CXCL13 and IL-33 as Immunomodulatory Adjuvants Combined with Respiratory Syncytial Virus Fusion (RSV F) Protein to Enhance Mucosal RSV Vaccination.

Respiratory syncytial virus (RSV) is a major pathogen responsible for lower respiratory tract infections, particularly in infants, young children, older adults, and immunocompromised individuals. Although several RSV vaccines and monoclonal antibody therapies have recently been approved, their protective efficacy is often short-lived and relies mainly on systemic immunity rather than mucosal immunity. As RSV is a mucosal pathogen, there is a compelling need to develop novel vaccine strategies capable of inducing robust mucosal immune responses. Inducible bronchus-associated lymphoid tissue (iBALT) is an ectopic lymphoid structure that plays a critical role in orchestrating the immune response to respiratory pathogens. iBALT is an important target for vaccine development, as it can support both innate humoral and cellular immune responses and contributes to the establishment of immune memory in the respiratory tract. The formation of iBALT is regulated by airway epithelial cells and the lung microenvironment through release of cytokines and chemokines, including interleukin 33 (IL-33) and C-X-C motif chemokine ligand 13 (CXCL13). In this review, we propose a novel mucosal vaccination strategy against RSV based on the combination of the RSV fusion (F) protein with immunomodulatory molecules, IL-33 and CXCL13, which are involved in the induction and regulation of iBALT. These immunostimulatory molecules may act synergistically to enhance the immune response to RSV infections. IL-33 promotes innate, mucosal, and adaptive immune responses and supports T cell activation, whereas CXCL13 facilitates B cell recruitment and organization within lymphoid structures. Although targeting iBALT represents a promising approach to improving RSV vaccine efficacy, further studies are required to determine the optimal regulation of iBALT in the airways.