Respiratory syncytial virus (RSV) is a pathogen that causes typical respiratory tract infections, with seasonal winter peaks in temperate climates [1]. Despite the relative antigenic stability of RSV and its fusion (F) protein, natural infection elicits only partial and short-lived immunity and does not consistently prevent subsequent infections [1-5]. RSV infections usually resolve without complications or sequelae in immunocompetent populations [6]. Among those at high risk, RSV may cause a potential disease burden comparable to that of influenza, including hospitalizations, intensive care unit admissions, and deaths [7-9].

In fact, in older adults aged ≥60 years, RSV can cause more serious respiratory illnesses, such as lower respiratory tract disease [10], especially in people with underlying medical conditions or those who are immunocompromised [11,12]. In older adults, RSV infections impose a significant disease burden [13], which has been underestimated [14-16]. A recent systematic review based on data from high-income countries reported that the pooled estimates were 1.62% (95% CI 0.84‐3.08) for the RSV-associated acute respiratory illnesses (RSV‐ARI) attack rate, 0.15% (95% CI 0.09‐0.22) for the hospitalization attack rate, and 7.13% (95% CI 5.40‐9.36) for in‐hospital case fatality rate [15]. According to 2019 global population data, the same review estimated that approximately 5 million cases of acute respiratory tract infection, 0.5 million hospitalizations, and 33,000 in-hospital deaths among older adults could be attributed to RSV in 2019 [15]. Based on the United Nations Department of Economic and Social Affairs population estimates for 2025, the number of RSV cases in older adults in high‐income countries could be as high as 10.9 million, RSV hospitalizations as high as 0.8 million, and the number of deaths due to RSV as high as 74,000 [15].

The severity of RSV-associated disease in older adults has been ascribed to waning humoral and cellular immune responses (immunosenescence) that were induced by previous RSV infections [5,17-21]. Thus, vaccination approaches to overcome waning immunity could help avoid serious RSV-associated diseases in older adults [22]. An effective RSV vaccine in older adults would likely need to boost or induce potent and durable RSV-neutralizing antibody responses, as well as restore and elicit RSV-specific T-cell responses [23]. Multiple RSV vaccines targeting the prefusion F (preF) protein and administered through various platforms—including adjuvanted protein subunit, bivalent preF, adenoviral-vectored, and mRNA-based technologies—have recently been evaluated in randomized clinical trials involving older adults [24-26]. A first-in-human study in healthy adults aged 18 to 85 years has reported that the RSV preF vaccine was safe, well tolerated, and highly immunogenic [27,28]. Because immunosenescence may reduce vaccine responses in older adults, the addition of an adjuvant to vaccine formulations may enhance immune responses [29,30]. Moreover, in preclinical studies, combined regimens containing Ad26.RSV.preF and recombinant RSV preF proteins showed greater humoral and cellular immunogenicity and improved protection compared with either component alone [31].

Although the RSV membrane protein F has become one of the major target proteins for RSV vaccine development, previous studies have identified safety issues with RSV vaccines in older adults, but the causes of these issues remain unclear. We systematically evaluated safety outcomes—including overall adverse events (AEs), vaccine-related AEs, and serious AEs—using subgroup and sensitivity analyses to investigate potential heterogeneity. This review incorporates randomized controlled trials (RCTs) published up to July 31, 2024, thereby integrating the most recent large-scale evidence that was unavailable to earlier meta-analyses. In addition, we conducted a rigorous quality assessment using the Newcastle-Ottawa Scale, augmented by comprehensive sensitivity analyses and publication bias assessments, all of which strengthened the validity and reliability of our findings relative to those of prior reviews. By explicitly addressing key research gaps and synthesizing current high-quality evidence, this study provides a robust, up-to-date evaluation of the safety and efficacy of RSV vaccines in older adults, offering actionable insights for clinical practice and future research.

This meta-analysis was prospectively registered with PROSPERO (CRD42024525116) prior to commencing the study search. The analysis adhered strictly to the methodological standards established by Cochrane for intervention evaluations and is reported in accordance with the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines.

This meta-analysis assessed the safety and efficacy of a novel RSV preF vaccine in preventing LRTIs and RSV-ARIs in older adults. A systematic review and meta-analysis of RCTs was conducted using 5 databases. The analysis indicated a low risk of publication bias, and the included studies exhibited high methodological quality [38]. Five studies showed a significant reduction in LRTI incidence, with low heterogeneity after removing 1 outlier. Four studies showed a significant decrease in RSV-ARI, with no heterogeneity. Safety data from 14 studies indicated more nonserious AEs in the vaccine group, mainly injection-site reactions, but no difference in serious AEs. Subgroup and sensitivity analyses supported efficacy consistency and identified minor variability in local reactions. Overall, the RSV preF vaccine significantly reduced the risk of LRTI and RSV-ARI in older adults without increasing serious AEs. According to our findings, the administration of the RSV preF vaccine significantly reduced the risk of RSV-ARI [39].

These results align with previous findings from randomized, placebo-controlled, multicountry trials that enrolled diverse populations of adults aged ≥60 years, similar to our study participants [24,26,40]. These trials included adults with age-related medical conditions representative of those seen in the general older adult population [15,41,42]. Comparable trial designs and participant characteristics enhance the consistency of outcomes between those studies and ours. The vaccine effectively mitigated the leading causes of lower LRTIs and ARIs among older adults. Our findings indicate that the vaccine provided a significant enhanced level of protection against these infections in the target population. Furthermore, these results suggest that vaccination may be the most effective strategy for safeguarding older adults.

Our meta-analysis identified a statistically significant higher incidence of general AEs and AEs related to vaccine components in the vaccinated older adult population compared with the placebo group, with notable heterogeneity observed. Although our analysis suggests that this heterogeneity may stem from the quality of the included studies and the diverse chemical compositions among vaccine subtypes, the latter factor appears to have more significant negative implications in real-world settings. Epidemiological evidence demonstrates that older adults with chronic medical conditions are at an increased risk of developing symptomatic RSV-ARI and severe RSV disease. Additionally, these individuals are more likely to require medically attended visits and to experience progression to more severe disease [43-47]. In reality, our study did not examine the variations in health status among the enrolled older adults across the included studies owing to ambiguous family medical histories. This limitation hinders our ability to ascertain whether the statistical differences and heterogeneity in AEs are attributable to the underlying risk factors associated with subclinical or suboptimal health statuses. Despite previous studies demonstrating that one subtype of the RSV preF vaccine was well tolerated and exhibited an acceptable safety profile, the majority of solicited adverse events were transient and of mild to moderate severity [24,40]. Notwithstanding the enrollment criteria that limited participation to medically stable individuals, the overall positive benefit-risk profile of the RSV preF vaccine in older adults with comorbidities warrants further investigation [40].

On the basis of the subgroup analysis, clinical interventions were identified as a significant source of heterogeneity for both overall AEs and AEs associated with the chemical compositions in the vaccine. Previous studies have indicated that, among various types of RSV preF vaccines, subunit vaccines demonstrate significantly greater safety and a lower incidence of solicited injection-site and systemic adverse reactions [39]. To accurately characterize safety in mRNA-based RSV preF vaccines using original sources, the phase 2 or 3 randomized trial of Moderna mRNA-1345 (RSV preF mRNA) in adults aged ≥60 years reported serious AEs in 2.8% of participants in both the vaccine and placebo groups, with investigators noting no evident safety concerns and only a small number of serious AEs judged related to vaccination; thus, there was no excess of serious AEs associated with the mRNA-1345 vaccine compared with placebo [48,49]. Several solicited injection site AEs, including tenderness to touch and injection site pain, were reported more frequently in the mRNA-treated groups compared with the placebo group. However, most AEs experienced by mRNA-treated participants were transient and graded as grade 1 or 2 [50,51]. Additionally, myalgia, nausea, and chills were the most frequently reported symptoms among recipients of adenovirus-vectored vaccines. However, these symptoms were infrequently observed in our vaccination group [52]. These differences may potentially be attributed to variations in the magnitude of the immune response elicited by different vaccine platforms, a hypothesis that warrants confirmation through further immunological evaluations [53,54].

The potential for AEs among older adults could negatively influence public attitudes toward the RSV vaccine. Previous surveys have indicated that concerns about vaccine safety and side effects are the most common reasons for vaccine refusal [55]. Wang et al [55] demonstrated that older adults are more likely to have limited awareness and knowledge of RSV, which contributes to a higher propensity for vaccine refusal. Additionally, they found a negative correlation between advancing age and both vaccine confidence and vaccination rates [56,57]. This finding is consistent with the common reasons for refusing COVID-19 and monkeypox vaccines reported in previous studies [58,59]. Furthermore, administering the RSV vaccine concurrently with one or more additional vaccines during the same visit may increase the incidence of local or systemic reactogenicity [60]. Current studies have exclusively focused on the safety of the RSV preF vaccine when coadministered with various influenza vaccines in older adults. These studies have indicated that coadministration of the RSV preF vaccine with influenza vaccines results in an acceptable safety and tolerability profile [61-63]. However, data on the safety of the RSV preF vaccine in older adults when coadministered with other vaccines recommended for this age group—such as COVID-19, pneumococcal, adult tetanus, diphtheria, and pertussis vaccines, as well as the recombinant zoster vaccine—are lacking [60]. In other words, the prior vaccination history should also be considered a key factor contributing to variations within the vaccine group, necessitating more detailed clinical investigations.

Our study had several limitations. First, the number of studies included was limited, and the variations in vaccine types and doses across these studies may have led to heterogeneity in the results. This is particularly evident in the small number of experiments focusing on LRTIs and related ARIs, which prevented further subgroup analyses. Moreover, these factors may have impacted the overall study results and restricted more detailed analyses. Future large-scale studies are essential to further investigate and validate these findings. Most of the studies included in our analysis were conducted on a global scale, and the results may have been influenced by the ethnic and regional diversity inherent in these study populations. Therefore, it is necessary to conduct regional and ethnic classification studies. Finally, it was challenging to accurately ascertain the health status of the survey participants at baseline. Any discrepancies in participant characteristics at baseline may have introduced heterogeneity into the results.

In conclusion, this meta-analysis provides strong evidence that RSV vaccination is a critical public health measure for older adults, offering substantial protection against RSV-related respiratory infections and a favorable safety profile, despite a higher frequency of mild-to-moderate AEs. The results showed that widespread RSV vaccination could significantly reduce the respiratory disease burden, lower health care use, and prevent thousands of hospitalizations and deaths annually. Consistent benefits across diverse populations and vaccine types support regulatory approval and inclusion in routine immunization programs for adults aged ≥60 years. Successful implementation will require addressing vaccine hesitancy with clear, evidence-based messaging, ensuring safe coadministration with other vaccines, and establishing surveillance systems to monitor real-world effectiveness and safety. Key research priorities include assessing long-term protection, optimal revaccination timing, evaluating performance in immunocompromised individuals, and analyzing cost-effectiveness for equitable resource use. As the global population ages and the burden of RSV increases, RSV vaccination should be considered not as an optional add-on but as an essential part of preventive care for older adults, with the potential to transform respiratory disease prevention.