Antibody Treatment of Ebola and Sudan Virus Infection via a Uniquely Exposed Epitope within the Glycoprotein Receptor-Binding Site

Howell, Katie A.; Qiu, Xiangguo; Brannan, Jennifer M.; Bryan, Christopher; Davidson, Edgar; Holtsberg, Frederick W.; Wec, Anna Z.; Shulenin, Sergey; Biggins, Julia E.; Douglas, R. Gordon; Enterlein, Sven; Turner, Hannah L.; Pallesen, Jesper; Murin, Charles D.; He, Shihua; Kroeker, Andrea; Vu, Hong; Herbert, Andrew S.; Fusco, Marnie L.; Nyakatura, Elisabeth K.; Lai, Jonathan R.; Keck, Zhen Yong; Foung, Steven K. H.; Saphire, Erica Ollmann; Zeitlin, Larry; Ward, Andrew B.; Chandran, Kartik; Doranz, Benjamin J.; Kobinger, Gary P.; Dye, John M.; Aman, M. Javad

doi:10.1016/j.celrep.2016.04.026

Cited by 85 publications

(96 citation statements)

References 55 publications

(144 reference statements)

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“…Serially diluted serum was mixed and incubated with 100 plaque-forming units of EBOV, and percent neutralization was determined relative to wells treated with media alone, as described in (55). Detailed methods are in the Supplementary Materials.…”

Section: Methodsmentioning

confidence: 99%

Longitudinal peripheral blood transcriptional analysis of a patient with severe Ebola virus disease

et al. 2017

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The 2013–2015 outbreak of Ebola virus disease in Guinea, Liberia, and Sierra Leone was unprecedented in the number of documented cases, but there have been few published reports on immune responses in clinical cases and their relationships with the course of illness and severity of Ebola virus disease. Symptoms of Ebola virus disease can include severe headache, myalgia, asthenia, fever, fatigue, diarrhea, vomiting, abdominal pain, and hemorrhage. Although experimental treatments are in development, there are no current U.S. Food and Drug Administration–approved vaccines or therapies. We report a detailed study of host gene expression as measured by microarray in daily peripheral blood samples collected from a patient with severe Ebola virus disease. This individual was provided with supportive care without experimental therapies at the National Institutes of Health Clinical Center from before onset of critical illness to recovery. Pearson analysis of daily gene expression signatures revealed marked gene expression changes in peripheral blood leukocytes that correlated with changes in serum and peripheral blood leukocytes, viral load, antibody responses, coagulopathy, multiple organ dysfunction, and then recovery. This study revealed marked shifts in immune and antiviral responses that preceded changes in medical condition, indicating that clearance of replicating Ebola virus from peripheral blood leukocytes is likely important for systemic viral clearance.

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Section: Methodsmentioning

confidence: 99%

Longitudinal peripheral blood transcriptional analysis of a patient with severe Ebola virus disease

et al. 2017

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“…A similar base-binder, 16F6, was also reported to neutralize SUDV only (Dias et al, 2011). Recently, we and others have identified several cross-neutralizing epitopes within the RBS (Howell et al, 2016; Keck et al, 2015) and the glycan cap (Bornholdt et al, 2016b; Flyak et al, 2016; Holtsberg et al, 2015), suggesting that development of broadly neutralizing antibodies (bNAbs) and cross protective vaccines may be feasible.…”

Section: Introductionmentioning

confidence: 99%

Immunization-Elicited Broadly Protective Antibody Reveals Ebolavirus Fusion Loop as a Site of Vulnerability

Zhao

Howell

et al. 2017

Cell

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Summary While neutralizing antibodies are highly effective against ebolavirus infections, current experimental ebolavirus vaccines primarily elicit species-specific antibody responses. Here we describe an immunization-elicited macaque antibody (CA45) that clamps the internal fusion loop with the N-terminus of the ebolavirus glycoproteins (GP) and potently neutralizes Ebola, Sudan, Bundibugyo, and Reston viruses. CA45, alone or in combination with an antibody that blocks receptor binding, provided full protection against all pathogenic ebolaviruses in mice, guinea pigs, and ferrets. Analysis of memory B cells from the immunized macaque suggests that elicitation of broadly neutralizing antibodies (bNAbs) for ebolaviruses is possible but difficult, potentially due to the rarity of bNAb clones and their precursors. Unexpectedly, germline-reverted CA45, while exhibiting negligible binding to full-length GP, bound a proteolytically remodeled GP with picomolar affinity, suggesting that engineered ebolavirus vaccines could trigger rare bNAb precursors more robustly. These findings have important implications for developing pan-ebolavirus vaccine and immunotherapeutic cocktails.

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“…It is unclear whether any of the therapies currently in development for EBOV infection, such as monoclonal antibodies and nucleos(t)ide analogues 7–11 , possess broad-spectrum activity against SUDV in the rigorous NHP models of SUDV infection. Recent reports have shown cross-protective efficacy of monoclonal antibodies in guinea pig and mouse models 12–16 , with no data in the NHP model to date.…”

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confidence: 99%

Rescue of non-human primates from advanced Sudan ebolavirus infection with lipid encapsulated siRNA

et al. 2016

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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 received siRNA-LNP beginning at 1, 2, 3, 4 or 5 days post-challenge. VP35-targeting siRNA-LNP treatment resulted in up to 100% survival, even when initiated when fever, viraemia and disease signs were evident. Treatment effectively controlled viral replication, mediating up to 4 log10 reductions after dosing. Mirroring clinical findings, a correlation between high viral loads and fatal outcome was observed, emphasizing the importance of stratifying efficacy according to viral load. In summary, strong survival benefit and rapid control of SUDV replication by VP35-targeting LNP confirm its therapeutic potential in combatting this lethal disease.

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Antibody Treatment of Ebola and Sudan Virus Infection via a Uniquely Exposed Epitope within the Glycoprotein Receptor-Binding Site

Cited by 85 publications

References 55 publications

Longitudinal peripheral blood transcriptional analysis of a patient with severe Ebola virus disease

Longitudinal peripheral blood transcriptional analysis of a patient with severe Ebola virus disease

Immunization-Elicited Broadly Protective Antibody Reveals Ebolavirus Fusion Loop as a Site of Vulnerability

Rescue of non-human primates from advanced Sudan ebolavirus infection with lipid encapsulated siRNA

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