Abstract
Background: Cytomegalovirus (CMV) establishes lifelong latency and is an important risk factor for increased morbidity and mortality in individuals who are immunosuppressed. mRNA-1647 is an investigational mRNA-based CMV vaccine that encodes glycoprotein B (gB) and pentamer, important antigenic targets of the human immune response to CMV infection. In a phase 1 trial in healthy adults, a 3-dose series of mRNA-1647 demonstrated a favorable safety profile and induced antigen-specific humoral and cellular responses. Herein, we report interim analyses of mRNA-1647–specific T-cell responses observed in a phase 2 trial in adults with prior allogeneic hematopoietic cell transplantation (HCT) and a phase 1b trial in healthy adults.
Methods: In a phase 2, observer-blind, placebo-controlled trial (NCT05683457), CMV-seropositive HCT recipients aged ≥18 years were randomly assigned (1:1) to receive 3 doses of mRNA-1647 150 μg or placebo on Days 42, 67, and 92 post-HCT, prior to CMV prophylaxis cessation and the critical risk period for CMV reactivation (Day 100 post-HCT). In an ongoing, open-label, phase 1b trial (NCT05397223), healthy adults aged 18-49 years were stratified by baseline CMV serostatus (2:1 seronegative:seropositive) and randomly assigned (1:1) to receive 2 doses (Days 1, and 57) or 3 doses (Days 1, 57, and 169) of mRNA-1647 100 μg. As an exploratory endpoint in both trials, CMV-specific T-cell responses (gB and pentamer) were assessed by intracellular cytokine staining and polyfunctionality analyses. Samples for T-cell analysis were collected from HCT recipients at baseline (Day 1) and after each dose (Days 52, 77, and 102) and from healthy adults at Days 57, 85, 169, and 197.
Results: In the phase 2 trial, 44 CMV-seropositive HCT recipients were randomly assigned to receive mRNA-1647 or placebo (n = 22 per group) at data cutoff (May 7, 2024); the median age was 65 years and 51.2% were male. In the phase 1b trial, 57 participants were randomly assigned to receive mRNA-1647 as a 2-dose (n = 28) or 3-dose (n = 29) schedule at data cutoff (May 31, 2024). For the 2- and 3-dose groups, respectively, the mean (range) age was 39 (18-49) years and 34 (19-49) years, 43% and 24% were male, and 32% (9/28) and 31% (9/29) were CMV-seropositive. mRNA-1647 induced polyfunctional CD4+T-cell responses against gB and pentamer post-dose 1 in both healthy adults and HCT recipients. These post-dose 1 responses were particularly notable in HCT recipients, given the relatively early administration of mRNA-1647 (Day 42) and timing of responses (Day 52) after transplant. After doses 2 and 3, robust antigen-specific CD4+ and CD8+ T-cell responses were observed in both groups. Notably, the magnitude of antigen-specific T-cell responses in HCT recipients generally reached comparable levels or exceeded those observed in healthy CMV-seropositive adults by 1 month after doses 2 and 3, acknowledging differences in vaccination dose and timing, and participants' immune status.
Conclusions: Starting at 1 month post-dose 2, mRNA-1647 elicited antigen-specific, highly polyfunctional CD4+and CD8+ T-cell responses in CMV-seropositive high-risk HCT recipients that were equivalent to or exceeded T-cell responses induced in healthy adults. These findings support continued evaluation of mRNA-1647 safety, immunogenicity, and efficacy in high-risk adult populations.
