Safety and immunogenicity of a phase 1/2 randomized clinical trial of a quadrivalent, mRNA-based seasonal influenza vaccine (mRNA-1010) in healthy adults: interim analysis

Abstract

Despite vaccine availability, influenza remains a substantial global public health concern. Here, we report interim findings on the primary and secondary objectives of the safety, reactogenicity, and humoral immunogenicity of a quadrivalent messenger RNA (mRNA) vaccine against seasonal influenza, mRNA-1010, from the first 2 parts of a 3-part, first-in-human, phase 1/2 clinical trial in healthy adults aged ≥18 years (NCT04956575). In the placebo-controlled Part 1, a single dose of mRNA-1010 (50 µg, 100 µg, or 200 µg) elicited hemagglutination inhibition (HAI) titers against vaccine-matched strains. In the active-comparator-controlled Part 2, mRNA-1010 (25 µg, 50 µg, or 100 µg) elicited higher HAI titers than a standard dose, inactivated seasonal influenza vaccine for influenza A strains and comparable HAI titers for influenza B strains. No safety concerns were identified; solicited adverse reactions were dose-dependent and more frequent after receipt of mRNA-1010 than the active comparator. These interim data support continued development of mRNA-1010.

Fig. 1. Participant disposition by study part.

One participant in the mRNA-1010 100-µg group in Part 2 of the study died due to cardiac arrest. This adverse event was considered by the investigator as unrelated to the study vaccination. 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 immunogenicity blood sampling timing to have baseline and ≥1 post-vaccination time point assessment, did not have influenza infection at baseline through Day 29 (as documented by polymerase chain reaction), and had no major protocol deviation that impacted the immune response. mRNA messenger RNA. *There was 1 dosing error in Part 1 (n = 1 participant randomized to mRNA-1010 200 µg but received 100 µg) and 2 dosing errors in Part 2 (n = 1 participant randomized to mRNA-1010 25 µg but received 50 µg; n = 1 participant randomized to mRNA-1010 50 µg but received active comparator).

Fig. 2. Summary of any solicited local and systemic adverse reactions within 7 days after vaccination by age group in each study part.

Percentages of participants in the solicited safety population reporting any solicited adverse reactions in Part 1 (a) or Part 2 (b). In Part 1, number of participants in the placebo group were 20 (18–49 years) and 24 (≥50 years); number of participants in the mRNA-1010 groups were 23 (50 µg), 21 (100 µg), and 23 (200 µg) for 18–49 years, and 22, (50 µg), 25 (100 µg), and 21 (200 µg) for ≥50 years. In Part 2, number of participants in the Afluria group were 21 (18–49 years), 19 (50–64 years), and 13 (≥65 years); number of participants in the mRNA-1010 groups were 60 (25 µg), 57 (50 µg), and 58 (100 µg) for 18–49 years; 58 (25 µg), 58 (50 µg), and 57 (100 µg), for 50–64 years; and 31 (25 µg), 31 (50 µg), and 30 (100 µg) for ≥65 years. mRNA, messenger RNA.

Fig. 3. GMTs and GMFRs of anti-hemagglutinin antibodies for vaccine-matched seasonal influenza strains in adults in Part 1.

Hemagglutination inhibition GMTs with associated 95% CIs against seasonal influenza A strains (A/Wisconsin/588/2019[H1N1]pdm09 and A/Hong Kong/45/2019[H3N2]) or influenza B strains (B/Washington/02/2019 (B/Victoria lineage) and B/Phuket/3073/2013 (B/Yamagata lineage)) are shown at Day 1 (baseline) and Day 29 (28 days after vaccination) among participants a 18–49 years and b ≥50 years of age in the per-protocol population for Part 1. Dots correspond to participant-level titers (18–49 years, n = 19 (placebo), 22 (mRNA-1010 50 µg), 21 (mRNA-1010 100 µg), and 22 (mRNA-1010 200 µg); ≥50 years, n = 22 (placebo), 21 (mRNA-1010 50 µg), 24 (mRNA-1010 100 µg), and 19 (mRNA-1010 200 µg). GMFRs at Day 29 from Day 1 are shown above each Day 29 bar plot. LLOQs were 10 (H1N1, B/Victoria, and B/Yamagata) or 14 (H3N2); ULOQs were 6400 (H1N1, H3N2, and B/Yamagata) or 3200 (B/Victoria). HAI GMTs <LLOQ were replaced by 0.5× LLOQ and values > ULOQ were converted to ULOQ. CI confidence interval, HAI hemagglutination inhibition, GMFR geometric mean fold-rise, GMT geometric mean titer, LLOQ lower limit of quantification, mRNA messenger RNA, ULOQ upper limit of quantification.

Fig. 4. GMTs and GMFRs of anti-hemagglutinin antibodies for vaccine-matched seasonal influenza strains in adults in Part 2.

Hemagglutination inhibition GMTs with associated 95% CIs against seasonal influenza A strains (A/Wisconsin/588/2019[H1N1]pdm09 and A/Cambodia/e0826360/2020[H3N2]) or influenza B strains (B/Washington/02/2019 (B/Victoria lineage) and B/Phuket/3073/2013 (B/Yamagata lineage)) are shown at Day 1 (baseline) and Day 29 (28 days after vaccination) among participants a 18–49 years, b 50–64 years, and c ≥65 years of age in the per-protocol population for Part 2. Dots corresponding to participant-level titers; numbers of participants in the Afluria groups were 20 (18–49 years), 20 (50–64 years), and 12 (≥65 years); numbers of participants in the mRNA-1010 groups were 55 (25 µg), 53 (50 µg), and 58 (100 µg) for 18–49 years; 57 (25 µg), 54 (50 µg), and 54 (100 µg) for 50–64 years; and 31 (25 µg), 31, (50 µg), and 30 (100 µg) for ≥65 years. GMFRs at Day 29 from Day 1 are shown above each Day 29 bar plot. LLOQs were 10 for each influenza strain; ULOQs were 6400 (H1N1 and B/Yamagata), 1280 (H3N2), or 3200 (B/Victoria). HAI GMTs <LLOQ were replaced by 0.5× LLOQ and values >ULOQ were converted to ULOQ. CI confidence interval, HAI hemagglutination inhibition, GMFR geometric mean fold-rise, GMT geometric mean titer, LLOQ lower limit of quantification, mRNA messenger RNA, ULOQ upper limit of quantification.

Fig. 5. Ratios of GMTs of anti-hemagglutinin antibodies after vaccination with mRNA-1010 compared with Afluria in adults in Part 2.

Ratios of HAI GMTs with associated 95% CIs against vaccine-matched seasonal influenza strains (A/Wisconsin/588/2019[H1N1]pdm09, A/Cambodia/e0826360/2020[H3N2], B/Washington/02/2019 (B/Victoria lineage), and B/Phuket/3073/2013 (B/Yamagata lineage)) at 28 days after vaccination with mRNA-1010 compared with Afluria are shown for participants a 18–49 years, b 50–64 years, and c ≥65 years of age in the per-protocol population for Part 2. Horizontal dotted line indicates a GMT ratio of 1, which reflects comparable GMTs between mRNA-1010 and Afluria. Numbers of participants in the Alfuria groups were 20 (18–49 years), 20 (50–64 years), and 12 ( ≥65 years); numbers of participants in the mRNA-1010 groups were 55 (25 µg), 53 (50 µg), and 58 (100 µg) for 18–49 years; 57 (25 µg), 54 (50 µg), and 54 (200 µg) for 50–64 years; and 31 (25 µg), 31 (50 µg), and 30 (100 µg) for ≥65 years. CI confidence interval, HAI hemagglutination inhibition, GMT geometric mean titer, LLOQ lower limit of quantification, mRNA messenger RNA, ULOQ upper limit of quantification.