Abstract
An adenovirus 5 vector encoding for mouse interferon alpha, subtype 5 (mDEF201) was evaluated for efficacy against lethal cowpox (Brighton strain) and vaccinia (WR strain) virus respiratory and systemic infections in mice. Two routes of mDEF201 administration were used, nasal sinus (5-µl) and pulmonary (50-µl), to compare differences in efficacy, since the preferred treatment of humans would be in a relatively small volume delivered intranasally. Lower respiratory infections (LRI), upper respiratory infections (URI), and systemic infections were induced by 50-µl intranasal, 10-µl intranasal, and 100-µl intraperitoneal virus challenges, respectively. mDEF201 treatments were given prophylactically either 24 h (short term) or 56d (long-term) prior to virus challenge. Single nasal sinus treatments of 106 and 107 PFU/mouse of mDEF201 protected all mice from vaccinia-induced LRI mortality (comparable to published studies with pulmonary delivered mDEF201). Systemic vaccinia infections responded significantly better to nasal sinus delivered mDEF201 than to pulmonary treatments. Cowpox LRI infections responded to 107 mDEF201 treatments, but a 106 dose was only weakly protective. Cowpox URI infections were equally treatable by nasal sinus and pulmonary delivered mDEF201 at 107 PFU/mouse. Dose-responsive prophylaxis with mDEF201, given one time only 56 d prior to initiating a vaccinia virus LRI infection, was 100% protective from 105 to 107 PFU/mouse. Improvements in lung hemorrhage score and lung weight were evident, as were decreases in liver, lung, and spleen virus titers. Thus, mDEF201 was able to treat different vaccinia and cowpox virus infections using both nasal sinus and pulmonary treatment regimens, supporting its development for humans.
Highlights
In a previous publication, we reported that an adenovirus vectored mouse interferon, administered intranasally (i.n.), was capable of protecting mice infected i.n. with vaccinia (WR strain) virus [1]
A single dose of mDEF201 was administered to mice via 5 ml to the nasal sinus or 50-ml to the lungs to combat different manifestations of cowpox and vaccinia virus infections, including primarily upper respiratory, primarily lower respiratory, and systemic infections
What was found in the present set of experiments was that mDEF201 was very effective when administered in a low volume to the nasal sinus
Summary
We reported that an adenovirus vectored mouse interferon (mDEF201), administered intranasally (i.n.), was capable of protecting mice infected i.n. with vaccinia (WR strain) virus [1] This infection model used a 50-ml virus inoculum that induced primarily a lower respiratory infection (LRI). Systemic infections were produced by intraperitoneal infection with virus [3], and primarily LRI and URI infections were developed by using either a large (50-ml) or small (5-ml) i.n. infection volume [4] These models are useful to address the efficacy of mDEF201 in treating various types of infections caused by cowpox and vaccinia viruses, as well as to determine whether changes in mDEF201
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