Interim Assessment of Safety and Immunogenicity From a Proof-of-Concept Phase 2 Trial of an mRNA-Based Cytomegalovirus Vaccine in Patients Who Have Undergone Allogeneic Hematopoietic Cell Transplantation

Abstract Background Cytomegalovirus (CMV) establishes lifelong latency and is a risk factor for increased mortality in immunosuppressed individuals. mRNA-1647, an investigational mRNA-based vaccine targeting CMV gB and pentamer antigens, demonstrated acceptable safety and generated antigen-specific humoral and cell-mediated immunogenicity in healthy adults. We present interim analyses of mRNA-1647 safety and immunogenicity from an observer-blind phase 2 trial (NCT05683457) in CMV-seropositive adults ≥18 years with prior allogeneic hematopoietic cell transplantation (HCT). Methods Participants were randomized 1:1 to receive a 3-dose primary series of mRNA-1647 150 μg or placebo on Days 42, 67, 92 post-HCT, prior to the critical risk period for CMV reactivation (Day 100 post-HCT and/or CMV prophylaxis cessation). Safety was a primary endpoint. Humoral immunity (secondary endpoint) was measured by cell-based neutralizing antibody (nAb) assays at baseline and 25 days after each dose. CMV-specific T cell responses (gB- and pentamer-specific) were assessed as exploratory endpoints by intracellular cytokine staining and polyfunctionality analyses at baseline and 10 days after each dose. Site personnel remain blinded to safety analyses. Results At data cutoff (7 May 2024), 44 participants were randomized to receive mRNA-1647 or placebo (n=22/group; median age 65 years, 51.2% male, 72.1% White). There were no substantial differences between groups in occurrences of acute or chronic graft-vs-host disease, disease relapse, or serious adverse events. In the mRNA-1647 group vs placebo, nAb GMTs against epithelial cell infection increased ∼2.2-fold after dose 2 and ∼3.2-fold after dose 3. nAb titers against fibroblast infection remained similar between groups. mRNA-1647 induced robust CD4+ and CD8+ T cell responses against CMV-specific glycoproteins (gB, gH, gL) after dose 2, with T cells exhibiting polyfunctionality of substantial magnitude (Figures 1, 2). Conclusion In high risk seropositive HCT recipients, mRNA-1647 increased nAbs against epithelial cell infection and demonstrated antigen-specific, polyfunctional CD4+ and CD8+ T cell responses. There were no safety concerns on blinded safety assessment. These data support the continued assessment of mRNA-1647 in this population. Disclosures Jessica S. Little, MD, Merck and Company, Inc.: Grant/Research Support|Moderna, Inc.: Grant/Research Support