Therapy and Long-Term Prophylaxis of Vaccinia Virus Respiratory Infections in Mice with an Adenovirus-Vectored Interferon Alpha (mDEF201)

Smee, Donald F.; Wong, Min-Hui; Russell, Andrew; Ennis, Jane; Turner, Jeffrey D.

doi:10.1371/journal.pone.0026330

Cited by 7 publications

(16 citation statements)

References 19 publications

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“…Post-infection treatment of DEF201 at 6 h post WEEV infection was also protective. Similar inhibition pattern by DEF201 was also observed for vaccinia virus (Smee et al, 2011), arenavirus (Gowen et al, 2011), SARS coronavirus (Kumaki et al, 2011), yellow fever virus (Julander et al, 2011) and chikungunya virus (Dagley et al, 2014). Pre-infection treatment with 10 6 -10 8 PFU DEF201 offered significant protection in vivo in a dose-dependent manner while post-infection treatment at early time-point post infection was effective.…”

Section: Discussionsupporting

confidence: 67%

“…Upon intranasal administration, the adenovirus vector transduces the IFN-a gene into nasal epithelial cells where IFN-a is expressed constitutively. In vivo studies showed that DEF201 could significantly increase the half-life of IFN-a and was protective for mice against viruses or bacteria infection including western equine encephalitis virus (Wu et al, 2007), vaccinia virus (Smee et al, 2011), arenavirus (Gowen et al, 2011), rift valley fever virus (Scharton et al, 2015), SARS coronavirus (Kumaki et al, 2011), yellow fever virus (Julander et al, 2011), chikungunya virus (Dagley et al, 2014) and Streptococcus pneumoniae (Damjanovic et al, 2014).…”

Section: Introductionmentioning

confidence: 99%

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Single dose of an adenovirus vectored mouse interferon-α protects mice from lethal EV71 challenge

Sun

Ennis²,

Turner³

et al. 2016

Antiviral Research

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Enterovirus 71 (EV71) causes hand-foot-and-mouth diseases as well as neurological complications in young children. Interferon (IFN) can inhibit the replication of many viruses with low cytotoxic effects. Previously, an adenovirus vectored mouse interferon-α (DEF201), subtype 5, was generated by Wu et al, 2007. In this study, the antiviral effects of DEF201 against EV71 were evaluated in a murine model. 6-day-old BALB/c mice were administered a single dose of DEF201 before or after infection with lethal dose of EV71. The survival rate, clinical symptoms, tissue viral loads and histology pathogenesis were evaluated. IFN gene expression following a single dose of DEF201 maintained high concentrations of 100-9000 pg/mL for more than 7 days in mice serum. Pre-infection administration of a single dose of 10 PFU of DEF201 offered full protection of the mice against EV71 infection compared with the empty Ad5 vector control. In addition, virus load in DEF201-treated mice muscle tissue was significantly decreased as compared with empty vector control. Histopathology analysis revealed that DEF201 significantly prevented the development of severe tissue damage with reduction of viral antigen in the murine muscle tissue. Post-infection treatment at 6 h offered full protection and partial protection at 12 h, indicating that DEF201 could be used as an anti-EV71 therapeutic agent in early stage of EV71 infection. In addition, our study showed that DEF201 enhanced the neutralization ability of serum in EV71-vaccinated mice, implying that DEF201 could promote the production of specific anti-EV71 antibodies. In conclusion, single dose of DEF201 is highly efficacious as a prophylactic agent against EV71 infection in vivo.

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Section: Discussionsupporting

confidence: 67%

Section: Introductionmentioning

confidence: 99%

Single dose of an adenovirus vectored mouse interferon-α protects mice from lethal EV71 challenge

Sun

Ennis²,

Turner³

et al. 2016

Antiviral Research

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“…This strategy has shown promise in yellow fever virus and arenavirus infection models (7,12). Similarly, a DEF201 construct expressing mouse IFN-␣ has been successfully used to prevent and treat severe acute respiratory syndrome coronavirus (SARS-CoV), vaccinia, and Ebola virus infections in mouse mod-els (13,23,25). The present study expands the spectrum of viral infections that can be effectively countered with a single dose of DEF201, examines the kinetics of cIFN-␣ expression following treatment, and demonstrates the long-lasting antiviral effects of DEF201 toward the prevention of phleboviral disease in a hamster model of RVFV infection.…”

mentioning

confidence: 99%

Extended Protection against Phlebovirus Infection Conferred by Recombinant Adenovirus Expressing Consensus Interferon (DEF201)

Gowen

Ennis²,

Sefing

et al. 2012

Antimicrob Agents Chemother

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Punta Toro virus (PTV; Bunyaviridae, Phlebovirus) is related to Rift Valley fever virus (RVFV), a pathogenic agent which causes severe disease in humans and livestock primarily in the sub-Saharan region of Africa. The recent range expansion of RVFV and the potential for its intentional release into naïve populations pose a significant threat to public health and agriculture. Studies modeling disease in rodents and nonhuman primates have shown that PTV and RVFV are highly sensitive to the antiviral effects of alpha interferon (IFN-␣), an important component of the innate antiviral host response. While recombinant IFN-␣ has high therapeutic value, its utility for the treatment of neglected tropical diseases is hindered by its short in vivo half-life and costly production of longer-lasting pegylated IFNs. Here, we demonstrate extended preexposure protection against lethal PTV challenge following a single intranasal administration of DEF201, which is a replication-deficient human adenovirus type 5 vector engineered to constitutively express consensus IFN-␣ (cIFN-␣) from transduced host cells. DEF201 was also efficacious when administered within 24 h as a postexposure countermeasure. Serum concentrations of cIFN-␣ could be detected as early as 8 h following treatment and persisted for more than 1 week. The prolonged antiphlebovirus prophylactic effect, low production costs, and ease of administration make DEF201 a promising agent for intervention during natural disease outbreaks and for countering possible bioterrorist acts. R ift Valley fever virus (RVFV; Bunyaviridae, Phlebovirus) has been the cause of numerous devastating epizootics throughout sub-Saharan Africa and, more recently, the Arabian Peninsula (3). It is a mosquito-borne virus that causes significant losses in livestock characterized by dramatic "abortion storms" resulting in near-complete mortality in newborn animals (5). RVFV transmission to humans occurs through the bites of infected mosquitoes or contact with tissue from infected animals. Because the virus is also infectious by the airborne route, it poses a potential bioterrorism threat, which is amplified by the fact that mosquitoes native to the United States can readily transmit RVFV and serve as vectors (24). Presently, there are no FDA-approved vaccines or antivirals to prevent or treat RVFV infection, which underscores the urgent need to develop new antiviral therapies.Several reports suggest that RVFV is sensitive to the effects of alpha interferon (IFN-␣) (15,16,18), a potent cytokine essential to the control of viral replication and dissemination (20). Studies employing the closely related Punta Toro virus (PTV), a less biohazardous, more accessible model for RVFV infection, have also demonstrated sensitivity toward agents that elicit type I IFN responses (8,22). In addition, a recent report described the antiphlebovirus activity of human consensus IFN-␣ (cIFN-␣) in cell culture and its prophylactic and therapeutic efficacy in hamsters challenged with PTV (10). Because recombinant IFN prote...

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“…), 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).…”

Section: Introductionmentioning

confidence: 99%

“…We primarily looked at one virus model, a vaccinia virus LRI induced by i.n. virus inoculation [1]. We have developed other infection models with cowpox and vaccinia viruses in healthy immunocompetent mice.…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2013

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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.

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Therapy and Long-Term Prophylaxis of Vaccinia Virus Respiratory Infections in Mice with an Adenovirus-Vectored Interferon Alpha (mDEF201)

Cited by 7 publications

References 19 publications

Single dose of an adenovirus vectored mouse interferon-α protects mice from lethal EV71 challenge

Single dose of an adenovirus vectored mouse interferon-α protects mice from lethal EV71 challenge

Extended Protection against Phlebovirus Infection Conferred by Recombinant Adenovirus Expressing Consensus Interferon (DEF201)

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

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