Respiratory Syncytial Virus (RSV) poses a significant global health concern as a major cause of lower respiratory tract infections (LRTIs). Over the last few years, substantial efforts have been directed towards developing vaccines and therapeutics to combat RSV, leading to a diverse landscape of vaccine candidates. Notably, two vaccines targeting the elderly and the first maternal vaccine have recently been approved. The majority of the vaccines and vaccine candidates rely solely on a prefusion-stabilized conformation known for its highly neutralizing epitopes. Although, so far, this antigen design appears to be successful for the elderly, our current understanding remains incomplete, requiring further improvement and refinement in this field. Pediatric vaccines still have a long journey ahead, and we must ensure that vaccines currently entering the market do not lose efficacy due to the emergence of mutations in RSV’s circulating strains. This review will provide an overview of the current status of vaccine designs and what to focus on in the future. Further research into antigen design is essential, including the exploration of the potential of alternative RSV proteins to address these challenges and pave the way for the development of novel and effective vaccines, especially in the pediatric population.

Respiratory syncytial virus (RSV) is a major cause of severe respiratory infections in infants, the elderly, and immunocompromised persons. Innate immune responses to RSV, which are crucial for containment of the infection yet may also be linked to severe disease, are well-studied in the main RSV target cells, respiratory epithelial cells, but the role of pulmonary macrophages (MΦs), key innate immune regulators, remains incompletely defined. This review addresses the interaction of RSV with MΦ, discussing the susceptibility of these cells to productive infection, and MΦ responses to RSV, including cytokine and chemokine release and inflammasome activation. Furthermore, factors contributing to variability in MΦ infectivity and responses, such as MΦ polarization, age, differences in RSV isolates, co-infections, and prior innate priming, are presented. Finally, the review highlights discrepancies observed across experimental models, MΦ origins, and RSV isolates used, complicating the interpretation of MΦ-RSV interactions, thereby underscoring the need for standardized methodologies.