Intranasal Delivery of an RSV A2-Derived Pre-F VLP Vaccine Induces Robust Mucosal and Systemic Immunity Against RSV B Strain Without Enhanced Disease.

Respiratory syncytial virus (RSV) is a contagious pathogen that infects respiratory epithelial cells and causes serious lower respiratory diseases in young children and the elderly. In this study, we evaluated the cross-protective efficacy of intranasally administered virus-like particles (VLPs) expressing the prefusion (pre-F) conformation of the RSV A2 fusion protein against RSV B challenge. The VLPs displayed higher reactivity against pre-F site Ø-specific mAbs, compared to the formalin-inactivated RSV vaccines. Intranasally administered pre-F VLPs vaccine induced a Th1-biased immune response in both local and systemic compartments. In the systemic compartment, it elicited a high IgG2a/IgG1 ratio in sera and strong IFN-γ production by splenic cells, reflecting a robust Th1-type systemic immune activation. It promoted significantly increased IgA levels in bronchoalveolar lavage fluid and lung tissues. Furthermore, no significant histopathological lesions were observed in the lungs of RSV A2-derived pre-F VLPs immunized mice compared to FI-RSV vaccinated mice. These results highlight the relevance of intranasal RSV A2-based pre-F VLP immunization in eliciting cross-protection against RSV B while minimizing the risk of vaccine-associated enhanced respiratory disease (VERD). Therefore, RSV A2-derived pre-F VLPs can be a potential safe and effective nasal vaccine candidate against RSV B infection by inducing Th1-skewed immune responses and reducing the risk of VERD.