A large systematic review and meta-analysis published in JMIR Public Health and Surveillance examines the efficacy and safety profiles of novel respiratory syncytial virus (RSV) prefusion F (preF) protein vaccines, addressing ongoing questions about these newer RSV vaccine platforms in an aging population at increased risk of severe respiratory disease.1 The findings support the use of RSV preF vaccines in reducing lower respiratory tract infections (LRTI) and RSV-associated acute respiratory illnesses (RSV-ARI) in adults aged 60 years and older.

RSV is increasingly recognized as a substantial contributor to morbidity and mortality in older adults. Based on 2019 data from high-income countries, RSV was estimated to cause approximately 5 million acute respiratory tract infections, 500,000 hospitalizations, and 33,000 in-hospital deaths annually among adults aged 60 years and older. Projections for 2025 suggest this burden could increase to 10.9 million cases, 800,000 hospitalizations, and 74,000 deaths, highlighting the need for effective preventive strategies in this population.2

Reducing Infections and Hospitalizations: Safety and Efficacy Data

Investigators identified randomized, placebo-controlled trials published through July 31, 2024. Fourteen high-quality trials met inclusion criteria, encompassing more than 100,000 older adults in efficacy analyses and more than 76,000 participants in safety evaluations. Across 5 trials involving 101,825 participants, RSV vaccination was associated with a statistically significant reduction in LRTIs compared with placebo.

Initial pooled analyses demonstrated heterogeneity, which investigators attributed to a single outlier study that enrolled participants with a higher baseline burden of respiratory disease. After exclusion of this study, a revised analysis of the 4 trials, including 99,931 participants, demonstrated a consistent and significant reduction in the incidence of LRTIs among vaccinated individuals, with heterogeneity largely resolved.

A parallel analysis of RSV-ARIs produced similar results. Following exclusion of the same heterogeneous study, the 4 randomized trials demonstrated a significant reduction in RSV-ARIs among vaccine recipients compared with placebo.

Safety outcomes were assessed across 14 trials involving 76,695 participants, with balanced representation between vaccine and placebo groups. Overall, adverse events (AEs) occurred more frequently among vaccinated participants, primarily injection site reactions such as pain, swelling, and redness. However, the analysis found no significant difference in serious AEs between vaccinated and placebo groups across all included studies.

Subgroup analyses were conducted across 14 studies to explore sources of variability in AE reporting. Stratification by median age below versus at or above 70 years showed minimal differences in overall AEs. However, heterogeneity in AEs related to vaccine components, including adjuvants and formulations containing Ad26.RSV.preF or recombinant RSV preF protein, was more pronounced in younger subgroups, suggesting potential age-related differences in tolerability.

When stratified by racial composition, studies with more than 80% White participants demonstrated significant heterogeneity in overall AEs, whereas those with 80% or fewer White participants did not. The authors cautioned that these findings could not be definitively attributed to race due to limited subgroup sizes and overlapping influences from vaccine formulation and study design.

Clinical Implications for Preventive Care

These findings align with recent large phase 3 trials and support current recommendations to incorporate RSV vaccination into routine preventive care for adults aged 60 years and older, particularly those with comorbid conditions that increase RSV-related risk.3,4,5

“Our findings indicate that the vaccine provided a significant enhanced level of protection against these infections in the target population,” the authors concluded. “Furthermore, these results suggest that vaccination may be the most effective strategy for safeguarding older adults.”

References

1. Xiao Q, Yang R, Zhang L, Tian Y, Wang X, Li W. Safety and efficacy of respiratory syncytial virus vaccination in older adults: systematic review and meta-analysis of randomized controlled trials. JMIR Public Health Surveill. 2025;11:e74271. doi:10.2196/74271

2. Savic M, Penders Y, Shi T, Branche A, Pirçon JY. Respiratory syncytial virus disease burden in adults aged 60 years and older in high-income countries: a systematic literature review and meta-analysis. Influenza Other Respir Viruses. 2023;17(1):e13031. doi:10.1111/irv.13031

3. Papi A, Ison MG, Langley JM, et al. Respiratory syncytial virus prefusion F protein vaccine in older adults. N Engl J Med. 2023;388(7):595-608. doi:10.1056/NEJMoa2209604

4. Falsey AR, Williams K, Gymnopoulou E, et al. Efficacy and safety of an Ad26.RSV.preF-RSV preF protein vaccine in older adults. N Engl J Med. 2023;388(7):609-620. doi:10.1056/NEJMoa2207566

5. Feldman RG, Antonelli-Incalzi R, Steenackers K, et al. Respiratory syncytial virus prefusion F protein vaccine is efficacious in older adults with underlying medical conditions. Clin Infect Dis. 2024;78(1):202-209. doi:10.1093/cid/ciad471