Research Project
6497474
DESCRIPTION: (Applicant's Abstract) A complication of the recovery phase after BMT is cytomegalovirus (HCMV) infection. Therapy using gancyclovir prophylaxis has decreased the mortality from HCMV infection in allogeneic BMT recipients. However side-effects which include delayed immune reconstitution limit its effectiveness in reducing overall mortality from BMT. Studies from several laboratories have indicated that control of CMV infection in BMT recipients is dependent on a strong cytotoxic T lymphocyte (CTL) response which is targeted mainly against the viral matrix protein pp65, and to a lesser degree against pp150. An adoptive immunotherapy strategy using CTL has proved successful but is impractical for general use in BMT centers. The applicant will develop an alternative strategy that uses small peptide fragments from the CTL viral target proteins pp65 and pp150 in the form of a vaccine as a means to simulate CTL in vivo. The vaccine is a peptide composed of a CTL epitope combined with a peptide which stimulates a T helper (TH) response and is lipidated on the amino terminus. He will first evaluate several different structural forms of the vaccine containing the HLA-A0201 restricted CTL epitope from pp65 and several different TH epitopes in a transgenic HLA-A2.1 mouse model. He will evaluate which of the vaccine molecules provide the strongest and longest-lived immunity by comparing the degree of lysis in vitro of human fibroblasts infected with HCMV mediated by murine splenic effector CTL. Based on the results of murine immunizations, a Phase I dose-escalating and safety trial will be conducted in asymptomatic HCMV seropositive human volunteers with a lipidated HLA-A0201 restricted CTL vaccine. Additional vaccines including those with 2 or 3 CTL epitopes will also be evaluated in human volunteers in a Phase I trial. In order to test whether the vaccine, which enhances CTL against HCMV in healthy volunteers, is also capable of protecting against infection, a Phase II trial will be conducted in HCMV seropositive BMT donors and recipients. BMT donors will be vaccinated according to a protocol determined by the Phase I trial and their HLA-matched siblings who undergo BMT will be monitored for the ability to resist viremia and/or pneumonia brought about by HCMV infection. Success of this protocol will be determined by the avoidance of gancyclovir post-BMT and reduction of early and late HCMV infection in the BMT recipient.
