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.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA077544-05
Application #
6497474
Study Section
Experimental Therapeutics Subcommittee 1 (ET)
Program Officer
Wu, Roy S
Project Start
1998-04-01
Project End
2004-03-31
Budget Start
2002-02-01
Budget End
2004-03-31
Support Year
5
Fiscal Year
2002
Total Cost
$279,778
Indirect Cost
Name
City of Hope
Department
Type
DUNS #
City
Duarte
State
CA
Country
United States
Zip Code
91010
Wussow, Felix; Chiuppesi, Flavia; Meng, Zhuo et al. (2018) Exploiting 2A peptides to elicit potent neutralizing antibodies by a multi-subunit herpesvirus glycoprotein complex. J Virol Methods 251:30-37
Diamond, Don Jeffrey; La Rosa, Corinna; Chiuppesi, Flavia et al. (2018) A fifty-year odyssey: prospects for a cytomegalovirus vaccine in transplant and congenital infection. Expert Rev Vaccines 17:889-911
Chiuppesi, Flavia; Nguyen, Jenny; Park, Soojin et al. (2018) Multiantigenic Modified Vaccinia Virus Ankara Vaccine Vectors To Elicit Potent Humoral and Cellular Immune Reponses against Human Cytomegalovirus in Mice. J Virol 92:
Wussow, Felix; Chiuppesi, Flavia; Contreras, Heidi et al. (2017) Neutralization of Human Cytomegalovirus Entry into Fibroblasts and Epithelial Cells. Vaccines (Basel) 5:
Fan, Qihua; Nelson, Cody S; Bialas, Kristy M et al. (2017) Plasmablast Response to Primary Rhesus Cytomegalovirus (CMV) Infection in a Monkey Model of Congenital CMV Transmission. Clin Vaccine Immunol 24:
La Rosa, Corinna; Longmate, Jeff; Martinez, Joy et al. (2017) MVA vaccine encoding CMV antigens safely induces durable expansion of CMV-specific T cells in healthy adults. Blood 129:114-125
Chiuppesi, Flavia; Kaltcheva, Teodora; Meng, Zhuo et al. (2017) Identification of a Continuous Neutralizing Epitope within UL128 of Human Cytomegalovirus. J Virol 91:
Limaye, Ajit P; La Rosa, Corinna; Longmate, Jeff et al. (2016) Plasma IL-10 Levels to Guide Antiviral Prophylaxis Prevention of Late-Onset Cytomegalovirus Disease, in High Risk Solid Kidney and Liver Transplant Recipients. Transplantation 100:210-6
Nakamura, Ryotaro; La Rosa, Corinna; Longmate, Jeffrey et al. (2016) Viraemia, immunogenicity, and survival outcomes of cytomegalovirus chimeric epitope vaccine supplemented with PF03512676 (CMVPepVax) in allogeneic haemopoietic stem-cell transplantation: randomised phase 1b trial. Lancet Haematol 3:e87-98
Cichocki, F; Cooley, S; Davis, Z et al. (2016) CD56dimCD57+NKG2C+ NK cell expansion is associated with reduced leukemia relapse after reduced intensity HCT. Leukemia 30:456-63

Showing the most recent 10 out of 79 publications