Cotton rat model for testing vaccines and antivirals against respiratory syncytial virus

Abstract

Respiratory syncytial virus is the leading cause of pneumonia and bronchiolitis in infants and is a serious health risk for elderly and immunocompromised individuals. No vaccine has yet been approved to prevent respiratory syncytial virus infection and the only available treatment is immunoprophylaxis of severe respiratory syncytial virus disease in high-risk infants with Palivizumab (Synagis®). The development of respiratory syncytial virus vaccine has been hampered by the phenomenon of enhanced respiratory syncytial virus disease observed during trials of a formalin-inactivated respiratory syncytial virus in 1960s. A search for effective respiratory syncytial virus therapeutics has been complicated by the fact that some of the most advanced respiratory syncytial virus antivirals, while highly effective in a prophylactic setting, had not demonstrated clinical efficacy when given after infection. A number of respiratory syncytial virus vaccines and antivirals are currently under development, including several vaccines proposed for maternal immunization. The cotton rat Sigmodon hispidus is an animal model of respiratory syncytial virus infection with demonstrated translational value. Special cohort scenarios, such as infection under conditions of immunosuppression and maternal immunization have been modeled in the cotton rat and are summarized here. In this review, we focus on the recent use of the cotton rat model for testing respiratory syncytial virus vaccine and therapeutic candidates in preclinical setting, including the use of special cohort models. An overview of published studies spanning the period of the last three years is provided. The emphasis, where possible, is made on candidates in the latest stages of preclinical development or currently in clinical trials.

A model of respiratory syncytial virus (RSV) infection of infants in newborn lambs

“…RSV animal models can be divided into two main groups, i.e., heterologous or cognate host-virus models. RSV can infect and replicate in heterologous host-virus models such as chimpanzees (Belshe et al 1977;Whitehead et al 1999), baboons (Papin et al 2013), sheep (Larios Mora et al 2015;Olivier et al 2009;Sow et al 2011b), cotton rats (Boukhvalova et al 2018;Prince et al 1978), ferrets (Stittelaar et al 2016), and mice (Graham et al 1988;Openshaw 2013;Taylor et al 1984), while related Orthopneumoviruses can be used as cognate host-virus models, such as murine pneumonia virus in mice model (Cook et al 1998) and bovine respiratory syncytial virus (BRSV) in calves (Blodörn et al 2015;Valarcher et al 2003).…”

“…Since the establishment of the cotton rat model for RSV in the 1970s (Prince et al 1978;Prince et al 1999), this animal model has been utilized in many vaccine, therapeutic, and pathogenesis studies that contributed to the current advancement and greater understanding of RSV infection. (Sow et al 2011b) 10 5 -10 6 pfu intranasal (Boukhvalova et al 2018) 10 4 -10 7 pfu intranasal (Taylor et al 1984) Virus replication and localization…”

“…It is considered the standard model for testing RSV therapeutics. A throughout review of cotton rat model for RSV has been published elsewhere and beyond the scope of this article (Boukhvalova and Blanco 2013;Boukhvalova et al 2018). However, several aspects of model comparison between the neonatal lamb and cotton rat will be described in later sections of this review.…”

Unveiling Integrated Functional Pathways Leading to Enhanced Respiratory Disease Associated With Inactivated Respiratory Syncytial Viral Vaccine

“…It is known that following FI-RSV immunization and subsequent infection with RSV, there is a skewed TH2 dominant response (17), accompanied by increased serum antibodies (Ab) against RSV with low neutralizing ability (18–20), and poor RSV specific IgG avidity (14) as reviewed in (21). Although antibody avidity has been shown to be a hallmark of FI-RSV induced VERD in the mouse model, in cotton rats and human infants it has been shown that avidity is not a contributing factor (22). In animal models, deficiencies in TLR stimulation (17) and the involvement of CD4 and CD8 T cells in mediating VERD have also been observed (21, 23, 24).…”

“…However, little is known about the molecular mechanisms underlining VERD pathogenesis in this model. Clearly, it would be of value to investigate the mechanisms of VERD using the cotton rat (33). Herein, we used a systems biology approach to investigate functional pathways involved in VERD in cotton rats.…”