Respiratory syncytial virus (RSV) is a ubiquitous single-stranded RNA virus responsible for seasonal epidemics of respiratory disease [1], [2]. Globally, 3.6 million hospitalizations were attributable to RSV in 2019 with over 100,000 deaths in children younger than five years [3]. RSV infection causes a range of symptoms, from mild, cold-like symptoms to respiratory failure and death. In infants, lower respiratory tract infection can manifest with bronchiolitis, or less commonly, viral pneumonia. Bronchiolitis in particular is characterized by lower airway mucous production, recruitment of inflammatory cells and shedding of epithelial cells into the airway lumen, leading to impaired gas exchange and increased work of breathing [4], [5]. This pathology is in striking contrast to older children, who are more likely to exhibit only mild symptoms. At the other end of the age spectrum, adults over 65 years of age, are also at increased risk of severe disease, particularly RSV associated pneumonia. Comorbidities associated with cardiac or pulmonary compromise are also risk factors for severe disease [6], [7]. In otherwise healthy individuals, however, age is the strongest predictor of disease severity, with young infants and older adults most commonly affected [8], [9].

Nearly all children are infected with RSV in the first few years of life, making RSV one of the most frequent and earliest pathogens to engage the immune system [1], [10], [11], [12]. Infection in early life, however, does not result in lasting protective immunity [11]. Recurrent seasonal infections occur throughout life, despite minimal antigenic variability [11], [13], [14]. Age-associated changes in the immune system occur from infancy to adulthood and influence pathogen-specific memory responses and disease outcomes that can shape the host response to RSV. The fetal immunologic environment is more tolerogenic, which is protective for the mother and the fetus [15]. The transition from the intrauterine environment requires immunologic development and education in post-natal and early childhood when infants are vulnerable to RSV infection. Neonatal immune responses can be less responsive, more inhibitory and less proinflammatory compared to their adult counterparts [16] with non-robust T helper type 1 (Th1) responses. As a result, newborns are often more susceptible to intracellular pathogens. In addition to the morbidity associated with acute RSV infections, early life exposure to RSV has been associated with perturbations in the immune system increasing the risk of wheezing [17], [18], [19], [20], [21].

With no effective anti-viral treatments available, current efforts are aimed at infection prevention. Two vaccines platforms based on the prefusion structure of the fusion (F) protein of RSV have recently been developed for those over 60 years of age [22], [23] given this population’s risk of severe disease, which is similar to that of influenza. A maternal vaccination strategy built on the stabilized prefusion structure of the F protein was also FDA approved in 2023 for administration between 32 and 36 weeks of gestation to provide passive protection for infants via placental transfer of maternal antibodies [24]. In addition, a monoclonal antibody that binds to the prefusion structure of the F protein, nirsevimab, has also been FDA approved, which has a longer half-life than the prior licensed monoclonal antibody and has the advantage of one administration per RSV season rather than monthly doses [25]. Gaps in scientific knowledge regarding mucosal immunity and age-dependent regulation of immune responses remain and limit infection-preventing vaccine development for the youngest and most vulnerable age groups.

This review will examine the mucosal, cellular, humoral and cytokine driven sources of anti-RSV immunity in children. Given logistical and safety limitations of studying RSV in infants, much of the data from human pediatric studies is observational or derived from murine models and in vitro studies. Overall, we will review age-attributable differences in the development of immunity to RSV and how differences between infection in children and adults provide insight into disease pathogenesis.