Animal models of respiratory syncytial virus infection

Abstract

Human respiratory syncytial virus (hRSV) is a major cause of respiratory disease and hospitalisation of infants, worldwide, and is also responsible for significant morbidity in adults and excess deaths in the elderly. There is no licensed hRSV vaccine or effective therapeutic agent. However, there are a growing number of hRSV vaccine candidates that have been developed targeting different populations at risk of hRSV infection. Animal models of hRSV play an important role in the preclinical testing of hRSV vaccine candidates and although many have shown efficacy in preclinical studies, few have progressed to clinical trials or they have had only limited success. This is, at least in part, due to the lack of animal models that fully recapitulate the pathogenesis of hRSV infection in humans. This review summarises the strengths and limitations of animal models of hRSV, which include those in which hRSV is used to infect non-human mammalian hosts, and those in which non-human pneumoviruses, such as bovine (b)RSV and pneumonia virus of mice (PVM) are studied in their natural host. Apart from chimpanzees, other non-human primates (NHP) are only semi-permissive for hRSV replication and experimental infection with large doses of virus result in little or no clinical signs of disease, and generally only mild pulmonary pathology. Other animal models such as cotton rats, mice, ferrets, guinea pigs, hamsters, chinchillas, and neonatal lambs are also only semi-permissive for hRSV. Nevertheless, mice and cotton rats have been of value in the development of monoclonal antibody prophylaxis for infants at high risk of severe hRSV infection and have provided insights into mechanisms of immunity to and pathogenesis of hRSV. However, the extent to which they predict hRSV vaccine efficacy and safety is unclear and several hRSV vaccine candidates that are completely protective in rodent models are poorly effective in chimpanzees and other NHP, such as African Green monkeys. Furthermore, interpretation of findings from many rodent and NHP models of vaccine-enhanced hRSV disease has been confounded by sensitisation to non-viral antigens present in the vaccine and challenge virus. Studies of non-human pneumoviruses in their native hosts are more likely to reflect the pathogenesis of natural hRSV infection, and experimental infection of calves with bRSV and of mice with PVM result in clinical disease and extensive pulmonary pathology. These animal models have not only been of value in studies on mechanisms of immunity to and the pathogenesis of pneumovirus infections but have also been used to evaluate hRSV vaccine concepts. Furthermore, the similarities between the epidemiology of bRSV in calves and hRSV in infants and the high level of genetic and antigenic similarity between bRSV and hRSV, make the calf model of bRSV infection a relevant model for preclinical evaluation of hRSV vaccine candidates which contain proteins that are conserved between hRSV and bRSV.

Keywords: Animal models; Respiratory syncytial virus.

Fig. 1

(A) Localisation of human (h)RSV antigen in bronchiolar epithelial cells of a child with an acute hRSV infection. HRSV antigen-positive cells are brown; (B) section of lung from a child with an acute hRSV infection showing acute bronchiolitis in a medium-sized airway with intraluminal cellular debris and inflammatory cells (A and B are adapted from , reprinted by permission from Macmillan Publishers Ltd: Modern Pathology, 20:108–119, Johnson et al., copyright 2007); (C) localisation of bovine (b)RSV antigen in bronchial, bronchiolar, and alveolar cells of a calf experimentally infected with bRSV, 6 days previously. BRSV antigen-positive cells are red (adapted from , reprinted from The American Journal of Pathology, 161:2195–2207, copyright 2002, with permission from Elsevier); (D) section of lung from a calf, inoculated intranasally and intracheally 6 days previously with bRSV, showing bronchiolitis with intraluminal cellular debris and inflammatory cells, and interstitial pneumonia; (E) section of chimpanzee lung, naturally infected with hRSV, showing alveolar and interstitial pneumonitis and bronchitis (reprinted from , J Com Pathol, 110:207–212, copyright 1994, with permission from Elsevier; (F) section of lung from an infant rhesus monkey infected by aerosol with hRSV, 7 days previously, showing mild lymphocytic and histiocytic inflammatory cell infiltrates in the walls and lumens of the terminal conducting airways, and in the septa and lumens of adjacent alveoli (adapted from , reprinted from Vaccine, 23:2928–2942, copyright 2005, with permission from Elsevier); (G) section of lung from a lamb infected by aerosol with hRSV, 8 days previously, showing viral antigen within epithelial cells lining the bronchioles (brown cells); (H) section of lung from a lamb infected by aerosol with hRSV, 8 days previously, showing bronchiolitis with degenerate/necrotic individual epithelial cells (thin arrow), occasional syncytial cells (long arrow), accumulation of degenerate neutrophils (short arrow), and occasional macrophages (G and H adapted from ; (I) section of lung from a cotton rat infected 5 days previously with hRSV, showing mild peribronchiolitis (adapted from , reprinted from Vaccine, 31:306–312, copyright 2013, with permission from Elsevier).