Cytomegalovirus glycoprotein-B vaccine with MF59 adjuvant in transplant recipients: a phase 2 randomised placebo-controlled trial

Abstract

SummaryBackgroundCytomegalovirus 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.MethodsWe 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.Findings67 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.InterpretationAlthough 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.Funding, Grant R01AI051355 and , Grant 078332. Sponsor: University College London (UCL).

The pentameric complex of human Cytomegalovirus: cell tropism, virus dissemination, immune response and vaccine development

“…In one trial, the gB/MF59 vaccine provided approximately 50 % efficacy against acquisition of HCMV infection in HCMV-seronegative women enrolled post-partum [106]. In another phase II study, this vaccine was effective in preventing viremia in 5/11 D + Rsolid organ transplant recipients (SOTR) compared to 0/5 subjects in the placebo group [107]. However, most of the antibodies elicited by gB in HCMV-seropositive individuals were not neutralizing [79,108].…”

Treatment of CMV infection after allogeneic hematopoietic stem cell transplantation

“…In a randomized, placebo-controlled phase II clinical trial on SOT -140 kidney or liver transplant patients -a subunit vaccine made up of purified glycoprotein B protein coupled with MF59 adjuvant led to a significantly shorter duration of viraemia, defined as viral loads higher than 200 genome/mL of blood, and a shorter duration of anti-viral therapy as compared with the placebo group. A strong antibody activity was seen without, however, a T cell-immunity involvement that determined a short durability of the immune response [117]. A second study employed a vectored vaccine, also known as ASP0013 or TransVax, with plasmids encoding CMV glycoprotein B and phosphoprotein pp65.…”

The Impact of Infection on Chronic Allograft Dysfunction and Allograft Survival After Solid Organ Transplantation

“…Prospective interventional studies assessing the efficacy and safety of screening and treatment of bacterial colonization of the urinary and respiratory tract in kidney and lung transplant recipients, respectively, are of particular importance in the current era of MDR bacteria. Finally, vaccination for certain pathogens, such as CMV and uropathogenic E coli, may continue to reduce the impact of infection after transplantation (203,204).…”