Respiratory syncytial virus (RSV) is a negative-sense, single-stranded RNA virus of the pneumovirus family. Although reinfection throughout life can occur, the virus poses a major health burden on vulnerable populations, such as infants, immunocompromised individuals, and persons aged >60 years. The infection begins with initial viral invasion of the upper respiratory tract, which spreads to the lower respiratory tract through infection of the small bronchiolar epithelium lining airways within the lung, and viral pneumonia marks the onset of severe disease [1]. Infection triggers a host proinflammatory response that results in necrosis of respiratory epithelial tissues and leads to obstruction of the airways through cellular debris and excessive mucus production [1]. Annually, there are an estimated 33 million cases of RSV-related respiratory infections globally, and the virus is the leading cause of lower respiratory tract infections in children [2]. According to the Center for Disease Control and Prevention, in the United States alone, approximately 58 000 to 80 000 children aged <5 years are hospitalized each year due to RSV infection. This high disease burden made the development of RSV vaccines and antiviral therapeutics a priority since the first discovery of the virus in 1956 [3].

Despites decades of vaccine development attempts, no RSV prophylaxis was available until recently when, in a major breakthrough, stabilization of the viral fusion (F) protein in a prefusion conformation was achieved [4]. Neutralizing antibodies generated from natural RSV infection predominantly target epitopes in prefusion F conformation [5], providing the basis for greater protective immune response of the stabilized vaccines. Currently, there are three approved RSV vaccines, all utilizing the stabilized F technology. Arexvy, produced by GSK, and Abrysvo, manufactured by Pfizer, are both subunit vaccines that use recombinant prefusion RSV F. These vaccines are Food and Drug Administration (FDA) approved for individuals aged ≥50 (Arexvy) or ≥60 (Abrysvo), who are at higher risk for RSV lower respiratory tract disease [6]. However, Abrysvo is currently the only RSV vaccine also approved for use in pregnant women to provide initial protection of infants after birth through increased titers of transplacentally acquired maternal antibodies [6]. Vaccination of mothers between 24 and 36 weeks of gestation provides protection to full-term babies for approximately 6 months after birth [7], but a phase III clinical trial suggested an increase in premature births compared to the placebo group. However, this finding was not statistically significant, a causal relationship could not be determined [8], and later studies that examined the problem have not returned additional data support for an increase in preterm births after maternal vaccination [7]. The most recently approved vaccine, mResvia, produced by Moderna, is an unadjuvanted mRNA-based vaccine that encodes for the RSV prefusion protein. It has been approved in people aged ≥60 years [6].

The Advisory Committee on Immunization Practices has recommended adults aged ≥60 years to obtain one of these three approved vaccinations [9]. Despite this recommendation, only 24% of US adults aged >60 years sought RSV vaccination in the 2023–2024 winter season, whereas uptake rates of the influenza vaccine were approximately 50% in this age group [10]. General vaccine hesitancy, coinciding with limited awareness of the RSV threat amongst adults in the United States, are considered major drivers for the low vaccination rates in this at-risk group [10]. Alongside the low vaccination rates of older adults, no direct vaccine is currently available to protect the most vulnerable population, infants born prematurely or with preexisting conditions such as congenital heart disease. In addition to providing limited protection to preterm infants, the initial discussion about a possible link between administering Abrysvo during pregnancy and premature births has increased vaccine hesitancy in pregnant women [7].

Passive vaccination through prophylactic monoclonal antibody treatments, palivizumab and nirsevimab, has received approval for use in specific high-risk populations. Due to high treatment costs, palivizumab has been reserved for only the most vulnerable infants at greatest risk of life-threatening RSV infection [11]. In contrast, recently approved nirsevimab is recommended for administration to infants in the RSV season up until 24 months of age. The more widespread use of nirsevimab is a result of it conferring predominantly pre-F antibodies, which contains more neutralizing epitopes than the post-F conformation, unlike palizumab, which provides a mix of F protein conformations [5]. Although both biologics are effective in preventing severe disease in high-risk and/or hospitalized infant, treatment costs and limited supply hinder universal administration to infants before their first RSV season 10, 12.

Due to the paucity of vaccines approved for infants and young children and the limitations of available biologics, there is an urgent need for the development of safe and effective antivirals against RSV. Aerosolized ribavirin is the only antiviral currently FDA approved for the treatment of severe RSV disease in children. However, use is restricted to patients with severe disease [13] due to moderate therapeutic benefit and toxicity concerns. A growing body of works on the impact of ribavirin on RSV disease in immunocompromised individuals, particularly recipients of lung transplants, has revealed limited efficacy [13]. A new generation of antiviral therapeutics is urgently needed to improve RSV disease management in at-risk patient populations of all age groups.