title: A novel therapeutic cytomegalovirus DNA vaccine in allogeneic haemopoietic stem-cell transplantation: a randomised, double-blind, placebo-controlled, phase 2 trial.
abstract: BACKGROUND
  Cytomegalovirus reactivation occurs within 6 months in 60-70% of cytomegalovirus-seropositive patients after allogeneic haemopoietic stem-cell transplantation (HSCT), mainly due to immunosuppression associated with the procedure. Pre-emptive antiviral therapy reduces incidence of cytomegalovirus disease but can be toxic. To reduce the potential for disease and subsequent need for such antiviral drugs, we aimed to assess safety and efficacy of a cytomegalovirus therapeutic DNA vaccine compared with placebo.
  
  
  METHODS
  In this exploratory double-blind, placebo-controlled, parallel group, phase 2 trial, up to 80 donor-recipient pairs and 80 unpaired recipients undergoing allogeneic HSCT were planned for enrolment at 16 transplant centres in the USA. Eligible recipients were cytomegalovirus-seropositive, 18-65 years old, without high-risk primary disease, T-cell depletion, previous vaccination for cytomegalovirus, or autoimmune diseases. We randomly allocated participants in both parallel groups in a 1:1 ratio to receive a cytomegalovirus therapeutic DNA vaccine (TransVax; Vical, San Diego, CA, USA) or placebo before conditioning and at 1, 3, and 6 months after transplantation. The vaccine contains plasmids encoding cytomegalovirus glycoprotein B and phosphoprotein 65 formulated with poloxamer CRL1005 and benzalkonium chloride. Randomisation was done by sequential allocation based on Pocock and Simon's method, and stratified by site, donor-recipient HLA matching status, and donor's cytomegalovirus serostatus. The primary outcome was the occurrence rate of clinically significant viraemia resulting in initiation of cytomegalovirus-specific antiviral therapy in the per-protocol assessable population. We assessed rates of adverse events in all participants who received at least one dose of vaccine or placebo. This study is registered with ClinicalTrials.gov, number NCT00285259.
  
  
  RESULTS
  We randomly allocated 108 participants (94 HSCT recipients and 14 paired donors) between June 29, 2006, and Dec 11, 2009. Enrolment of the paired arm was halted in February 2008 for logistical reasons. Safety was assessed in all participants; the efficacy population was restricted to 74 unpaired recipients. Groups were balanced for demographic and clinical variables. 19 (48%) of 40 vaccine recipients required cytomegalovirus-specific antiviral therapy, compared with 21 (62%) of 34 controls (p=0·145). However, during follow-up vaccine significantly reduced the occurrence and recurrence of cytomegalovirus viraemia and improved the time-to-event for viraemia episodes compared with placebo. The vaccine was well-tolerated; only one participant discontinued after an allergic reaction. Incidence of common adverse events after HSCT (eg, graft-versus-host disease or secondary infections) did not differ between groups.
  
  
  CONCLUSIONS
  We show proof of concept for an immunotherapeutic cytomegalovirus vaccine (TransVax) for clinically significant viraemia in the HSCT setting. The reported safety and efficacy outcomes support further development in a phase 3 trial, notwithstanding a lack of significant reduction in the use of cytomegalovirus-specific antiviral therapy compared with placebo in this phase 2 trial.
  
  
  BACKGROUND
  Vical and US National Institute of Allergy and Infectious Diseases.
authors.affiliation: Department of Blood and Marrow Transplantation, H Lee Moffitt Cancer Center and Research Institute and University of South Florida, Tampa, FL, USA.
authors.forename: Mohamed A
authors.initials: MA
authors.lastname: Kharfan-Dabaja
authors.forename: Michael
authors.initials: M
authors.lastname: Boeckh
authors.forename: Marissa B
authors.initials: MB
authors.lastname: Wilck
authors.forename: Amelia A
authors.initials: AA
authors.lastname: Langston
authors.forename: Alice H
authors.initials: AH
authors.lastname: Chu
authors.forename: Mary K
authors.initials: MK
authors.lastname: Wloch
authors.forename: Don F
authors.initials: DF
authors.lastname: Guterwill
authors.forename: Larry R
authors.initials: LR
authors.lastname: Smith
authors.forename: Alain P
authors.initials: AP
authors.lastname: Rolland
authors.forename: Richard T
authors.initials: RT
authors.lastname: Kenney
mesh_terms: D000328:Adult; D000368:Aged; D000914:Antibodies, Viral / Q000097:blood; D003587:Cytomegalovirus / Q000276:immunology*; D003586:Cytomegalovirus Infections / Q000276:immunology / Q000517:prevention & control / Q000628:therapy* / Q000821:virology; D022482:Cytomegalovirus Vaccines / Q000008:administration & dosage* / Q000276:immunology; D004311:Double-Blind Method; D018380:Hematopoietic Stem Cell Transplantation / Q000379:methods*; D006801:Humans; D008297:Male; D008875:Middle Aged; D012044:Regression Analysis; D019444:Vaccines, DNA / Q000008:administration & dosage* / Q000276:immunology; D014759:Viral Envelope Proteins / Q000235:genetics / Q000276:immunology; D014766:Viremia / Q000276:immunology / Q000628:therapy / Q000821:virology; D055815:Young Adult
chemical_list: D000914:Antibodies, Viral; D022482:Cytomegalovirus Vaccines; D019444:Vaccines, DNA; D014759:Viral Envelope Proteins; C040495:glycoprotein B, Simplexvirus