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preliminary report: isolation of ebola virus from monkeys imported to usa.an epizootic caused by an ebola-related filovirus and by simian haemorrhagic fever virus began among cynomolgus monkeys in a us quarantine facility after introduction of monkeys from the philippines. this incident, the first in which a filovirus has been isolated from non-human primates without deliberate infection, raises the possibility that cynomolgus monkeys could be a reservoir of ebola virus infection.19901968529
immunoglobulin g enzyme-linked immunosorbent assay using truncated nucleoproteins of reston ebola virus.we developed an immunoglobulin g (igg) enzyme-linked immunosorbent assay (elisa), using partial recombinant nucleoproteins (rnp) of reston ebola virus (ebo-r) and zaire ebola virus (ebo-z). we examined the reaction of 10 sera from cynomolgus macaques naturally infected with ebo-r to each of the partial rnp in the igg elisa. all the sera reacted to the c-terminal halves of the rnp of both ebo-r and ebo-z. most of the sera reacted to the rdeltac (amino acid (aa) 360-739), and rdelta6 (aa 451-551) ...200312825739
pathogenesis of ebola hemorrhagic fever in primate models: evidence that hemorrhage is not a direct effect of virus-induced cytolysis of endothelial cells.ebola virus (ebov) infection causes a severe and often fatal hemorrhagic disease in humans and nonhuman primates. whether infection of endothelial cells is central to the pathogenesis of ebov hemorrhagic fever (hf) remains unknown. to clarify the role of endothelial cells in ebov hf, we examined tissues of 21 ebov-infected cynomolgus monkeys throughout time, and also evaluated ebov infection of primary human umbilical vein endothelial cells and primary human lung-derived microvascular endothelia ...200314633609
pathogenesis of ebola hemorrhagic fever in cynomolgus macaques: evidence that dendritic cells are early and sustained targets of infection.ebola virus (ebov) infection causes a severe and fatal hemorrhagic disease that in many ways appears to be similar in humans and nonhuman primates; however, little is known about the development of ebov hemorrhagic fever. in the present study, 21 cynomolgus monkeys were experimentally infected with ebov and examined sequentially over a 6-day period to investigate the pathological events of ebov infection that lead to death. importantly, dendritic cells in lymphoid tissues were identified as earl ...200314633608
accelerated vaccination for ebola virus haemorrhagic fever in non-human primates.containment of highly lethal ebola virus outbreaks poses a serious public health challenge. although an experimental vaccine has successfully protected non-human primates against disease, more than six months was required to complete the immunizations, making it impractical to limit an acute epidemic. here, we report the development of accelerated vaccination against ebola virus in non-human primates. the antibody response to immunization with an adenoviral (adv) vector encoding the ebola glycop ...200312904795
antigen capture enzyme-linked immunosorbent assay for specific detection of reston ebola virus nucleoprotein.antigen capture enzyme-linked immunosorbent assay (elisa) is one of the most useful methods to detect ebola virus rapidly. we previously developed an antigen capture elisa using a monoclonal antibody (mab), 3-3d, which reacted not only to the nucleoprotein (np) of zaire ebola virus (ebo-z) but also to the nps of sudan (ebo-s) and reston ebola (ebo-r) viruses. in this study, we developed antigen capture elisas using two novel mabs, res2-6c8 and res2-1d8, specific to the np of ebo-r. res2-6c8 and ...200312853385
histopathology of natural ebola virus subtype reston infection in cynomolgus macaques during the philippine outbreak in 1996.we investigated the livers, spleens, kidneys and lungs collected from 24 cynomolgus macaques (macaca fascicularis) naturally infected with ebola virus subtype reston (ebo-r) during the philippine outbreak in 1996, in order to reveal the histopathologic findings. these macaques showed necrotic hepatocytes with inclusions, slight to massive fibrin deposition in splenic cords, depletion of lymphoid cells in the white pulp of the spleen, and fibrin thrombi in some organs. immunohistochemical analysi ...200212451705
induction of immune responses in mice and monkeys to ebola virus after immunization with liposome-encapsulated irradiated ebola virus: protection in mice requires cd4(+) t cells.ebola zaire virus (ebo-z) causes severe hemorrhagic fever in humans, with a high mortality rate. it is thought that a vaccine against ebo-z may have to induce both humoral and cell-mediated immune responses to successfully confer protection. because it is known that liposome-encapsulated antigens induce both antibody and cellular responses, we evaluated the protective efficacy of liposome-encapsulated irradiated ebo-z [l(ev)], which contains all of the native ebo-z proteins. in a series of exper ...200212186901
infections by viruses of the families bunyaviridae and filoviridae.rift valley fever is the most important bunyaviral disease of animals in africa. the virus, transmitted by mosquitoes, causes abortions and mortality in young animals in addition to haemorrhagic fevers in humans. although vaccines against this virus are available, the uses of these vaccines are limited because of deleterious effects or incomplete protection, justifying further studies to improve the existing vaccines or to develop others. nairobi sheep disease is transmitted by ticks. the diseas ...200011189728
threat to humans from virus infections of non-human primates.several hundred distinct non human primate species are recognised, and they are likely to harbour a similar range of viruses to humans. simians such as cynomolgus and rhesus macaques, african green monkeys, and marmosets are widely used for biomedical research, but despite this extensive close contact very few simian viruses have been shown to pose a threat of infection or illness to humans. herpesvirus simiae is the best recognised zoonotic hazard of simians. it is an alphaherpes virus of asiat ...199710398488
us policy for disease control among imported nonhuman primates.in 1990, in response to the occurrence of ebola virus (subsequently identified as subtype reston) infection among cynomolgus monkeys imported from the philippines, the united states implemented strict disease control measures for handling nonhuman primates during transit and quarantine and initiated importer facility compliance inspections. disease control measures emphasized protection of workers from exposure, use of containment facilities and procedures, measures to prevent spread of infectio ...19999988196
evaluation of immune globulin and recombinant interferon-alpha2b for treatment of experimental ebola virus infections.a passive immunization strategy for treating ebola virus infections was evaluated using balb/ c mice, strain 13 guinea pigs, and cynomolgus monkeys. guinea pigs were completely protected by injection of hyperimmune equine igg when treatment was initiated early but not after viremia had developed. in contrast, mice were incompletely protected even when treatment was initiated on day 0, the day of virus inoculation. in monkeys treated with one dose of igg on day 0, onset of illness and viremia was ...19999988188
detection and molecular characterization of ebola viruses causing disease in human and nonhuman primates.ebola (ebo) viruses were detected in specimens obtained during the hemorrhagic fever outbreak among humans in kikwit, democratic republic of the congo (drc), in 1995 (subtype zaire) and during an outbreak of disease in cynomolgus macaques in alice, texas, and the philippines in 1996 (subtype reston). reverse transcriptase-polymerase chain reaction assays were developed and proven effective for detecting viral rna in body fluids and tissues of infected individuals. little change was seen in the n ...19999988180
ebola (subtype reston) virus among quarantined nonhuman primates recently imported from the philippines to the united states.in april 1996, laboratory testing of imported nonhuman primates (as mandated by quarantine regulations) identified 2 cynomolgus macaques (macaca fascicularis) infected with ebola (subtype reston) virus in a us-registered quarantine facility. the animals were part of a shipment of 100 nonhuman primates recently imported from the philippines. two additional infected animals, who were thought to be in the incubation phase, were identified among the remaining 48 animals in the affected quarantine ro ...19999988173
[microscopic study of species specific features of hemostatic impairment in ebola virus infected monkeys].pathological changes were studied in the blood vessels of baboons, green, rhesus, and cynomolgus monkeys at the end-stage ebola (zaire) infection. marked microvascular lesions (capillary stasis, blood engorgement, thrombosis with blood cells, neutrophil accumulation, endothelial edema) were found in all the monkeys. these changes clearly indicate impaired organ blood supply. multiple hemorrhages were formed by diapedesis without vascular wall destruction. fibrin deposition and thrombi were featu ...19989608279
passive immunization of ebola virus-infected cynomolgus monkeys with immunoglobulin from hyperimmune horses.a commercially available immunoglobulin g (igg) from horses, hyperimmunized to ebola virus, was evaluated for its ability to protect cynomolgus monkeys against disease following i.m. inoculation with 1 000 pfu ebola virus (zaire '95 strain). six monkeys were treated immediately after infection by i.m. infection of 6.0 ml igg; these animals developed passive elisa titers of 1:160 to 1:320 to ebola, two days afer inoculation. however, the beneficial effects of igg treatment were limited to a delay ...19968800795
experimental infection of cynomolgus macaques with ebola-reston filoviruses from the 1989-1990 u.s. epizootic.this study describes the pathogenesis of the ebola-reston (ebo-r) subtype of ebola virus for experimentally infected cynomolgus monkeys. the disease course of ebo-r in macaques was very similar to human disease and to experimental diseases in macaques following ebo-zaire and ebo-sudan infections. cynomolgus monkeys infected with ebo-r in this experiment developed anorexia, occasional nasal discharge, and splenomegaly, petechial facial hemorrhages and severe subcutaneous hemorrhages in venipunctu ...19968800793
update: nonhuman primate importation.beginning in november 1989, a number of cynomolgus monkeys (macaca fascicularis) imported into the united states were found to have been infected with a previously unrecognized ebola-like filovirus. this report summarizes findings of surveillance and serologic testing of nonhuman primates imported under special permits from june 1990 through september 1991.19911656185
outbreak of fatal illness among captive macaques in the philippines caused by an ebola-related filovirus.following the detection of an ebola-like virus in cynomolgus macaques recently imported into the united states from the philippines, studies were initiated to document transmission at export facilities located in the latter country. at one export facility, 52.8% of 161 monkeys that died over a 2.5-month period were shown to be infected with this virus using an enzyme-linked immunosorbent assay to detect antigen in liver homogenates. a case fatality rate of 82.4% was documented for the infected m ...19921621890
association of ebola-related reston virus particles and antigen with tissue lesions of monkeys imported to the united states.during 1989-1990, an epizootic involving a filovirus closely related to ebola virus occurred in a reston, virginia, primate-holding facility. tissues were collected from cynomolgus monkeys and examined by electron microscopy and immunohistochemistry for ebola-related viral antigen. viral replication was extensive in fixed tissue macrophages, interstitial fibroblasts of many organs, circulating macrophages and monocytes, and was observed less frequently in vascular endothelial cells, hepatocytes, ...19921597531
enzyme immunosorbent assay for ebola virus antigens in tissues of infected primates.a sandwich enzyme immunosorbent assay (eia) using a mixture of mouse monoclonal antibodies for antigen capture and polyclonal hyperimmune rabbit anti-ebola virus serum for antigen detection was developed and evaluated on the tissues of monkeys naturally or experimentally infected with strains of ebola viruses. when compared with virus isolation, the antigen detection eia was both sensitive and specific: 44 of 45 (97.7%) liver homogenates and 38 of 41 (92.7%) spleen homogenates that were culture ...19921572982
filovirus contamination of cell cultures.the filoviruses marburg and ebola comprise a newly recognized family of viruses. the first filovirus to be isolated was marburg virus in 1967. this virus was imported in shipments of african green monkeys from uganda and infected several cell-culture technicians, with serious illness resulting. the rarity of marburg and ebola virus transmission, decreasing use of imported african monkeys, and quarantine efforts have presumably been responsible for the lack of additional episodes until 1989, when ...19921478345
combined simian hemorrhagic fever and ebola virus infection in cynomolgus monkeys.simian hemorrhagic fever (shf) virus and a new strain of ebola virus were isolated concurrently in recently imported cynomolgus monkeys (macaca fascicularis) being maintained in a quarantine facility. ebola virus had never been isolated in the u.s. previously and was presumed to be highly pathogenic for humans. a chronology of events including measures taken to address the public health concerns is presented. the clinicopathologic features of the disease were abrupt anorexia, splenomegaly, marke ...19921318446
analysis of the expressed heavy chain variable-region genes of macaca fascicularis and isolation of monoclonal antibodies specific for the ebola virus' soluble glycoprotein.the cynomolgus macaque, macaca fascicularis, is frequently used in immunological and other biomedical research as a model for man; understanding it's antibody repertoire is, therefore, of fundamental interest. the expressed variable-region gene repertoire of a single m. fascicularis, which was immune to the ebola virus, was studied. using 5' rapid amplification of cdna ends with immunoglobulin (ig)g-specific primers, we obtained 30 clones encoding full-length variable, diversity, and joining dom ...200516215733
vesicular stomatitis virus-based vaccines protect nonhuman primates against aerosol challenge with ebola and marburg viruses.considerable progress has been made over the last decade in developing candidate preventive vaccines that can protect nonhuman primates against ebola and marburg viruses. a vaccine based on recombinant vesicular stomatitis virus (vsv) seems to be particularly robust as it can also confer protection when administered as a postexposure treatment. while filoviruses are not thought to be transmitted by aerosol in nature the inhalation route is among the most likely portals of entry in the setting of ...200818930776
disease modeling for ebola and marburg viruses.the filoviruses ebola and marburg are zoonotic agents that are classified as both biosafety level 4 and category a list pathogens. these viruses are pathogenic in humans and cause isolated infections or epidemics of viral hemorrhagic fever, mainly in central africa. their natural reservoir has not been definitely identified, but certain species of african bat have been associated with ebola and marburg infections. currently, there are no licensed options available for either treatment or prophyl ...200919132113
single-injection vaccine protects nonhuman primates against infection with marburg virus and three species of ebola virus.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 (vsv) that expresses a single filovirus glycoprotein (gp) in place of the vsv glycoprotein (g). here, we performed a proof-of-concept study in order to determine the potential of having one single-injection vaccine capable of protecting nonhuman pr ...200919386702
multiplex analysis of cytokines in the blood of cynomolgus macaques naturally infected with ebola virus (reston serotype).ebola virus (ebo) causes the most severe form of viral hemorrhagic fever in humans and nonhuman primates with up to 90% of infections culminating in death. the requirement of maximum containment laboratories for ebola virus research has limited opportunities to study the pathogenesis of ebo infections. while tissue damage does occur, often it would appear not to be sufficient to explain death, indicating that soluble mediators play an important role in disease progression. in previous studies, f ...200111596094
development of a preventive vaccine for ebola virus infection in primates.outbreaks of haemorrhagic fever caused by the ebola virus are associated with high mortality rates that are a distinguishing feature of this human pathogen. the highest lethality is associated with the zaire subtype, one of four strains identified to date. its rapid progression allows little opportunity to develop natural immunity, and there is currently no effective anti-viral therapy. therefore, vaccination offers a promising intervention to prevent infection and limit spread. here we describe ...200011117750
pathogenesis of marburg hemorrhagic fever in cynomolgus macaques.marburg virus (marv) infection causes a severe and often fatal hemorrhagic disease in primates; however, little is known about the development of marv hemorrhagic fever. in this study we evaluated the progression of marv infection in nonhuman primates.201121987738
durability of a vesicular stomatitis virus-based marburg virus vaccine in nonhuman primates.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 immunizatio ...201424759889
pathogenic potential of filoviruses: role of geographic origin of primate host and virus strain.african filoviruses have caused outbreaks of fulminating hemorrhagic fever among humans. in 1989, related filoviruses were isolated from cynomolgus monkeys imported into the united states from the philippines. the pathogenic potential of these new filoviruses was compared in 16 asian monkeys (macaca fascicularis-cynomolgus) and 16 african monkeys (cercopithecus aethiops-african green) using african filoviruses from zaire (ebola virus) and sudan or asian filoviruses (reston and pennsylvania). afr ...19921527410
ebola virus-like particle-based vaccine protects nonhuman primates against lethal ebola virus challenge.currently, there are no licensed vaccines or therapeutics for the prevention or treatment of infection by the highly lethal filoviruses, ebola virus (ebov) and marburg virus (marv), in humans. we previously had demonstrated the protective efficacy of virus-like particle (vlp)-based vaccines against ebov and marv infection in rodents.200717940980
advanced antisense therapies for postexposure protection against lethal filovirus infections.currently, no vaccines or therapeutics are licensed to counter ebola or marburg viruses, highly pathogenic filoviruses that are causative agents of viral hemorrhagic fever. here we show that administration of positively charged phosphorodiamidate morpholino oligomers (pmoplus), delivered by various dosing strategies initiated 30-60 min after infection, protects>60% of rhesus monkeys against lethal zaire ebola virus (zebov) and 100% of cynomolgus monkeys against lake victoria marburg virus (marv) ...201020729866
adenovirus-vectored vaccine provides postexposure protection to ebola virus-infected nonhuman primates.ebola virus (ebov) causes lethal disease in up to 90% of ebov-infected humans. among vaccines, only the vesicular stomatitis virus platform has been successful in providing postexposure protection in nonhuman primates. here, we show that an adjuvanted human adenovirus serotype 5 (ad5)-vectored vaccine (ad5-zaire ebov glycoprotein) protected 67% (6 of 9) and 25% (1 of 4) of cynomolgus macaques when administered 30 minutes and 24 hours following ebov challenge, respectively. the treatment also pro ...201525957963
codon-optimized filovirus dna vaccines delivered by intramuscular electroporation protect cynomolgus macaques from lethal ebola and marburg virus challenges.cynomolgus macaques were vaccinated by intramuscular electroporation with dna plasmids expressing codon-optimized glycoprotein (gp) genes of ebola virus (ebov) or marburg virus (marv) or a combination of codon-optimized gp dna vaccines for ebov, marv, sudan virus and ravn virus. when measured by elisa, the individual vaccines elicited slightly higher igg responses to ebov or marv than did the combination vaccines. no significant differences in immune responses of macaques given the individual or ...025996997
particle-to-pfu ratio of ebola virus influences disease course and survival in cynomolgus macaques.this study addresses the role of ebola virus (ebov) specific infectivity in virulence. filoviruses are highly lethal, enveloped, single-stranded negative-sense rna viruses that can cause hemorrhagic fever. no approved vaccines or therapies exist for filovirus infections, and infectious virus must be handled in maximum containment. efficacy testing of countermeasures, in addition to investigations of pathogenicity and immune response, often requires a well-characterized animal model. for ebov, an ...201525903348
postmortem stability of ebola virus.the ongoing ebola virus outbreak in west africa has highlighted questions regarding stability of the virus and detection of rna from corpses. we used ebola virus-infected macaques to model humans who died of ebola virus disease. viable virus was isolated <7 days posteuthanasia; viral rna was detectable for 10 weeks.201525897646
single immunization with a monovalent vesicular stomatitis virus-based vaccine protects nonhuman primates against heterologous challenge with bundibugyo ebolavirus.the recombinant vesicular stomatitis virus (rvsv) vector-based monovalent vaccine platform expressing a filovirus glycoprotein has been demonstrated to provide protection from lethal challenge with ebola (ebov) and marburg (marv) viruses both prophylactically and after exposure. this platform provides protection between heterologous strains within a species; however, protection from lethal challenge between species has been largely unsuccessful. to determine whether the rvsv-ebov vaccines have t ...201121987745
next-generation sequencing reveals a controlled immune response to zaire ebola virus challenge in cynomolgus macaques immunized with vesicular stomatitis virus expressing zaire ebola virus glycoprotein (vsvδg/ebovgp).vesicular stomatitis virus expressing zaire ebola virus (ebov) glycoprotein (vsvδg/ebovgp) could be used as a vaccine to meet the 2014 ebola virus outbreak. to characterize the host response to this vaccine, we used mrna sequencing to analyze peripheral blood mononuclear cells (pbmcs) from cynomolgus macaques after vsvδg/ebovgp immunization and subsequent ebov challenge. we found a controlled transcriptional response that transitioned to immune regulation as the ebov was cleared. this observatio ...201525589554
generation and characterization of protective antibodies to marburg virus.marburg virus (marv) and ebola virus (ebov) have been a source of epidemics and outbreaks for several decades. we present here the generation and characterization of the first protective antibodies specific for wild-type marv. non-human primates (nhp), cynomolgus macaques, were immunized with viral-replicon particles expressing the glycoproteins (gp) of marv (ci67 isolate). an antibody fragment (single-chain variable fragment, scfv) phage display library was built after four immunogen injections ...201728287337
assessment and improvement of indian-origin rhesus macaque and mauritian-origin cynomolgus macaque genome annotations using deep transcriptome sequencing data.the genome annotations of rhesus (macaca mulatta) and cynomolgus (macaca fascicularis) macaques, two of the most common non-human primate animal models, are limited.201424810475
an inactivated rabies virus-based ebola vaccine, filorab1, adjuvanted with glucopyranosyl lipid a in stable emulsion confers complete protection in nonhuman primate challenge models.the 2013-2016 west african ebola virus (ebov) disease outbreak was the largest filovirus outbreak to date. over 28 000 suspected, probable, or confirmed cases have been reported, with a 53% case-fatality rate. the magnitude and international impact of this ebov outbreak has highlighted the urgent need for a safe and efficient ebov vaccine. to this end, we demonstrate the immunogenicity and protective efficacy of filorab1, a recombinant, bivalent, inactivated rabies virus-based ebov vaccine, in r ...201627456709
protection against filovirus diseases by a novel broad-spectrum nucleoside analogue bcx4430.filoviruses are emerging pathogens and causative agents of viral haemorrhagic fever. case fatality rates of filovirus disease outbreaks are among the highest reported for any human pathogen, exceeding 90% (ref. 1). licensed therapeutic or vaccine products are not available to treat filovirus diseases. candidate therapeutics previously shown to be efficacious in non-human primate disease models are based on virus-specific designs and have limited broad-spectrum antiviral potential. here we show t ...201424590073
ebola virus infections in nonhuman primates are temporally influenced by glycoprotein poly-u editing site populations in the exposure material.recent experimentation with the variants of the ebola virus that differ in the glycoprotein's poly-uridine site, which dictates the form of glycoprotein produced through a transcriptional stutter, has resulted in questions regarding the pathogenicity and lethality of the stocks used to develop products currently undergoing human clinical trials to combat the disease. in order to address these concerns and prevent the delay of these critical research programs, we designed an experiment that permi ...201526703716
macaque monoclonal antibodies targeting novel conserved epitopes within filovirus glycoprotein.filoviruses cause highly lethal viral hemorrhagic fever in humans and nonhuman primates. current immunotherapeutic options for filoviruses are mostly specific to ebola virus (ebov), although other members of filoviridae such as sudan virus (sudv), bundibugyo virus (bdbv), and marburg virus (marv) have also caused sizeable human outbreaks. here we report a set of pan-ebolavirus and pan-filovirus monoclonal antibodies (mabs) derived from cynomolgus macaques immunized repeatedly with a mixture of e ...201526468532
delayed disease progression in cynomolgus macaques infected with ebola virus makona strain.in late 2013, the largest documented outbreak of ebola hemorrhagic fever started in guinea and has since spread to neighboring countries, resulting in almost 27,000 cases and >11,000 deaths in humans. in march 2014, ebola virus (ebov) was identified as the causative agent. this study compares the pathogenesis of a new ebov strain, makona, which was isolated in guinea in 2014 with the prototype strain from the 1976 ebov outbreak in the former zaire. both strains cause lethal disease in cynomolgus ...201526402165
mucosal immunization of cynomolgus macaques with the vsvdeltag/zebovgp vaccine stimulates strong ebola gp-specific immune responses.zaire ebolavirus (zebov) produces a lethal viral hemorrhagic fever in humans and non-human primates.200919440245
recombinant vesicular stomatitis virus vaccine vectors expressing filovirus glycoproteins lack neurovirulence in nonhuman primates.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 ...201222448291
use of immunoelectron microscopy to show ebola virus during the 1989 united states epizootic.a filovirus, serologically related to ebola virus, was detected by "post-embedment" immunoelectron microscopical examination of ma-104 cells. these had been infected by inoculation with serum samples obtained during the 1989 epizootic in cynomolgus monkeys (macaca fascicularis), imported from the philippines and maintained at reston, virginia, usa, a primate holding facility. the immunoelectron microscopy method, when used in conjunction with standard transmission electron microscopy (tem) of in ...19902229429
ebola virus infection in imported primates--united states.in late november 1989, ebola virus was isolated from cynomolgus monkeys (macaca fascicularis) imported into the united states from the philippines via amsterdam and new york. during quarantine in a primate facility in virginia, numerous macaques died, some with findings consistent with simian hemorrhagic fever (shf). the us army medical research institute of infectious diseases tested 10 animals and, from 3, isolated shf from tissues and serum; however, 5 other animals of the 10 tested were posi ...19902302743
demonstration of cross-protective vaccine immunity against an emerging pathogenic ebolavirus species.a major challenge in developing vaccines for emerging pathogens is their continued evolution and ability to escape human immunity. therefore, an important goal of vaccine research is to advance vaccine candidates with sufficient breadth to respond to new outbreaks of previously undetected viruses. ebolavirus (ebov) vaccines have demonstrated protection against ebov infection in nonhuman primates (nhp) and show promise in human clinical trials but immune protection occurs only with vaccines whose ...201020502688
depletion of peripheral blood t lymphocytes and nk cells during the course of ebola hemorrhagic fever in cynomolgus macaques.during the course of an experimentally induced ebola virus (ebova) infection of cynomolgus macaques, peripheral blood mononuclear cells were isolated and characterized by multi-color flow cytometry. both cd4+ and cd8+ lymphocyte counts decreased 60-70% during the first 4 days after infection. among cd8+ lymphocytes, this decline was greatest among the cd8(lo) population, which was composed mostly of cd3- cd16+ nk cells. in contrast, the number of cd20+ b lymphocytes in the blood did not signific ...200415357905
vesicular stomatitis virus-based vaccines protect nonhuman primates against bundibugyo ebolavirus.ebola virus (ebov) causes severe and often fatal hemorrhagic fever in humans and nonhuman primates (nhps). currently, there are no licensed vaccines or therapeutics for human use. recombinant vesicular stomatitis virus (rvsv)-based vaccine vectors, which encode an ebov glycoprotein in place of the vsv glycoprotein, have shown 100% efficacy against homologous sudan ebolavirus (sebov) or zaire ebolavirus (zebov) challenge in nhps. in addition, a single injection of a blend of three rvsv vectors co ...201324367715
towards broad protection against ebolaviruses.the ebola and marburg viruses (from the filovirus family) induce deadly hemorrhagic fevers for which there is currently no licensed vaccine or treatment. frequent outbreaks have occurred in sub-saharan africa, in humans and nonhuman primates over the last 15 years or so and constitute a major public health problem. of particular concern, a new species of ebolavirus recently emerged in uganda, highlighting the high potential of these viruses to evolve and the need to develop 'broad-spectrum' vacc ...201021073307
homologous and heterologous protection of nonhuman primates by ebola and sudan virus-like particles.filoviruses cause hemorrhagic fever resulting in significant morbidity and mortality in humans. several vaccine platforms that include multiple virus-vectored approaches and virus-like particles (vlps) have shown efficacy in nonhuman primates. previous studies have shown protection of cynomolgus macaques against homologous infection for ebola virus (ebov) and marburg virus (marv) following a three-dose vaccine regimen of ebov or marv vlps, as well as heterologous protection against ravn virus (r ...201525793502
CD8+ cellular immunity mediates rAd5 vaccine protection against Ebola virus infection of nonhuman primates.Vaccine-induced immunity to Ebola virus infection in nonhuman primates (NHPs) is marked by potent antigen-specific cellular and humoral immune responses; however, the immune mechanism of protection remains unknown. Here we define the immune basis of protection conferred by a highly protective recombinant adenovirus virus serotype 5 (rAd5) encoding Ebola virus glycoprotein (GP) in NHPs. Passive transfer of high-titer polyclonal antibodies from vaccinated Ebola virus-immune cynomolgus macaques to ...201121857654
mabs and ad-vectored ifn-α therapy rescue ebola-infected nonhuman primates when administered after the detection of viremia and symptoms.zmab is a promising treatment against ebola virus (ebov) disease that has been shown to protect 50% (two of four) of nonhuman primates (nhps) when administered 2 days post-infection (dpi). to extend the treatment window and improve protection, we combined zmab with adenovirus-vectored interferon-α (ad-ifn) and evaluated efficacy in ebov-infected nhps. seventy-five percent (three of four) and 100% (four of four) of cynomolgus and rhesus macaques survived, respectively, when treatment was initiate ...201324132638
successful treatment of ebola virus-infected cynomolgus macaques with monoclonal antibodies.ebola virus (ebov) is considered one of the most aggressive infectious agents and is capable of causing death in humans and nonhuman primates (nhps) within days of exposure. recent strategies have succeeded in preventing acquisition of infection in nhps after treatment; however, these strategies are only successful when administered before or minutes after infection. the present work shows that a combination of three neutralizing monoclonal antibodies (mabs) directed against the ebola envelope g ...201222700957
animal models for ebola and marburg virus infections.ebola and marburg hemorrhagic fevers (ehf and mhf) are caused by the filoviridae family, ebolavirus and marburgvirus (ebolavirus and marburgvirus), respectively. these severe diseases have high mortality rates in humans. although ehf and mhf are endemic to sub-saharan africa. a novel filovirus, lloviu virus, which is genetically distinct from ebolavirus and marburgvirus, was recently discovered in spain where filoviral hemorrhagic fever had never been reported. the virulence of this virus has no ...201324046765
venezuelan equine encephalitis virus replicon particle vaccine protects nonhuman primates from intramuscular and aerosol challenge with ebolavirus.there are no vaccines or therapeutics currently approved for the prevention or treatment of ebolavirus infection. previously, a replicon vaccine based on venezuelan equine encephalitis virus (veev) demonstrated protective efficacy against marburg virus in nonhuman primates. here, we report the protective efficacy of sudan virus (sudv)- and ebola virus (ebov)-specific veev replicon particle (vrp) vaccines in nonhuman primates. vrp vaccines were developed to express the glycoprotein (gp) of either ...201323408633
transmission of ebola virus from pigs to non-human primates.ebola viruses (ebov) cause often fatal hemorrhagic fever in several species of simian primates including human. while fruit bats are considered natural reservoir, involvement of other species in ebov transmission is unclear. in 2009, reston-ebov was the first ebov detected in swine with indicated transmission to humans. in-contact transmission of zaire-ebov (zebov) between pigs was demonstrated experimentally. here we show zebov transmission from pigs to cynomolgus macaques without direct contac ...201223155478
successful post-exposure prophylaxis of ebola infected non-human primates using ebola glycoprotein-specific equine igg.herein we describe production of purified equine igg obtained from horses immunized with plasmid dna followed by boosting with kunjin replicon virus-like particles both encoding a modified ebola glycoprotein. administration of the equine igg over 5 days to cynomolgus macaques infected 24 hours previously with a lethal dose of ebola virus suppressed viral loads by more than 5 logs and protected animals from mortality. animals generated their own ebola glycoprotein-specific igg responses 9-15 days ...201728155869
implementation of a non-human primate model of ebola disease: infection of mauritian cynomolgus macaques and analysis of virus populations.ebola virus (ebov) haemorrhagic fever remains a threat to global public health with an urgent need for an effective treatment. in order to achieve these goals, access to non-human primate (nhp) laboratory models is an essential requirement. here, we present the first nhp-ebov laboratory model readily available to the european scientific community, based on infection of mauritian cynomolgus macaques using a central-african ebov strain and increasing virus challenge dose (10, 100, or 1000 focus fo ...201728132865
favipiravir pharmacokinetics in nonhuman primates and insights for future efficacy studies of hemorrhagic fever viruses.favipiravir is an rna polymerase inhibitor that showed strong antiviral efficacy in vitro and in small-animal models of several viruses responsible for hemorrhagic fever (hf), including ebola virus. the aim of this work was to characterize the complex pharmacokinetics of favipiravir in nonhuman primates (nhps) in order to guide future efficacy studies of favipiravir in large-animal models. four different studies were conducted in 30 uninfected cynomolgus macaques of chinese (n = 17) or mauritian ...201727736754
infection with the makona variant results in a delayed and distinct host immune response compared to previous ebola virus variants.zaire ebolavirus (zebov) continues to pose a significant threat to human health as highlighted by the recent epidemic that originated in west africa and the ongoing outbreak in the democratic republic of the congo. although the zebov variant responsible for this epidemic (makona) shares significant genetic similarity with previously identified variants (kikwit and mayinga), recent reports suggest slower disease progression in nonhuman primates. however, the pathogenesis caused by the new variant ...201728852031
clinical laboratory values as early indicators of ebola virus infection in nonhuman primates.the ebola virus (ebov) outbreak in west africa during 2013-2016 demonstrated the need to improve ebola virus disease (evd) diagnostics and standards of care. this retrospective study compared laboratory values and clinical features of 3 nonhuman primate models of lethal evd to assess associations with improved survival time. in addition, the study identified laboratory values useful as predictors of survival, surrogates for ebov viral loads, and triggers for initiation of therapeutic interventio ...201728726603
post-exposure treatment of non-human primates lethally infected with ebola virus with ebotab, a purified ovine igg product.despite sporadic outbreaks of ebola virus (ebov) over the last 4 decades and the recent public health emergency in west africa, there are still no approved vaccines or therapeutics for the treatment of acute ebov disease (evd). in response to the 2014 outbreak, an ovine immunoglobulin therapy was developed, termed ebotab. after promising results in the guinea pig model of ebov infection, ebotab was tested in the cynomolgus macaque non-human primate model of lethal ebov infection. to ensure strin ...201728642489
insights into reston virus spillovers and adaption from virus whole genome sequences.reston virus (family filoviridae) is unique among the viruses of the ebolavirus genus in that it is considered non-pathogenic in humans, in contrast to the other members which are highly virulent. the virus has however, been associated with several outbreaks of highly lethal hemorrhagic fever in non-human primates (nhps), specifically cynomolgus monkeys (macaca fascicularis) originating in the philippines. in addition, reston virus has been isolated from domestic pigs in the philippines. to bett ...201728542463
low potential for mechanical transmission of ebola virus via house flies (musca domestica).ebola virus (ebov) infection results in high morbidity and mortality and is primarily transmitted in communities by contact with infectious bodily fluids. while clinical and experimental evidence indicates that ebov is transmitted via mucosal exposure, the ability of non-biting muscid flies to mechanically transmit ebov following exposure to the face had not been assessed.201728468673
a conserved transcriptional response to intranasal ebola virus exposure in nonhuman primates prior to onset of fever.ebola virus disease (evd), caused by ebola virus (ebov), is a severe illness characterized by case fatality rates of up to 90%. the sporadic nature of outbreaks in resource-limited areas has hindered the ability to characterize the pathogenesis of evd at all stages of infection but particularly early host responses. pathogenesis is often studied in nonhuman primate (nhp) models of disease that replicate major aspects of human evd. typically, nhp models use a large infectious dose, are carried ou ...201829593102
antiviral efficacy of favipiravir against ebola virus: a translational study in cynomolgus macaques.despite repeated outbreaks, in particular the devastating 2014-2016 epidemic, there is no effective treatment validated for patients with ebola virus disease (evd). among the drug candidates is the broad-spectrum polymerase inhibitor favipiravir, which showed a good tolerance profile in patients with evd (jiki trial) but did not demonstrate a strong antiviral efficacy. in order to gain new insights into the antiviral efficacy of favipiravir and improve preparedness and public health management o ...201829584730
predictive and comparative analysis of ebolavirus proteins.ebolavirus is the pathogen for ebola hemorrhagic fever (ehf). this disease exhibits a high fatality rate and has recently reached a historically epidemic proportion in west africa. out of the 5 known ebolavirus species, only reston ebolavirus has lost human pathogenicity, while retaining the ability to cause ehf in long-tailed macaque. significant efforts have been spent to determine the three-dimensional (3d) structures of ebolavirus proteins, to study their interaction with host proteins, and ...201526158395
a seroepidemiologic study of reston ebolavirus in swine in the philippines.ebola viruses cause viral hemorrhagic fever in humans and non-human primates and are endemic in africa. reston ebolavirus (rebov) has caused several epizootics in cynomolgus monkeys (macaca fascicularis) but is not associated with any human disease. in late 2008, rebov infections were identified in swine for the first time in the philippines.201222709971
[marburg and ebola hemorrhagic fevers--pathogens, epidemiology and therapy].marburg and ebola hemorrhagic fevers are severe, systemic viral diseases affecting humans and non-human primates. they are characterized by multiple symptoms such as hemorrhages, fever, headache, muscle and abdominal pain, chills, sore throat, nausea, vomiting and diarrhea. elevated liver-associated enzyme levels and coagulopathy are also associated with these diseases. marburg and ebola hemorrhagic fevers are caused by (lake victoria) marburg virus and different species of ebola viruses, respec ...201425282746
persistent marburg virus infection in the testes of nonhuman primate survivors.sexual transmission of filoviruses was first reported in 1968 after an outbreak of marburg virus (marv) disease and recently caused flare-ups of ebola virus disease in the 2013-2016 outbreak. how filoviruses establish testicular persistence and are shed in semen remain unknown. we discovered that persistent marv infection of seminiferous tubules, an immune-privileged site that harbors sperm production, is a relatively common event in crab-eating macaques that survived infection after antiviral t ...201830173956
vaccine-mediated induction of an ebolavirus cross-species antibody binding to conserved epitopes on the glycoprotein heptad repeat 2/membrane-proximal external junction.the membrane-proximal external regions (mper) of the human immunodeficiency virus envelope glycoprotein (gp) generate broadly reactive antibody responses and are the focus of vaccine development efforts. the conservation of amino acids within filovirus gp heptad repeat region (hr)2/mper suggests that it may also represent a target for a pan-filovirus vaccine. we immunized a cynomolgus macaque against ebola virus (ebov) using a deoxyribonucleic acid/adenovirus 5 prime/boost strategy, sequenced me ...201830137549
cynomolgus macaque (macaca fascicularis) immunoglobulin heavy chain locus description.cynomolgus macaques (macaca fascicularis) have become an important animal model for biomedical research. in particular, it is the animal model of choice for the development of vaccine candidates associated with emerging dangerous pathogens. despite their increasing importance as animal models, the cynomolgus macaque genome is not fully characterized, hindering molecular studies for this model. more importantly, the lack of knowledge about the immunoglobulin (ig) locus organization directly impac ...201627233955
from bench to almost bedside: the long road to a licensed ebola virus vaccine.the ebola virus (ebov) disease epidemic during 2014-16 in west africa has accelerated the clinical development of several vaccine candidates that have demonstrated efficacy in the gold standard nonhuman primate (nhp) model, namely cynomolgus macaques. areas covered: this review discusses the pre-clinical research and if available, clinical evaluation of the currently available ebov vaccine candidates, while emphasizing the translatability of pre-clinical data generated in the nhp model to clinic ...201729148858
protective efficacy and long-term immunogenicity in cynomolgus macaques by ebola virus glycoprotein synthetic dna vaccines.there remains an important need for prophylactic anti-ebola virus vaccine candidates that elicit long-lasting immune responses and can be delivered to vulnerable populations that are unable to receive live-attenuated or viral vector vaccines.201930304515
ebola viral dynamics in nonhuman primates provides insights into virus immuno-pathogenesis and antiviral strategies.despite several clinical trials implemented, no antiviral drug could demonstrate efficacy against ebola virus. in non-human primates, early initiation of polymerase inhibitors favipiravir and remdesivir improves survival, but whether they could be effective in patients is unknown. here we analyze the impact of antiviral therapy by using a mathematical model that integrates virological and immunological data of 44 cynomolgus macaques, left untreated or treated with favipiravir. we estimate that f ...201830275474
distinct biological phenotypes of marburg and ravn virus infection in macaques.filoviruses are among the most pathogenic infectious agents known to human, with high destructive potential, as evidenced by the recent ebola virus epidemic in west africa. as members of the filovirus family, marburgviruses have caused similar devastating outbreaks, albeit with lower case numbers. in this study we compare the pathogenesis of ravn virus (ravv) and marburg virus (marv) strains angola, musoke, and ozolin in rhesus and cynomolgus macaques, the 2 nonhuman primate species most commonl ...201830215737
virus-encoded mirnas in ebola virus disease.ebola virus (ebov) is a negative-strand rna virus that replicates in the cytoplasm and causes an often-fatal hemorrhagic fever. ebov, like other viruses, can reportedly encode its own micrornas (mirnas) to subvert host immune defenses. mirnas are short noncoding rnas that can regulate gene expression by hybridizing to multiple mrnas, and viral mirnas can enhance viral replication and infectivity by regulating host or viral genes. to date, only one ebov mirna has been examined in human infection. ...201829691416
transcriptome analysis of circulating immune cell subsets highlight the role of monocytes in zaire ebola virus makona pathogenesis.existing models of ebola virus disease (evd) suggest antigen-presenting cells are initial targets ofzaire ebolavirus(zebov).in vitrostudies have shown that zebov infection of monocytes and macrophages results in the production of inflammatory mediators, which may cause lymphocyte apoptosis. however, these findings have not been corroborated byin vivostudies. in this study, we report the first longitudinal analysis of transcriptional changes in purified monocytes, t-cells, and b-cells isolated fr ...201729123522
comparison of transcriptomic platforms for analysis of whole blood from ebola-infected cynomolgus macaques.ebola virus disease (evd) is a serious illness with mortality rates of 20-90% in various outbreaks. evd is characterized by robust virus replication and strong host inflammatory response. analyzing host immune responses has increasingly involved multimodal approaches including transcriptomics to profile gene expression. we studied cynomolgus macaques exposed to ebola virus makona via different routes with the intent of comparing rna-seq to a nanostring ncounter codeset targeting 769 non-human pr ...201729116224
delayed time-to-treatment of an antisense morpholino oligomer is effective against lethal marburg virus infection in cynomolgus macaques.marburg virus (marv) is an ebola-like virus in the family filovirdae that causes sporadic outbreaks of severe hemorrhagic fever with a case fatality rate as high as 90%. avi-7288, a positively charged antisense phosphorodiamidate morpholino oligomer (pmoplus) targeting the viral nucleoprotein gene, was evaluated as a potential therapeutic intervention for marv infection following delayed treatment of 1, 24, 48, and 96 h post-infection (pi) in a nonhuman primate lethal challenge model. a total of ...201626901785
early transcriptional changes within liver, adrenal gland, and lymphoid tissues significantly contribute to ebola virus pathogenesis in cynomolgus macaques.ebola virus (ebov) continues to pose a significant threat to human health, as evidenced by the 2013-2016 epidemic in west africa and the ongoing outbreak in the democratic republic of the congo. ebov causes hemorrhagic fever, organ damage, and shock culminating in death, with case fatality rates as high as 90%. this high lethality combined with the paucity of licensed medical countermeasures makes ebov a critical human pathogen. although ebov infection results in significant damage to the liver ...202032213610
single low-dose vsv-ebov vaccination protects cynomolgus macaques from lethal ebola challenge.ebola virus (ebov), variant makona, was the causative agent of the 2013-2016 west african epidemic responsible for almost 30,000 human infections and over 11,000 fatalities. during the epidemic, the development of several experimental vaccines was accelerated through human clinical trials. one of them, the vesicular stomatitis virus (vsv)-based vaccine vsv-ebov, showed promising efficacy in a phase 3 clinical trial in guinea and is currently used in the ongoing ebov outbreak in the northeastern ...201931631035
a vp35 mutant ebola virus lacks virulence but can elicit protective immunity to wild-type virus challenge.zaire ebolavirus (ebov) vp35 protein is a suppressor of type i interferon (ifn) production, an inhibitor of dendritic cell maturation, and a putative virulence determinant. here, a recombinant ebov encoding a mutant vp35 virus (vp35m) is demonstrated to activate rig-i-like receptor signaling and innate antiviral pathways. when inoculated into cynomolgus macaques, vp35m exhibits dramatic attenuation as compared to wild-type ebov (wtebov), with 20 or 300 times the standard 100% lethal challenge do ...201931533029
rvsvδg-zebov-gp (also designated v920) recombinant vesicular stomatitis virus pseudotyped with ebola zaire glycoprotein: standardized template with key considerations for a risk/benefit assessment.the brighton collaboration viral vector vaccines safety working group (v3swg) was formed to evaluate the safety and characteristics of live, recombinant viral vector vaccines. a recent publication by the v3swg described live, attenuated, recombinant vesicular stomatitis virus (rvsv) as a chimeric virus vaccine for hiv-1 (clarke et al., 2016). the rvsv vector system is being explored as a platform for development of multiple vaccines. this paper reviews the molecular and biological features of th ...201931384731
virus inoculation and treatment regimens for evaluating anti-filovirus monoclonal antibody efficacy in vivo.the development of monoclonal antibodies to treat disease caused by filoviruses, particularly ebola virus, has risen steeply in recent years thanks to several key studies demonstrating their remarkable therapeutic potential. the increased drive to develop new and better monoclonal antibodies has necessarily seen an increase in animal model efficacy testing, which is critical to the pre-clinical development of any novel countermeasure. primary and secondary efficacy testing against filoviruses ty ...201932835206
antiviral innate responses induced by vsv-ebov vaccination contribute to rapid protection.ebola virus (ebov) is a single-stranded rna virus that causes ebola virus disease (evd), characterized by excessive inflammation, lymphocyte apoptosis, hemorrhage, and coagulation defects leading to multiorgan failure and shock. recombinant vesicular stomatitis virus expressing the ebov glycoprotein (vsv-ebov), which is highly efficacious against lethal challenge in nonhuman primates, is the only vaccine that successfully completed a phase iii clinical trial. additional studies showed vsv-ebov p ...201931138743
intramuscular exposure of macaca fascicularis to low doses of low passage- or cell culture-adapted sudan virus or ebola virus.the filoviruses ebola virus (ebov) and sudan virus (sudv) can cause severe diseases, and there are currently no licensed countermeasures available for use against them. transmission occurs frequently via contact with bodily fluids from infected individuals. however, it can be difficult to determine when or how someone became infected, or the quantity of infectious virus to which they were exposed. evidence suggests the infectious dose is low, but the majority of published studies use high exposu ...201830453499
ribavirin does not potentiate favipiravir antiviral activity against ebola virus in non-human primates.in spite of recurrent and dramatic outbreaks, there are no therapeutics approved against ebola virus disease. favipiravir, a rna polymerase inhibitor active against several rna viruses, recently demonstrated significant but not complete protection in a non-human primate model of ebola virus disease. in this study, we assessed the benefit of the combination of favipiravir and ribavirin, another broad spectrum antiviral agent, in the same model.202032135218
antibodies are necessary for rvsv/zebov-gp-mediated protection against lethal ebola virus challenge in nonhuman primates.ebola viruses cause hemorrhagic disease in humans and nonhuman primates with high fatality rates. these viruses pose a significant health concern worldwide due to the lack of approved therapeutics and vaccines as well as their potential misuse as bioterrorism agents. although not licensed for human use, recombinant vesicular stomatitis virus (rvsv) expressing the filovirus glycoprotein (gp) has been shown to protect macaques from ebola virus and marburg virus infections, both prophylactically an ...201323319647
development of a lethal intranasal exposure model of ebola virus in the cynomolgus macaque.ebola virus (ebov) is a filovirus that can cause ebola virus disease (evd). no approved vaccines or therapies exist for filovirus infections, despite an urgent need. the development and testing of effective countermeasures against ebov requires use of animal models and a thorough understanding of how the model aligns with evd in humans. the majority of published studies report outcomes of parenteral exposures for emulating needle stick transmission. however, based on data from evd outbreaks, clo ...201729109373
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