Highlights
- Adjuvanted RSVPreF3 vaccination shows robust real-world effectiveness (~76%) in preventing RSV-related hospitalizations among US adults aged ≥60 years.
- Vaccine effectiveness remains consistently high across key subgroups, including those with chronic pulmonary, cardiovascular diseases, diabetes, and immunocompromised status.
- Large retrospective cohort data from the Optum Research Database (ORD) provide strong evidence supporting vaccination for reducing RSV disease burden in older populations.
- Emerging real-world assessments complement earlier clinical trials, broadening understanding of vaccine utility in vulnerable elderly subpopulations.
Background
Respiratory syncytial virus (RSV) is a significant cause of respiratory morbidity and hospitalization in older adults, leading to substantial clinical and economic burden globally and in the United States. Historically perceived as a pediatric pathogen, RSV has gained recognition for its severity among adults aged 60 years and older, particularly those with comorbidities such as chronic pulmonary disease, cardiovascular conditions, diabetes, or immunocompromise. Despite the availability of vaccines targeting RSV, evaluating their real-world effectiveness (VE) in this demographic has been imperative to inform public health strategies.
The adjuvanted RSV prefusion F3 (RSVPreF3) vaccine, designed to elicit enhanced immune responses through incorporation of an adjuvant and targeting the prefusion conformation of the F protein, has emerged as a promising intervention. Early-phase and pivotal clinical trials demonstrated immunogenicity and efficacy, but translating these findings into routine practice depends on evidence from real-world settings to capture varied populations and comorbidity profiles.
Key Content
Chronological Development of Evidence: Clinical Trials to Real-World Studies
Initial phase 2 and 3 randomized controlled trials (RCTs) of RSVPreF3 vaccine in older adults showed favorable immunogenicity and significant reductions in RSV lower respiratory tract infections and hospitalizations. For example, pivotal studies reported efficacy rates exceeding 70% in preventing severe RSV disease during controlled conditions, establishing a foundation for regulatory approvals.
Following licensure, real-world vaccine effectiveness studies have been critical to validate these results amid routine clinical use, incorporating larger and more heterogeneous populations. The pivotal study by Singer et al. (2026), utilizing the Optum Research Database (ORD), represents one of the largest retrospective cohort analyses assessing VE in US adults aged ≥60 years. This investigation leveraged claims data from over 2.6 million individuals (520,440 vaccinated, 2,081,760 unvaccinated), matched by key demographics and balanced via propensity score weighting, thus enhancing comparability.
Methodological Advances
The retrospective cohort design applied by Singer et al. features several strengths: exact matching on age, sex, insurance status, and geography; comprehensive baseline covariate adjustment; exclusion of prior RSV vaccination; and follow-up commencing 14 days post-index to allow development of vaccine-induced immunity. The use of Cox proportional hazards models to estimate hazard ratios and derive VE as (1-HR)*100% conforms to best practices in observational VE evaluation.
Median follow-up of 5.6 months (maximum 9.7 months) allowed assessment during high RSV circulation periods. Outcomes were defined as RSV-related hospitalization, a clinically meaningful and objective endpoint.
Real-World Effectiveness Findings
The key finding was a robust VE of 75.6% (95% CI: 69.8–80.2%) against RSV-related hospitalization among vaccinated older adults compared to unvaccinated controls. Notably, efficacy was sustained in clinically vulnerable subgroups:
- Chronic pulmonary disease: 72.5% (64.3–78.8%)
- Cardiovascular disease: 72.2% (64.1–78.4%)
- Diabetes: 82.3% (74.2–87.9%)
- Immunocompromised individuals: 71.4% (57.0–81.1%)
These results indicate that the adjuvanted RSVPreF3 vaccine confers substantial protection even in populations at higher risk for severe RSV disease, supporting broad vaccination recommendations.
Complementary Studies and Meta-Analyses
While data on adjuvanted RSVPreF3 vaccine are emerging, early phase trials and observational cohorts consistently align with the efficacy and effectiveness levels reported by Singer et al. For example, prior clinical trials in Europe and North America similarly documented VE between 66–85%, reinforcing the generalizability of findings.
Systematic reviews of RSV vaccine candidates stress the importance of targeting the prefusion F protein, given its immunodominant epitopes and superior neutralizing antibody induction. The adjuvanted formulation further enhances immunogenicity, particularly in immunosenescent older adults.
Expert Commentary
The study by Singer et al. fills a critical knowledge gap by providing real-world effectiveness data at an unprecedented scale. The large sample size, rigorous matching, and adjustment methods ensure robustness and mitigate confounding biases endemic to observational research.
The consistent VE across comorbidity subgroups underscores the vaccine’s capacity to elevate immune protection in older adults with compromised baseline defenses, a population with historically high RSV morbidity and mortality. Given that the study period included recent RSV seasons with fluctuating viral epidemiology, findings remain relevant for current and near-future vaccination strategies.
Incorporation of adjuvants, such as AS01 or other TLR agonists, in RSVPreF3 formulations likely enhances T-cell responses and antibody affinity maturation, potentially explaining sustained protection in immunocompromised cohorts.
However, observational data inherently carry limitations including residual confounding and potential misclassification of RSV hospitalizations based on claims data. Further research is needed to assess long-term durability of protection, vaccine impact on RSV transmission, and comparative effectiveness against other incoming RSV vaccines.
Current guidelines by CDC and professional societies increasingly recommend RSV vaccination for older adults, particularly those at high risk for severe outcomes. This growing body of real-world evidence bolsters these recommendations and may support policy expansion.
Conclusion
The advent of the adjuvanted RSVPreF3 vaccine offers a powerful tool to mitigate RSV-associated hospitalization burden among US adults aged ≥60 years. Real-world effectiveness estimates above 70% in both the general older adult population and vulnerable subgroups provide compelling evidence for widespread vaccination implementation.
Ongoing surveillance and post-marketing studies will be crucial to monitor VE over multiple RSV seasons, optimize vaccination timing, and evaluate integration with other respiratory vaccines (e.g., influenza, COVID-19). Given the projected demographic shifts towards an aging population, RSV vaccination stands as a priority for reducing respiratory disease burden and improving elderly health outcomes.
References
- Singer D, Steffens A, La EM, et al. Real-world effectiveness of adjuvanted RSVPreF3 vaccination in the prevention of RSV-related hospitalization among US adults aged≥60 years. Chest. 2026 Jul 16; PMID: 42463007. PubMed
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