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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.

SUBMITTER: Boukhvalova MS

PROVIDER: S-EPMC5987903 | biostudies-literature | 2018 Jan-Dec

REPOSITORIES: biostudies-literature

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

Boukhvalova M S MS Yim K C KC Blanco Jcg J

Antiviral chemistry & chemotherapy 20180101

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<sup>®</sup>). The development of respiratory syncytial virus vaccine has been hampered by the phenomenon ...[more]

PMID: 29768937

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Project description:The lack of a vaccine against respiratory syncytial virus (RSV) is a challenging and serious gap in preventive medicine. Herein, we characterize the immunogenicity of an adenovirus serotype 5-based RSV vaccine encoding the fusion (F) protein (Ad5.RSV-F) and the protection provided following immunization with Ad5.RSV-F and assess its potential for producing enhanced disease in a cotton rat (CR) model. Animals were immunized intranasally (i.n.) and/or intramuscularly (i.m.) and subsequently challenged with RSV/A/Tracy (i.n.) to assess protection. Robust immune responses were seen in CRs vaccinated with Ad5.RSV-F given i.m. or i.n., and these responses correlated with reduced replication of the virus in noses and lungs after challenge. Neutralizing antibody responses following immunization with a single dose of Ad5.RSV-F at 1 × 10(11) viral particles (v.p.) elicited antibody titers 64- to 256-fold greater than those seen after natural infection. CRs boosted with Ad5.RSV-F i.n. 28 days after an i.m. dose also had significant increases in neutralizing antibody titers. Antibody affinity for different F-protein antigenic sites revealed substantial differences between antibodies elicited by Ad5.RSV-F and those seen after RSV infection; differences in antibody profiles were also seen between CRs given Ad5.RSV-F i.m. and CRs given Ad5.RSV-F i.n. Ad5.RSV-F priming did not result in enhanced disease following live-virus challenge, in contrast to the histopathology seen in CRs given the formalin-inactivated RSV/A/Burnett vaccine.Respiratory syncytial virus (RSV) is the most common cause of acute lower respiratory infection in infants and young children and a serious health threat in the immunocompromised and the elderly. Infection severity increased in children in an immunization trial, hampering the over 4-decade-long quest for a successful RSV vaccine. In this study, we show that a genetically engineered RSV-F-encoding adenoviral vector provides protective immunity against RSV challenge without enhanced lung disease in cotton rats (CRs). CRs were vaccinated under a number of different regimens, and the immunity induced by the recombinant adenoviral RSV vaccine administered by use of an intramuscular prime-intranasal boost regimen may provide the best protection for young infants and children at risk of RSV infection, since this population is naive to adenoviral preformed immunity. Overall, this report describes a potential RSV vaccine candidate that merits further evaluation in a phase I clinical study in humans.

Dataset Information

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

Publications

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

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