Evaluation of Different Strategies for Post-Exposure Treatment of Ebola Virus Infection in Rodents

Richardson, Jeffery; Wong, Gary; Pillet, Stéphane; Schindle, Samantha; Ennis, Jane; Turner, Jeffrey D.; Strong, James E.; Kobinger, Gary P.

doi:10.4172/2157-2526.s1-007

Cited by 13 publications

(4 citation statements)

References 48 publications

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“…Safety and toxicity studies on DEF201 in rodents indicate tolerability meeting regulatory requirements. Furthermore, combination studies to increase the effectiveness of an adenovirus-based EBOV vaccine showed that DEF201 was superior to all other interventions tested in improving survival, due to its ability to enhance the EBOV-specific adaptive immune response, hamper EBOV replication, and produce high levels of IFN-␣ for days in a cost-effective manner (19). Combining a broad-spectrum intervention with an EBOV-specific therapy may extend the treatment window while enhancing survival beyond the current limits.…”

mentioning

confidence: 99%

Monoclonal Antibodies Combined with Adenovirus-Vectored Interferon Significantly Extend the Treatment Window in Ebola Virus-Infected Guinea Pigs

Qiu

Wong

Fernando

et al. 2013

J Virol

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Ebola virus is one of the most virulent human pathogens, and infection with the Zaire ebolavirus (EBOV) species results in up to 90% mortality (1). Ebola outbreaks are mostly concentrated in remote areas of sub-Saharan Africa (2), but evidence of prior Ebola infection of swine in the Philippines (3), the presence of Ebola virus antibodies among orangutans in Indonesia (4) and bats in China (5), and the existence of an Ebola virus-like filovirus among European insectivorous bats (6) indicates that Ebola virus may be more widespread than previously thought. Since pigs have been established as a new intermediate host for Ebola (3), with effective transmission to nonhuman primates (NHPs) (7), there is the potential for Ebola to overwhelm larger populations should the virus be introduced in more-populous areas. Therefore, preventative and therapeutic strategies need to be developed to protect the population at large.While several prophylactic vaccine candidates against EBOV have shown preclinical promise in NHPs (8), the options for postexposure intervention are limited. A major reason is that EBOV typically kills its host within 6 to 10 days after the onset of symptoms (8), thereby providing a very small window for intervention before death from multiple organ failure. A recent promising treatment is a combination of three Ebola virus glycoprotein-specific murine monoclonal antibodies (MAbs), 1H3, 2G4, and 4G7, that protects 100% and 50% of NHPs when administered 24 and 48 h, respectively, after lethal EBOV infection (9-11). Another combination of chimeric humanized MAbs produced in plants was also able to save lethally infected NHPs, with 2 of 3 infected animals surviving when the MAbs were administered either 24 or 48 h after EBOV challenge (12). These findings constitute a substantial improvement in the length of the therapeutic window over previous postexposure strategies, which required administration within 60 min of exposure to EBOV in order to result in at least partial survival of NHPs. Ideally, an optimized treatment would be capable of saving infected individuals even when given hours before death.DEF201 is a replication-defective recombinant human adenovirus of serotype 5 (AdHu5) expressing consensus human alpha interferon (IFN-␣) (13). It was previously investigated as a broadspectrum antiviral and shown to be effective against several viral pathogens (14-18). While IFN-␣ treatment has been associated with various amounts of toxicity in the past, these adverse effects are mostly due to the short half-life of the protein, thereby necessitating extremely high doses in order to have a biologically relevant impact. Adenovirus-vectored administration of the IFN-␣ gene allows for steady delivery of the protein, which avoids the bolus dose effect of recombinant IFN-␣. Safety and toxicity studies on DEF201 in rodents indicate tolerability meeting regulatory requirements. Furthermore, combination studies to increase the effectiveness of an adenovirus-based EBOV vaccine showed that DEF201 was superior to all othe...

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confidence: 99%

Monoclonal Antibodies Combined with Adenovirus-Vectored Interferon Significantly Extend the Treatment Window in Ebola Virus-Infected Guinea Pigs

Qiu

Wong

Fernando

et al. 2013

J Virol

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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.…”

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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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“…Upon further vaccine development, AdCAGoptZGP was combined with an AdHu5-expressing alpha interferon (Ad-IFN-␣), providing both an antiviral activity to EBOV and adjuvant effect to Ad-CAGoptZGP. Ad-CAGoptZGP/ Ad-IFN-␣ elicited complete protection in both mice and guinea pigs when administered 30 to 60 min after lethal challenge with adapted EBOV (postexposure treatment) (35).…”

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confidence: 99%

Airway Delivery of an Adenovirus-Based Ebola Virus Vaccine Bypasses Existing Immunity to Homologous Adenovirus in Nonhuman Primates

Richardson

Pillet

Bello

et al. 2013

J Virol

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b Anti-adenovirus serotype 5 antibodies are capable of neutralizing adenovirus serotype 5-based vaccines. In mice and guinea pigs, intranasal delivery of adenovirus serotype 5-based vaccine bypasses induced adenovirus serotype 5 preexisting immunity, resulting in protection against species-adapted Ebola virus challenge. In this study, nonhuman primates were vaccinated with adenovirus serotype 5-based vaccine either intramuscularly or via the airway route (intranasally/intratracheally) in the presence or absence of adenovirus serotype 5 preexisting immunity. Immune responses were evaluated to determine the effect of both the vaccine delivery route and preexisting immunity before and after a lethal Ebola virus (Zaïre strain Kikwit 95) challenge. Intramuscular vaccination fully protected nonhuman primates in the absence of preexisting immunity, whereas the presence of preexisting immunity abrogated vaccine efficacy and resulted in complete mortality. In contrast, the presence of preexisting immunity to adenovirus serotype 5 did not alter the survival rate of nonhuman primates receiving the adenovirus serotype 5-based Ebola virus vaccine in the airway. This study shows that airway vaccination with adenovirus serotype 5-based Ebola virus vaccine can efficiently bypass preexisting immunity to adenovirus serotype 5 and induce protective immune responses, albeit at lower efficacy than that using an intramuscular vaccine delivery route.

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Evaluation of Different Strategies for Post-Exposure Treatment of Ebola Virus Infection in Rodents

Cited by 13 publications

References 48 publications

Monoclonal Antibodies Combined with Adenovirus-Vectored Interferon Significantly Extend the Treatment Window in Ebola Virus-Infected Guinea Pigs

Monoclonal Antibodies Combined with Adenovirus-Vectored Interferon Significantly Extend the Treatment Window in Ebola Virus-Infected Guinea Pigs

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

Airway Delivery of an Adenovirus-Based Ebola Virus Vaccine Bypasses Existing Immunity to Homologous Adenovirus in Nonhuman Primates

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