Efficacy of CMX001 as a Post Exposure Antiviral in New Zealand White Rabbits Infected with Rabbitpox Virus, a Model for Orthopoxvirus Infections of Humans

Rice, Amanda D.; Adams, Mathew M.; Wallace, Greg; Burrage, Andrew M.; Lindsey, Scott F.; Smith, Andrew; Swetnam, Daniele M.; Manning, Brandi R.; Gray, Stacey A.; Lampert, Bernhard; Foster, Scott A.; Lanier, Randall; Robertson, Alice; Painter, George R.; Moyer, Richard W.

doi:10.3390/v3010047

Cited by 61 publications

(57 citation statements)

References 16 publications

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“…These results show that BCV is an effective agent against multiple variola virus strains in vitro. Previous studies have demonstrated in vivo antiviral activity of BCV in numerous animal models of orthopoxvirus infection, including ectromelia virus in mice and rabbitpox virus in rabbits (12,13). Therefore, the current results support further development of BCV for the treatment of smallpox.…”

supporting

confidence: 59%

In Vitro Efficacy of Brincidofovir against Variola Virus

Olson

Smith

Foster

et al. 2014

Antimicrob Agents Chemother

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b Brincidofovir (CMX001), a lipid conjugate of the acyclic nucleotide phosphonate cidofovir, is under development for smallpox treatment using "the Animal Rule," established by the FDA in 2002. Brincidofovir reduces mortality caused by orthopoxvirus infection in animal models. Compared to cidofovir, brincidofovir has increased potency, is administered orally, and shows no evidence of nephrotoxicity. Here we report that the brincidofovir half-maximal effective concentration (EC 50 ) against five variola virus strains in vitro averaged 0.11 M and that brincidofovir was therefore nearly 100-fold more potent than cidofovir.A lthough smallpox was declared eradicated by the World Health Organization in 1980, the etiologic agent (variola virus [VARV]) remains a category A select agent (subject to select agent regulations [42CFR, part 73]) or a "Highest Priority" biological threat due to its high mortality rate and ease of transmission (1). Vaccination using a closely related live orthopoxvirus (vaccinia virus) prevents smallpox but is associated with potentially severe complications and therefore is not recommended for routine use in the absence of an immediate threat of a VARV release or smallpox outbreak. The vaccine is also contraindicated in immunocompromised individuals, including the very young or old, pregnant women, and those receiving immunosuppressive therapies (2). In the event of a VARV release, there would be a need for antiviral drugs to treat individuals exposed to or infected with smallpox.Brincidofovir(BCV,CMX001,hexadecyloxypropyl-cidofovir[HDP-CDV]), a lipid-conjugated acyclic nucleotide phosphonate, has broad-spectrum in vitro activity against double-stranded DNA viruses, including herpesviruses, adenoviruses, and poxviruses (3). BCV has completed two phase 2 clinical trials for the prevention of clinically significant cytomegalovirus infection in hematopoietic stem cell transplant patients and is currently in phase 3 trials. Simultaneously, BCV has been in development for the treatment of smallpox under the Animal Rule, which states that when developing medical countermeasures for threat agents where human challenge studies are not ethical or feasible (e.g., VARV), FDA may grant approval based on animal model studies which demonstrate that the drug is reasonably likely to have clinical benefit in humans (http: //www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatory Information/Guidances/UCM078923.pdf) (3, 4).Upon entering a cell, the lipid moiety of BCV is cleaved to release free cidofovir, which is then phosphorylated to cidofovir diphosphate (CDV-PP). CDV-PP inhibits viral DNA polymerase by serving as an alternate substrate, resulting in the inhibition of viral DNA synthesis (5-7). Among the orthopoxviruses, BCV has proven activity in animal models against vaccinia virus, rabbitpox virus (a subspecies of vaccinia), and ectromelia virus and in vitro against monkeypox virus (3). BCV has also been shown to be active against VARV in vitro (8); however, due to regulations restricting its use, these...

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supporting

confidence: 59%

In Vitro Efficacy of Brincidofovir against Variola Virus

Olson

Smith

Foster

et al. 2014

Antimicrob Agents Chemother

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“…In rabbits, a single dose of 20 mg/kg BCV administered up to 4 days postchallenge rescued animals from lethality after intradermal infection with rabbitpox virus, with additional doses providing added therapeutic benefit (23). In mice, five daily administrations of BCV at 6.7 mg/kg, 8 mg/kg, and 10 mg/kg were sufficient to protect mice from lethality induced by infection with cowpox virus, ectromelia virus, and VACV, respectively (22,35).…”

Section: Discussionmentioning

confidence: 94%

“…Inside cells, brincidofovir is metabolized to CDV and subsequently phosphorylated to CDV-PP. Brincidofovir has potent broad-spectrum antiviral activity, including against poxviruses in vitro, and was shown to provide protection from lethality in several animal models, including mouse intranasal infections with ectromelia virus, cowpox virus, and VACV and a rabbit/rabbitpox virus intradermal challenge model (21)(22)(23). Because BCV's mechanism of action involves inhibition of viral replication, its potential effect on the elicitation of protective immunity by live smallpox vaccines is of interest.…”

mentioning

confidence: 99%

Postchallenge Administration of Brincidofovir Protects Healthy and Immune-Deficient Mice Reconstituted with Limited Numbers of T Cells from Lethal Challenge with IHD-J-Luc Vaccinia Virus

Zaitseva

McCullough

Cruz

et al. 2015

J Virol

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Protection from lethality by postchallenge administration of brincidofovir (BCV, CMX001) was studied in normal and immune-deficient (nude, nu/nu) BALB/c mice infected with vaccinia virus (VACV). Whole-body bioluminescence imaging was used to record total fluxes in the nasal cavity, lungs, spleen, and liver and to enumerate pox lesions on tails of mice infected via the intranasal route with 10 5 PFU of recombinant IHD-J-Luc VACV expressing luciferase. Areas under the flux curve (AUCs) were calculated for individual mice to assess viral loads. A three-dose regimen of 20 mg/kg BCV administered every 48 h starting either on day 1 or day 2 postchallenge protected 100% of mice. Initiating BCV treatment earlier was more efficient in reducing viral loads and in providing protection from pox lesion development. All BCV-treated mice that survived challenge were also protected from rechallenge with IHD-J-Luc or WRvFire VACV without additional treatment. In immune-deficient mice, BCV protected animals from lethality and reduced viral loads while animals were on the drug. Viral recrudescence occurred within 4 to 9 days, and mice succumbed ϳ10 to 20 days after treatment termination. Nude mice reconstituted with 10 5 T cells prior to challenge with 10 4 PFU of IHD-J-Luc and treated with BCV postchallenge survived the infection, cleared the virus from all organs, and survived rechallenge with 10 5 PFU of IHD-J-Luc VACV without additional BCV treatment. Together, these data suggest that BCV protects immunocompetent and partially T cell-reconstituted immune-deficient mice from lethality, reduces viral dissemination in organs, prevents pox lesion development, and permits generation of VACV-specific memory. IMPORTANCEMass vaccination is the primary element of the public health response to a smallpox outbreak. In addition to vaccination, however, antiviral drugs are required for individuals with uncertain exposure status to smallpox or for whom vaccination is contraindicated. Whole-body bioluminescence imaging was used to study the effect of brincidofovir (BCV) in normal and immunedeficient (nu/nu) mice infected with vaccinia virus, a model of smallpox. Postchallenge administration of 20 mg/kg BCV rescued normal and immune-deficient mice partially reconstituted with T cells from lethality and significantly reduced viral loads in organs. All BCV-treated mice that survived infection were protected from rechallenge without additional treatment. In immunedeficient mice, BCV extended survival. The data show that BCV controls viral replication at the site of challenge and reduces viral dissemination to internal organs, thus providing a shield for the developing adaptive immunity that clears the host of virus and builds virus-specific immunological memory. Smallpox was eradicated following a global immunization program using live vaccinia virus (VACV) vaccine implemented by the World Health Organization (WHO). Routine smallpox vaccination was subsequently discontinued due to a low but significant risk of severe adverse reactions. A...

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“…Body temperature has been observed to be an excellent indicator of both disease and the host response to infection (9,17,18,20). Therefore, the timing of the change in body temperature, as well as the maximum, is important in gauging the level of response to an infection.…”

Section: Intradermal Versus Scarification Infection Of Rabbits the Omentioning

confidence: 99%

“…Criteria for euthanizing the rabbits included openmouth breathing, severe difficulty in breathing, or a loss of body weight greater than 20% from the beginning initial weight. These criteria are the established euthanasia criteria for the rabbit model previously published and correspond to mortality; however, no animals were permitted to succumb to disease (9,17,18). In all animals noted in this publication, euthanasia was dictated by severe respiratory failure, defined as less than 40 breaths per minute and/or open-mouth breathing upon stimulation.…”

Section: Cells and Viruses (I) Cell Culturementioning

confidence: 99%

Protective Properties of Vaccinia Virus-Based Vaccines: Skin Scarification Promotes a Nonspecific Immune Response That Protects against Orthopoxvirus Disease

Rice

Adams

Lindsey

et al. 2014

J Virol

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The process of vaccination introduced by Jenner generated immunity against smallpox and ultimately led to the eradication of the disease. Procedurally, in modern times, the virus is introduced into patients via a process called scarification, performed with a bifurcated needle containing a small amount of virus. What was unappreciated was the role that scarification itself plays in generating protective immunity. In rabbits, protection from lethal disease is induced by intradermal injection of vaccinia virus, whereas a protective response occurs within the first 2 min after scarification with or without virus, suggesting that the scarification process itself is a major contributor to immunoprotection. IMPORTANCEThese results show the importance of local nonspecific immunity in controlling poxvirus infections and indicate that the process of scarification should be critically considered during the development of vaccination protocols for other infectious agents.

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Efficacy of CMX001 as a Post Exposure Antiviral in New Zealand White Rabbits Infected with Rabbitpox Virus, a Model for Orthopoxvirus Infections of Humans

Cited by 61 publications

References 16 publications

In Vitro Efficacy of Brincidofovir against Variola Virus

In Vitro Efficacy of Brincidofovir against Variola Virus

Postchallenge Administration of Brincidofovir Protects Healthy and Immune-Deficient Mice Reconstituted with Limited Numbers of T Cells from Lethal Challenge with IHD-J-Luc Vaccinia Virus

Protective Properties of Vaccinia Virus-Based Vaccines: Skin Scarification Promotes a Nonspecific Immune Response That Protects against Orthopoxvirus Disease

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