Control of CMV infection in allogeneic stem cell transplant recipients using attenuated MVA-based CMV subunit vaccine

While we are seeking to confirm a therapeutic benefit of CMVPepVax in hematopoietic cell transplant (HCT) recipients, broadening the population that would benefit from a vaccination strategy is best approached by employing a delivery vector that expresses full length cytomegalovirus (CMV) antigens. We have used modified vaccinia Ankara (MVA) virus for that purpose in collaboration with NCI-NExT to manufacture a candidate for clinical testing. The clinical manufacturing of CMV-MVA took place at City of Hope, and IND-directed toxicology at SRI (Birmingham, Ala.). We propose three clinical trials that will comprehensively evaluate our clinical vaccine candidate. Trial 1 will be conducted in healthy volunteers stratified by age and poxvirus exposure who are equivalent health-wise to immunocompetent HCT donors as required by the Food and Drug Administration and will establish the safety and dose level for a second  trial in HCT. A double-blind phase II trial is proposed in which 150 HLA matched MRD will be randomized equally to receive either vaccine or placebo. Immune responses and clinical correlates of vaccine-stimulated protection will be followed in recipients whose donors are enrolled in Trial 2. In Trial 3, we propose to directly immunize 150 HCT recipients undergoing unrelated (8/8 HLA matches) URD-HCT. This approach is justified since recipients are at high-risk for CMV reactivation and do not have consistently accessible donors. Trials 2 and 3 will each enroll 150 HCT subjects, randomized equally to vaccine or placebo and both will have 90% power to detect a 50% reduction in viremia (60% to 30%) in the vaccine arm. Safety monitoring employing defined stopping rules will guard against adverse events for recipients in both trials. Combined results from carrying out both Trials 2 and 3 will provide a precise immunoprophylaxis strategy for control of CMV disease in the HCT setting. We will discover the optimal formula for immunizing both donors and recipients to prevent CMV viremia and minimize usage of potentially toxic antiviral agents. Success with this CMV vaccine would have a significant clinical and cost-saving effect on recipient management after MRD or URD HCT. The next two projects involve our rapid development of a prophylactic clinical CMV vaccine that has strong relevance to the pediatric population.
Ryotaro Nakamura, M.D.
Staff physician, Department of Hematology & Hematopoietic Cell Transplantation
Principal Investigator for Trials 2 and 3

John A. Zaia, M.D.
Chair, Department of Virology
Principal Investigator of IRB 08173
Jennifer Drake, C.C.R.P.
Study Coordinator

Cindy Slape, R.N.
Clinical Research Nurse
Corinna La Rosa, Ph.D.
Associate Research Professor
Conducts the laboratory investigations

Joy Martinez
Senior Research Associate
Conducts stability testing and coordinates release testing
Staff of the Department of Hematology & Hematopoietic Cell Transplantation
Recruits and consents patients