Effects of Nasal or Pulmonary Delivered Treatments with an Adenovirus Vectored Interferon (mDEF201) on Respiratory and Systemic Infections in Mice Caused by Cowpox and Vaccinia Viruses

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.

Drug Development against Smallpox: Present and Future

“…For prophylactic or therapeutic aspects, the development of third-generation vaccines (minimizing potential adverse effects) that can be administered to immunocompromised people is a major step forward. Nonspecific treatment, such as vectored interferon, could also be an option for first responders and medical personnel in the event an orthopoxvirus is used as a bioterrorist weapon (95).…”

Post-exposure intranasal IFNα suppresses replication and neuroinvasion of Venezuelan Equine Encephalitis virus within olfactory sensory neurons

“…Similarly, Type I IFN treatment has been evaluated in other viruses considered to be potential biological weapons, including other encephalitic alphaviruses and hemorrhagic filoviruses, arenaviruses, phleboviruses [44][45][46][47][48][49][50][51]. However, similar studies evaluating the effectiveness intranasal IFN administration against intranasal/aerosol infection are limited [52,53]. Our study demonstrates that the nasal cavity, including OSNs, responds rapidly to intranasal administration of IFN with detectable changes of ISG expression within 12 h. The antiviral state initiated following early IFN treatment after VEEV infection leads to suppression VEEV replication in the nasal cavity, preventing early expansion of VEEV infection and escape of VEEV into the blood.…”

Overcoming tumor resistance by heterologous adeno-poxvirus combination therapy

“…However, even if IFN-I or IFN-γ were able to slow down virus replication in SKOV3Luc cells in vitro ( Figure 3b , c ), these cytokines were unlikely the sole factors responsible for the tumor antiviral defense in vivo , as tumors in the mice ultimately progressed despite continued injections, whereas IFN-pretreated SKOV3Luc cells in culture succumbed. A recent study showed that pretreatment of mice with a replication defective human adenovirus vector expressing murine IFN-α generated a systemic protective antiviral response against lethal wild-type vaccinia virus challenge, 45 demonstrating that innate responses are able to control even vaccinia virus, despite that such inhibition is not apparent in cultured cancer cells. Therefore, our conclusion is that the in vivo microenvironment and/or mouse stroma protects the SKOV3Luc cells from the viruses through additional mechanisms not apparent in vitro , but that such resistance can still be reduced or delayed by reciprocal virus complementation.…”