To ensure that vaccination offers the best protection against an infectious disease, sequence identity between the vaccine and the circulating strain is paramount. During replication of nucleic acid, random mutations occur due to the level of polymerase fidelity. In traditional influenza vaccine manufacture, vaccine viruses are propagated in fertilized chicken eggs, which can result in egg-adaptive mutations in the antigen-encoding genes. Whilst this improves infection and replication in eggs, mutations may reduce the effectiveness of egg-based influenza vaccines against circulating human viruses. In contrast, egg-adaptive mutations are avoided when vaccine viruses are propagated in Madin-Darby canine kidney (MDCK) cell lines during manufacture of cell-based inactivated influenza vaccines. The first mammalian cell-only strain was included in Flucelvax^® Quadrivalent in 2017. A sequence analysis of the viruses selected for inclusion in this vaccine (n = 15 vaccine strains, containing both hemagglutinin and neuraminidase) demonstrated that no mutations occur in the antigenic sites of either hemagglutinin or neuraminidase, indicating that cell adaptation does not occur during production of this cell-based vaccine. The development of this now entirely mammalian-based vaccine system, which incorporates both hemagglutinin and neuraminidase, ensures that the significant protective antigens are equivalent to the strains recommended by the World Health Organization (WHO) in both amino acid sequence and glycosylation pattern. The inclusion of both proteins in a vaccine may provide an advantage over recombinant vaccines containing hemagglutinin alone. Findings from real world effectiveness studies support the use of cell-based influenza vaccines.

Antigenic drift is a major driver of viral evolution and a primary reason why influenza vaccines must be reformulated annually. Mismatch between vaccine and circulating viral strains negatively affects vaccine effectiveness and often contributes to higher rates of influenza‐related hospitalizations and deaths, particularly in years dominated by A(H3N2). Several countries recommend enhanced influenza vaccines for older adults, who are at the highest risk of severe influenza complications and mortality. The immunogenicity of enhanced vaccines against heterologous A(H3N2) strains has been examined in nine studies to date. In six studies, an enhanced, licensed MF59‐adjuvanted trivalent inactivated influenza vaccine (aIIV3) consistently increased heterologous antibody titers relative to standard influenza vaccine, with evidence of a broad heterologous immune response across multiple genetic clades. In one study, licensed high‐dose trivalent inactivated influenza vaccine (HD‐IIV3) also induced higher heterologous antibody titers than standard influenza vaccine. In a study comparing a higher dose licensed quadrivalent recombinant influenza vaccine (RIV4) with HD‐IIV3 and aIIV3, no significant differences in antibody titers against a heterologous strain were observed, although seroconversion rates were higher with RIV4 versus comparators. With the unmet medical need for improved influenza vaccines, the paucity of studies especially with enhanced vaccines covering mismatched strains highlights a need for further investigation of cross‐protection in older adults.

Seasonal vaccination is the mainstay of human influenza prevention. Licensed influenza vaccines are regularly updated to account for viral mutations and antigenic drift and are standardised for their haemagglutinin content. However, vaccine effectiveness remains suboptimal. Neuraminidase (NA) evolves more gradually than hemagglutinin and has been demonstrated to provide added clinical benefits. However, NA is not currently a mandated or standardised component of influenza vaccines. Here, we collated expert opinions on the importance of NA in influenza vaccines in a two-stage Delphi survey. Nine statements about NA were formulated by a steering committee based on a targeted literature review. In the survey’s first round, panellists recruited from three continents were requested to report on their agreement with each statement and estimate the strength of evidence for each statement. Panellists were also requested to explain their choice of answer and suggest revisions to the statements. Consensus was considered reached if ≥ 75% of panellists agreed with a statement. If consensus was not reached for a statement, this statement was revised and included in the survey’s second round. Nine panellists with a broad range of NA-related expertise, including clinical, research, and public health experience, completed the survey. They agreed that anti-NA responses acquired via natural infection or vaccination are associated with protective immunity independently of haemagglutinin and that NA provided additional advantages including improving disease severity metrics. The experts identified several knowledge gaps concerning heterologous cross-reactivity of vaccine-induced anti-NA antibodies, correlations between anti-NA titres and reduced transmission or infection risks, and differences in anti-NA responses to seasonal influenza vaccines. NA is an important influenza vaccine component and is associated with specific benefits. These benefits would likely be greater if NA content were standardised. Additional research is needed to optimise vaccines for anti-NA effects.

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.

The authors would like to make the following corrections to this published paper

Background/objective: Older adults experience a disproportionate burden of severe influenza. In the P303 trial (NCT058279789), mRNA-1010 showed greater immunogenicity versus high-dose inactivated influenza vaccine (HD-IIV4) in adults ≥65 years of age. Here, we used a correlate-of-protection framework to estimate the relative VE (rVE) of mRNA-1010 compared with HD-IIV4. Methods: A sigmoidal function was used to model the relationship between geometric mean haemagglutinin assay inhibition (HAI) titers (GMTs) and vaccine efficacy (VE) using data from the P304 trial (NCT06602024), which compared mRNA-1010 and the standard-dose IIV4 in adults ≥50 years of age. The model was then applied to GMTs from the P303 trial to estimate rVE of mRNA-1010 vs. HD-IIV4 in adults ≥65 years. Temporal waning and weighting of case distributions were incorporated to provide a season-integrated estimate. Simulations were performed for three influenza seasons (A/H1N1-dominant, A/H3N2-dominant, and balanced), with a sensitivity analysis varying vaccination and epidemic peak timing. Results: At Day 29, rVE for mRNA-1010 vs. HD-IIV4 was 24.1% (95% CI: 18.2–29.5%) against A/H1N1, 14.5% (8.3–20.3%) against A/H3N2, and 21.0% (16.0–25.8%) against B/Victoria. The season-integrated rVE was 12.4% (3.4–21.3%) across all three strains, with point estimates ranging from 11.6% to 12.6%. Similar findings were seen across simulated seasons, with rVE estimates ranging from 8.8% to 14.3% when varying vaccination timing, peak timing, and strain dominance. Conclusions: Based on this CoP framework, mRNA-1010 was projected to have higher VE than HD-IIV4 in adults ≥65 years of age across a range of simulated epidemiological conditions.