Differential histopathology and chemokine gene expression in lung tissues following respiratory syncytial virus (RSV) challenge of formalin-inactivated RSV- or BBG2Na-immunized mice

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 his topathologic lesions induced and chemokine gene expression profiles in lung tissues. These data were compared and contrasted with data generated follo wing primary and/or secondary RSV infection or RSV challenge following vacc ination 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 Fl-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 res ulted in rare but mild peribronchiolitis and perivascularitis, with no evid ence of alveolitis or interstitial inflammation. Importantly, mice vaccinat ed with a broad dose range (20 to 0.02 mug) of a clinical formulation of BB G2Na in aluminium phosphate demonstrated histopathology similar to that obs erved in secondary RSV infection. At the molecular level, FI-RSV priming wa s characterized by a rapid and strong up-regulation of eotaxin and monocyte chemotactic protein 3 (MCP-3) relative gene expression (potent lymphocyte and eosinophil chemoattractants) that was sustained through late time point s, early but intermittent up-regulation of GRO/melanoma growth stimulatory activity gene and inducible protein 10 gene expression, while macrophage in flammatory protein 2 (MIP-2) and especially MCP-1 were up-regulated only at late time points. By comparison, primary RSV infection or BBG2Na priming r esulted in considerably lower eotaxin and MCP-3 gene expression increases p ostchallenge, while expression of lymphocyte or monocyte chemoattractant ch emokine genes (MIP-1 beta, MCP-1, and MIP-2) were of higher magnitude and k inetics at early, but not late, time points. Our combined histopathologic a nd chemokine gene expression data provide a basis for differentiating betwe en aberrant FI-RSV-induced immune responses and normal responses associated with RSV infection in the mouse model. Consequently, our data suggest that BBG2Na may constitute a safe RSV subunit vaccine for use in seronegative i nfants.