Suboptimal vaccine effectiveness against seasonal influenza is a significant public health concern, partly explained by antigenic differences between vaccine viruses and viruses circulating in the environment. Haemagglutinin mutations within vaccine viruses acquired during serial passage in eggs have been identified as a source of antigenic variation between vaccine and circulating viruses. This study retrospectively compared the antigenic similarity of circulating influenza isolates with egg- and cell-propagated reference viruses to assess any observable trends over a 16-year period. Using annual and interim reports published by the Worldwide Influenza Centre, London, for the 2002–2003 to 2017–2018 influenza seasons, we assessed the proportions of circulating viruses which showed antigenic similarity to reference viruses by season. Egg-propagated reference viruses were well matched against circulating viruses for A/H1N1 and B/Yamagata. However, A/H3N2 and B/Victoria cell-propagated reference viruses appeared to be more antigenically similar to circulating A/H3N2 and B/Victoria viruses than egg-propagated reference viruses. These data support the possibility that A/H3N2 and B/Victoria viruses are relatively more prone to egg-adaptive mutation. Cell-propagated A/H3N2 and B/Victoria reference viruses were more antigenically similar to circulating A/H3N2 and B/Victoria viruses over a 16-year period than were egg-propagated reference viruses.

This US-based, prospective observational cohort study evaluated the safety of a quadrivalent inactivated influenza vaccine (IIV4; Afluria Quadrivalent) in pregnant persons immunized over four influenza seasons between 2017 and 2021. Pregnancy outcomes included live birth, stillbirth, spontaneous abortion, and elective termination. Infant events of interest were major congenital malformations (MCMs), preterm birth (<37 weeks gestational age), and low birth weight (LBW). Data were descriptive; prevalence point estimates were reported with 95% confidence intervals (CI). A total of 483 pregnant persons were given IIV4 and evaluated; 477 (98.8%) reported a live birth, and there were 2 stillbirths, 4 spontaneous abortions, and no elective terminations or maternal deaths. The prevalence rates of infant events were as follows: preterm birth, 7.2% (upper 95% CI, 9.6%); LBW, 5.4% (upper 95% CI, 7.4%); and MCMs, 0.8% (upper 95% CI, 1.9%). Point estimates and upper 95% CIs of the observed prevalence rates were lower than or similar to background prevalence in the general US population. Our findings suggest no evidence of a safety concern with vaccinating this group at high risk of influenza complications and are consistent with published data from databases and surveillance systems that monitor the safety of influenza vaccines in pregnant persons.

Objective: To evaluate pregnancy and infant outcomes among persons immunized with a cell-based quadrivalent inactivated influenza vaccine (IIV4c) during routine pregnancy care. Design : Prospective observational cohort. Setting : US-based obstetrics/gynecology clinics. Population: Pregnant persons. This US-based, prospective observational cohort study evaluated the safety of quadrivalent inactivated influenza vaccine (IIV4c; Flucelvax^® Quad) in pregnant persons immunized over 3 influenza seasons between 2017 and 2020. Pregnant persons were immunized with IIV4c as part of routine care, after which their health care provides HCPs with all observational data to a single coordinating center. Follow-up data were collected at the end of the second trimester and/or at the time of pregnancy outcome. A scientific advisory committee reviewed the data. Prevalence point estimates were reported with 95% confidence intervals (CIs). Pregnancy outcomes included: live birth, stillbirth, spontaneous abortion, elective termination, and maternal death. Infant outcomes included: preterm birth (<37 weeks gestational age), low birth weight (<2500 g), or major congenital malformations (MCMs). Of the 665 evaluable participants, 659 (99.1%) had a live birth. No stillbirths (0% [95% CI 0.0–0.6]), 4 spontaneous abortions (1.9% [0.5–4.8]), and 1 elective termination (0.5% [0.0–2.6]) were reported. Among 673 infants, 9.2% (upper 95% CI 11.5%) were born prematurely, 5.8% (upper 95% CI 7.6%) had low birth weight, and 1.9% (upper 95% CI 3.1%) were reported to have an MCM. No maternal deaths were reported. Of the 2 infants who died shortly after birth, one was adjudicated as not related to the vaccine; the other’s cause could not be determined due to maternal loss to follow-up. The prevalence of adverse pregnancy outcomes or preterm birth, low birth weight, or MCMs in newborns was similar in persons vaccinated with IIV4c compared to the rates observed in US surveillance systems. The safety profile of IIV4c in pregnant persons is consistent with previously studied influenza vaccines.

The optimal formulation of an adjuvanted cell-based quadrivalent influenza vaccine (aQIVc) was investigated in Phase 2, observer-blind, multicentre, dose-finding (V201_01, NCT04782323) and dose-confirmation (V201_07, NCT05501561) studies in participants aged ≥50 years. In V201_01, participants were randomised to one of seven investigational aQIVc formulations or non-adjuvanted QIVc (15 μg haemagglutinin antigen [HA] per strain). Investigational formulations contained 15, 30, or 45 μg HA per strain, and 1×, 2×, and 3× the dose of MF59 adjuvant included in Fluad®. In V201_07, participants were randomised to aQIVc [45,1×], aQIVc [45,2×], QIVc [45,0×: 45 μg HA, 0×MF59] or QIVc [15,0×: 15 μg HA, 0× MF59]. Primary objective: to assess the immunogenicity of aQIVc formulations vs. QIVc 28 days post-vaccination. In V201_01, 838 participants (47.3% aged ≥65 years; 56.6% female; 55.9% White) were exposed. Generally, covariate-adjusted geometric mean titre ratios (GMTr) of aQIVc vs. QIVc at Day 29 (per-protocol set [PPS; n = 810]) increased with antigen and adjuvant dose but were similar between 2× and 3× adjuvant. In V201_07, 1051 participants (47.9% aged ≥65 years; 58.0% female; 83.7% White) were exposed (PPS; n = 1022). GMTr for aQIVc [45,2×] vs. QIVc [15,0×] ranged from 1.27 (95% confidence interval [CI], 1.04, 1.55) to 1.86 (1.52, 2.27) and were superior (lower limit of 95% CI >1.0) for all strains. GMTr of aQIVc [45,2×] vs. QIVc [45,0×] were superior for A/H1N1, A/H3N2, and B/Yamagata, and non-inferior for B/Victoria. Neither study presented safety concerns. In V201_07, rates of solicited adverse events (Day 1-7 post-vaccination) were highest with aQIVc [45,2×] (71.1%) and lowest with QIVc [15,0×] (50.4%); most events were mild (Grade 1) or moderate (Grade 2) severity across all groups. aQIVc [45,2×] demonstrated the highest immune response of all formulations tested, with no safety concerns, and was selected for further investigation in a Phase 3 study (NCT06015282). Clinical trial registry: NCT04782323 (https://clinicaltrials.gov/study/NCT04782323; registered date 2021-03-01), NCT05501561 (https://clinicaltrials.gov/study/NCT05501561; registered date 2022-08-11).

Background: Self-amplifying mRNA vaccines have the potential to increase the magnitude and duration of protection against COVID-19 by boosting neutralizing antibody titers and cellular responses. Methods: In this study, we used the immunogenicity data from a phase 3 randomized trial comparing the immunogenicity of ARCT-154, a self-amplifying mRNA COVID-19 vaccine, with BNT162b2 mRNA COVID-19 vaccine to estimate the relative vaccine efficacy (rVE) of the two vaccines over time in younger (<60 years) and older (≥60 years) adults. Results: By day 181 post-vaccination, the rVE against symptomatic and severe Wuhan-Hu-1 disease was 9.2–11.0% and 1.2–1.5%, respectively, across age groups whereas the rVE against symptomatic and severe Omicron BA.4/5 disease was 26.8–48.0% and 5.2–9.3%, respectively, across age groups. Sensitivity analysis showed that varying the threshold titer for 50% protection against severe disease up to 10% of convalescent sera revealed incremental benefits of ARCT-154 over BNT162b2, with an rVE of up to 28.0% against Omicron BA.4/5 in adults aged ≥60 year. Conclusions: Overall, the results of this study indicate that ARCT-154 elicits broader and more durable immunogenicity against SARS-CoV-2, translating to enhanced disease protection, particularly for older adults against Omicron BA.4/5.