P4.027: Safety and Immunogenicity of mRNA-1647 in Participants Aged 9-15 Years: Interim Results from the Phase 1/2a Study

Background: Development of a safe and effective cytomegalovirus (CMV) vaccine is a public health imperative, as reflected by its designation as one of the highest priority vaccine targets. mRNA-1647 is an investigational vaccine consisting of 6 mRNA sequences encoding the CMV glycoprotein B (gB) and pentamer antigens.

Methods: This multi-part phase 1/2a open-label, dose-ranging, observer-blind, placebo- controlled trial evaluated the safety and immunogenicity of mRNA-1647 in participants aged 9-15 years (NCT05575492). In Part 1 reported herein, CMV-seronegative and CMV-seropositive males and females aged 9-15 years (referred to as ‘younger participants’) were enrolled to receive mRNA-1647 (25, 50, or 100 μg) at Months 0, 2, and 6. Females aged 16-25 years (‘older participants’) received mRNA-1647 100 μg on the same schedule. Interim data through 7 months (1 month after dose 3) are presented.

Results: A total of 210 younger (CMV-seronegative, n=150; CMV-seropositive, n=60) and 100 older (CMV-seronegative, n=50; CMV-seropositive, n=50) participants were included. Solicited adverse reactions (ARs) within 7 days of any dose were reported by 62/70 (88.6%), 64/70 (91.4%), and 66/70 (94.3%) of younger participants receiving mRNA-1647 25, 50, and 100 μg, respectively, and by 97/100 (97.0%) of older participants receiving mRNA-1647 100 μg (Figure 1). Most ARs were grade 1-2; the most common local and systemic ARs across dose level were injection-site pain (younger: 185/210 [88.1%]; older: 94/100 [94.0%]) and headache (younger: 133/210 [63.3%]); older: 80/100 [80.0%]), respectively. Grade 3 ARs were reported by 40/210 [19.0%] of younger and 33/100 [33.0%] of older participants; no Grade 4 ARs were reported. There were no deaths and no related serious adverse events through Month 7; one adverse event led to trial discontinuation (older participant; depression). In CMV-seronegative younger participants, neutralizing antibody (nAb) geometric mean titers (GMTs) increased after each dose independent of dose level; GMTs were above the benchmark (baseline GMT of CMV-seropositive participants) from Months 3 through 7 for nAbs against epithelial cell infection, and at Months 3 and 7 for nAbs against fibroblast infection (Figure 2). Regardless of dose level, 3 mRNA-1647 doses produced GMCs above the benchmark at Month 7 for anti-gB binding antibodies (bAb), and from Months 3 through 7 for anti-pentamer bAbs. In CMV-seropositive younger participants, nAb GMTs increased after dose 1, did not increase appreciably after doses 2 and 3, and remained stable through Month 7. nAb GMTs and bAb GMCs in the CMV-seronegative younger participants were comparable to those of the mRNA-1647 100 µg older participants.

Conclusion: This dose-finding trial marks the first pediatric trial of the candidate CMV vaccine mRNA-1647. mRNA-1647 was generally well-tolerated with no safety concerns identified, and antigen-specific immunogenicity was demonstrated at all dose levels regardless of CMV serostatus. These data supported the selection of the 100-µg dose for advancement into late-stage development.