Updated Data Underscore Continued Benefits of COVID-19, RSV, and Influenza Vaccination in 2025–2026 Season

Key Highlights:

• Persistent community SARS-CoV-2 infections can evolve rapidly within hosts but rarely result in onward transmission.
• The 2024–2025 COVID-19 vaccine was associated with a 64% reduction in COVID-19-related mortality over 6 months among U.S. veterans.
• Vaccines against COVID-19, RSV, and influenza offer measurable protection against hospitalization in the 2025–2026 season, with vaccine effectiveness estimates ranging from ~46 % for adult COVID-19 to ≥68 % for RSV prophylaxis in infants and older adults.

Evolution in Community Persistent COVID-19 Infections¹

Using data from the UK Office for National Statistics COVID-19 Infection Survey (April 2020–March 2023), investigators characterized within-host SARS-CoV-2 evolution in 576 community-based persistent infections, defined as sustained or rebounding high viral RNA titers for ≥26 days with ≥2 sequences. The analysis included cases involving seven major lineages: Alpha, Delta, BA.1, BA.2, BA.4, BA.5, and XBB. (Table 1).

Table 1. Distribution of persistent SARS-CoV-2 infections by lineage

Persistent infection was more frequent in men than women (58% vs 42%; P < .0001) and in adults > 60 years (P = .0027). The median genome-wide evolutionary rate was 7.9×10−4 substitutions/site/year (IQR, 7.0–9.0×10−4), exceeding typical between-host within-lineage rates for alpha, delta, and omicron sublineages. Rate heterogeneity across individuals was driven predominantly by nonsynonymous changes; synonymous rates were relatively uniform. Most infections exhibited low nucleotide diversity at baseline with subsequent accumulation of variants.

While longer infections showed higher evolutionary rates, the researchers found no association with age, sex, vaccination status, previous infection, or viral lineage. Nonsynonymous mutations concentrated in spike’s N-terminal and receptor-binding domains; ORF6 showed the lowest nonsynonymous diversity, consistent with strong purifying selection. Among 84 infections lasting ≥ 56 days, no clear evidence of transmission after the first month was detected.

Across infections, the research team identified 379 recurrent mutations, including lineage-defining substitutions and several associated with treatment resistance; many recurrent mutations had low population prevalence or predicted negative between-host fitness, and frequent de novo reversions to the Wuhan-Hu-1 reference were observed.

Overall, a minority of high–viral load persistent infections displayed accelerated evolution, suggesting genomic surveillance and targeted clinical management may be most impactful when focused on prolonged, high-titer infections.

Vaccine effectiveness of 2024–2025 COVID-19 dose in U.S. veterans²

In a large observational cohort study of veterans conducted within the Department of Veterans Affairs (VA) health care system, researchers assessed the effectiveness of the 2024–2025 season COVID‑19 vaccine. Between September 3 and December 31, 2024, a total of 295,971 participants met eligibility criteria; 164,132 received both the COVID-19 vaccine and the seasonal influenza vaccine on the same day, and 131,839 received the influenza vaccine only. Participants were followed for up to 180 days. The primary outcomes were COVID-19–associated emergency department visits, hospitalizations, and deaths, with inverse-probability–weighted models used to estimate vaccine effectiveness.

The authors found that at 6 months, vaccine effectiveness was 29.3% (95% CI, 19.1–39.2) against COVID-19–associated emergency-department visits (risk difference per 10 000 persons, 18.3), 39.2% (95% CI, 21.6–54.5) against hospitalizations (risk difference per 10 000 persons, 7.5), and 64.0% (95% CI, 23.0–85.8) against COVID-19–associated death (risk difference per 10 000 persons, 2.2). Vaccine effectiveness against a composite of these outcomes was 28.3% (95% CI, 18.2–38.2; risk difference, 18.2 per 10 000). Effectiveness estimates were consistent across age groups (<65, 65–75, >75 years), comorbidity status, and immune-competence status. These data suggest that the 2024–2025 COVID-19 vaccine was associated with meaningful reductions in severe clinical outcomes among U.S. veterans.

Updated Evidence on Respiratory Virus Vaccination 2025–26³

In a comprehensive systematic review published in the New England Journal of Medicine, Scott et al. evaluated the most current evidence on U.S.-licensed vaccines targeting COVID‑19, respiratory syncytial virus infection (RSV), and influenza for the 2025–2026 immunization season. The authors identified 17,263 records, of which 511 studies met inclusion criteria, encompassing both randomized trials and observational effectiveness studies. The pooled vaccine effectiveness (VE) against hospitalization was approximately 46–50 % for COVID-19 in adults and 37 % in immunocompromised adults, with higher observed VE in children in one case–control study (65%).

For RSV, maternal immunization, infant monoclonal antibody prophylaxis (nirsevimab), and vaccination in older adults each achieved VE of 68% or greater against hospitalization. Influenza vaccine effectiveness in adults aged 18–64 was estimated at 48% and in children up to 67% for hospitalization prevention. Safety outcomes were consistent with prior experience: myocarditis after COVID-19 vaccination in male adolescents occurred at 1.3–3.1 per 100 000 doses, and a small excess risk (~18 cases per million) of Guillain-Barré syndrome was noted with the RSV preF vaccine in older adults.

The authors concluded that current peer-reviewed evidence supports continued use of these vaccines for the three major respiratory viruses in the 2025–2026 season. They also noted that vaccine effectiveness is moderate and varies by pathogen, population subgroup, and circulating variant. The review underscored the ongoing need for targeted immunization strategies and continual data evaluation, especially given evolving advisory processes and virus variant dynamics.

References:

1. Ghafari M, Kemp SA, Hall M, et al. SARS-CoV-2 genomic diversity and within-host evolution in individuals with persistent infection in the UK: an observational, longitudinal, population-based surveillance study. Lancet Microbe. 2025;6(9):101154. doi:10.1016/j.lanmic.2025.101154
2. Cai M, Xie Y, Al-Aly Z. Association of 2024-2025 Covid-19 Vaccine with Covid-19 Outcomes in U.S. Veterans. N Engl J Med. 2025;393(16):1612-1623. doi:10.1056/NEJMoa2510226
3. Scott J, Abers MS, Marwah HK, et al. Updated Evidence for Covid-19, RSV, and Influenza Vaccines for 2025-2026. N Engl J Med. Published online October 29, 2025. doi:10.1056/NEJMsa2514268