 This study demonstrates the immunogenicity, efficacy, and safety of virus-like particle, VLP, vaccines containing ISVF, G, or F and G proteins in cotton rats. The results show that ISV-specific antibodies were effectively induced by vaccination with FVLP or FGVLP vaccines, and after challenge, long ISV clearance was observed with all four vaccines. However, upon ISV infection, cotton rats with RSV-VLP vaccines were protected against airway hypersponsiveness and weight loss, while FIRSV vaccination exhibited vaccine-enhanced disease of airway obstruction, weight loss, and severe histopathology with eosinophilia and mucous production. FGVLP and FVLP vaccines did not cause pulmonary inflammation, whereas GVLP-induced moderate lung inflammation with eosinophilia and mucous production. Additionally, FVLP and FGVLP vaccines were found to be effective in inducing antibody secreting cell responses in bone marrow and lymphoid organs, as well as avoiding the induction of T helper type two cytokines. These results provide further evidence to develop a safe RSV vaccine based on VLP platforms. This article was authored by Heisik Wang, Kehai Kim, Yuri Lee, and others.