Introduction

Noble Life Sciences, in partnership with IBT Bioservices, has optimized a cotton rat RSV model and successfully demonstrated its use to test the efficacy of a therapeutic agent against RSV. RSV is a major human pathogen causing mild to severe respiratory infections in infants and young children, resulting in up to 125,000 hospitalizations and 400 deaths among infants annually. Because treatment options are limited, a significant need exists for economically attractive, viable vaccines and therapeutic agents for normal-risk infants and children.

The cotton rates considered the model of choice for preclinical development of RSV vaccines and therapeutic agents because:

In addition to RSV, the cotton rat has been found to be susceptible to a wide variety of human viral pathogens including influenza.

Methodology

Three groups of cotton rats (n=28 per group) were infected intranasally with RSV strain A2 at 3 x 10 3, 4 x 10 4, or 3 x 10 5 plaque-forming units (PFU s ). The kinetics of viral infection were determined by euthanizing four rats in each group at daily intervals post infections. Lungs were harvested from all euthanized animals. Sections of lung tissue were prepared for H&E staining. The remainder of the lung tissue was homogenized. Viral titers of lung homogenate were determined via plaque assay and qPCR. Bronchoalveolar lavage fluids (BALF) can also be used to follow the course of infection. To demonstrate the use of this model for testing the efficacy of anti – RSV test agents, o n e group of four rats was treated with an anti – RSV monoclonal antibody (Syn a gis) as a test agent. The animals were dosed twice daily at 200 mg/kg and challenged with 4 x 10 4 RSV strain A2. Animals were euthanized on day five and viral titers in the lung homogenates were determined by plaque assay.

Results

Viral titers in lung homogenates of animals infected with RSV increased from day 1 through days 4–5 post-challenge and then declined through day 7 (see figure at right).In general, titers in lung homogenates were higher in groups challenged with higher levels of virus.

Lung histopathology is another indicator of morbidity in the cotton rat model.H&E staining of lung tissue sections revealed marked interstitial pneumonia (loss of the normal thin alveolar walls), as seen in figure at left, and inflammatory infiltrates are commonly observed around proliferating bronchioles (note*)