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in vitro and in vivo characterization of recombinant ebola viruses expressing enhanced green fluorescent protein.to facilitate an understanding of the molecular aspects of the pathogenesis of zaire ebolavirus (zebov) infection, we generated 2 different recombinant viruses expressing enhanced green fluorescent protein (egfp) from additional transcription units inserted at different positions in the virus genome. these viruses showed in vitro phenotypes similar to that of wild-type zebov (wt-zebov) and were stable over multiple passages. infection with one of the viruses expressing egfp produced only mild di ...200717940966
recombinant human activated protein c for the postexposure treatment of ebola hemorrhagic fever.infection of primates with zaire ebolavirus (zebov) leads to hypotension, coagulation disorders, and an impaired immune response and, in many ways, resembles severe sepsis. rapid decreases in plasma levels of protein c are a prominent feature of severe sepsis and zebov hemorrhagic fever (zhf). currently, recombinant human activated protein c (rhapc [xigris; eli lilly]) is licensed for treating human patients with severe sepsis who are at high risk of death. the aim of this study was to test the ...200717940975
recombinant vesicular stomatitis virus vector mediates postexposure protection against sudan ebola hemorrhagic fever in nonhuman primates.recombinant vesicular stomatitis virus (vsv) vectors expressing homologous filoviral glycoproteins can completely protect rhesus monkeys against marburg virus when administered after exposure and can partially protect macaques after challenge with zaire ebolavirus. here, we administered a vsv vector expressing the sudan ebolavirus (sebov) glycoprotein to four rhesus macaques shortly after exposure to sebov. all four animals survived sebov challenge, while a control animal that received a nonspec ...200818385248
vesicular stomatitis virus-based ebola vaccine is well-tolerated and protects immunocompromised nonhuman primates.ebola virus (ebov) is a significant human pathogen that presents a public health concern as an emerging/re-emerging virus and as a potential biological weapon. substantial progress has been made over the last decade in developing candidate preventive vaccines that can protect nonhuman primates against ebov. among these prospects, a vaccine based on recombinant vesicular stomatitis virus (vsv) is particularly robust, as it can also confer protection when administered as a postexposure treatment. ...200819043556
aerosol exposure to zaire ebolavirus in three nonhuman primate species: differences in disease course and clinical pathology.there is little known concerning the disease caused by zaire ebolavirus (zebov) when inhaled, the likely route of exposure in a biological attack. cynomolgus macaques, rhesus macaques, and african green monkeys were exposed to aerosolized zebov to determine which species might be the most relevant model of the human disease. a petechial rash was noted on cynomolgus and rhesus macaques after fever onset but not on african green monkeys. fever duration was shortest in rhesus macaques (62.7±16.3 h) ...201121651988
real-time monitoring of cardiovascular function in rhesus macaques infected with zaire ebolavirus.nine rhesus macaques were implanted with multisensor telemetry devices and internal jugular vein catheters before being infected with zaire ebolavirus. all animals developed viremia, fever, a hemorrhagic rash, and typical changes of ebola hemorrhagic fever in clinical laboratory tests. three macaques unexpectedly survived this usually lethal disease, making it possible to compare physiological parameters in lethally challenged animals and survivors. after the onset of fever, lethal illness was c ...201121987736
Host response dynamics following lethal infection of rhesus macaques with Zaire ebolavirus.To gain further insight into the interdependent pathogenic processes in Ebola hemorrhagic fever (EHF), we have examined the dynamics of host responses in individual rhesus macaques infected with Zaire ebolavirus over the entire disease course. Examination of coagulation parameters revealed that decreased coagulation inhibitor activity triggered severe coagulopathy as indicated by prolonged coagulation times and decreased fibrinogen levels. This has been proposed as one of the significant mechani ...201121987781
pathology of experimental aerosol zaire ebolavirus infection in rhesus macaques.there is limited knowledge of the pathogenesis of human ebolavirus infections and no reported human cases acquired by the aerosol route. there is a threat of ebolavirus as an aerosolized biological weapon, and this study evaluated the pathogenesis of aerosol infection in 18 rhesus macaques. important and unique findings include early infection of the respiratory lymphoid tissues, early fibrin deposition in the splenic white pulp, and perivasculitis and vasculitis in superficial dermal blood vess ...201223262834
passive immunotherapy: assessment of convalescent serum against ebola virus makona infection in nonhuman primates.convalescent serum and blood were used to treat patients during outbreaks of zaire ebolavirus (zebov) infection in 1976 and 1995, with inconclusive results. during the recent 2013-2016 west african epidemic, serum/plasma from survivors of zebov infection was used to treat patients in the affected countries and several repatriated patients. the effectiveness of this strategy remains unknown.201627571900
protective efficacy of neutralizing monoclonal antibodies in a nonhuman primate model of ebola hemorrhagic fever.ebola virus (ebov) is the causative agent of severe hemorrhagic fever in primates, with human case fatality rates up to 90%. today, there is neither a licensed vaccine nor a treatment available for ebola hemorrhagic fever (ehf). single monoclonal antibodies (mabs) specific for zaire ebolavirus (zebov) have been successfully used in passive immunization experiments in rodent models, but have failed to protect nonhuman primates from lethal disease. in this study, we used two clones of human-mouse ...201222558378
determination of specific antibody responses to the six species of ebola and marburg viruses by multiplexed protein microarrays.infectious hemorrhagic fevers caused by the marburg and ebola filoviruses result in human mortality rates of up to 90%, and there are no effective vaccines or therapeutics available for clinical use. the highly infectious and lethal nature of these viruses highlights the need for reliable and sensitive diagnostic methods. we assembled a protein microarray displaying nucleoprotein (np), virion protein 40 (vp40), and glycoprotein (gp) antigens from isolates representing the six species of filoviru ...201425230936
rescue of non-human primates from advanced sudan ebolavirus infection with lipid encapsulated sirna.although significant progress has been made in developing therapeutics against zaire ebolavirus, these therapies do not protect against other ebola species such as sudan ebolavirus (sudv). here, we describe an rna interference therapeutic comprising sirna targeting the sudv vp35 gene encapsulated in lipid nanoparticle (lnp) technology with increased potency beyond formulations used in tkm-ebola clinical trials. twenty-five rhesus monkeys were challenged with a lethal dose of sudv. twenty animals ...201627670117
quantification of viral and host biomarkers in the liver of rhesus macaques: a longitudinal study of zaire ebolavirus strain kikwit (ebov/kik).zaire ebolavirus (ebov) causes ebola virus disease (evd), which carries a fatality rate between 25% and 90% in humans. liver pathology is a hallmark of terminal evd; however, little is known about temporal disease progression. we used multiplexed fluorescent immunohistochemistry and in situ hybridization in combination with whole slide imaging and image analysis (ia) to quantitatively characterize temporospatial signatures of viral and host factors as related to ebov pathogenesis. eighteen rhesu ...202032275904
safety, tolerability, pharmacokinetics, and immunogenicity of the therapeutic monoclonal antibody mab114 targeting ebola virus glycoprotein (vrc 608): an open-label phase 1 study.mab114 is a single monoclonal antibody that targets the receptor-binding domain of ebola virus glycoprotein, which prevents mortality in rhesus macaques treated after lethal challenge with zaire ebolavirus. here we present expedited data from vrc 608, a phase 1 study to evaluate mab114 safety, tolerability, pharmacokinetics, and immunogenicity.201930686586
human polyclonal antibodies produced by transchromosomal cattle provide partial protection against lethal zaire ebolavirus challenge in rhesus macaques.antibody therapy has been used to treat a variety of diseases and the success of zmapp and other monoclonal antibody-based therapies during the 2014-2016 west african ebola outbreak has shown this countermeasure can be a successful therapy for ebola hemorrhagic fever. this study utilized transchromosomal bovines (tcb) vaccinated with a dna plasmid encoding ebola virus glycoprotein sequence to produce human polyclonal antibodies directed against ebola virus glycoprotein. when administered 1 day p ...201830053153
an adenovirus serotype 2-vectored ebolavirus vaccine generates robust antibody and cell-mediated immune responses in mice and rhesus macaques.ebolavirus vaccines based on several adenoviral vectors have been investigated in preclinical studies and clinical trials. the use of adenovirus serotype 2 as a vector for ebolavirus vaccine has not been reported. herein, we generated rad2-zgp, a recombinant replication-incompetent adenovirus serotype 2 expressing codon-optimized zaire ebolavirus glycoprotein, and evaluated its immunogenicity in mice and rhesus macaques. rad2-zgp induced significant antibody and cell-mediated immune responses at ...201829872043
a novel ebola virus antibody-dependent cell-mediated cytotoxicity (ebola adcc) assay.ebolaviruses are highly virulent pathogens that cause ebola viral disease (evd). data from non-human primate (nhp) models and from human survivors of evd suggest that anti-ebola antibodies play an integral role in protection. antibody-dependent cell-mediated cytotoxicity (adcc) is a potential mechanism through which anti-ebola antibodies may mediate protection. we developed a robust ebola-specific adcc assay for use in ongoing trials of ebola vaccines. stable cell lines for inducible zaire ebola ...201829894746
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