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

Abstract

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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Rift Valley Fever Virus Infection in Golden Syrian Hamsters

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Post-exposure vaccination with MP-12 lacking NSs protects mice against lethal Rift Valley fever virus challenge

“…Because MP-12 NSs is functional and inhibits host innate immune responses (Billecocq et al, 2008), we interpreted the efficacy of rMP12-C13type and rMP12-mPKRN167 to be due to induction of host innate immune responses by those viruses at an early stage of wt RVFV infection. We previously showed that mice infected with Punta Toro virus could be treated post-exposure with a replication-incompetent adenovirus encoding consensus human IFN-α (Gowen et al, 2012). Studies to elucidate the precise mechanism of protection elicited by post-exposure vaccination with rMP12-C13type or rMP12-mPKRN167 will be forthcoming.…”