanisms of T cell dysfunction that underlie poor responses to therapeutic vaccination,” Wherry says. “In addition, we will examine approaches where a therapeutic vaccine is combined with other therapeutics, such as cytokines or costimulatory molecules, that may be able to overcome the weak proliferative potential of the responding T cells.”