A Human Respiratory Syncytial Virus (RSV) Primate Model of Enhanced Pulmonary Pathology Induced with a Formalin-Inactivated RSV Vaccine but Not a Recombinant FG Subunit Vaccine

Tj, Kakuk; Soike, K.; Rj, Brideau; Rm, Zaya; Sl, Cole; Zhang, Junyi; Ed, Roberts; Pa, Wells

doi:10.1093/infdis/167.3.553

Cited by 98 publications

(63 citation statements)

References 22 publications

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“…Intratracheal challenge with RSV 3 months after the third vaccination elicited a hypersensitivity response associated with lung eosinophilia, and two out of seven FI-RSV-vaccinated animals died 12 days after RSV challenge with pulmonary hyperinflation (37). This result is compatible with those of other studies showing decreased lung viral titer following RSV challenge in association with enhanced pathology (85).…”

Section: Primatessupporting

confidence: 89%

Immune Responses and Disease Enhancement during Respiratory Syncytial Virus Infection

2005

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Respiratory syncytial virus (RSV) is one of the commonest and most troublesome viruses of infancy. It causes most cases of bronchiolitis, which is associated with wheezing in later childhood. In primary infection, the peak of disease typically coincides with the development of specific T- and B-cell responses, which seem, in large part, to be responsible for disease. Animal models clearly show that a range of immune responses can enhance disease severity, particularly after vaccination with formalin-inactivated RSV. Prior immune sensitization leads to exuberant chemokine production, an excessive cellular influx, and an overabundance of cytokines during RSV challenge. Under different circumstances, specific mediators and T-cell subsets and antibody-antigen immune complex deposition are incriminated as major factors in disease. Animal models of immune enhancement permit a deep understanding of the role of specific immune responses in RSV disease, assist in vaccine design, and indicate which immunomodulatory therapy might be beneficial to children with bronchiolitis

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Section: Primatessupporting

confidence: 89%

Immune Responses and Disease Enhancement during Respiratory Syncytial Virus Infection

2005

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“…The prolonged duration of signs of lower respiratory tract disease in the infant baboon provides an excellent endpoint to assess the effects of antivirals and vaccines in reducing or preventing RSV-related illness. No other nonhuman primate model has been reported to demonstrate tachypnea or reduced oxygenation following infection with RSV (5,11,17,26,27,30).…”

Section: Discussionmentioning

confidence: 99%

“…Although RSV infection in chimpanzees causes profuse rhinorrhea, it has not resulted in LRTI (3). RSV infection in owl monkeys (27), cebus monkeys (9) (30), bonnet monkeys (26), cynomolgus macaques (8), and African Green monkeys (17) results in histological evidence of mild interstitial pneumonia, but these animals have not developed tachypnea or hypoxia. None of these studies evaluated the effect of RSV on infant animals.…”

mentioning

confidence: 99%

Infant baboons infected with respiratory syncytial virus develop clinical and pathological changes that parallel those of human infants

Papin

Wolf

Kosanke

et al. 2013

American Journal of Physiology-Lung Cellular and Molecular Phys

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infection of the lower respiratory tract is the leading cause of respiratory failure among infants in the United States of America and annually results in Ͼ300,000 deaths worldwide. Despite the importance of RSV, there is no licensed vaccine, and no specific form of therapy. This is largely due to the absence of an appropriate animal model for the evaluation of vaccines and therapeutic agents. We inoculated anesthetized infant (4 wk) baboons (Papio anubis) with a human strain of RSV intranasally or intratracheally. Baboons were monitored daily for clinical changes. Anesthetized baboons were intubated at various intervals, and bronchoalveolar lavage (BAL) was performed for viral culture and determination of leukocyte counts. Sham-infected baboons served as controls. Necropsies were performed on infected baboons on days 1, 3, 5, 8, or 13 after inoculation, with pathological analysis and immunohistochemical staining of lung tissues to detect RSV antigen. Infected baboons developed tachypnea and reduced oxygenation peaking from 4 to 8 days after infection and persisting for Ն14 days. Virus was recoverable in BAL fluid up to 8 days following infection. Necropsy revealed intense interstitial pneumonia, sloughing of the bronchiolar epithelium, and obstruction of the bronchiolar lumen with inflammatory cells and sloughed epithelial cells. RSV antigen was identified in bronchiolar and alveolar epithelium. We conclude that RSV-infected infant baboons develop clinical and pathological changes that parallel those observed in human infants with RSV infection. The infant baboon represents a muchneeded model for studying the pathogenesis of RSV infection and evaluating antivirals and vaccines. interstitial pneumonia; bronchiolitis; baboon model; animal models; respiratory syncytial virus vaccine RESPIRATORY SYNCYTIAL VIRUS (RSV) is the most important respiratory pathogen of early life. RSV infection, in the form of interstitial pneumonia and bronchiolitis, annually results in Ͼ120,000 hospitalizations in the United States of America and Ͼ300,000 deaths worldwide (21, 24). RSV lower respiratory tract infection (LRTI) in infancy also may predispose to the development of childhood asthma (33). Despite the considerable impact of RSV infection, there is no approved vaccine and no effective specific form of therapy. The lack of an appropriate animal model has resulted in an incomplete understanding of the pathophysiology of the disease and an inability to evaluate the safety and efficacy of vaccines and pharmacological agents. An animal model developing clinical and pathological manifestations similar to those of human infants with RSV infection would provide a significant step toward overcoming these problems. To reflect human disease, an appropriate animal model should develop tachypnea, reduced oxygenation, and interstitial and peribronchiolar inflammation with obstruction of the bronchiolar lumen by invading leukocytes and exfoliated epithelial cells following infection. These manifestations should be most prominent in an infant...

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“…Chimpanzees are scarce, extremely expensive, and available only through primate breeding programs. Experimental RSV infections in owl monkeys, rhesus monkeys, African green monkeys, cebus monkeys, squirrel monkeys, bonnet monkeys, and baboons have also been described (9,64,(111)(112)(113)128). The cost and required maintenance of these species are less than those for chimpanzees, but these species still require specialized housing and handling methods.…”

Section: Rsv-asthma Link In Experimental Animal Modelsmentioning

confidence: 99%

Epidemiologic, Experimental, and Clinical Links between Respiratory Syncytial Virus Infection and Asthma

2008

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SUMMARY Virtually all children experience respiratory syncytial virus (RSV) infection at least once during the first 2 years of life, but only a few develop bronchiolitis and more severe disease requiring hospitalization, usually in the first 6 months of life. Children who recover from RSV-induced bronchiolitis are at increased risk for the development of recurrent wheeze and asthma in later childhood. Recent studies suggest that there is an association between RSV-induced bronchiolitis and asthma within the first decade of life but that this association is not significant after age 13. Despite the considerable progress made in our understanding of several aspects of respiratory viral infections, further work needs to be done to clarify the molecular mechanisms of early interactions between virus and host cell and the role of host gene products in the infection process. This review provides a critical appraisal of the literature in epidemiology and experimental research which links RSV infection to asthma. Studies to date demonstrate that there is a significant association between RSV infection and childhood asthma and that preventing severe primary RSV infections can decrease the risk of childhood asthma.

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A Human Respiratory Syncytial Virus (RSV) Primate Model of Enhanced Pulmonary Pathology Induced with a Formalin-Inactivated RSV Vaccine but Not a Recombinant FG Subunit Vaccine

Cited by 98 publications

References 22 publications

Immune Responses and Disease Enhancement during Respiratory Syncytial Virus Infection

Immune Responses and Disease Enhancement during Respiratory Syncytial Virus Infection

Infant baboons infected with respiratory syncytial virus develop clinical and pathological changes that parallel those of human infants

Epidemiologic, Experimental, and Clinical Links between Respiratory Syncytial Virus Infection and Asthma

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