The Experts below are selected from a list of 2424 Experts worldwide ranked by ideXlab platform
Heinz Feldmann - One of the best experts on this subject based on the ideXlab platform.
-
Vaccines Against Ebola and Marburg Virus Infections
2016Co-Authors: Thomas W Geisbert, Heinz FeldmannAbstract:The Filoviruses, Marburg virus and Ebola virus, cause severe hemorrhagic fever with a high mortality rate in humans and nonhuman primates. Among the most-promising Filovirus vaccines under development is a system based on recombinant vesicular stomatitis virus (rVSV) that expresses a single Filovirus glycoprotein (GP) in place of the VSV glycoprotein (G). Importantly, a single injection of blended rVSV-based Filovirus vaccines was shown to completely protect nonhuman primates against Marburg virus and 3 different species of Ebola virus. These rVSV-based vaccines have also shown utility when administered as a postexposure treatment against Filovirus infections, and a rVSV-based Ebola virus vaccine was recently used to treat a potential laboratory exposure. Here, we review the history of rVSV-based vaccines and pivotal animal studies showing their utility in combating Ebola and Marburg virus infections. Marburg virus (MARV) and Ebola virus (EBOV) are sig-nificant human pathogens that present a public health concern as emerging or reemerging viruses and as po-tential biological weapons. No vaccine or antiviral drug for MARV or EBOV is currently licensed and available for human use. Although Marburg and Ebola hemorrhagi
-
Stat1-Deficient Mice Are Not an Appropriate Model for Efficacy Testing of Recombinant
2016Co-Authors: Vesicular Stomatitis, Lisa Kercher, Joshua Marceau, Anthony York, Julie Callsion, Donald J. Gardner, Andrea Marzi, Thomas W Geisbert, Heinz FeldmannAbstract:Stat1−/ − mice lack a response to interferon α, β, and γ, allowing for replication of nonadapted wild-type (wt) Ebolavirus and Marburgvirus. We sought to establish a mouse model for efficacy testing of live attenuated re-combinant vesicular stomatitis virus (rVSV)–based Filovirus vaccine vectors using wt Ebolavirus and Marburg-virus challenge strains. While infection of immunocompetent mice with different rVSV-based Filovirus vectors did not cause disease, infection of Stat1−/ − mice with the same vectors resulted in systemic infection and lethal outcome for the majority of tested rVSVs. Despite differences in viral loads, organ tropism was remarkably similar between rVSV Filovirus vaccine vectors and rVSVwt, with the exception of the brain. In conclusion, Stat1−/−mice are not an appropriate immunocompromised mouse model for efficacy testing of live attenuated, replication-competent rVSV vaccine vectors. Keywords. Vesicular stomatitis virus; Ebolavirus; Marburgvirus; vaccine; Stat1-deficient mice. Ebolavirus and Marburgvirus, members of the family Filoviridae, cause viral hemorrhagic fever in nonhuman primates and humans [1]. While outbreaks of Filovirus hemorrhagic fever have occurred mainly in their en-demic area in Central Africa, currently, the biggest doc-umented Ebola virus (EBOV) outbreak is still ongoing in West African countries such as Guinea, Liberia and Sierra Leone. Not only has the virus spread from there into neighboring Mali, it was also introduced to Sene
-
Durability of a Vesicular Stomatitis Virus-Based Marburg Virus Vaccine in Nonhuman Primates
2016Co-Authors: Chad E. Mire, Heinz Feldmann, Joan B. Geisbert, Krystle N. Agans, Krista M. Versteeg, Benjamin A Satterfield, Elizabeth A Fritz, Lisa E Hensley, Thomas W GeisbertAbstract:The Filoviruses, Marburg virus (MARV) and Ebola virus, causes severe hemorrhagic fever with high mortality in humans and nonhuman primates. A promising Filovirus vaccine under development is based on a recombinant vesicular stomatitis virus (rVSV) that expresses individual Filovirus glycoproteins (GPs) in place of the VSV glycoprotein (G). These vaccines have shown 100 % efficacy against Filovirus infection in nonhuman primates when challenge occurs 28–35 days after a single injection immunization. Here, we examined the ability of a rVSV MARV-GP vaccine to provide protection when challenge occurs more than a year after vaccination. Cynomolgus macaques were immunized with rVSV-MARV-GP and challenged with MARV approximately 14 months after vaccination. Immunization resulted in the vaccine cohort of six animals having anti-MARV GP IgG throughout the pre-challenge period. Following MARV challenge none of the vaccinated animals showed any signs of clinical disease or viremia and all were completely protected from MARV infection. Two unvaccinated control animals exhibited signs consistent with MARV infection and both succumbed. Importantly, these data are the first to show 100% protective efficacy against any high dose Filovirus challenge beyond 8 weeks after final vaccination. These finding
-
considerations in the use of nonhuman primate models of ebola virus and marburg virus infection
The Journal of Infectious Diseases, 2015Co-Authors: James E Strong, Heinz FeldmannAbstract:Abstract The Filoviruses, Ebola virus and Marburg virus, are zoonotic pathogens that cause severe hemorrhagic fever in humans and nonhuman primates (NHPs), with case-fatality rates ranging from 23% to 90%. The current outbreak of Ebola virus infection in West Africa, with >26 000 cases, demonstrates the long-underestimated public health danger that Filoviruses pose as natural human pathogens. Currently, there are no vaccines or treatments licensed for human use. Licensure of any medical countermeasure may require demonstration of efficacy in the gold standard cynomolgus or rhesus macaque models of Filovirus infection. Substantial progress has been made over the last decade in characterizing the Filovirus NHP models. However, there is considerable debate over a variety of experimental conditions, including differences among Filovirus isolates used, routes and doses of exposure, and euthanasia criteria, all of which may contribute to variability of results among different laboratories. As an example of the importance of understanding these differences, recent data with Ebola virus shows that an addition of a single uridine residue in the glycoprotein gene at the editing site attenuates the virus. Here, we draw on decades of experience working with Filovirus-infected NHPs to provide a perspective on the importance of various experimental conditions.
-
Stat1-Deficient Mice Are Not an Appropriate Model for Efficacy Testing of Recombinant Vesicular Stomatitis Virus-Based Filovirus Vaccines.
The Journal of infectious diseases, 2015Co-Authors: Andrea Marzi, Lisa Kercher, Joshua Marceau, Anthony York, Julie Callsion, Donald J. Gardner, Thomas W Geisbert, Heinz FeldmannAbstract:Stat1(-/-) mice lack a response to interferon α, β, and γ, allowing for replication of nonadapted wild-type (wt) Ebolavirus and Marburgvirus. We sought to establish a mouse model for efficacy testing of live attenuated recombinant vesicular stomatitis virus (rVSV)-based Filovirus vaccine vectors using wt Ebolavirus and Marburgvirus challenge strains. While infection of immunocompetent mice with different rVSV-based Filovirus vectors did not cause disease, infection of Stat1(-/-) mice with the same vectors resulted in systemic infection and lethal outcome for the majority of tested rVSVs. Despite differences in viral loads, organ tropism was remarkably similar between rVSV Filovirus vaccine vectors and rVSVwt, with the exception of the brain. In conclusion, Stat1(-/-) mice are not an appropriate immunocompromised mouse model for efficacy testing of live attenuated, replication-competent rVSV vaccine vectors.
Thomas W Geisbert - One of the best experts on this subject based on the ideXlab platform.
-
Vaccines Against Ebola and Marburg Virus Infections
2016Co-Authors: Thomas W Geisbert, Heinz FeldmannAbstract:The Filoviruses, Marburg virus and Ebola virus, cause severe hemorrhagic fever with a high mortality rate in humans and nonhuman primates. Among the most-promising Filovirus vaccines under development is a system based on recombinant vesicular stomatitis virus (rVSV) that expresses a single Filovirus glycoprotein (GP) in place of the VSV glycoprotein (G). Importantly, a single injection of blended rVSV-based Filovirus vaccines was shown to completely protect nonhuman primates against Marburg virus and 3 different species of Ebola virus. These rVSV-based vaccines have also shown utility when administered as a postexposure treatment against Filovirus infections, and a rVSV-based Ebola virus vaccine was recently used to treat a potential laboratory exposure. Here, we review the history of rVSV-based vaccines and pivotal animal studies showing their utility in combating Ebola and Marburg virus infections. Marburg virus (MARV) and Ebola virus (EBOV) are sig-nificant human pathogens that present a public health concern as emerging or reemerging viruses and as po-tential biological weapons. No vaccine or antiviral drug for MARV or EBOV is currently licensed and available for human use. Although Marburg and Ebola hemorrhagi
-
Stat1-Deficient Mice Are Not an Appropriate Model for Efficacy Testing of Recombinant
2016Co-Authors: Vesicular Stomatitis, Lisa Kercher, Joshua Marceau, Anthony York, Julie Callsion, Donald J. Gardner, Andrea Marzi, Thomas W Geisbert, Heinz FeldmannAbstract:Stat1−/ − mice lack a response to interferon α, β, and γ, allowing for replication of nonadapted wild-type (wt) Ebolavirus and Marburgvirus. We sought to establish a mouse model for efficacy testing of live attenuated re-combinant vesicular stomatitis virus (rVSV)–based Filovirus vaccine vectors using wt Ebolavirus and Marburg-virus challenge strains. While infection of immunocompetent mice with different rVSV-based Filovirus vectors did not cause disease, infection of Stat1−/ − mice with the same vectors resulted in systemic infection and lethal outcome for the majority of tested rVSVs. Despite differences in viral loads, organ tropism was remarkably similar between rVSV Filovirus vaccine vectors and rVSVwt, with the exception of the brain. In conclusion, Stat1−/−mice are not an appropriate immunocompromised mouse model for efficacy testing of live attenuated, replication-competent rVSV vaccine vectors. Keywords. Vesicular stomatitis virus; Ebolavirus; Marburgvirus; vaccine; Stat1-deficient mice. Ebolavirus and Marburgvirus, members of the family Filoviridae, cause viral hemorrhagic fever in nonhuman primates and humans [1]. While outbreaks of Filovirus hemorrhagic fever have occurred mainly in their en-demic area in Central Africa, currently, the biggest doc-umented Ebola virus (EBOV) outbreak is still ongoing in West African countries such as Guinea, Liberia and Sierra Leone. Not only has the virus spread from there into neighboring Mali, it was also introduced to Sene
-
Durability of a Vesicular Stomatitis Virus-Based Marburg Virus Vaccine in Nonhuman Primates
2016Co-Authors: Chad E. Mire, Heinz Feldmann, Joan B. Geisbert, Krystle N. Agans, Krista M. Versteeg, Benjamin A Satterfield, Elizabeth A Fritz, Lisa E Hensley, Thomas W GeisbertAbstract:The Filoviruses, Marburg virus (MARV) and Ebola virus, causes severe hemorrhagic fever with high mortality in humans and nonhuman primates. A promising Filovirus vaccine under development is based on a recombinant vesicular stomatitis virus (rVSV) that expresses individual Filovirus glycoproteins (GPs) in place of the VSV glycoprotein (G). These vaccines have shown 100 % efficacy against Filovirus infection in nonhuman primates when challenge occurs 28–35 days after a single injection immunization. Here, we examined the ability of a rVSV MARV-GP vaccine to provide protection when challenge occurs more than a year after vaccination. Cynomolgus macaques were immunized with rVSV-MARV-GP and challenged with MARV approximately 14 months after vaccination. Immunization resulted in the vaccine cohort of six animals having anti-MARV GP IgG throughout the pre-challenge period. Following MARV challenge none of the vaccinated animals showed any signs of clinical disease or viremia and all were completely protected from MARV infection. Two unvaccinated control animals exhibited signs consistent with MARV infection and both succumbed. Importantly, these data are the first to show 100% protective efficacy against any high dose Filovirus challenge beyond 8 weeks after final vaccination. These finding
-
Stat1-Deficient Mice Are Not an Appropriate Model for Efficacy Testing of Recombinant Vesicular Stomatitis Virus-Based Filovirus Vaccines.
The Journal of infectious diseases, 2015Co-Authors: Andrea Marzi, Lisa Kercher, Joshua Marceau, Anthony York, Julie Callsion, Donald J. Gardner, Thomas W Geisbert, Heinz FeldmannAbstract:Stat1(-/-) mice lack a response to interferon α, β, and γ, allowing for replication of nonadapted wild-type (wt) Ebolavirus and Marburgvirus. We sought to establish a mouse model for efficacy testing of live attenuated recombinant vesicular stomatitis virus (rVSV)-based Filovirus vaccine vectors using wt Ebolavirus and Marburgvirus challenge strains. While infection of immunocompetent mice with different rVSV-based Filovirus vectors did not cause disease, infection of Stat1(-/-) mice with the same vectors resulted in systemic infection and lethal outcome for the majority of tested rVSVs. Despite differences in viral loads, organ tropism was remarkably similar between rVSV Filovirus vaccine vectors and rVSVwt, with the exception of the brain. In conclusion, Stat1(-/-) mice are not an appropriate immunocompromised mouse model for efficacy testing of live attenuated, replication-competent rVSV vaccine vectors.
-
A Single-Vector, Single-Injection Trivalent Filovirus Vaccine: Proof of Concept Study in Outbred Guinea Pigs
The Journal of Infectious Diseases, 2015Co-Authors: Chad E. Mire, Thomas W Geisbert, Joan B. Geisbert, Krystle N. Agans, Krista M. Versteeg, Natalia Mamaeva, John H. ConnorAbstract:The Filoviruses, Marburg marburgvirus (MARV), Zaire ebolavirus (ZEBOV), and Sudan ebolavirus (SEBOV), cause severe and often fatal hemorrhagic fever in humans and nonhuman primates (NHPs). Monovalent recombinant vesicular stomatitis virus (rVSV)-based vaccine vectors, which encode a Filovirus glycoprotein (GP) in place of the VSV glycoprotein, have shown 100% efficacy against homologous Filovirus challenge in rodent and NHP studies. Here, we examined the utility of a single-vector, single-injection trivalent rVSV vector expressing MARV, ZEBOV, and SEBOV GPs to protect against MARV-, ZEBOV-, and SEBOV-induced disease in outbred Hartley guinea pigs where we observed protection from effects of all 3 Filoviruses.
Ravi Durvasula - One of the best experts on this subject based on the ideXlab platform.
-
generation and selection of a panel of pan Filovirus single chain antibodies using cell free ribosome display
American Journal of Tropical Medicine and Hygiene, 2019Co-Authors: Chunyan Ye, Elizabeth C. Clarke, Steven B. Bradfute, Ravi Durvasula, Adinarayana KunamneniAbstract:Filoviruses, which include ebolaviruses and marburgvirus, can cause outbreaks of highly lethal hemorrhagic fever. This disease causes significant morbidity and mortality in humans and non-human primates, with human fatality rates reaching 90% during some outbreaks. Currently, there is lack of licensed vaccines or antivirals for these viruses. Since early symptoms of Filovirus infection mimic more common diseases, there is a strong unmet public health and biodefense need for broad-spectrum Filovirus rapid diagnostics. We have generated a panel of mouse single-chain Fv-antibodies (scFvs) to Filovirus glycoproteins (GPs) using cell-free ribosome display and determined their cross-reactivity profiles to all known Filovirus species. Two scFvs (4-2 and 22-1) were able to detect all known Ebolavirus and Marburgvirus species. This is the first report on ribosome display scFvs that can detect a broad set of Filovirus GPs, which demonstrates the potential for use in diagnostics.
-
generation and selection of a panel of pan Filovirus single chain antibodies using cell free ribosome display
American Journal of Tropical Medicine and Hygiene, 2019Co-Authors: Chunyan Ye, Elizabeth C. Clarke, Steven B. Bradfute, Ravi Durvasula, Adinarayana KunamneniAbstract:Filoviruses, which include ebolaviruses and marburgvirus, can cause outbreaks of highly lethal hemorrhagic fever. This disease causes significant morbidity and mortality in humans and non-human primates, with human fatality rates reaching 90% during some outbreaks. Currently, there is lack of licensed vaccines or antivirals for these viruses. Since early symptoms of Filovirus infection mimic more common diseases, there is a strong unmet public health and biodefense need for broad-spectrum Filovirus rapid diagnostics. We have generated a panel of mouse single-chain Fv-antibodies (scFvs) to Filovirus glycoproteins (GPs) using cell-free ribosome display and determined their cross-reactivity profiles to all known Filovirus species. Two scFvs (4-2 and 22-1) were able to detect all known Ebolavirus and Marburgvirus species. This is the first report on ribosome display scFvs that can detect a broad set of Filovirus GPs, which demonstrates the potential for use in diagnostics.
-
generation and selection of a panel of pan Filovirus single chain antibodies using cell free ribosome display
bioRxiv, 2018Co-Authors: Adinarayana Kunamneni, Chunyan Ye, Elizabeth C. Clarke, Steven B. Bradfute, Ravi DurvasulaAbstract:Filoviruses, which include ebolaviruses and marburgvirus, can cause outbreaks of highly lethal hemorrhagic fever. This disease causes significant morbidity and mortality in humans and non-human primates, with human fatality rates reaching 90% during some outbreaks. Currently, there are a lack of licensed vaccines or antivirals for these viruses. Since early symptoms of Filovirus infection mimic more common diseases, there is a strong unmet public health and biodefense need for broad-spectrum Filovirus rapid diagnostics. We have generated a panel of mouse single-chain Fv-antibodies (scFvs) to Filovirus glycoproteins (GP) using cell-free ribosome display and determined their cross-reactivity profiles to all known Filovirus species. Two scFvs were able to detect all known Ebolavirus and Marburgvirus species. This is the first report on ribosome display scFvs that can detect a broad set of Filovirus GPs, which demonstrates their potential use in the development of a new generation of rapid diagnostic immunoassays.
Adinarayana Kunamneni - One of the best experts on this subject based on the ideXlab platform.
-
generation and selection of a panel of pan Filovirus single chain antibodies using cell free ribosome display
American Journal of Tropical Medicine and Hygiene, 2019Co-Authors: Chunyan Ye, Elizabeth C. Clarke, Steven B. Bradfute, Ravi Durvasula, Adinarayana KunamneniAbstract:Filoviruses, which include ebolaviruses and marburgvirus, can cause outbreaks of highly lethal hemorrhagic fever. This disease causes significant morbidity and mortality in humans and non-human primates, with human fatality rates reaching 90% during some outbreaks. Currently, there is lack of licensed vaccines or antivirals for these viruses. Since early symptoms of Filovirus infection mimic more common diseases, there is a strong unmet public health and biodefense need for broad-spectrum Filovirus rapid diagnostics. We have generated a panel of mouse single-chain Fv-antibodies (scFvs) to Filovirus glycoproteins (GPs) using cell-free ribosome display and determined their cross-reactivity profiles to all known Filovirus species. Two scFvs (4-2 and 22-1) were able to detect all known Ebolavirus and Marburgvirus species. This is the first report on ribosome display scFvs that can detect a broad set of Filovirus GPs, which demonstrates the potential for use in diagnostics.
-
generation and selection of a panel of pan Filovirus single chain antibodies using cell free ribosome display
American Journal of Tropical Medicine and Hygiene, 2019Co-Authors: Chunyan Ye, Elizabeth C. Clarke, Steven B. Bradfute, Ravi Durvasula, Adinarayana KunamneniAbstract:Filoviruses, which include ebolaviruses and marburgvirus, can cause outbreaks of highly lethal hemorrhagic fever. This disease causes significant morbidity and mortality in humans and non-human primates, with human fatality rates reaching 90% during some outbreaks. Currently, there is lack of licensed vaccines or antivirals for these viruses. Since early symptoms of Filovirus infection mimic more common diseases, there is a strong unmet public health and biodefense need for broad-spectrum Filovirus rapid diagnostics. We have generated a panel of mouse single-chain Fv-antibodies (scFvs) to Filovirus glycoproteins (GPs) using cell-free ribosome display and determined their cross-reactivity profiles to all known Filovirus species. Two scFvs (4-2 and 22-1) were able to detect all known Ebolavirus and Marburgvirus species. This is the first report on ribosome display scFvs that can detect a broad set of Filovirus GPs, which demonstrates the potential for use in diagnostics.
-
generation and selection of a panel of pan Filovirus single chain antibodies using cell free ribosome display
bioRxiv, 2018Co-Authors: Adinarayana Kunamneni, Chunyan Ye, Elizabeth C. Clarke, Steven B. Bradfute, Ravi DurvasulaAbstract:Filoviruses, which include ebolaviruses and marburgvirus, can cause outbreaks of highly lethal hemorrhagic fever. This disease causes significant morbidity and mortality in humans and non-human primates, with human fatality rates reaching 90% during some outbreaks. Currently, there are a lack of licensed vaccines or antivirals for these viruses. Since early symptoms of Filovirus infection mimic more common diseases, there is a strong unmet public health and biodefense need for broad-spectrum Filovirus rapid diagnostics. We have generated a panel of mouse single-chain Fv-antibodies (scFvs) to Filovirus glycoproteins (GP) using cell-free ribosome display and determined their cross-reactivity profiles to all known Filovirus species. Two scFvs were able to detect all known Ebolavirus and Marburgvirus species. This is the first report on ribosome display scFvs that can detect a broad set of Filovirus GPs, which demonstrates their potential use in the development of a new generation of rapid diagnostic immunoassays.
Chad E. Mire - One of the best experts on this subject based on the ideXlab platform.
-
Durability of a Vesicular Stomatitis Virus-Based Marburg Virus Vaccine in Nonhuman Primates
2016Co-Authors: Chad E. Mire, Heinz Feldmann, Joan B. Geisbert, Krystle N. Agans, Krista M. Versteeg, Benjamin A Satterfield, Elizabeth A Fritz, Lisa E Hensley, Thomas W GeisbertAbstract:The Filoviruses, Marburg virus (MARV) and Ebola virus, causes severe hemorrhagic fever with high mortality in humans and nonhuman primates. A promising Filovirus vaccine under development is based on a recombinant vesicular stomatitis virus (rVSV) that expresses individual Filovirus glycoproteins (GPs) in place of the VSV glycoprotein (G). These vaccines have shown 100 % efficacy against Filovirus infection in nonhuman primates when challenge occurs 28–35 days after a single injection immunization. Here, we examined the ability of a rVSV MARV-GP vaccine to provide protection when challenge occurs more than a year after vaccination. Cynomolgus macaques were immunized with rVSV-MARV-GP and challenged with MARV approximately 14 months after vaccination. Immunization resulted in the vaccine cohort of six animals having anti-MARV GP IgG throughout the pre-challenge period. Following MARV challenge none of the vaccinated animals showed any signs of clinical disease or viremia and all were completely protected from MARV infection. Two unvaccinated control animals exhibited signs consistent with MARV infection and both succumbed. Importantly, these data are the first to show 100% protective efficacy against any high dose Filovirus challenge beyond 8 weeks after final vaccination. These finding
-
A Single-Vector, Single-Injection Trivalent Filovirus Vaccine: Proof of Concept Study in Outbred Guinea Pigs
The Journal of Infectious Diseases, 2015Co-Authors: Chad E. Mire, Thomas W Geisbert, Joan B. Geisbert, Krystle N. Agans, Krista M. Versteeg, Natalia Mamaeva, John H. ConnorAbstract:The Filoviruses, Marburg marburgvirus (MARV), Zaire ebolavirus (ZEBOV), and Sudan ebolavirus (SEBOV), cause severe and often fatal hemorrhagic fever in humans and nonhuman primates (NHPs). Monovalent recombinant vesicular stomatitis virus (rVSV)-based vaccine vectors, which encode a Filovirus glycoprotein (GP) in place of the VSV glycoprotein, have shown 100% efficacy against homologous Filovirus challenge in rodent and NHP studies. Here, we examined the utility of a single-vector, single-injection trivalent rVSV vector expressing MARV, ZEBOV, and SEBOV GPs to protect against MARV-, ZEBOV-, and SEBOV-induced disease in outbred Hartley guinea pigs where we observed protection from effects of all 3 Filoviruses.
-
deep sequencing identifies noncanonical editing of ebola and marburg virus rnas in infected cells
Mbio, 2014Co-Authors: Thomas W Geisbert, Chad E. Mire, Reed S Shabman, Omar J Jabado, Timothy B Stockwell, Megan R Edwards, Milind Mahajan, Christopher F. BaslerAbstract:ABSTRACT Deep sequencing of RNAs produced by Zaire ebolavirus (EBOV) or the Angola strain of Marburgvirus (MARV-Ang) identified novel viral and cellular mechanisms that diversify the coding and noncoding sequences of viral mRNAs and genomic RNAs. We identified previously undescribed sites within the EBOV and MARV-Ang mRNAs where apparent cotranscriptional editing has resulted in the addition of non-template-encoded residues within the EBOV glycoprotein (GP) mRNA, the MARV-Ang nucleoprotein (NP) mRNA, and the MARV-Ang polymerase (L) mRNA, such that novel viral translation products could be produced. Further, we found that the well-characterized EBOV GP mRNA editing site is modified at a high frequency during viral genome RNA replication. Additionally, editing hot spots representing sites of apparent adenosine deaminase activity were found in the MARV-Ang NP 3′-untranslated region. These studies identify novel Filovirus-host interactions and reveal production of a greater diversity of filoviral gene products than was previously appreciated. IMPORTANCE This study identifies novel mechanisms that alter the protein coding capacities of Ebola and Marburg virus mRNAs. Therefore, Filovirus gene expression is more complex and diverse than previously recognized. These observations suggest new directions in understanding the regulation of Filovirus gene expression.
-
durability of a vesicular stomatitis virus based marburg virus vaccine in nonhuman primates
PLOS ONE, 2014Co-Authors: Chad E. Mire, Krystle N. Agans, Benjamin A Satterfield, Krista Versteeg, Elizabeth A Fritz, Heinz FeldmannAbstract:The Filoviruses, Marburg virus (MARV) and Ebola virus, causes severe hemorrhagic fever with high mortality in humans and nonhuman primates. A promising Filovirus vaccine under development is based on a recombinant vesicular stomatitis virus (rVSV) that expresses individual Filovirus glycoproteins (GPs) in place of the VSV glycoprotein (G). These vaccines have shown 100% efficacy against Filovirus infection in nonhuman primates when challenge occurs 28–35 days after a single injection immunization. Here, we examined the ability of a rVSV MARV-GP vaccine to provide protection when challenge occurs more than a year after vaccination. Cynomolgus macaques were immunized with rVSV-MARV-GP and challenged with MARV approximately 14 months after vaccination. Immunization resulted in the vaccine cohort of six animals having anti-MARV GP IgG throughout the pre-challenge period. Following MARV challenge none of the vaccinated animals showed any signs of clinical disease or viremia and all were completely protected from MARV infection. Two unvaccinated control animals exhibited signs consistent with MARV infection and both succumbed. Importantly, these data are the first to show 100% protective efficacy against any high dose Filovirus challenge beyond 8 weeks after final vaccination. These findings demonstrate the durability of VSV-based Filovirus vaccines.
-
recombinant vesicular stomatitis virus vaccine vectors expressing Filovirus glycoproteins lack neurovirulence in nonhuman primates
PLOS Neglected Tropical Diseases, 2012Co-Authors: Chad E. Mire, Heinz Feldmann, Keith G. Mansfield, Joan B. Geisbert, Andrew D Miller, Angela Carville, Susan V Westmoreland, Lisa E Hensley, Thomas W GeisbertAbstract:The Filoviruses, Marburg virus and Ebola virus, cause severe hemorrhagic fever with high mortality in humans and nonhuman primates. Among the most promising Filovirus vaccines under development is a system based on recombinant vesicular stomatitis virus (rVSV) that expresses an individual Filovirus glycoprotein (GP) in place of the VSV glycoprotein (G). The main concern with all replication-competent vaccines, including the rVSV Filovirus GP vectors, is their safety. To address this concern, we performed a neurovirulence study using 21 cynomolgus macaques where the vaccines were administered intrathalamically. Seven animals received a rVSV vector expressing the Zaire ebolavirus (ZEBOV) GP; seven animals received a rVSV vector expressing the Lake Victoria marburgvirus (MARV) GP; three animals received rVSV-wild type (wt) vector, and four animals received vehicle control. Two of three animals given rVSV-wt showed severe neurological symptoms whereas animals receiving vehicle control, rVSV-ZEBOV-GP, or rVSV-MARV-GP did not develop these symptoms. Histological analysis revealed major lesions in neural tissues of all three rVSV-wt animals; however, no significant lesions were observed in any animals from the Filovirus vaccine or vehicle control groups. These data strongly suggest that rVSV Filovirus GP vaccine vectors lack the neurovirulence properties associated with the rVSV-wt parent vector and support their further development as a vaccine platform for human use.