A BALB/c mouse model of enhanced pulmonary pathology following vaccination with formalin-inactivated alum-adsorbed respiratory syncytial virus (FI-RSV) and live RSV challenge was used to determine the type and kinetics of histopathologic lesions induced and chemokine gene expression profiles in lung tissues. These data were compared and contrasted with data generated following primary and/or secondary RSV infection or RSV challenge following vaccination with a promising subunit vaccine, BBG2Na. Severe peribronchiolitis and perivascularitis coupled with alveolitis and interstitial inflammation were the hallmarks of lesions in the lungs of FI-RSV-primed mice, with peak histopathology evident on days 5 and 9. In contrast, primary RSV infection resulted in no discernible lesions, while challenge of RSV-primed mice resulted in rare but mild peribronchiolitis and perivascularitis, with no evidence of alveolitis or interstitial inflammation. Importantly, mice vaccinated with a broad dose range ( Respiratory syncytial virus (RSV), a Pneumovirus of the family Paramyxoviridae, is a major respiratory pathogen. Infection often results in acute bronchiolitis or pneumonia in infants and young children and can result in persistently abnormal pulmonary function throughout childhood. In addition, adults become reinfected despite enhanced serum antibody responses. Consequently, development of an RSV vaccine is considered a World Health Organization priority. The occurrence of a severe pulmonary disease, characterized by the presence of abnormally numerous inflammatory cells (18), after subsequent natural infection in children given a formalin-inactivated RSV (FI-RSV) vaccine has greatly interfered in the development of a successful and safe RSV vaccine (21).We explored a subunit approach to the development of a RSV vaccine and have described the construction and expression of a RSV (Long strain) G envelope glycoprotein fragment as part of a chimeric protein in Escherichia coli (20,25). The polypeptide of amino acids 130 to 230 of the G protein (G2Na) is fused to BB, the albumin-binding domain of streptococcal protein G, producing BBG2Na. The immune responses induced by BBG2Na demonstrate a potent lung protective efficacy against RSV challenge in both mouse and cotton rat models of RSV infection (25). Importantly, this potent protective efficacy was maintained irrespective of whether BBG2Na was administered intraperitoneally (i.p.), intramuscularly (i.m.) or subcutaneously (s.c.) (15). The G2Na fragment contains at least five murine B-cell protectopes, one of which incorporates a stretch of amino acid residues that are completely conserved among all known RSV subgroup A and B human isolates (9) and all of which overlap with peptide reactivities in human RSV convalescent sera (24). Furthermore, we recently reported that immunizations with BBG2Na do not induce evidence of pulmonary inflammation upon RSV challenge, as demonstrated by the absence of aberrant and massive lung infiltration of macrophages, eosinophils, and T cells (23). ...