Cytomegalovirus chimeric epitope vaccine supplemented with PF03512676 (CMVPepVax) in allogeneic hematopoietic stem cell transplantation: viremia, immunogenicity and survival outcomes in a randomised phase 1b trial

BACKGROUND: Cytomegalovirus (CMV) seropositive recipients of allogeneic hematopoietic cell transplantation (HCT) are at risk for CMV reactivation. Stimulating viral immunity by vaccination may achieve CMV viremia control, without the need for antivirals. The aim of the trial is to assess safety, immunogenicity, and possible clinical benefit of CMVPepVax vaccine in HCT recipients. METHODS: In this randomised, open-label phase 1b trial, HCT recipients were enrolled at a single USA transplant center. Eligible patients were CMV seropositive, HLA A*0201-positive, 18–75 years, receiving HCT from matched related or unrelated donors. Patients were reassessed on day 28 post-HCT for eligibility, and 36 patients were randomised either to the vaccine (VA) or observation arm (OA), in blocks stratified by CMV donor serostatus. CMVPepVax was administered subcutaneously on days 28 and 56. CMVPepVax is a chimeric peptide composed of a cytotoxic CD8 T-cell epitope from CMV-pp65, and a tetanus T-helper epitope. It is formulated with the adjuvant PF03512676 (Pfizer Inc) a Toll-like receptor 9 agonist, which augments cellular immunity. The primary outcome was safety; secondary outcomes included immunogenicity, prevention of CMV reactivation, and clinical outcomes. Statistical analyses included all 36 randomized patients and were performed as per protocol. This study is registered as NCT01588015@www.clinicaltrials.gov. This trial is closed to accrual and a final analysis is presented in this report. FINDINGS: Between October 31, 2012, and November 5, 2014, 36 HCT recipients were randomised into the study. CMVPepVax was administered to 18 patients, with no adverse effect on HCT or rate of acute GVHD, and no unexpected adverse events. One serious adverse event (grade 1 fever) was attributed to CMVPepVax vaccination and resolved within 48 hours. Higher relapse free survival (1 versus 7 events, logrank p=0·015), a 2 fold increase in CMV-pp65 CD8 T cells during the first 100 days post-HCT (p=0·025), less CMV reactivation (1 versus 6 events, logrank p=0·039) and usage of antivirals (15 versus 263 days, p=0·03) were found in VA compared to OA recipients. INTERPRETATION: The results demonstrate safety and immunogenicity of CMVPepVax, and the prospect of significant clinical benefits that warrant testing in a phase 2 trial.