title: Cytomegalovirus glycoprotein-B vaccine with MF59 adjuvant in transplant recipients: a phase 2 randomised placebo-controlled trial.
abstract: BACKGROUND
  Cytomegalovirus end-organ disease can be prevented by giving ganciclovir when viraemia is detected in allograft recipients. Values of viral load correlate with development of end-organ disease and are moderated by pre-existing natural immunity. Our aim was to determine whether vaccine-induced immunity could do likewise.
  
  
  METHODS
  We undertook a phase-2 randomised placebo controlled trial in adults awaiting kidney or liver transplantation at the Royal Free Hospital, London, UK. Exclusion criteria were pregnancy, receipt of blood products (except albumin) in the previous 3 months, and simultaneous multiorgan transplantation. 70 patients seronegative and 70 seropositive for cytomegalovirus were randomly assigned from a scratch-off randomisation code in a 1:1 ratio to receive either cytomegalovirus glycoprotein-B vaccine with MF59 adjuvant or placebo, each given at baseline, 1 month and 6 months later. If a patient was transplanted, no further vaccinations were given and serial blood samples were tested for cytomegalovirus DNA by real-time quantitative PCR (rtqPCR). Any patient with one blood sample containing more than 3000 cytomegalovirus genomes per mL received ganciclovir until two consecutive undetectable cytomegalovirus DNA measurements. Safety and immunogenicity were coprimary endpoints and were assessed by intention to treat in patients who received at least one dose of vaccine or placebo. This trial is registered with ClinicalTrials.gov, NCT00299260.
  
  
  RESULTS
  67 patients received vaccine and 73 placebo, all of whom were evaluable. Glycoprotein-B antibody titres were significantly increased in both seronegative (geometric mean titre 12,537 (95% CI 6593-23,840) versus 86 (63-118) in recipients of placebo recipients; p<0.0001) and seropositive (118,395; 64,503-217,272) versus 24,682 (17,909-34,017); p<0.0001) recipients of vaccine. In those who developed viraemia after transplantation, glycoprotein-B antibody titres correlated inversely with duration of viraemia (p=0.0022). In the seronegative patients with seropositive donors, the duration of viraemia (p=0.0480) and number of days of ganciclovir treatment (p=0.0287) were reduced in vaccine recipients.
  
  
  CONCLUSIONS
  Although cytomegalovirus disease occurs in the context of suppressed cell-mediated immunity post-transplantation, humoral immunity has a role in reduction of cytomegalovirus viraemia. Vaccines containing cytomegalovirus glycoprotein B merit further assessment in transplant recipients.
  
  
  BACKGROUND
  National Institute of Allergy and Infectious Diseases, Grant R01AI051355 and Wellcome Trust, Grant 078332.
  
  
  BACKGROUND
  University College London (UCL).
authors.affiliation: Centre for Virology, UCL Medical School, London, UK. p.griffiths@medsch.ucl.ac.uk
authors.forename: Paul D
authors.initials: PD
authors.lastname: Griffiths
authors.forename: Anna
authors.initials: A
authors.lastname: Stanton
authors.forename: Erin
authors.initials: E
authors.lastname: McCarrell
authors.forename: Colette
authors.initials: C
authors.lastname: Smith
authors.forename: Mohamed
authors.initials: M
authors.lastname: Osman
authors.forename: Mark
authors.initials: M
authors.lastname: Harber
authors.forename: Andrew
authors.initials: A
authors.lastname: Davenport
authors.forename: Gareth
authors.initials: G
authors.lastname: Jones
authors.forename: David C
authors.initials: DC
authors.lastname: Wheeler
authors.forename: James
authors.initials: J
authors.lastname: O'Beirne
authors.forename: Douglas
authors.initials: D
authors.lastname: Thorburn
authors.forename: David
authors.initials: D
authors.lastname: Patch
authors.forename: Claire E
authors.initials: CE
authors.lastname: Atkinson
authors.forename: Sylvie
authors.initials: S
authors.lastname: Pichon
authors.forename: Paul
authors.initials: P
authors.lastname: Sweny
authors.forename: Marisa
authors.initials: M
authors.lastname: Lanzman
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Woodford
authors.forename: Emily
authors.initials: E
authors.lastname: Rothwell
authors.forename: Natasha
authors.initials: N
authors.lastname: Old
authors.forename: Ruth
authors.initials: R
authors.lastname: Kinyanjui
authors.forename: Tanzina
authors.initials: T
authors.lastname: Haque
authors.forename: Sowsan
authors.initials: S
authors.lastname: Atabani
authors.forename: Suzanne
authors.initials: S
authors.lastname: Luck
authors.forename: Steven
authors.initials: S
authors.lastname: Prideaux
authors.forename: Richard S B
authors.initials: RS
authors.lastname: Milne
authors.forename: Vincent C
authors.initials: VC
authors.lastname: Emery
authors.forename: Andrew K
authors.initials: AK
authors.lastname: Burroughs
mesh_terms: D000276:Adjuvants, Immunologic / Q000008:administration & dosage; D000328:Adult; D000368:Aged; D000914:Antibodies, Viral / Q000302:isolation & purification; D003587:Cytomegalovirus / Q000235:genetics / Q000276:immunology / Q000302:isolation & purification*; D003586:Cytomegalovirus Infections / Q000175:diagnosis* / Q000517:prevention & control*; D022482:Cytomegalovirus Vaccines / Q000008:administration & dosage* / Q000494:pharmacology; D004279:DNA, Viral / Q000302:isolation & purification; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D006801:Humans; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000009:adverse effects*; D016030:Kidney Transplantation; D016031:Liver Transplantation; D008297:Male; D008875:Middle Aged; D016377:Organ Transplantation; D016133:Polymerase Chain Reaction; D011136:Polysorbates / Q000008:administration & dosage*; D013185:Squalene / Q000008:administration & dosage*; D013997:Time Factors; D016896:Treatment Outcome; D014759:Viral Envelope Proteins / Q000008:administration & dosage* / Q000494:pharmacology; D014766:Viremia / Q000175:diagnosis / Q000517:prevention & control
chemical_list: D000276:Adjuvants, Immunologic; D000914:Antibodies, Viral; D022482:Cytomegalovirus Vaccines; D004279:DNA, Viral; D007166:Immunosuppressive Agents; C089950:MF59 oil emulsion; D011136:Polysorbates; D014759:Viral Envelope Proteins; C040495:glycoprotein B, Simplexvirus; D013185:Squalene