The Experts below are selected from a list of 159 Experts worldwide ranked by ideXlab platform
Richard W. Moyer - One of the best experts on this subject based on the ideXlab platform.
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Efficacy of CMX001 as a prophylactic and presymptomatic antiviral agent in New Zealand white rabbits infected with Rabbitpox Virus, a model for orthopoxVirus infections of humans.
Viruses, 2011Co-Authors: Amanda D. Rice, Scott Foster, Mathew M. Adams, Bernhard Lampert, Randall Lanier, Alice Robertson, George R. Painter, Richard W. MoyerAbstract:CMX001, a lipophilic nucleotide analog formed by covalently linking 3-(hexdecyloxy)propan-1-ol to cidofovir (CDV), is being developed as a treatment for smallpox. CMX001 has dramatically increased potency versus CDV against all dsDNA Viruses and, in contrast to CDV, is orally available and has shown no evidence of nephrotoxicity in healthy volunteers or severely ill transplant patients to date. Although smallpox has been eliminated from the environment, treatments are urgently being sought due to the risk of smallpox being used as a bioterrorism agent and for monkeypox Virus, a zoonotic disease of Africa, and adverse reactions to smallpox Virus vaccinations. In the absence of human cases of smallpox, new treatments must be tested for efficacy in animal models. Here we first review and discuss the Rabbitpox Virus (RPV) infection of New Zealand White rabbits as a model for smallpox to test the efficacy of CMX001 as a prophylactic and early disease antiviral. Our results should also be applicable to monkeypox Virus infections and for treatment of adverse reactions to smallpox vaccination.
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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
MDPI AG, 2011Co-Authors: Scott Foster, Richard W. Moyer, Daniele M. Swetnam, Brandi R. Manning, Stacey A. Gray, Bernhard Lampert, Randall Lanier, Alice Robertson, George Painter, Andrew J. SmithAbstract:CMX001, a lipophilic nucleotide analog formed by covalently linking 3-(hexdecyloxy)propan-1-ol to cidofovir (CDV), is being developed as a treatment for smallpox. In the absence of human cases of smallpox, new treatments must be tested for efficacy in animal models. Previously, we demonstrated the efficacy of CMX001 in protecting New Zealand White rabbits from mortality following intradermal infection with Rabbitpox Virus as a model for smallpox, monkeypox and for treatment of adverse reactions to smallpox vaccination. Here we extend these studies by exploring different dosing regimens and performing randomized, blinded, placebo-controlled studies. In addition, because Rabbitpox Virus can be transmitted via naturally generated aerosols (animal to animal transmission), we report on studies to test the efficacy of CMX001 in protecting rabbits from lethal Rabbitpox Virus disease when infection occurs by animal to animal transmission. In all cases, CMX001 treatment was initiated at the onset of observable lesions in the ears to model the use of CMX001 as a treatment for symptomatic smallpox. The results demonstrate that CMX001 is an effective treatment for symptomatic Rabbitpox Virus infection. The Rabbitpox model has key similarities to human smallpox including an incubation period, generalized systemic disease, the occurrence of lesions which may be used as a trigger for initiating therapy, and natural animal to animal spread, making it an appropriate model
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Rabbitpox Virus and Vaccinia Virus Infection of Rabbits as a Model for Human Smallpox
Journal of Virology, 2007Co-Authors: Mathew M. Adams, Amanda D. Rice, Richard W. MoyerAbstract:The threat of smallpox release and use as a bioweapon has encouraged the search for new vaccines and antiviral drugs, as well as development of new small-animal models in which their efficacy can be determined. Here, we reinvestigate a rabbit model in which the intradermal infection of rabbits with very low doses of either Rabbitpox Virus (RPV) or vaccinia Virus Western Reserve (VV-WR) recapitulates many of the clinical features of human smallpox. Following intradermal inoculation with RPV, rabbits develop systemic disease characterized by extensive viremia, numerous secondary lesions on the skin and mucocutaneous tissues, severe respiratory disease, death by 9 days postinfection, and, importantly, natural aerosol transmission between animals. Contrary to previous reports, intradermal infection with VV-WR also resulted in a very similar lethal systemic disease in rabbits, again with natural aerosol transmission between animals. When sentinel and index animals were cohoused, transmission rates approached 100% with either Virus, with sentinel animals exhibiting a similar, severe disease. Lower rates of transmission were observed when index and sentinel animals were housed in separate cages. Sentinel animals infected with RPV with one exception succumbed to the disease. However, the majority of VV-WR-infected sentinel animals, while becoming seriously ill, survived. Finally, we tested the efficacy of the drug 1-O-hexadecyloxypropyl-cidofovir in the RPV/rabbit model and found that an oral dose of 5 mg/kg twice a day for 5 days beginning 1 day before infection was able to completely protect rabbits from lethal disease.
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Suppressors of a Host Range Mutation in the Rabbitpox Virus Serpin SPI-1 Map to Proteins Essential for Viral DNA Replication
Journal of virology, 2005Co-Authors: Benjamin G. Luttge, Richard W. MoyerAbstract:The orthopoxVirus serpin SPI-1 is an intracellular serine protease inhibitor that is active against cathepsin G in vitro. Rabbitpox Virus (RPV) mutants with deletions of the SPI-1 gene grow on monkey kidney cells (CV-1) but do not plaque on normally permissive human lung carcinoma cells (A549). This reduced-host-range (hr) phenotype suggests that SPI-1 may interact with cellular and/or other viral proteins. We devised a genetic screen for suppressors of SPI-1 hr mutations by first introducing a mutation into SPI-1 (T309R) at residue P14 of the serpin reactive center loop. The SPI-1 T309R serpin is inactive as a protease inhibitor in vitro. Introduction of the mutation into RPV leads to the same restricted hr phenotype as deletion of the SPI-1 gene. Second-site suppressors were selected by restoration of growth of the RPV SPI-1 T309R hr mutant on A549 cells. Both intragenic and extragenic suppressors of the T309R mutation were identified. One novel intragenic suppressor mutation, T309C, restored protease inhibition by SPI-1 in vitro. Extragenic suppressor mutations were mapped by a new procedure utilizing overlapping PCR products encompassing the entire genome in conjunction with marker rescue. One suppressor mutation, which also rendered the Virus temperature sensitive for growth, mapped to the DNA polymerase gene (E9L). Several other suppressors mapped to gene D5R, an NTPase required for DNA replication. These results unexpectedly suggest that the host range function of SPI-1 may be associated with viral DNA replication by an as yet unknown mechanism.
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Microarray analysis of A549 cells infected with Rabbitpox Virus (RPV): a comparison of wild-type RPV and RPV deleted for the host range gene, SPI-1.
Virology, 2003Co-Authors: Lauren M Brum, M. Cecilia Lopez, Juan C. Varela, Henry V. Baker, Richard W. MoyerAbstract:A documented consequence of poxVirus infections is global inhibition of host protein synthesis and reduction in mRNA levels. We examined this mRNA decrease by infecting A549 cells, derived from a human lung carcinoma, with Rabbitpox Virus (RPV), or RPV deleted for the serine protease inhibitor SPI-1 (RPVΔSPI-1), which exhibits a growth defect on A549 cells. At various times postinfection, mRNA profiles were analyzed using Affymetrix U95AV2 microarrays. There was a decline in overall cellular mRNA levels beginning at 2.5 hpi, and by 5 hpi, mRNA levels were drastically reduced for the majority of genes. However, several mRNAs increased, including those of heat-shock genes. Finally, a comparison of host mRNA profiles of RPV- to RPVΔSPI-1-infected cells revealed subtle differences in mRNA levels at 5 and 12 hpi. In summary, while there was a global decrease of host mRNA levels, the induction of selected mRNAs may be required for a successful poxVirus infection.
Aysegul Nalca - One of the best experts on this subject based on the ideXlab platform.
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Rabbitpox: a model of airborne transmission of smallpox.
The Journal of general virology, 2010Co-Authors: Aysegul Nalca, Donald K. NicholsAbstract:Smallpox is a human disease caused by infection with variola Virus, a member of the genus OrthopoxVirus. Although smallpox has been eradicated, concern that it might be reintroduced through bioterrorism has therefore led to intensive efforts to develop new vaccines and antiviral drugs against this disease. Because these vaccines and therapeutics cannot be tested in human trials, it is necessary to test such medical countermeasures in different animal models. Although several orthopoxViruses cause disease in laboratory animals, only Rabbitpox Virus (RPXV) infection of rabbits shows patterns of natural airborne transmission similar to smallpox. Studies have shown that a smallpox-like disease can be produced in rabbits in a controlled fashion through exposure to a small-particle RPXV aerosol, and Rabbitpox spreads from animal to animal by the airborne route in a laboratory setting. This model can therefore be utilized to test drugs and vaccines against variola Virus and other aerosolized orthopoxViruses.
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Evaluation of the efficacy of modified vaccinia Ankara (MVA)/IMVAMUNE against aerosolized Rabbitpox Virus in a rabbit model.
Vaccine, 2009Co-Authors: Nicole L. Garza, Josh M. Hatkin, Virginia Livingston, Donald K. Nichols, Paul Chaplin, Ariane Volkmann, Diana Fisher, Aysegul NalcaAbstract:Infection of rabbits with aerosolized Rabbitpox Virus (RPXV) produces a disease similar to monkeypox and smallpox in humans and provides a valuable, informative model system to test medical countermeasures against orthopoxViruses. Due to the eradication of smallpox, the evaluation of the efficacy of new-generation smallpox vaccines depends on relevant well-developed animal studies for vaccine licensure. In this study, we tested the efficacy of IMVAMUNE® [Modified Vaccinia Virus Ankara-Bavarian Nordic (MVA-BN®)] for protecting rabbits against aerosolized RPXV. Rabbits were vaccinated with either phosphate-buffered saline (PBS), Dryvax®, a single low dose of IMVAMUNE®, a single high dose of IMVAMUNE®, or twice with a high dose of IMVAMUNE®. Aerosol challenge with a lethal dose of RPXV was performed 4 weeks after the last vaccination. All PBS control animals succumbed to the disease or were euthanized because of the disease within 7 days postexposure. The rabbits vaccinated with Dryvax®, a low dose of IMVAMUNE®, or a single high dose of IMVAMUNE® showed minimal to moderate clinical signs of the disease, but all survived the challenge. The only clinical sign displayed by rabbits that had been vaccinated twice with a high dose of IMVAMUNE® was mild transient anorexia in just two out of eight rabbits. This study shows that IMVAMUNE® can be a very effective vaccine against aerosolized RPXV.
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Rapid and high-throughput pan-OrthopoxVirus detection and identification using PCR and mass spectrometry.
PloS one, 2009Co-Authors: Mark W. Eshoo, Chris A. Whitehouse, Aysegul Nalca, Scott T. Zoll, Joseph A. Ecker, Thomas A. Hall, Thuy Trang D. Pennella, David D. Duncan, Anjali Desai, Emily MoradiAbstract:The genus OrthopoxVirus contains several species of related Viruses, including the causative agent of smallpox (Variola Virus). In addition to smallpox, several other members of the genus are capable of causing human infection, including monkeypox, cowpox, and other zoonotic rodent-borne poxViruses. Therefore, a single assay that can accurately identify all orthopoxViruses could provide a valuable tool for rapid broad orthopoVirus identification. We have developed a pan-OrthopoxVirus assay for identification of all members of the genus based on four PCR reactions targeting OrthopoxVirus DNA and RNA helicase and polymerase genes. The amplicons are detected using electrospray ionization-mass spectrometry (PCR/ESI-MS) on the Ibis T5000 system. We demonstrate that the assay can detect and identify a diverse collection of orthopoxViruses, provide sub-species information and characterize Viruses from the blood of Rabbitpox infected rabbits. The assay is sensitive at the stochastic limit of PCR and detected Virus in blood containing approximately six plaque-forming units per milliliter from a Rabbitpox Virus-infected rabbit.
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Evaluation of the Efficacy of Modified Vaccinia Ankara (MVA)/IMVAMUNE (registered trademark) Against Aerosolized Rabbitpox Virus in a Rabbit Model
2009Co-Authors: Nicole L. Garza, Josh M. Hatkin, Virginia Livingston, Donald K. Nichols, Paul Chaplin, Ariane Volkmann, Diana Fisher, Aysegul NalcaAbstract:Abstract : Infection of rabbits with aerosolized Rabbitpox Virus (RPXV) produces a disease similar to monkeypox and smallpox in humans and provides a valuable, informative model system to test medical countermeasures against orthopoxViruses. Due to the eradication of smallpox, efficacy evaluation of new-generation smallpox vaccines depends on relevant well-developed animal efficacy studies for vaccine licensure. In this study, we tested the efficacy of IMVAMUNE [Modified Vaccinia Virus Ankara-Bavarian Nordic (MVA-BN )] for protecting rabbits against aerosolized RPXV. Rabbits were vaccinated with either phosphate-buffered saline (PBS), Dryvax , a single low dose of IMVAMUNE , a single high dose of IMVAMUNE , or twice with a high dose of IMVAMUNE . Aerosol challenge with a lethal dose of RPXV was performed 4 weeks after the last vaccination. All PBS control animals succumbed to the disease or were euthanized because of the disease within 7 days postchallenge. The rabbits vaccinated with Dryvax , a low dose of IMVAMUNE , or a single high dose of IMVAMUNE showed minimal to moderate clinical signs of the disease, and all of them recovered. The only clinical sign displayed by rabbits that had been vaccinated twice with a high dose of IMVAMUNE was mild transient anorexia in just two animals. This study shows that IMVAMUNE can be a very effective vaccine against aerosolized RPXV.
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Rapid and High-Throughput pan-OrthopoxVirus Detection and Identification using PCR and Mass
2009Co-Authors: Mark W. Eshoo, Chris A. Whitehouse, Aysegul Nalca, Scott T. Zoll, Joseph A. Ecker, Thomas A. Hall, Thuy Trang D. Pennella, David D. Duncan, Anjali Desai, Emily K. MoradiAbstract:The genus OrthopoxVirus contains several species of related Viruses, including the causative agent of smallpox (Variola Virus). In addition to smallpox, several other members of the genus are capable of causing human infection, including monkeypox, cowpox, and other zoonotic rodent-borne poxViruses. Therefore, a single assay that can accurately identify all orthopoxViruses could provide a valuable tool for rapid broad orthopoVirus identification. We have developed a pan-OrthopoxVirus assay for identification of all members of the genus based on four PCR reactions targeting OrthopoxVirus DNA and RNA helicase and polymerase genes. The amplicons are detected using electrospray ionization-mass spectrometry (PCR/ESI-MS) on the Ibis T5000 system. We demonstrate that the assay can detect and identify a diverse collection of orthopoxViruses, provide sub-species information and characterize Viruses from the blood of Rabbitpox infected rabbits. The assay is sensitive at the stochastic limit of PCR and detected Virus in blood containing approximately six plaque-forming units per milliliter from a Rabbitpox Virus-infected rabbit
Grant Mcfadden - One of the best experts on this subject based on the ideXlab platform.
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Functional Comparisons among Members of the PoxVirus T1/35kDa Family of Soluble CC-Chemokine Inhibitor Glycoproteins☆
Virology, 1998Co-Authors: Ali Salem Lalani, Grant Mcfadden, Bruce T. Seet, Rajkumari Singh, Jeffrey K. Harrison, Traci L. Ness, David J. Kelvin, Richard W. MoyerAbstract:Many poxViruses express a 35±40-kDa secreted protein, termed a T1o (for leporipoxViruses) or a35kDao (for orthopoxViruses), that binds CC-chemokines with high affinity but is unrelated to any known cellular proteins. Many previously identified poxVirus cytokine-binding proteins display strict species ligand-binding specificity. Because the T1 and 35kDa proteins share only 40% amino acid identity, we compared the abilities of purified myxoma Virus-T1 (M-T1) and vaccinia Virus (strain Lister)and Rabbitpox Virus-35kDa proteins to inhibit human CC-chemokines in vitro. All three proteins were equally effective in preventing several human CC-chemokines from binding to target chemokine receptors and blocking subsequent intracellular calcium release. The inhibitory affinities were comparable (Ki 5 0.07±1.02 nM). These proteins also displayed similar abilities to inhibit (IC50 5 6.3±10.5 nM) human macrophage inflammatory protein-1a-mediated chemotaxis of human monocytes. None of the viral proteins blocked interleukin-8-mediated calcium flux or chemotaxis of human neutrophils, confirming that the biological specificity of the T1/35kDa family is targeted inhibition of CC-chemokines. Despite the significant sequence divergence between the leporipoxVirus T1 and orthopoxVirus 35kDa proteins, our data suggest that their CC-chemokine binding and inhibitory properties appear to be species nonspecific and that the critical motifs most likely reside within the limited regions of conservation. © 1998 Academic Press
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The T1/35kDa family of poxVirus-secreted proteins bind chemokines and modulate leukocyte influx into Virus-infected tissues.
Virology, 1997Co-Authors: Kathryn Graham, Joanne L. Macen, Ali Salem Lalani, Richard W. Moyer, Traci L. Ness, Ian Clark-lewis, Michele Barry, Alexandra Lucas, Grant McfaddenAbstract:Abstract Immunomodulatory proteins encoded by the larger DNA Viruses interact with a wide spectrum of immune effector molecules that regulate the antiviral response in the infected host. Here we show that certain poxViruses, including myxoma Virus, Shope fibroma Virus, Rabbitpox Virus, vaccinia Virus (strain Lister), cowpox Virus, and raccoonpox Virus, express a new family of secreted proteins which interact with members of both the CC and CXC superfamilies of chemokines. However, swinepox Virus and vaccinia Virus (strain WR) do not express this activity. Using a recombinant poxViruses, the myxoma M-T1 and Rabbitpox Virus 35kDa secreted proteins were identified as prototypic members of this family of chemokine binding proteins. Members of this T1/35kDa family of poxVirus-secreted proteins share multiple stretches of identical sequence motifs, including eight conserved cysteine residues, but are otherwise unrelated to any cellular genes in the database. The affinity of the CC chemokine RANTES interaction with M-T1 was assessed by Scatchard analysis and yielded a K d of approximately 73 n M. In rabbits infected with a mutant Rabbitpox Virus, in which the 35kDa gene is deleted, there was an increased number of extravasating leukocytes in the deep dermis during the early phases of infection. These observations suggest that members of the T1/35kDa class of secreted viral proteins bind multiple members of the chemokine superfamily in vitro and modulate the influx of inflammatory cells into Virus-infected tissues in vivo.
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Differential inhibition of the Fas- and granule-mediated cytolysis pathways by the orthopoxVirus cytokine response modifier A/SPI-2 and SPI-1 protein.
Proceedings of the National Academy of Sciences of the United States of America, 1996Co-Authors: Joanne L. Macen, Grant Mcfadden, Richard W. Moyer, R S Garner, P Y Musy, M A Brooks, P C Turner, R C BleackleyAbstract:Cytotoxic T lymphocytes are important effectors of antiviral immunity, and they induce target cell death either by secretion of cytoplasmic granules containing perforin and granzymes or by signaling through the Fas cell surface antigen. Although it is not known whether the granule-mediated and Fas-mediated cytolytic mechanisms share common components, proteinase activity has been implicated as an important feature of both pathways. The orthopoxViruses cowpox Virus and Rabbitpox Virus each encode three members of the serpin family of proteinase inhibitors, designated SPI-1, SPI-2, and SPI-3. Of these, SPI-2 (also referred to as cytokine response modifier A in cowpox Virus) has been shown to inhibit the proteolytic activity of both members of the interleukin 1 beta converting enzyme family and granzyme B. We report here that cells infected with cowpox or Rabbitpox Viruses exhibit resistance to cytolysis by either cytolytic mechanism. Whereas mutation of the cytokine response modifier A/SPI-2 gene was necessary to relieve inhibition of Fasmediated cytolysis, in some cell types mutation of SPI-1, in addition to cytokine response modifier A/SPI-2, was necessary to completely abrogate inhibition. In contrast, viral inhibition of granule-mediated killing was unaffected by mutation of cytokine response modifier A/SPI-2 alone, and it was relieved only when both the cytokine response modifier A/SPI-2 and SPI-1 genes were inactivated. These results suggest that an interleukin 1 beta converting enzyme-like enzymatic activity is involved in both killing mechanisms and indicate that two viral proteins, SPI-1 and cytokine response modifier A/SPI-2, are necessary to inhibit both cytolysis pathways.
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Species Specificity of Ectromelia Virus and Vaccinia Virus Interferon-γ Binding Proteins
Virology, 1995Co-Authors: Karen L. Mossman, Chris Upton, R.m.l. Buller, Grant McfaddenAbstract:Abstract Interferon-γ functions within the immune system as a potent anti-viral and immunoregulatory cytokine. In order to successfully replicate within a host cell, poxViruses have evolved a number of strategies to counteract the pleiotropic effects of interferon-γ. In particular, the leporipoxVirus myxoma Virus was shown to express an extracellular soluble interferon-γ receptor homolog, denoted M-T7, which is capable of inhibiting the anti-viral activities of rabbit interferon-γ (C. Upton, K. Mossman, and G. McFadden, 1992, Science 258, 1369-1372). Here, we demonstrate that expression of soluble interferonγ receptor homologs appears to be characteristic of all poxViruses tested, including Shope fibroma Virus, vaccinia Virus (strains WR and IHDW), ectromelia Virus, cowpox Virus, and Rabbitpox Virus. We have cloned, sequenced, and characterized the interferon-γ binding protein in supernatants from ectromelia Virus-infected cells, and demonstrate the capability of this soluble protein to bind human, murine, and rabbit interferon-γ with similar affinity. We also investigate the properties of the vaccinia Virus interferon-γ binding protein and demonstrate that this protein binds human and rabbit interferon-γ with similar affinity and binds murine interferon-γ with a significantly lower relative affinity. The implications of these studies with respect to viral pathogenesis and the evolutionary relationship between a Virus and its host are discussed.
Amanda D. Rice - One of the best experts on this subject based on the ideXlab platform.
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The NYCBH vaccinia Virus deleted for the innate immune evasion gene, E3L, protects rabbits against lethal challenge by Rabbitpox Virus
Vaccine, 2011Co-Authors: Karen L. Denzler, Amanda D. Rice, Greg Wallace, Andrew M. Burrage, Scott F. Lindsey, Andrew J. Smith, Brandi R. Manning, Amy L. Macneill, Nobuko Fukushima, Daniele M. SwetnamAbstract:Abstract Vaccinia Virus deleted for the innate immune evasion gene, E3L, has been shown to be highly attenuated and yet induces a protective immune response against challenge by homologous Virus in a mouse model. In this manuscript the NYCBH vaccinia Virus vaccine strain was compared to NYCBH vaccinia Virus deleted for E3L (NYCBHΔE3L) in a Rabbitpox Virus (RPV) challenge model. Upon scarification, both vaccines produced a desired skin lesion, although the lesion produced by NYCBHΔE3L was smaller. Both vaccines fully protected rabbits against lethal challenge by escalating doses of RPV, from 10 LD 50 to 1000 LD 50 . A single dose of NYCBHΔE3L protected rabbits from weight loss, fever, and clinical symptoms following the lowest dose challenge of 10 LD 50 , however it allowed a moderate level of RPV replication at the challenge site, some spread to external skin and mucosal surfaces, and increased numbers of secondary lesions as compared to vaccination with NYCBH. Alternately, two doses of NYCBHΔE3L fully protected rabbits from weight loss, fever, and clinical symptoms, following challenge with 100–1000 LD 50 RPV, and it prevented development of secondary lesions similar to protection seen with NYCBH. Finally, vaccination with either one or two doses of NYCBHΔE3L resulted in similar neutralizing antibody titers following RPV challenge as compared to titers obtained by vaccination with NYCBH. These results support the efficacy of the attenuated NYCBHΔE3L in protection against an orthologous poxVirus challenge.
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Efficacy of CMX001 as a prophylactic and presymptomatic antiviral agent in New Zealand white rabbits infected with Rabbitpox Virus, a model for orthopoxVirus infections of humans.
Viruses, 2011Co-Authors: Amanda D. Rice, Scott Foster, Mathew M. Adams, Bernhard Lampert, Randall Lanier, Alice Robertson, George R. Painter, Richard W. MoyerAbstract:CMX001, a lipophilic nucleotide analog formed by covalently linking 3-(hexdecyloxy)propan-1-ol to cidofovir (CDV), is being developed as a treatment for smallpox. CMX001 has dramatically increased potency versus CDV against all dsDNA Viruses and, in contrast to CDV, is orally available and has shown no evidence of nephrotoxicity in healthy volunteers or severely ill transplant patients to date. Although smallpox has been eliminated from the environment, treatments are urgently being sought due to the risk of smallpox being used as a bioterrorism agent and for monkeypox Virus, a zoonotic disease of Africa, and adverse reactions to smallpox Virus vaccinations. In the absence of human cases of smallpox, new treatments must be tested for efficacy in animal models. Here we first review and discuss the Rabbitpox Virus (RPV) infection of New Zealand White rabbits as a model for smallpox to test the efficacy of CMX001 as a prophylactic and early disease antiviral. Our results should also be applicable to monkeypox Virus infections and for treatment of adverse reactions to smallpox vaccination.
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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
Viruses, 2011Co-Authors: Amanda D. Rice, Mathew M. Adams, Greg Wallace, Andrew M. Burrage, Scott F. Lindsey, Andrew J. Smith, Daniele M. Swetnam, Brandi R. Manning, Stacey A. Gray, Bernhard LampertAbstract:CMX001, a lipophilic nucleotide analog formed by covalently linking 3-(hexdecyloxy)propan-1-ol to cidofovir (CDV), is being developed as a treatment for smallpox. In the absence of human cases of smallpox, new treatments must be tested for efficacy in animal models. Previously, we demonstrated the efficacy of CMX001 in protecting New Zealand White rabbits from mortality following intradermal infection with Rabbitpox Virus as a model for smallpox, monkeypox and for treatment of adverse reactions to smallpox vaccination. Here we extend these studies by exploring different dosing regimens and performing randomized, blinded, placebo-controlled studies. In addition, because Rabbitpox Virus can be transmitted via naturally generated aerosols (animal to animal transmission), we report on studies to test the efficacy of CMX001 in protecting rabbits from lethal Rabbitpox Virus disease when infection occurs by animal to animal transmission. In all cases, CMX001 treatment was initiated at the onset of observable lesions in the ears to model the use of CMX001 as a treatment for symptomatic smallpox. The results demonstrate that CMX001 is an effective treatment for symptomatic Rabbitpox Virus infection. The Rabbitpox model has key similarities to human smallpox including an incubation period, generalized systemic disease, the occurrence of lesions which may be used as a trigger for initiating therapy, and natural animal to animal spread, making it an appropriate model.
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Rabbitpox Virus and Vaccinia Virus Infection of Rabbits as a Model for Human Smallpox
Journal of Virology, 2007Co-Authors: Mathew M. Adams, Amanda D. Rice, Richard W. MoyerAbstract:The threat of smallpox release and use as a bioweapon has encouraged the search for new vaccines and antiviral drugs, as well as development of new small-animal models in which their efficacy can be determined. Here, we reinvestigate a rabbit model in which the intradermal infection of rabbits with very low doses of either Rabbitpox Virus (RPV) or vaccinia Virus Western Reserve (VV-WR) recapitulates many of the clinical features of human smallpox. Following intradermal inoculation with RPV, rabbits develop systemic disease characterized by extensive viremia, numerous secondary lesions on the skin and mucocutaneous tissues, severe respiratory disease, death by 9 days postinfection, and, importantly, natural aerosol transmission between animals. Contrary to previous reports, intradermal infection with VV-WR also resulted in a very similar lethal systemic disease in rabbits, again with natural aerosol transmission between animals. When sentinel and index animals were cohoused, transmission rates approached 100% with either Virus, with sentinel animals exhibiting a similar, severe disease. Lower rates of transmission were observed when index and sentinel animals were housed in separate cages. Sentinel animals infected with RPV with one exception succumbed to the disease. However, the majority of VV-WR-infected sentinel animals, while becoming seriously ill, survived. Finally, we tested the efficacy of the drug 1-O-hexadecyloxypropyl-cidofovir in the RPV/rabbit model and found that an oral dose of 5 mg/kg twice a day for 5 days beginning 1 day before infection was able to completely protect rabbits from lethal disease.
Scott Foster - One of the best experts on this subject based on the ideXlab platform.
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Efficacy of delayed brincidofovir treatment against a lethal Rabbitpox Virus challenge in New Zealand White rabbits.
Antiviral Research, 2017Co-Authors: Irma M. Grossi, Scott Foster, Thomas M. Brundage, Melicia R. Gainey, Robert Krile, John A. Dunn, Jody M. KhouriAbstract:Abstract In the event of a bioterror attack with variola Virus (smallpox), exposure may only be identified following onset of fever. To determine if antiviral therapy with brincidofovir (BCV; CMX001) initiated at, or following, onset of fever could prevent severe illness and death, a lethal Rabbitpox model was used. BCV is in advanced development as an antiviral for the treatment of smallpox under the US Food and Drug Administration's ‘Animal Rule’. This pivotal study assessed the efficacy of immediate versus delayed treatment with BCV following onset of symptomatic disease in New Zealand White rabbits intradermally inoculated with a lethal Rabbitpox Virus (RPXV), strain Utrecht. Infected rabbits with confirmed fever were randomized to blinded treatment with placebo, BCV, or BCV delayed by 24, 48, or 72 h. The primary objective evaluated the survival benefit with BCV treatment. The assessment of reduction in the severity and progression of clinical events associated with RPXV were secondary objectives. Clinically and statistically significant reductions in mortality were observed when BCV was initiated up to 48 h following the onset of fever; survival rates were 100%, 93%, and 93% in the immediate treatment, 24-h, and 48-h delayed treatment groups, respectively, versus 48% in the placebo group (p
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The efficacy and pharmacokinetics of brincidofovir for the treatment of lethal Rabbitpox Virus infection: a model of smallpox disease.
Antiviral Research, 2015Co-Authors: Lawrence C. Trost, Laurie Keilholz, Jody M. Khouri, Michelle L. Rose, James Long, Stephen J. Godin, Scott FosterAbstract:Brincidofovir (BCV) has broad-spectrum in vitro activity against dsDNA Viruses, including smallpox, and is being developed as a treatment for smallpox as well as infections caused by other dsDNA Viruses. BCV has previously been shown to be active in multiple animal models of smallpox. Here we present the results of a randomized, blinded, placebo-controlled study of the efficacy and pharmacokinetics of a novel, "humanized" regimen of BCV for treatment of New Zealand White rabbits infected with a highly lethal inoculum of Rabbitpox Virus, a well characterized model of smallpox. Compared with placebo, a dose-dependent increase in survival was observed in all BCV-treatment groups. Concentrations of cidofovir diphosphate (CDV-PP), the active antiviral, in rabbit peripheral blood mononuclear cells (PBMCs) were determined for comparison to those produced in humans at the dose proposed for treatment of smallpox. CDV-PP exposure in PBMCs from rabbits given BCV scaled to human exposures at the dose proposed for treatment of smallpox, which is also currently under evaluation for other indications. The results of this study demonstrate the activity of BCV in the Rabbitpox model of smallpox and the feasibility of scaling doses efficacious in the model to a proposed human dose and regimen for treatment of smallpox.
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Efficacy of CMX001 as a prophylactic and presymptomatic antiviral agent in New Zealand white rabbits infected with Rabbitpox Virus, a model for orthopoxVirus infections of humans.
Viruses, 2011Co-Authors: Amanda D. Rice, Scott Foster, Mathew M. Adams, Bernhard Lampert, Randall Lanier, Alice Robertson, George R. Painter, Richard W. MoyerAbstract:CMX001, a lipophilic nucleotide analog formed by covalently linking 3-(hexdecyloxy)propan-1-ol to cidofovir (CDV), is being developed as a treatment for smallpox. CMX001 has dramatically increased potency versus CDV against all dsDNA Viruses and, in contrast to CDV, is orally available and has shown no evidence of nephrotoxicity in healthy volunteers or severely ill transplant patients to date. Although smallpox has been eliminated from the environment, treatments are urgently being sought due to the risk of smallpox being used as a bioterrorism agent and for monkeypox Virus, a zoonotic disease of Africa, and adverse reactions to smallpox Virus vaccinations. In the absence of human cases of smallpox, new treatments must be tested for efficacy in animal models. Here we first review and discuss the Rabbitpox Virus (RPV) infection of New Zealand White rabbits as a model for smallpox to test the efficacy of CMX001 as a prophylactic and early disease antiviral. Our results should also be applicable to monkeypox Virus infections and for treatment of adverse reactions to smallpox vaccination.
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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
MDPI AG, 2011Co-Authors: Scott Foster, Richard W. Moyer, Daniele M. Swetnam, Brandi R. Manning, Stacey A. Gray, Bernhard Lampert, Randall Lanier, Alice Robertson, George Painter, Andrew J. SmithAbstract:CMX001, a lipophilic nucleotide analog formed by covalently linking 3-(hexdecyloxy)propan-1-ol to cidofovir (CDV), is being developed as a treatment for smallpox. In the absence of human cases of smallpox, new treatments must be tested for efficacy in animal models. Previously, we demonstrated the efficacy of CMX001 in protecting New Zealand White rabbits from mortality following intradermal infection with Rabbitpox Virus as a model for smallpox, monkeypox and for treatment of adverse reactions to smallpox vaccination. Here we extend these studies by exploring different dosing regimens and performing randomized, blinded, placebo-controlled studies. In addition, because Rabbitpox Virus can be transmitted via naturally generated aerosols (animal to animal transmission), we report on studies to test the efficacy of CMX001 in protecting rabbits from lethal Rabbitpox Virus disease when infection occurs by animal to animal transmission. In all cases, CMX001 treatment was initiated at the onset of observable lesions in the ears to model the use of CMX001 as a treatment for symptomatic smallpox. The results demonstrate that CMX001 is an effective treatment for symptomatic Rabbitpox Virus infection. The Rabbitpox model has key similarities to human smallpox including an incubation period, generalized systemic disease, the occurrence of lesions which may be used as a trigger for initiating therapy, and natural animal to animal spread, making it an appropriate model
