The goal of Project VIII is to use the example of varicella-zoster virus (VZV) to examine the role of virus-specific host responses in protective immunity after allogeneic and autologous BMT (in Projects I and II). These clinical investigations are intended to identify strategies for immune modulation using viral vaccines in an effort to reduce the impact of herpes virus infections in BMT recipients by enhancing immune mechanisms that inhibit virus replication.
The specific aims of this project will be to determine 1) whether T-cell immunity to VZV can be enhanced in allogeneic transplant recipients by immunizing the donor with live varicella vaccine; 2) whether autologous and/or allogeneic BMT recipients can respond to immunization with killed varicella vaccine after transplant; 3) whether a protocol of donor immunization followed by immunization of allogeneic BMT recipients enhances the reconstitution of VZV immunity; and 4) whether VZV immunization reduces the incidence of VZV reactivation, manifesting as herpes zoster, after BMT. The new information about methods to induce herpes virus-specific immunity derived from these experiments with VZV should be relevant to the prevention of other viral infections after BMT. The efficacy of vaccine strategies for boosting T-cell immunity in BMT recipients will be determined by testing VZV-specific helper T-cell proliferation and the cytotoxic T-lymphocyte (CTL) response to the VZV proteins, gp I and IE-62. Whether immunization shortens the interval to recovery of these VZV specific T-cell responses after BMT will be evaluated in BMT recipients during the first 100 days after transplant. The final goal of this project will be to prove that immunomodulation of antiviral immunity shown by in vitro assays of T-cell responses actually translates into a clinical reduction of symptomatic episodes of VZV reactivation in a placebo-controlled vaccine study. Since a major effort is currently being made to develop vaccines for other human herpes viruses, this study should yield information relevant to the potential for immunoenhancement with these vaccines in BMT populations.
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