Postexposure protection of non-human primates against a lethal Ebola virus challenge with RNA interference: a proof-of-concept study

Geisbert, Thomas W.; Lee, Amy Ch; Robbins, Marjorie; Geisbert, Joan B.; Honko, Anna N.; Sood, Vandana; Johnson, Joshua C.; Jong, Susan de; Tavakoli, Iran; Judge, Adam D.; Hensley, Lisa E.; MacLachlan, Ian

doi:10.1016/s0140-6736(10)60357-1

Cited by 415 publications

(332 citation statements)

References 28 publications

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“…Nonetheless, these data suggest that cholesterol-reducing treatments are potential candidates for therapeutics to counteract the pathogenicity induced through Ebola GP; these treatments could also be employed after infection with Ebola virus as an addition to the established post exposure regimens [53][54][55][56][57][58][59][60] . Cyclodextrins have been patented as antiviral agents for the treatment of infections resulting from various enveloped viruses 61 .…”

Section: Resultsmentioning

confidence: 99%

Inhibition of Ebola virus glycoprotein-mediated cytotoxicity by targeting its transmembrane domain and cholesterol

et al. 2015

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The high pathogenicity of the Ebola virus reflects multiple concurrent processes on infection. Among other important determinants, Ebola fusogenic glycoprotein (GP) has been associated with the detachment of infected cells and eventually leads to vascular leakage and haemorrhagic fever. Here we report that the membrane-anchored GP is sufficient to induce the detachment of adherent cells. The results show that the detachment induced through either full-length GP 1,2 or the subunit GP 2 depends on cholesterol and the structure of the transmembrane domain. These data reveal a novel molecular mechanism in which GP regulates Ebola virus assembly and suggest that cholesterol-reducing agents could be useful as therapeutics to counteract GP-mediated cell detachment.

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Section: Resultsmentioning

confidence: 99%

Inhibition of Ebola virus glycoprotein-mediated cytotoxicity by targeting its transmembrane domain and cholesterol

et al. 2015

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“…The four treated animals that survived challenge experienced little to no viremia and had few, if any, of the clinical symptoms observed in the two controls. With a caveat that direct comparisons between studies performed in different laboratories are difficult, this is in contrast to the course of disease seen in survivors treated with other EBOV therapeutic candidates in advanced development (siRNA, PMOs, and VSV) in which surviving animals experience varying levels of morbidity (3)(4)(5). Further, MB-003 RAMP provided this level of protection out to 48 h p.i.…”

Section: Discussionmentioning

confidence: 99%

“…Currently there are no licensed vaccines or treatments against EBOV infection. Candidate postexposure interventions in advanced development include siRNA and phosphorodiamidate morpholino oligomers (PMOs) antisense strategies, as well as postexposure immunization with a vesicular stomatitis virus (VSV)-based vaccine (3)(4)(5). All of these interventions have demonstrated reduced mortality in NHPs when delivered 0.5-1 h postinfection (p.i.…”

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confidence: 99%

Delayed treatment of Ebola virus infection with plant-derived monoclonal antibodies provides protection in rhesus macaques

Olinger

Pettitt

Kim

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

353

344

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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. In a pivotal followup experiment, we found significant protection (P < 0.05) when MB-003 treatment began 24 or 48 h postinfection (four of six survived vs. zero of two controls). In all experiments, surviving animals that received MB-003 experienced little to no viremia and had few, if any, of the clinical symptoms observed in the controls. The results represent successful postexposure in vivo efficacy by a mAb mixture and suggest that this immunoprotectant should be further pursued as a postexposure and potential therapeutic for Ebola virus exposure.passive immunization | therapy

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“…In the recent past, experimental postexposure treatments for filovirus infections have included hyperimmune equine IgG (9), EBOV-specific human monoclonal IgG antibody (16), wholeblood transfusions from convalescent survivors (8), recombinant IFN (13), recombinant nematode anticoagulant protein C2 (19), recombinant human activated protein C (20,21), recombinant vesicular stomatitis virus vectors (22)(23)(24)(25), siRNAs (26), and phosphorodiamidate morpholino oligomers (27). A summary of these efforts is detailed in Table 2.…”

Section: Discussionmentioning

confidence: 99%

Postexposure antibody prophylaxis protects nonhuman primates from filovirus disease

Dye

Herbert²,

Kuehne³

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

246

215

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Antibody therapies to prevent or limit filovirus infections have received modest interest in recent years, in part because of early negative experimental evidence. We have overcome the limitations of this approach, leveraging the use of antibody from nonhuman primates (NHPs) that survived challenge to filoviruses under controlled conditions. By using concentrated, polyclonal IgG antibody from these survivors, we treated filovirus-infected NHPs with multiple doses administered over the clinical phase of disease. In the first study, Marburg virus (MARV)-infected NHPs were treated 15 to 30 min postexposure with virus-specific IgG, with additional treatments on days 4 and 8 postexposure. The postexposure IgG treatment was completely protective, with no signs of disease or detectable viremia. MARV-specific IgM antibody responses were generated, and all macaques survived rechallenge with MARV, suggesting that they generated an immune response to virus replication. In the next set of studies, NHPs were infected with MARV or Ebola virus (EBOV), and treatments were delayed 48 h, with additional treatments on days 4 and 8 postexposure. The delayed treatments protected both MARV- and EBOV-challenged NHPs. In both studies, two of the three IgG-treated NHPs had no clinical signs of illness, with the third NHP developing mild and delayed signs of disease followed by full recovery. These studies clearly demonstrate that postexposure antibody treatments can protect NHPs and open avenues for filovirus therapies for human use using established Food and Drug Administration-approved polyclonal or monoclonal antibody technologies.

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Postexposure protection of non-human primates against a lethal Ebola virus challenge with RNA interference: a proof-of-concept study

Abstract: Defense Threat Reduction Agency.

Cited by 415 publications

References 28 publications

Inhibition of Ebola virus glycoprotein-mediated cytotoxicity by targeting its transmembrane domain and cholesterol

Inhibition of Ebola virus glycoprotein-mediated cytotoxicity by targeting its transmembrane domain and cholesterol

Delayed treatment of Ebola virus infection with plant-derived monoclonal antibodies provides protection in rhesus macaques

Postexposure antibody prophylaxis protects nonhuman primates from filovirus disease

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