Safety and Immunogenicity of mRNA-1010, an Investigational Seasonal Influenza Vaccine, in Healthy Adults: Final Results From a Phase 1/2 Randomized Trial

Abstract

Background: Seasonal influenza remains a global public health concern. A messenger RNA (mRNA)-based quadrivalent seasonal influenza vaccine, mRNA-1010, was investigated in a first-in-human, phase 1/2 clinical trial conducted in 3 parts.

Methods: In parts 1 to 3 of this stratified observer-blind study, adults aged ≥18 years were randomly assigned to receive a single dose (6.25-200 µg) of mRNA-1010 or placebo (part 1) or an active comparator (Afluria; parts 2 and 3). Primary study objectives were assessment of safety, reactogenicity, and humoral immunogenicity of mRNA-1010, placebo (part 1), or active comparator (parts 2 and 3). Exploratory end points included assessment of cellular immunogenicity (part 1) and antigenic breadth against vaccine heterologous strains (A/H3N2; parts 1 and 2).

Results: In all study parts, solicited adverse reactions were reported more frequently for mRNA-1010 than placebo or Afluria, and most were grade 1 or 2 in severity. No vaccine-related serious adverse events or deaths were reported. In parts 1 and 2, a single dose of mRNA-1010 (25-200 µg) elicited robust day 29 hemagglutination inhibition titers that persisted through 6 months. In part 3, lower doses of mRNA-1010 (6.25-25 µg) elicited day 29 hemagglutination inhibition titers that were higher or comparable to those of Afluria for influenza A strains. When compared with Afluria, mRNA-1010 (50 µg) elicited broader A/H3N2 antibody responses (part 2). mRNA-1010 induced greater T-cell responses than placebo at day 8 that were sustained or stronger at day 29 (part 1).

Conclusions: Data support the continued development of mRNA-1010 as a seasonal influenza vaccine.

Clinical trials registration: NCT04956575 (https://clinicaltrials.gov/study/NCT04956575).

Keywords: influenza; messenger RNA; phase 1/2; randomized clinical trial; vaccine.

Figure 1.

Participant disposition by study part. All randomly assigned participants who received study vaccination were included in the safety population; participants were included in the group based on the actual vaccine received. The immunogenicity per-protocol population included all randomly assigned participants who received vaccination and complied with baseline and ≥1 postvaccination time point blood sampling, did not have influenza infection at baseline through day 29 (as documented by polymerase chain reaction), and had no major protocol deviation that affected the immune response. ^a There was 1 dosing error in part 1 (1 participant randomly assigned to mRNA-1010 at 200 µg but received 100 µg) and 2 dosing errors in part 2 (1 participant randomly assigned to mRNA-1010 at 25 µg but received 50 µg; 1 participant randomly assigned to mRNA-1010 at 50 µg but received active comparator). ^b Participants could contribute to multiple reasons for exclusion from the immunogenicity per-protocol population. ^c Participants were considered to have completed the study if they completed the final study visit at day 181. mRNA, messenger RNA.

Figure 2.

Ratios of GMTs of antihemagglutinin antibodies after vaccination with mRNA-1010 as compared with Afluria at day 29 for parts 2 and 3. Ratios of hemagglutination inhibition GMTs with associated 95% CIs against vaccine-matched seasonal influenza strains at day 29 after vaccination with mRNA-1010 as compared with Afluria in participants aged (A) 18 to 49 years in parts 2 and 3, (B) ≥50 years in part 3, and (C) 50 to 64 years and ≥65 years in part 2. Horizontal dotted line indicates a GMT ratio of 1, which shows comparable GMTs between mRNA-1010 and Afluria. Numbers of participants in the Afluria groups were as follows: 20 (18–49 years), 20 (50–64 years), and 12 (≥65 years) in part 2 and 32 (18–49 years) and 16 (≥50 years) in part 3. Numbers of participants aged 18 to 49 years in the mRNA-1010 groups were as follows: 34 (6.25 µg), 32 (12.5 µg), 31 (25 µg; part 3), 55 (25 µg; part 2), 53 (50 µg), and 57 (100 µg). In part 2, the numbers of participants in mRNA-1010 groups aged 50 to 64 years were 58 (25 µg), 54 (50 µg), and 54 (100 µg), and the numbers of those aged ≥65 years were 31 (25 µg), 31 (50 µg), and 30 (100 µg). In part 3, the numbers of participants aged ≥50 years in the mRNA-1010 groups were 15 (6.25 µg), 15 (12.5 µg), and 15 (25 µg). The numbers of participants are from the per-protocol population. Lower limits of quantitation were 10 for each influenza strain; upper limits of quantitation were 6400 (H1N1 and B/Yamagata), 1280 (H3N2), and 3200 (B/Victoria). GMT, geometric mean titer; mRNA, messenger RNA.

Figure 3.

Persistence of antihemagglutinin antibodies after mRNA-1010 vaccination for all ages (≥18 years) in parts 1 and 2. Geometric mean titers with associated 95% CIs against vaccine-matched seasonal influenza strains at (A) days 1 (baseline), 8, 29, and 181 across all age groups combined for part 1 and (B) days 1 (baseline), 29, 91, and 181 across all age groups combined for part 2. Horizontal dotted line indicates 1:40 titer associated with a 50% reduction in risk of infection [16]. In part 1, the number of participants in the placebo group was 41. The numbers of participants in the mRNA-1010 groups were 43 (50 µg), 44 (100 µg), and 41 (200 µg). In part 2, the number of participants in the Afluria group was 52. The numbers of participants in mRNA-1010 groups were 144 (25 µg), 138 (50 µg), and 141 (100 µg). Numbers of participants were derived from the per-protocol population for both study parts. Days 1 and 29 titers were simultaneously tested, with days 8 and 181 titers tested noncontemporaneously. HAI, hemagglutination inhibition; mRNA, messenger RNA.

Figure 4.

Antigenic breadth of mRNA-1010 against vaccine-heterologous A/H3N2 strains at day 29 in part 2. A, Geometric mean fold rise of titers from baseline to day 29 with associated 95% CI among mRNA-1010 (50 µg) and Afluria recipients against vaccine-matched H3N2 (A/Cambodia/e0826360/2020) and vaccine-heterologous H3N2 strains (A/Newcastle/01/2021, A/Delaware/39/2019, and A/Darwin/11/2021). Numbers of participants for the vaccine-matched strain were 52 (Afluria) and 138 (mRNA-1010, 50 µg); for vaccine-heterologous strains, 52 (Afluria) and 139 (mRNA-1010, 50 µg). Numbers of participants for the vaccine-matched strain and vaccine-heterologous strains were derived from the per-protocol population for part 2 of the study. B, Phylogenetic tree demonstrating real-time tracking of A/H3N2 clades (adapted from Nextstrain.org) [27].

Figure 5.

Frequency of type 1 polyfunctional CD4+ T cells after ex vivo stimulation with vaccine strain–specific peptide pools among recipients receiving mRNA-1010 and placebo in part 1. Three type 1 cytokines (IFN-γ, IL-2, and TNF-α) and CD40L functional markers were measured to assess T-cell response. Populations of CD4+ T cells coexpressing all 3 type 1 cytokines and CD40L functional markers from baseline to day 29 are presented. Numbers of participants in the placebo and mRNA-1010 groups were as follows: 23 (placebo), 19 (50 µg), 28 (100 µg), and 24 (200 µg). Boxes represent the 25th and 75th percentiles; whiskers represent the minimum and maximum values. Symbols represent individual-level data. IFN-γ, interferon γ; IL-2, interleukin 2; TNF-α, tumor necrosis factor α.