Immunogenicity and safety of mRNA-based seasonal influenza vaccines encoding hemagglutinin and neuraminidase

Abstract

Current influenza vaccines induce immune responses to hemagglutinin (HA), a surface glycoprotein of seasonal influenza viruses, but have suboptimal effectiveness. mRNA vaccines may improve protection by targeting additional antigens such as neuraminidase (NA), for which immune responses independently correlate with protection. In this phase 1/2 trial (NCT05333289), healthy adults 18-75 years were randomly assigned to receive different doses of mRNA-1020 or mRNA-1030 (encoding HA and NA at different ratios), mRNA-1010 (encoding HA), or a licensed active comparator (recombinant HA). Primary endpoints were safety and reactogenicity, and HA and NA antibody responses against vaccine-matched influenza strains. Most common local and systemic solicited ARs were injection site pain and fatigue. There were no vaccine-related serious adverse events nor significant associated safety concerns through 181 days. mRNA-1020 and mRNA-1030 elicited high HA-specific immune responses and induced NA-specific immune responses with no additional reactogenicity at equivalent dose levels beyond an mRNA-based, HA-only-containing vaccine.

Fig. 1. Participant disposition.

The full analysis set consisted of all randomly assigned participants who received the investigational product. The per-protocol population consisted of all participants in the full analysis set who complied with the injection schedule and the timings of immunogenicity blood sampling to have a baseline and at least one post-injection assessment, did not have influenza infection at baseline through day 29, and had no major protocol deviations that impacted the immune response. The safety population consisted of all randomly assigned participants who received the investigational product. The solicited safety population consisted of all participants in the safety population who contributed any solicited adverse reaction data. Data cutoff date of May 24, 2023.

Fig. 2. Local (panel A) and systemic (panel B) solicited adverse reactions within 7 days after vaccination (solicited safety population).

Percentages of participants in the solicited safety population, which consisted of all participants in the safety population (all randomly assigned participants who received the investigational product) who contributed any solicited adverse reaction data: recombinant vaccine, n = 71; mRNA-1010 50 µg, n = 71, mRNA-1020 50 µg, n = 71; mRNA-1020 100 µg, n = 67; mRNA-1020 150 µg, n = 70; mRNA-1030 25 µg, n = 71; mRNA-1030 50 µg, n = 72; mRNA-1030 100 µg, n = 72. Adverse reactions were graded in intensity by the extent to which they affected the participant’s daily activities as mild (grade 1), moderate (grade 2), severe (grade 3), or life-threatening (grade 4). When there were multiple adverse reactions of a specific term within 7 days, the worst grade was selected. In this study, no participants had a grade 4 solicited adverse reaction.

Fig. 3. Anti-hemagglutinin antibody geometric mean titer and geometric mean fold rise (per-protocol population).

HAI assay geometric mean titers against seasonal influenza A and B strains (A/Wisconsin/588/2019(H1N1)pdm09; A/Cambodia/e0826360/2020(H3N2); B/Washington/02/2019 [B/Victoria lineage]; B/Phuket/3073/2013 [B/Yamagata lineage]) were measured at day 1 (baseline) and day 29 (28 days after vaccination). Antibody titers ULOQ were converted to the ULOQ. LLOQ were 10 for A/H1N1, A/H3N2, B/Victoria, and B/Yamagata. ULOQ were 1280 for A/H3N2, 3200 for B/Victoria, and 6400 for A/H1N1 and B/Yamagata. Dots correspond to participant-level titers. Error bars represent 95% confidence intervals. GMFR at day 29 from day 1 are shown above each day 29 bar plot. Number of participants (n) based on the per-protocol population, which consists of all participants who received study vaccine, complied with the timing of immunogenicity blood sampling to have a baseline and ≥ 1 post-baseline assessment, did not have influenza infection at baseline through day 29 (as documented by RT-PCR testing), and had no major protocol deviations that impacted the immune response. GMFR = geometric mean fold rise, HAI = hemagglutination inhibition, LLOQ = lower limit(s) of quantitation, RT-PCR = reverse transcription-polymerase chain reaction, ULOQ = upper limit(s) of quantitation.

Fig. 4. Persistence of hemagglutination inhibition (panel A) and neuraminidase inhibition (panel B) responses through to day 181 (per-protocol population).

GMTs with associated 95% CI against vaccine-matched seasonal influenza A and B strains via the (A) HAI assay and (B) NAI assay at day 1 (baseline), day 8, day 29, and day 181. Horizontal dotted line indicates 1:40 titer associated with a 50% reduction in risk of infection. Number of participants (n) based on the per-protocol population, which consists of all participants who received study vaccine, complied with the timing of immunogenicity blood sampling to have a baseline and ≥1 post-baseline assessment, did not have influenza infection at baseline through day 29 (as documented by RT-PCR testing), and had no major protocol deviations that impacted the immune response. CI = confidence interval, GMT = geometric mean titer, HAI = hemagglutination inhibition, NAI = neuraminidase inhibition, RT-PCR = reverse transcription-polymerase chain reaction.

Fig. 5. Anti-neuraminidase antibody geometric mean titer and geometric mean fold rise (per-protocol population).

NAI assay geometric mean titers against seasonal influenza A and B strains (A/Wisconsin/588/2019 (H1N1)pdm09; A/Cambodia/e0826360/2020 (H3N2); B/Washington/02/2019 [B/Victoria lineage]; B/Phuket/3073/2013 [B/Yamagata lineage]) were measured at day 1 (baseline) and day 29 (28 days after vaccination). Antibody titers ULOQ were converted to the ULOQ. LLOQ were 24 for A/H3N2, 80 for B/Victoria and B/Yamagata, and 160 for A/H1N1. ULOQ were 12,177 for B/Victoria, 20,480 for A/H3N2, 40,960 for A/H1N1, and 81,920 for B/Yamagata. Dots correspond to participant-level titers. Error bars represent 95% confidence intervals. GMFR at day 29 from day 1 are shown above each day 29 bar plot. Number of participants (n) based on the per-protocol population, which consists of all participants who received study vaccine, complied with the timing of immunogenicity blood sampling to have a baseline and ≥ 1 post-baseline assessment, did not have influenza infection at baseline through day 29 (as documented by RT-PCR testing), and had no major protocol deviations that impacted the immune response. GMFR = geometric mean fold rise, LLOQ = lower limit(s) of quantitation, NAI = neuraminidase inhibition, RT-PCR = reverse transcription-polymerase chain reaction, ULOQ = upper limit(s) of quantitation.