Discussion
deaths
INFLUENZA A, EVENTS, INFLUENZA B, INFLUENZA
This manuscript presents interim analysis findings from 2 parts of a phase 1/2, first-in-human clinical trial on the safety and immunogenicity of an investigational mRNA-based quadrivalent vaccine against seasonal influenza (mRNA-1010) in healthy adults ≥18 years. The placebo-controlled Part 1 of this study showed that a single dose of mRNA-1010 (50 µg, 100 µg, or 200 µg) elicited HAI antibodies against vaccine-matched strains at 28 days after vaccination in both younger and older healthy adults. Based on the comparable immunogenicity across the mRNA-1010 dose levels in Part 1, a lower dose level range of mRNA-1010 (25 µg, 50 µg, or 100 µg) was evaluated in a larger number of participants in Part 2. Findings in Part 2 suggest that mRNA-1010 could elicit higher immunogenicity than a standard-dose influenza vaccine for influenza A strains and comparable immunogenicity for influenza B strains in medically stable adults. Higher responses for influenza A strains remain important, as the A/H3N2 strain in particular causes a larger burden of severe outcomes in older adultsIn both parts of the trial, no treatment-related SAEs were reported nor any safety concerns identified. In Part 1 of the trial, the frequency and severity of solicited ARs generally increased in a dose-dependent manner and was higher among younger (18–49 years) than older (≥50 years) adults. In Part 2, all three mRNA-1010 dose levels had an acceptable reactogenicity profile. For all age groups, solicited ARs were more common with mRNA-1010 than Afluria and were typically grade 1 or grade 2 in severity. No grade 4 solicited ARs were reported for any vaccine group and grade 3 events were less frequent for lower dose levels and for older adults (≥65 years). Overall, these safety data support the continued evaluation of mRNA-1010.A single dose of mRNA-1010 (50 µg, 100 µg, or 200 µg) in Part 1 of the trial elicited HAI antibodies against all vaccine-included strains at Day 29 in adults irrespective of participant age. Overall, the 50-µg dose level induced HAI titers that were comparable to those elicited by higher dose levels (100 µg and 200 µg). In both younger and older adults, the GMFRs from baseline exceeded 4-fold for influenza A strains, which is notable, as influenza A strains are the primary drivers of influenza-related hospitalizations and deaths, particularly in older adultsOverall, these first-in-human safety and immunogenicity findings in adults aged ≥18 years support the continued investigation of mRNA-1010 against seasonal influenza and highlight the potential of the mRNA platform to improve the effectiveness of influenza vaccines. Vaccines using mRNA technology are readily amenable to both antigenic drift and shift in influenza strains, allowing for rapid deployment of vaccines that are more closely matched to currently circulating strains and can avoid aberrant mutations in vaccine antigens caused by egg- or cell-culture approachesStudy strengths include the randomized, observer-blind, placebo-controlled (Part 1) and active comparator (Part 2) design. The study design did not specify any hypothesis testing; thus, the sample sizes of participants enrolled (Part 1, In conclusion, the interim analysis findings from the placebo-controlled Part 1 and active comparator controlled Part 2 of this phase 1/2 trial of mRNA-1010 in adults aged ≥18 years raised no safety concerns and showed that the vaccine was immunogenic against all tested influenza strains in both younger and older adults. Further, the investigational mRNA-1010 vaccine elicited either higher or comparable immune responses to a standard-dose, quadrivalent inactivated vaccine. These findings support the continued clinical development of mRNA-1010 to combat seasonal influenza.