Ebola Hemorrhagic Fever: Evaluation of Passive Immunotherapy in Nonhuman Primates

Jahrling, Peter B.; Geisbert, Joan B.; Swearengen, James R.; Larsen, Tom; Geisbert, Thomas W.

doi:10.1086/520587

Cited by 113 publications

(75 citation statements)

References 13 publications

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“…However, the authors involved with the study concluded that a number of factors other than administration of convalescent blood could have contributed to the high survival observed among these patients. Two preclinical studies in NHPs have attempted to replicate this study with the use of either convalescent NHP whole blood 121 or convalescent NHP serum 122 (TABLE 1). In an initial study, four rhesus monkeys were treated with homologous convalescent whole blood from rhesus macaque donors immediately after EBOV (Kikwit strain) challenge and again on day 3 or 4 after exposure 121 .…”

Section: Box 4 | Screening Systems For Drug Developmentmentioning

confidence: 99%

“…Two preclinical studies in NHPs have attempted to replicate this study with the use of either convalescent NHP whole blood 121 or convalescent NHP serum 122 (TABLE 1). In an initial study, four rhesus monkeys were treated with homologous convalescent whole blood from rhesus macaque donors immediately after EBOV (Kikwit strain) challenge and again on day 3 or 4 after exposure 121 . Serum levels of anti-EBOV antibodies were comparable to levels associated with protective vaccination; however, all treated animals succumbed to the infection with no delay in death versus controls 121 .…”

Section: Box 4 | Screening Systems For Drug Developmentmentioning

confidence: 99%

“…In an initial study, four rhesus monkeys were treated with homologous convalescent whole blood from rhesus macaque donors immediately after EBOV (Kikwit strain) challenge and again on day 3 or 4 after exposure 121 . Serum levels of anti-EBOV antibodies were comparable to levels associated with protective vaccination; however, all treated animals succumbed to the infection with no delay in death versus controls 121 . In a more recent study, four rhesus monkeys were treated with pooled homologous convalescent serum from rhesus macaque donors on days 3, 6, and 9 after EBOV (Makona strain) challenge 122 .…”

Section: Box 4 | Screening Systems For Drug Developmentmentioning

confidence: 99%

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Post-exposure treatments for Ebola and Marburg virus infections

Cross

Mire

Feldmann

et al. 2018

Nat Rev Drug Discov

107

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| The filoviruses -Ebola virus and Marburg virus -cause lethal haemorrhagic fever in humans and non-human primates (NHPs). Filoviruses present a global health threat both as naturally acquired diseases and as potential agents of bioterrorism. In the recent 2013-2016 outbreak of Ebola virus, the most promising therapies for post-exposure use with demonstrated efficacy in the gold-standard NHP models of filovirus disease were unable to show statistically significant protection in patients infected with Ebola virus. This Review briefly discusses these failures and what has been learned from these experiences, and summarizes the current status of post-exposure medical countermeasures in development, including antibodies, small interfering RNA and small molecules. We outline how our current knowledge could be applied to the identification of novel interventions and ways to use interventions more effectively. R E V I E W SNATURE REVIEWS | DRUG DISCOVERY VOLUME 17 | JUNE 2018 | 413 © 2 0 1 8 M a c m i l l a n P u b l i s h e r s L i m i t e d , p a r t o f S p r i n g e r N a t u r e . A l l r i g h t s r e s e r v e d . AstheniaMuscular weakness. MyalgiaMuscular pain. ArthralgiaJoint pain. LeukopeniaA condition of having a low number of circulating leukocytes, including neutrophils, eosinophils, basophils, lymphocytes and monocytes. LymphocytopeniaA condition of having a low number of circulating leukocytes, including natural killer cells, T cells and B cells. ThrombocytopeniaA condition of having a low number of circulating thrombocytes, also known as platelets.and Ebolavirus. The Marburgvirus genus contains a single species, Marburg marburgvirus, which contains two members, Marburg virus (MARV) and Ravn virus (RAVV). The Ebolavirus genus consists of five distinct species: Bundibugyo ebolavirus (BDBV), Reston ebolavirus (RESTV), Sudan ebolavirus (SUDV), Tai Forest ebolavirus (TAFV; previously termed 'Côte d'Ivoire ebolavirus' but more commonly known as 'Ivory Coast ebolavirus') and Zaire ebolavirus (EBOV). MARV, RAVV, BDBV, SUDV and EBOV are important human pathogens, with case fatality rates often up to 90% for MARV, RAVV and EBOV, and around 55% for SUDV 8,10 . On the basis of two small outbreaks in 2007 and 2012, BDBV seems to be the least pathogenic, with a case fatality rate of about 40-48% 11,12 . In 1994, TAFV was associated with a number of deaths in chimpanzees and a single symptomatic but non-lethal human infection in the Republic of Côte d'Ivoire 13,14 . RESTV is lethal for macaques but is not thought to cause disease in humans 15 . An outbreak of RESTV was reported in pigs in the Philippines in 2008; however, it remains uncertain whether the disease observed in the pigs was caused by RESTV or other agents reported to have co-infected the animals 16 . Clinical manifestationsClinical and laboratory signs of disease caused by filovirus infection are nonspecific and usually associated with an incubation period of 2-21 days (mean 4-10 days) 8,17 . Illness begins with an abrupt onset of fever, astheni...

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Section: Box 4 | Screening Systems For Drug Developmentmentioning

confidence: 99%

Section: Box 4 | Screening Systems For Drug Developmentmentioning

confidence: 99%

Section: Box 4 | Screening Systems For Drug Developmentmentioning

confidence: 99%

See 1 more Smart Citation

Post-exposure treatments for Ebola and Marburg virus infections

Cross

Mire

Feldmann

et al. 2018

Nat Rev Drug Discov

107

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“…26). Similarly, neutralizing polyclonal antibody also failed to protect NHPs (27). However, protection with polyclonal antibody against another filovirus, Marburg, has recently been reported (John Dye et al; Chemical and Biological Defense Science and Technology Conference, 15-19 November 2010 in Orlando, FL), suggesting that, with the right specificity, protection against EBOV should be achievable.…”

Section: Discussionmentioning

confidence: 98%

Enhanced potency of a fucose-free monoclonal antibody being developed as an Ebola virus immunoprotectant

Zeitlin

Pettitt

Scully

et al. 2011

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

210

195

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No countermeasures currently exist for the prevention or treatment of the severe sequelae of Filovirus (such as Ebola virus; EBOV) infection. To overcome this limitation in our biodefense preparedness, we have designed monoclonal antibodies (mAbs) which could be used in humans as immunoprotectants for EBOV, starting with a murine mAb (13F6) that recognizes the heavily glycosylated mucin-like domain of the virion-attached glycoprotein (GP). Point mutations were introduced into the variable region of the murine mAb to remove predicted human T-cell epitopes, and the variable regions joined to human constant regions to generate a mAb (h-13F6) appropriate for development for human use. We have evaluated the efficacy of three variants of h-13F6 carrying different glycosylation patterns in a lethal mouse EBOV challenge model. The pattern of glycosylation of the various mAbs was found to correlate to level of protection, with aglycosylated h-13F6 providing the least potent efficacy (ED 50 = 33 μg). A version with typical heterogenous mammalian glycoforms (ED 50 = 11 μg) had similar potency to the original murine mAb. However, h-13F6 carrying complex N-glycosylation lacking core fucose exhibited superior potency (ED 50 = 3 μg). Binding studies using Fcγ receptors revealed enhanced binding of nonfucosylated h-13F6 to mouse and human FcγRIII. Together the results indicate the presence of Fc N-glycans enhances the protective efficacy of h-13F6, and that mAbs manufactured with uniform glycosylation and a higher potency glycoform offer promise as biodefense therapeutics.passive immunization | antibody glycosylation | antibody-dependent cellular cytotoxicity | antiviral

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“…Passive transfer of serum collected from survivors of Junin virus or Lassa virus has proven effective provided treatments are initiated soon after infection (4)(5)(6). However, antibody passive transfer experiments have been largely unsuccessful in treating filovirus infections (7). During a 1995 outbreak of EBOV in Kikwit, Democratic Republic of the Congo, seven of eight patients who exhibited symptoms and detectable EBOV antigen in their blood survived disease after treatment with whole blood from convalescent EBOV survivors (8).…”

mentioning

confidence: 99%

Postexposure antibody prophylaxis protects nonhuman primates from filovirus disease

Dye

Herbert²,

Kuehne³

et al. 2012

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

245

220

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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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Ebola Hemorrhagic Fever: Evaluation of Passive Immunotherapy in Nonhuman Primates

Cited by 113 publications

References 13 publications

Post-exposure treatments for Ebola and Marburg virus infections

Post-exposure treatments for Ebola and Marburg virus infections

Enhanced potency of a fucose-free monoclonal antibody being developed as an Ebola virus immunoprotectant

Postexposure antibody prophylaxis protects nonhuman primates from filovirus disease

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