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ebola virus: a comparison, at ultrastructural level, of the behaviour of the sudan and zaire strains in monkeys.histopathological and electron microscopical examination of human liver specimens collected during the ebola haemorrhagic fever outbreaks in zaire and sudan indicated that zairean strains of the virus produced more extensive lesions. experimental infection of rhesus monkeys wiht zairean and sudanese strains of ebola virus produced similar changes to those found in man. in zairean strain infections large numbers of virus particles were found in the liver, lung and spleen accompanied by extensive ...1978106868
pathophysiology of shock and hemorrhage in a fulminating viral infection (ebola).eleven rhesus monkeys were monitored intensively during experimental infection with ebola virus. prominent neutrophilia with left shift and lymphopenia were the earliest abnormalities and were statistically significant by day 4 (p less than .02 and p less than .01, respectively). by day 4 falls in platelet counts were not statistically significant, whereas in vitro platelet aggregation was markedly depressed, progressing rapidly to complete failure by the time of maximum illness. intraplatelet p ...19854045253
haematological and biochemical monitoring of ebola infection in rhesus monkeys: implications for patient management.patients with severe viral infections such as lassa or ebola may be denied adequate laboratory investigations because of justifiable fears among laboratory staff. this study in monkeys was designed to provide comprehensive haematological and biochemical monitoring in a contained environment during all stages of ebola infection. marked neutrophilia, depletion of lymphocytes, and early failure of platelet aggregation preceded a consumption coagulopathy with a microangiopathic haemolytic anaemia, t ...19836138602
lethal experimental infections of rhesus monkeys by aerosolized ebola virus.the potential of aerogenic infection by ebola virus was established by using a head-only exposure aerosol system. virus-containing droplets of 0.8-1.2 microns were generated and administered into the respiratory tract of rhesus monkeys via inhalation. inhalation of viral doses as low as 400 plaque-forming units of virus caused a rapidly fatal disease in 4-5 days. the illness was clinically identical to that reported for parenteral virus inoculation, except for the occurrence of subcutaneous and ...19957547435
[experimental ebola fever in macaca mulatta].aerogenic infection of m. rhesus with ebola virus causes in them a disease similar in the principal clinical and virological parameters a grave form of ebola fever in humans, as it is described in literature. rapid development of symptoms of total intoxication in the presence of fever, hemorrhagic diathesis, and high viremia are indicative of the infection severity in monkeys.19957676671
transmission of ebola virus (zaire strain) to uninfected control monkeys in a biocontainment laboratory.secondary transmission of ebola virus infection in humans is known to be caused by direct contact with infected patients or body fluids. we report transmission of ebola virus (zaire strain) to two of three control rhesus monkeys (macaca mulatta) that did not have direct contact with experimentally inoculated monkeys held in the same room. the two control monkeys died from ebola virus infections at 10 and 11 days after the last experimentally inoculated monkey had died. the most likely route of i ...19958551825
lethal experimental infection of rhesus monkeys with ebola-zaire (mayinga) virus by the oral and conjunctival route of exposure.the source of infection or mode of transmission of ebola virus to human index cases of ebola fever has not been established. field observations in outbreaks of ebola fever indicate that secondary transmission of ebola virus is linked to improper needle hygiene, direct contact with infected tissue or fluid samples, and close contact with infected patients. while it is presumed that the virus infects through either breaks in the skin or contact with mucous membranes, the only two routes of exposur ...19968712894
characterization of a new marburg virus isolated from a 1987 fatal case in kenya.in 1987, an isolated case of fatal marburg disease was recognized during routine clinical haemorrhagic fever virus surveillance conducted in kenya. this report describes the isolation and partial characterization of the new marburg virus (strain ravn) isolated from this case. the ravn isolate was indistinguishable from reference marburg virus strains by cross-neutralization testing. virus particles and aggregates of marburg nucleocapsid matrix in ravn-infected vero cells, were visualized by immu ...19968800792
[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
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
haematological, biochemical and coagulation changes in mice, guinea-pigs and monkeys infected with a mouse-adapted variant of ebola zaire virus.ebola zaire virus from the 1976 outbreak (ebo-z) was recently adapted to the stage of lethal virulence in balb/c mice through serial passage. in the present study, various parameters were examined in groups of mice and guinea-pigs and in three rhesus monkeys after infection with mouse-adapted ebo-z. the virus caused fatal disease not only in mice but also in guinea-pigs, in which the course of illness resembled that produced by guinea-pig-adapted ebo-z. mice, guinea-pigs and monkeys showed simil ...200111798241
treatment of ebola virus infection with a recombinant inhibitor of factor viia/tissue factor: a study in rhesus monkeys.infection with the ebola virus induces overexpression of the procoagulant tissue factor in primate monocytes and macrophages, suggesting that inhibition of the tissue-factor pathway could ameliorate the effects of ebola haemorrhagic fever. here, we tested the notion that blockade of fviia/tissue factor is beneficial after infection with ebola virus.200314683653
demand for nonhuman primate resources in the age of biodefense.the demand for nonhuman primates will undoubtedly increase to meet biomedical needs in this current age of biodefense. the availability of funding has increased the research on select agents and has created a requirement to validate results in relevant primate models. this review provides a description of current and potential biological threats that are likely to require nonhuman primates for the development of vaccines and therapeutics. primates have been an invaluable resource in the dissecti ...200515644560
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
gene-specific countermeasures against ebola virus based on antisense phosphorodiamidate morpholino oligomers.the filoviruses marburg virus and ebola virus (ebov) quickly outpace host immune responses and cause hemorrhagic fever, resulting in case fatality rates as high as 90% in humans and nearly 100% in nonhuman primates. the development of an effective therapeutic for ebov is a daunting public health challenge and is hampered by a paucity of knowledge regarding filovirus pathogenesis. this report describes a successful strategy for interfering with ebov infection using antisense phosphorodiamidate mo ...200616415982
generation of an adenoviral vaccine vector based on simian adenovirus 21.adenoviral vectors can be used to generate potent humoral and cellular immune responses to transgene products. use of adenoviral vectors based on non-human isolates may allow for their utilization in populations harbouring neutralizing antibodies to common human serotypes. a vector chimera was constructed using simian adenovirus 22 (a serotype belonging to the species human adenovirus e) and simian adenovirus 21 (a serotype belonging to the species human adenovirus b) expressing the ebola (zaire ...200616894185
effective post-exposure treatment of ebola infection.ebola viruses are highly lethal human pathogens that have received considerable attention in recent years due to an increasing re-emergence in central africa and a potential for use as a biological weapon. there is no vaccine or treatment licensed for human use. in the past, however, important advances have been made in developing preventive vaccines that are protective in animal models. in this regard, we showed that a single injection of a live-attenuated recombinant vesicular stomatitis virus ...200717238284
neutralizing antibody fails to impact the course of ebola virus infection in monkeys.prophylaxis with high doses of neutralizing antibody typically offers protection against challenge with viruses producing acute infections. in this study, we have investigated the ability of the neutralizing human monoclonal antibody, kz52, to protect against ebola virus in rhesus macaques. this antibody was previously shown to fully protect guinea pigs from infection. four rhesus macaques were given 50 mg/kg of neutralizing human monoclonal antibody kz52 intravenously 1 d before challenge with ...200717238286
successful topical respiratory tract immunization of primates against ebola virus.ebola virus causes outbreaks of severe viral hemorrhagic fever with high mortality in humans. the virus is highly contagious and can be transmitted by contact and by the aerosol route. these features make ebola virus a potential weapon for bioterrorism and biological warfare. therefore, a vaccine that induces both systemic and local immune responses in the respiratory tract would be highly beneficial. we evaluated a common pediatric respiratory pathogen, human parainfluenza virus type 3 (hpiv3), ...200717428868
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
pathologic findings associated with delayed death in nonhuman primates experimentally infected with zaire ebola virus.zaire ebola virus infection in macaques causes a fatal disease with a pathogenesis similar to that in humans. during several independent therapy studies, we noted altered tissue tropism in 6 rhesus macaques that survived longer than those with a typical disease course. the mean time to death for these 6 macaques was 21.7 days, which is significantly longer than the average mean time to death of 8.3 days for 20 untreated historical control animals. in addition to living significantly longer, thes ...200717940967
marburg virus angola infection of rhesus macaques: pathogenesis and treatment with recombinant nematode anticoagulant protein c2.the procoagulant tissue factor (tf) is thought to play a role in the coagulation disorders that characterize filoviral infections. in this study, we evaluated the pathogenesis of lethal infection with the angola strain of marburg virus (marv-ang) in rhesus macaques and tested the efficacy of recombinant nematode anticoagulant protein c2 (rnapc2), an inhibitor of tf/factor viia, as a potential treatment.200717940973
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
mucosal parainfluenza virus-vectored vaccine against ebola virus replicates in the respiratory tract of vector-immune monkeys and is immunogenic.we previously used human parainfluenza virus type 3 (hpiv3) as a vector to express the ebola virus (ebov) gp glycoprotein. the resulting hpiv3/ebogp vaccine was immunogenic and protective against ebov challenge in a non-human primate model. however, it remained unclear whether the vaccine would be effective in adults due to preexisting immunity to hpiv3. here, the immunogenicity of hpiv3/ebogp was compared in hpiv3-naive and hpiv3-immune rhesus monkeys. after a single dose of hpiv3/ebogp, the ti ...201020129638
postexposure protection of non-human primates against a lethal ebola virus challenge with rna interference: a proof-of-concept study.we previously showed that small interfering rnas (sirnas) targeting the zaire ebola virus (zebov) rna polymerase l protein formulated in stable nucleic acid-lipid particles (snalps) completely protected guineapigs when administered shortly after a lethal zebov challenge. although rodent models of zebov infection are useful for screening prospective countermeasures, they are frequently not useful for prediction of efficacy in the more stringent non-human primate models. we therefore assessed the ...201020511019
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
respiratory tract immunization of non-human primates with a newcastle disease virus-vectored vaccine candidate against ebola virus elicits a neutralizing antibody response.we previously developed a respiratory tract vaccine candidate against ebola virus (ebov) based on human parainfluenza virus type 3 (hpiv3), a respiratory paramyxovirus, expressing the ebov gp envelope protein (hpiv3/gp) from an added gene. two doses of this vaccine candidate delivered by the intranasal and intratracheal route protected monkeys against intraperitoneal challenge with ebov; however, concerns exist that the vaccine candidate may have reduced immunogenicity in the adult human populat ...201021034822
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
simian hemorrhagic fever virus infection of rhesus macaques as a model of viral hemorrhagic fever: clinical characterization and risk factors for severe disease.simian hemorrhagic fever virus (shfv) has caused sporadic outbreaks of hemorrhagic fevers in macaques at primate research facilities. shfv is a bsl-2 pathogen that has not been linked to human disease; as such, investigation of shfv pathogenesis in non-human primates (nhps) could serve as a model for hemorrhagic fever viruses such as ebola, marburg, and lassa viruses. here we describe the pathogenesis of shfv in rhesus macaques inoculated with doses ranging from 50 pfu to 500,000 pfu. disease se ...201122014505
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
aerosolized ebola vaccine protects primates and elicits lung-resident t cell responses.direct delivery of aerosolized vaccines to the respiratory mucosa elicits both systemic and mucosal responses. this vaccine strategy has not been tested for ebola virus (ebov) or other hemorrhagic fever viruses. here, we examined the immunogenicity and protective efficacy of an aerosolized human parainfluenza virus type 3-vectored vaccine that expresses the glycoprotein (gp) of ebov (hpiv3/ebogp) delivered to the respiratory tract. rhesus macaques were vaccinated with aerosolized hpiv3/ebogp, li ...201526168222
cytomegalovirus-based vaccine expressing ebola virus glycoprotein protects nonhuman primates from ebola virus infection.ebolaviruses pose significant public health problems due to their high lethality, unpredictable emergence, and localization to the poorest areas of the world. in addition to implementation of standard public health control procedures, a number of experimental human vaccines are being explored as a further means for outbreak control. recombinant cytomegalovirus (cmv)-based vectors are a novel vaccine platform that have been shown to induce substantial levels of durable, but primarily t-cell-biase ...201626876974
therapeutic treatment of marburg and ravn virus infection in nonhuman primates with a human monoclonal antibody.as observed during the 2013-2016 ebola virus disease epidemic, containment of filovirus outbreaks is challenging and made more difficult by the lack of approved vaccine or therapeutic options. marburg and ravn viruses are highly virulent and cause severe and frequently lethal disease in humans. monoclonal antibodies (mabs) are a platform technology in wide use for autoimmune and oncology indications. previously, we described human mabs that can protect mice from lethal challenge with marburg vir ...201728381540
pathogenicity comparison between the kikwit and makona ebola virus variants in rhesus macaques.enhanced virulence and/or transmission of west african ebola virus (ebov) variants, which are divergent from their central african counterparts, are suspected to have contributed to the sizable toll of the recent ebola virus disease (evd) outbreak. this study evaluated the pathogenicity and shedding in rhesus macaques infected with 1 of 2 west african isolates (ebov-c05 or ebov-c07) or a central african isolate (ebov-k). all animals infected with ebov-c05 or ebov-c07 died of evd, whereas 2 of 3 ...201627651412
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
efficacy of vesicular stomatitis virus-ebola virus postexposure treatment in rhesus macaques infected with ebola virus makona.the ebola virus (ebov) epidemic in west africa increased the focus on vaccine development against this hemorrhagic fever-causing pathogen, and as a consequence human clinical trials for a few selected platforms were accelerated. one of these vaccines is vesicular stomatitis virus (vsv)-ebov, also known as rvsv-zebov, a fast-acting vaccine against ebov and so far the only vaccine with reported efficacy against ebov infections in humans in phase iii clinical trials. in this study, we analyzed the ...201627496978
potent neutralizing monoclonal antibodies against ebola virus infection.ebola virus infections cause a deadly hemorrhagic disease for which no vaccines or therapeutics has received regulatory approval. here we show isolation of three (q206, q314 and q411) neutralizing monoclonal antibodies (mabs) against the surface glycoprotein (gp) of ebola virus identified in west africa in 2014 through sequential immunization of chinese rhesus macaques and antigen-specific single b cell sorting. these mabs demonstrated potent neutralizing activities against both pseudo and live ...201627181584
circulating microrna profiles of ebola virus infection.early detection of ebola virus (ebov) infection is essential to halting transmission and adjudicating appropriate treatment. however, current methods rely on viral identification, and this approach can misdiagnose presymptomatic and asymptomatic individuals. in contrast, disease-driven alterations in the host transcriptome can be exploited for pathogen-specific diagnostic biomarkers. here, we present for the first time ebov-induced changes in circulating mirna populations of nonhuman primates (n ...201627098369
therapeutic efficacy of the small molecule gs-5734 against ebola virus in rhesus monkeys.the most recent ebola virus outbreak in west africa, which was unprecedented in the number of cases and fatalities, geographic distribution, and number of nations affected, highlights the need for safe, effective, and readily available antiviral agents for treatment and prevention of acute ebola virus (ebov) disease (evd) or sequelae. no antiviral therapeutics have yet received regulatory approval or demonstrated clinical efficacy. here we report the discovery of a novel small molecule gs-5734, ...201626934220
necrotizing scleritis, conjunctivitis, and other pathologic findings in the left eye and brain of an ebola virus-infected rhesus macaque (macaca mulatta) with apparent recovery and a delayed time of death.a 3.5-year-old adult female rhesus macaque (macaca mulatta) manifested swelling of the left upper eyelid and conjunctiva and a decline in clinical condition 18 days following intramuscular challenge with ebola virus (ebov; kikwit-1995), after apparent clinical recovery. histologic lesions with strong ebov antigen staining were noted in the left eye (scleritis, conjunctivitis, and peri-optic neuritis), brain (choriomeningoencephalitis), stomach, proximal duodenum, and pancreas. spleen, liver, and ...201626153408
considerations in the use of nonhuman primate models of ebola virus and marburg virus infection.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 ma ...201526063223
lipid nanoparticle sirna treatment of ebola-virus-makona-infected nonhuman primates.the current outbreak of ebola virus in west africa is unprecedented, causing more cases and fatalities than all previous outbreaks combined, and has yet to be controlled. several post-exposure interventions have been employed under compassionate use to treat patients repatriated to europe and the united states. however, the in vivo efficacy of these interventions against the new outbreak strain of ebola virus is unknown. here we show that lipid-nanoparticle-encapsulated short interfering rnas (s ...201525901685
optimized microrna purification from trizol-treated plasma.micrornas (mirnas) represent new and potentially informative diagnostic targets for disease detection and prognosis. however, little work exists documenting the effect of trizol, a common viral inactivation and nucleic acid extraction reagent, on mirna purification. here, we developed an optimized protocol for mirna extraction from plasma samples by evaluating five different rna extraction kits, trizol phase separation, purification additives, and initial plasma sample volume. this method was th ...201525765146
a single phosphorodiamidate morpholino oligomer targeting vp24 protects rhesus monkeys against lethal ebola virus infection.ebola viruses (ebov) cause severe disease in humans and nonhuman primates with high mortality rates and continue to emerge in new geographic locations, including several countries in west africa, the site of a large ongoing outbreak. phosphorodiamidate morpholino oligomers (pmos) are synthetic antisense molecules that are able to target mrnas in a sequence-specific fashion and suppress translation through steric hindrance. we previously showed that the use of pmos targeting a combination of vp35 ...201525670780
characterization of clinical and immunological parameters during ebola virus infection of rhesus macaques.the rhesus macaque serves as an animal model for ebola virus (ebov) infection. a thorough understanding of ebov infection in this species would aid in further development of filovirus therapeutics and vaccines. in this study, pathological and immunological data from ebov-infected rhesus macaques are presented. changes in blood chemistries, hematology, coagulation, and immune parameters during infection, which were consistently observed in the animals, are presented. in an animal that survived ch ...201525514385
euthanasia assessment in ebola virus infected nonhuman primates.multiple products are being developed for use against filoviral infections. efficacy for these products will likely be demonstrated in nonhuman primate models of filoviral disease to satisfy licensure requirements under the animal rule, or to supplement human data. typically, the endpoint for efficacy assessment will be survival following challenge; however, there exists no standardized approach for assessing the health or euthanasia criteria for filovirus-exposed nonhuman primates. consideratio ...201425421892
reversion of advanced ebola virus disease in nonhuman primates with zmapp.without an approved vaccine or treatments, ebola outbreak management has been limited to palliative care and barrier methods to prevent transmission. these approaches, however, have yet to end the 2014 outbreak of ebola after its prolonged presence in west africa. here we show that a combination of monoclonal antibodies (zmapp), optimized from two previous antibody cocktails, is able to rescue 100% of rhesus macaques when treatment is initiated up to 5 days post-challenge. high fever, viraemia a ...201425171469
marburg virus infection in nonhuman primates: therapeutic treatment by lipid-encapsulated sirna.marburg virus (marv) and the closely related filovirus ebola virus cause severe and often fatal hemorrhagic fever (hf) in humans and nonhuman primates with mortality rates up to 90%. there are no vaccines or drugs approved for human use, and no postexposure treatment has completely protected nonhuman primates against marv-angola, the strain associated with the highest rate of mortality in naturally occurring human outbreaks. studies performed with other marv strains assessed candidate treatments ...201425143366
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
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
therapeutic intervention of ebola virus infection in rhesus macaques with the mb-003 monoclonal antibody cocktail.ebola virus (ebov) remains one of the most lethal transmissible infections and is responsible for high fatality rates and substantial morbidity during sporadic outbreaks. with increasing human incursions into endemic regions and the reported possibility of airborne transmission, ebov is a high-priority public health threat for which no preventive or therapeutic options are currently available. recent studies have demonstrated that cocktails of monoclonal antibodies are effective at preventing mo ...201323966302
interferon-β therapy prolongs survival in rhesus macaque models of ebola and marburg hemorrhagic fever.there is a clear need for novel, effective therapeutic approaches to hemorrhagic fever due to filoviruses. ebola virus hemorrhagic fever is associated with robust interferon (ifn)-α production, with plasma concentrations of ifn-α that greatly (60- to 100-fold) exceed those seen in other viral infections, but little ifn-β production. while all of the type i ifns signal through the same receptor complex, both quantitative and qualitative differences in biological activity are observed after stimul ...201323255566
delayed treatment of ebola virus infection with plant-derived monoclonal antibodies provides protection in rhesus macaques.filovirus infections can cause a severe and often fatal disease in humans and nonhuman primates, including great apes. here, three anti-ebola virus mouse/human chimeric mabs (c13c6, h-13f6, and c6d8) were produced in chinese hamster ovary and in whole plant (nicotiana benthamiana) cells. in pilot experiments testing a mixture of the three mabs (mb-003), we found that mb-003 produced in both manufacturing systems protected rhesus macaques from lethal challenge when administered 1 h postinfection. ...201223071322
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
evolving rna virus pandemics: hiv, hcv, ebola, dengue, chikunguya, and now zika!the zika virus (zikv), a flavivirus related to yellow fever, dengue, and west nile, originated in the zika forest in uganda and was discovered in a rhesus monkey in 1947. the disease now has "explosive" pandemic potential, with outbreaks in africa, southeast asia, the pacific islands, and the americas. to date, the cdc has issued travel alerts for at least 30 countries and territories in latin america, the caribbean, polynesia, and cape verde in africa.201627028271
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
the convergence of a virus, mosquitoes, and human travel in globalizing the zika epidemic.the zika virus was first identified in 1947 in the zika forest of uganda. it was discovered in a rhesus monkey that had been placed in a cage on a sentinel platform in the forest by the virus research institute. when this writer visited the institute and the zika forest in 1961, work was underway to identify mosquito species at various levels of the tree canopy. this was done through the placement of traps at various levels of a 120-foot-high steel tower which this writer climbed. at that time, ...201626969497
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
high dose sertraline monotherapy fails to protect rhesus macaques from lethal challenge with ebola virus makona.the recent epidemic of ebola virus disease in west africa resulted in an unprecedented number of cases and deaths. due to the scope of the outbreak combined with the lack of available approved treatment options, there was strong motivation to investigate any potential drug which had existing data reporting anti-ebola activity. drugs with demonstrated antiviral activity in the nonhuman primate models already approved for another indication or for which there was existing safety data were consider ...201728725019
identification and pathological characterization of persistent asymptomatic ebola virus infection in rhesus monkeys.ebola virus (ebov) persistence in asymptomatic humans and ebola virus disease (evd) sequelae have emerged as significant public health concerns since the 2013-2016 evd outbreak in western africa. until now, studying how ebov disseminates into and persists in immune-privileged sites was impossible due to the absence of a suitable animal model. here, we detect persistent ebov replication coinciding with systematic inflammatory responses in otherwise asymptomatic rhesus monkeys that had survived in ...201728715405
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
single-cell profiling of ebola virus disease in vivo reveals viral and host dynamics.ebola virus (ebov) causes epidemics with high mortality yet remains understudied due to the challenge of experimentation in high-containment and outbreak settings. here, we used single-cell transcriptomics and cytof-based single-cell protein quantification to characterize peripheral immune cells during ebov infection in rhesus monkeys. we obtained 100,000 transcriptomes and 15,000,000 protein profiles, finding that immature, proliferative monocyte-lineage cells with reduced antigen-presentation ...202033159858
prior vaccination with rvsv-zebov does not interfere with but improves efficacy of postexposure antibody treatment.a replication-competent vesicular stomatitis virus vaccine expressing the ebola virus (ebov) glycoprotein (gp) (rvsv-zebov) was successfully used during the 2013-16 ebov epidemic. additionally, chimeric and human monoclonal antibodies (mab) against the ebov gp have shown promise in animals and humans when administered therapeutically. uncertainty exists regarding the efficacy of postexposure antibody treatments in the event of a known exposure of a recent rvsv-zebov vaccinee. here, we model a wo ...202032719371
kikwit ebola virus disease progression in the rhesus monkey animal model.ongoing ebola virus disease outbreaks in the democratic republic of the congo follow the largest recorded outbreak in western africa (2013-2016). to combat outbreaks, testing of medical countermeasures (therapeutics or vaccines) requires a well-defined, reproducible, animal model. here we present ebola virus disease kinetics in 24 chinese-origin rhesus monkeys exposed intramuscularly to a highly characterized, commercially available kikwit ebola virus filovirus animal non-clinical group (fang) s ...202032674252
peripheral neuronopathy associated with ebola virus infection in rhesus macaques: a possible cause of neurological signs and symptoms in human ebola patients.neurological signs and symptoms are the most common complications of ebola virus disease. however, the mechanisms underlying the neurologic manifestations in ebola patients are not known. in this study, peripheral ganglia were collected from 12 rhesus macaques that succumbed to ebola virus (ebov) disease from 5 to 8 days post exposure. ganglionitis, characterized by neuronal degeneration, necrosis, and mononuclear leukocyte infiltrates, was observed in the dorsal root, autonomic, and enteric gan ...202032498080
filoviruses infect rhesus macaque synoviocytes in vivo and primary human synoviocytes in vitro.the most commonly reported symptom of post-ebola virus disease syndrome in survivors is arthralgia, yet involvement of the joints in acute or convalescent ebola virus infection is not well characterized in human patients or animal models. through immunohistochemistry, we found that the lining synovial intima of the stifle (knee) is a target for acute infection by ebola virus/kikwit, ebola virus/makona-c05, and marburg virus/angola in the rhesus macaque model. furthermore, histologic analysis, im ...202032479821
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
immune correlates of postexposure vaccine protection against marburg virus.postexposure immunization can prevent disease and reduce transmission following pathogen exposure. the rapid immunostimulatory properties of recombinant vesicular stomatitis virus (rvsv)-based vaccines make them suitable postexposure treatments against the filoviruses ebola virus and marburg virus (marv); however, the mechanisms that drive this protection are undefined. previously, we reported 60-75% survival of rhesus macaques treated with rvsv vectors expressing marv glycoprotein (gp) 20-30 mi ...202032080323
a bivalent, spherical virus-like particle vaccine enhances breadth of immune responses against pathogenic ebola viruses in rhesus macaques.the 2013-2016 ebola outbreak in west africa led to accelerated efforts to develop vaccines against these highly virulent viruses. a live, recombinant vesicular stomatitis virus-based vaccine has been deployed in outbreak settings and appears highly effective. vaccines based on replication-deficient adenovirus vectors either alone or in combination with a multivalent modified vaccinia ankara (mva) ebola vaccine also appear promising and are progressing in clinical evaluation. however, the ability ...202032075939
development of an antibody cocktail for treatment of sudan virus infection.antibody-based therapies are a promising treatment option for managing ebolavirus infections. several ebola virus (ebov)-specific and, more recently, pan-ebolavirus antibody cocktails have been described. here, we report the development and assessment of a sudan virus (sudv)-specific antibody cocktail. we produced a panel of sudv glycoprotein (gp)-specific human chimeric monoclonal antibodies (mabs) using both plant and mammalian expression systems and completed head-to-head in vitro and in vivo ...202032015126
characterization of ebola virus disease (evd) in rhesus monkeys for development of evd therapeutics.recent ebola virus (ebov) outbreaks in west africa and the democratic republic of the congo have highlighted the urgent need for approval of medical countermeasures for treatment and prevention of ebov disease (evd). until recently, when successes were achieved in characterizing the efficacy of multiple experimental evd therapeutics in humans, the only feasible way to obtain data regarding potential clinical benefits of candidate therapeutics was by conducting well-controlled animal studies. non ...202031941095
cytomegalovirus-vectored vaccines for hiv and other pathogens.: the use of cytomegalovirus (cmv) as a vaccine vector to express antigens against multiple infectious diseases, including simian immunodeficiency virus, ebola virus, plasmodium, and mycobacterium tuberculosis, in rhesus macaques has generated extraordinary levels of protective immunity against subsequent pathogenic challenge. moreover, the mechanisms of immune protection have altered paradigms about viral vector-mediated immunity against ectopically expressed vaccine antigens. further optimizat ...202031634191
development and characterization of two gp-specific monoclonal antibodies, which synergistically protect non-human primates against ebola lethal infection.ebola fever is an acute highly contagious viral disease characterized by severe course, high mortality and development of hemorrhagic syndrome (tendency to skin hemorrhage and bleeding of mucous membranes). the mortality rate of the disease 60-90%. nowadays, there are no licensed specific therapeutic agents for ebola in the world. monoclonal antibodies (mabs) having viral neutralizing activity with high specificity to the gp protein of the ebola virus are considered as candidate highly effective ...201931593751
impact of intensive care unit supportive care on the physiology of ebola virus disease in a universally lethal non-human primate model.there are currently limited data for the use of specific antiviral therapies for the treatment of ebola virus disease (evd). while there is anecdotal evidence that supportive care may be effective, there is a paucity of direct experimental data to demonstrate a role for supportive care in evd. we studied the impact of icu-level supportive care interventions including fluid resuscitation, vasoactive medications, blood transfusion, hydrocortisone, and ventilator support on the pathophysiology of e ...201931520194
chimpanzee adenoviral vector prime-boost regimen elicits potent immune responses against ebola virus in mice and rhesus macaques.in the last few decades, ebola virus (ebov) has emerged periodically and infected people in africa, resulting in an extremely high mortality rate. with no available prophylaxis or cure so far, a highly effective ebola vaccine is urgently needed. in this study, we developed a novel chimpanzee adenovirus-based prime-boost vaccine by exploiting two recombinant replication-deficient chimpanzee adenoviral vectors, adc7 and adc68, which express glycoproteins (gp) of the ebov strain identified in the 2 ...201931339465
the cytokine response profile of ebola virus disease in a large cohort of rhesus macaques treated with monoclonal antibodies.ebola virus (ebov) is a highly pathogenic filovirus that causes outbreaks of a severe hemorrhagic fever known as ebov disease (evd). ebola virus disease is characterized in part by a dysregulated immune response and massive production of both pro- and anti-inflammatory cytokines. to better understand the immune response elicited by evd in the context of treatment with experimental anti-ebov antibody cocktails, we analyzed 29 cytokines in 42 ebov-infected rhesus macaques. in comparison to the sur ...201930949520
characterization of the plasma proteome of nonhuman primates during ebola virus disease or melioidosis: a host response comparison.in-depth examination of the plasma proteomic response to infection with a wide variety of pathogens can assist in the development of new diagnostic paradigms, while providing insight into the interdependent pathogenic processes which encompass a host's immunological and physiological responses. ebola virus (ebov) causes a highly lethal infection termed ebola virus disease (evd) in primates and humans. the gram negative non-spore forming bacillus burkholderia pseudomallei (bp) causes melioidosis ...201930774579
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
ebola virus causes intestinal tract architectural disruption and bacterial invasion in non-human primates.in the 2014⁻2016 west africa ebola virus (ebov) outbreak, there was a significant concern raised about the potential for secondary bacterial infection originating from the gastrointestinal tract, which led to the empiric treatment of many patients with antibiotics. this retrospective pathology case series summarizes the gastrointestinal pathology observed in control animals in the rhesus ebov-kikwit intramuscular 1000 plaque forming unit infection model. all 31 non-human primates (nhps) exhibite ...201830241284
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
new insights into marburg virus disease pathogenesis in the rhesus macaque model.previously, several studies have been performed to delineate the development and progression of marburg virus infection in nonhuman primates (nhps), primarily to clarify the mechanisms of severe (fatal) disease. after the 2013-2016 ebola virus disease (evd) epidemic in western africa, there has been a reassessment of the available filovirus animal models and the utility of these to faithfully recapitulate human disease. the high lethality of the nhp models has raised doubts as to their ability t ...201830053050
fully human immunoglobulin g from transchromosomic bovines treats nonhuman primates infected with ebola virus makona isolate.transchromosomic bovines (tc-bovines) adaptively produce fully human polyclonal immunoglobulin (ig)g antibodies after exposure to immunogenic antigen(s). the national interagency confederation for biological research and collaborators rapidly produced and then evaluated anti-ebola virus igg immunoglobulins (collectively termed sab-139) purified from tc-bovine plasma after sequential hyperimmunization with an ebola virus makona isolate glycoprotein nanoparticle vaccine. sab-139 was characterized ...201830010950
efficacy of human monoclonal antibody monotherapy against bundibugyo virus infection in nonhuman primates.the 2013-2016 ebola virus disease (evd) epidemics in west africa highlighted a need for effective therapeutics for treatment of the disease caused by filoviruses. monoclonal antibodies (mabs) are promising therapeutic candidates for prophylaxis or treatment of virus infections. data about efficacy of human mab monotherapy against filovirus infections in preclinical nonhuman primate models are limited.201829982718
a replicating single-cycle adenovirus vaccine against ebola virus.recent west african ebola virus (ebov) epidemics have led to testing different anti-ebov vaccines, including a replication-defective adenovirus (rd-ad) vector (chad3-ebov) and an infectious, replication-competent recombinant vesicular stomatitis virus expressing the ebov glycoprotein (rvsv-ebov; also known as rvsv-zebov). while rd-ads elicit protection, when scaled up to human trials, the level of protection may be much lower than that of vaccines containing viruses that can replicate. although ...201829982595
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
recently identified mutations in the ebola virus-makona genome do not alter pathogenicity in animal models.ebola virus (ebov), isolate makona, the causative agent of the west african ebov epidemic, has been the subject of numerous investigations to determine the genetic diversity and its potential implication for virus biology, pathogenicity, and transmissibility. despite various mutations that have emerged over time through multiple human-to-human transmission chains, their biological relevance remains questionable. recently, mutations in the glycoprotein gp and polymerase l, which emerged and stabi ...201829742435
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