scholarly journals Development of a Well-Characterized Rhesus Macaque Model of Ebola Virus Disease for Support of Product Development

2021 ◽  
Vol 9 (3) ◽  
pp. 489
Author(s):  
Kendra J. Alfson ◽  
Yenny Goez-Gazi ◽  
Michal Gazi ◽  
Hilary Staples ◽  
Marc Mattix ◽  
...  
Keyword(s):  
Rhesus Macaque ◽  
Ebola Virus ◽  
Virus Disease ◽  
Rna Virus ◽  
Rhesus Macaques ◽  
Systemic Disease ◽  
Clinical Pathology ◽  
Macaque Model ◽  
Progression Of Disease ◽  
Ebov Infection

Ebola virus (EBOV) is a negative-sense RNA virus that can infect humans and nonhuman primates with severe health consequences. Development of countermeasures requires a thorough understanding of the interaction between host and pathogen, and the course of disease. The goal of this study was to further characterize EBOV disease in a uniformly lethal rhesus macaque model, in order to support development of a well-characterized model following rigorous quality standards. Rhesus macaques were intramuscularly exposed to EBOV and one group was euthanized at predetermined time points to characterize progression of disease. A second group was not scheduled for euthanasia in order to analyze survival, changes in physiology, clinical pathology, terminal pathology, and telemetry kinetics. On day 3, sporadic viremia was observed and pathological evidence was noted in lymph nodes. By day 5, viremia was detected in all EBOV exposed animals and pathological evidence was noted in the liver, spleen, and gastrointestinal tissues. These data support the notion that EBOV infection in rhesus macaques is a rapid systemic disease similar to infection in humans, under a compressed time scale. Biomarkers that correlated with disease progression at the earliest stages of infection were observed thereby identifying potential “trigger-to-treat” for use in therapeutic studies.

scholarly journals Mucosal Challenge Ferret Models of Ebola Virus Disease

Pathogens ◽  
2021 ◽  
Vol 10 (3) ◽  
pp. 292
Author(s):  
Trevor Brasel ◽  
Jason E. Comer ◽  
Shane Massey ◽  
Jeanon Smith ◽  
Jennifer Smith ◽  
...  
Keyword(s):  
Disease Progression ◽  
Intranasal Administration ◽  
Ebola Virus ◽  
Advanced Disease ◽  
Virus Disease ◽  
Small Animal ◽  
Clinical Pathology ◽  
Small Animal Model ◽  
Post Challenge ◽  
Mustela Putorius

Recent studies have shown the domestic ferret (Mustela putorius furo) to be a promising small animal model for the study of Ebola virus (EBOV) disease and medical countermeasure evaluation. To date, most studies have focused on traditional challenge routes, predominantly intramuscular and intranasal administration. Here, we present results from a non-clinical pathogenicity study examining oronasal, oral, and ocular mucosal challenge routes in ferrets. Animals were challenged with 1, 10, or 100 plaque forming units EBOV followed by monitoring of disease progression and biosampling. Ferrets administered virus via oronasal and oral routes met euthanasia criteria due to advanced disease 5–10 days post-challenge. Conversely, all ferrets dosed via the ocular route survived until the scheduled study termination 28-day post-challenge. In animals that succumbed to disease, a dose/route response was not observed; increases in disease severity, febrile responses, serum and tissue viral load, alterations in clinical pathology, and gross/histopathology findings were similar between subjects. Disease progression in ferrets challenged via ocular administration was unremarkable throughout the study period. Results from this study further support the ferret as a model for EBOV disease following oral and nasal mucosa exposure.

scholarly journals New Insights Into Marburg Virus Disease Pathogenesis in the Rhesus Macaque Model

2018 ◽  
Author(s):  
Timothy K Cooper ◽  
Jennifer Sword ◽  
Joshua C Johnson ◽  
Amanda Bonilla ◽  
Randy Hart ◽  
...  
Keyword(s):  
Rhesus Macaque ◽  
Virus Disease ◽  
Marburg Virus ◽  
Disease Pathogenesis ◽  
Macaque Model

scholarly journals Statins Suppress Ebola Virus Infectivity by Interfering with Glycoprotein Processing

mBio ◽  
2018 ◽  
Vol 9 (3) ◽  
Author(s):  
Punya Shrivastava-Ranjan ◽  
Mike Flint ◽  
Éric Bergeron ◽  
Anita K. McElroy ◽  
Payel Chatterjee ◽  
...  
Keyword(s):  
Ebola Virus ◽  
Virus Disease ◽  
Statin Treatment ◽  
Ebola Virus Disease ◽  
Health Concern ◽  
Virus Infectivity ◽  
Viral Glycoprotein ◽  
Antiviral Effects ◽  
Ebov Infection ◽  
Glycoprotein Processing

ABSTRACTEbola virus (EBOV) infection is a major public health concern due to high fatality rates and limited effective treatments. Statins, widely used cholesterol-lowering drugs, have pleiotropic mechanisms of action and were suggested as potential adjunct therapy for Ebola virus disease (EVD) during the 2013–2016 outbreak in West Africa. Here, we evaluated the antiviral effects of statin (lovastatin) on EBOV infectionin vitro. Statin treatment decreased infectious EBOV production in primary human monocyte-derived macrophages and in the hepatic cell line Huh7. Statin treatment did not interfere with viral entry, but the viral particles released from treated cells showed reduced infectivity due to inhibition of viral glycoprotein processing, as evidenced by decreased ratios of the mature glycoprotein form to precursor form. Statin-induced inhibition of infectious virus production and glycoprotein processing was reversed by exogenous mevalonate, the rate-limiting product of the cholesterol biosynthesis pathway, but not by low-density lipoprotein. Finally, statin-treated cells produced EBOV particles devoid of the surface glycoproteins required for virus infectivity. Our findings demonstrate that statin treatment inhibits EBOV infection and suggest that the efficacy of statin treatment should be evaluated in appropriate animal models of EVD.IMPORTANCETreatments targeting Ebola virus disease (EVD) are experimental, expensive, and scarce. Statins are inexpensive generic drugs that have been used for many years for the treatment of hypercholesterolemia and have a favorable safety profile. Here, we show the antiviral effects of statins on infectious Ebola virus (EBOV) production. Our study reveals a novel molecular mechanism in which statin regulates EBOV particle infectivity by preventing glycoprotein processing and incorporation into virus particles. Additionally, statins have anti-inflammatory and immunomodulatory effects. Since inflammation and dysregulation of the immune system are characteristic features of EVD, statins could be explored as part of EVD therapeutics.

Characterization of an Anti-Ebola virus Hyperimmune Globulin Derived from Convalescent Plasma

2021 ◽  
Author(s):  
Jonathan M Ciencewicki ◽  
Andrew S Herbert ◽  
Nadia Storm ◽  
Nicole M Josleyn ◽  
Kathleen Huie ◽  
...  
Keyword(s):  
Ebola Virus ◽  
Virus Disease ◽  
Fold Increase ◽  
Surface Glycoprotein ◽  
Post Exposure Prophylaxis ◽  
Emerging Viruses ◽  
Live Virus ◽  
Glycoprotein Antigen ◽  
Ebov Infection ◽  
Exposure Prophylaxis

Abstract Backrgound Convalescent plasma has been used to treat many viral diseases including Ebola. The manufacture of a purified anti-Ebola virus (EBOV) intravenous immunoglobulin (IVIG) from pooled convalescent plasma is described in this paper. Methods An ELISA targeting an EBOV surface glycoprotein antigen was used to determine the immunoglobulin titer of pooled plasma and purified anti-EBOV IVIG. Anti-EBOV IVIG was also tested in neutralization assays using a vesicular stomatitis virus pseudovirion expressing EBOV glycoprotein on its surface and with live EBOV. Finally, the efficacy of the anti-EBOV IVIG was assessed in a mouse model of EBOV infection. Results In the ELISA, the anti-EBOV IVIG was shown to have a seven-fold increase in IgG titer over pooled convalescent plasma. In both the pseudovirion and live virus assays, the anti-EBOV IVIG showed approximately five- to six-fold increased potency over pooled plasma. Anti-EBOV IVIG also significantly improved survivability in mice infected with the virus when administered concurrently or two days after infection. Conclusions These data support this purified anti-EBOV IVIG merits additional investigation and clinical trials for treatment and post-exposure prophylaxis of Ebola virus disease. The experience gained can be applied to manufacture hyperimmune globulins against other emerging viruses.

scholarly journals Anti-α4β7 monoclonal antibody–conjugated nanoparticles block integrin α4β7 on intravaginal T cells in rhesus macaques

2020 ◽  
Vol 6 (34) ◽  
pp. eabb9853
Author(s):  
Sidi Yang ◽  
Geraldine Arrode-Bruses ◽  
Ines Frank ◽  
Brooke Grasperge ◽  
James Blanchard ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
T Cells ◽  
Single Dose ◽  
Side Effects ◽  
Rhesus Macaque ◽  
Rhesus Macaques ◽  
Vaginal Infection ◽  
Macaque Model ◽  
Immunodeficiency Virus ◽  
Vaginal Tract

Intravenous administration of anti-α4β7 monoclonal antibody in macaques decreases simian immunodeficiency virus (SIV) vaginal infection and reduces gut SIV loads. Because of potential side effects of systemic administration, a prophylactic strategy based on mucosal administration of anti-α4β7 antibody may be safer and more effective. With this in mind, we developed a novel intravaginal formulation consisting of anti-α4β7 monoclonal antibody–conjugated nanoparticles (NPs) loaded in a 1% hydroxyethylcellulose (HEC) gel (NP-α4β7 gel). When intravaginally administered as a single dose in a rhesus macaque model, the formulation preferentially bound to CD4+ or CD3+ T cells expressing high levels of α4β7, and occupied ~40% of α4β7 expressed by these subsets and ~25% of all cells expressing α4β7. Blocking of the α4β7 was restricted to the vaginal tract without any changes detected systemically.

scholarly journals Inflammatory and Humoral Immune Response during Ebola Virus Infection in Survivor and Fatal Cases Occurred in Sierra Leone during the 2014–2016 Outbreak in West Africa

Viruses ◽  
2019 ◽  
Vol 11 (4) ◽  
pp. 373 ◽  
Author(s):  
Francesca Colavita ◽  
Mirella Biava ◽  
Concetta Castilletti ◽  
Simone Lanini ◽  
Rossella Miccio ◽  
...  
Keyword(s):  
Immune Response ◽  
Inflammatory Response ◽  
Sierra Leone ◽  
Ebola Virus ◽  
Virus Disease ◽  
Late Phase ◽  
Treatment Center ◽  
Humoral Immune ◽  
Western Africa ◽  
Ebov Infection

Ebola virus (EBOV) infection is characterized by an excessive inflammatory response, a loss of lymphocytes and a general paralysis of the immune system, however pathophysiological mechanisms are not fully understood. In a cohort of 23 fatal and 21 survivors of ebola virus disease (EVD) cases admitted to the Emergency Ebola-Treatment-Center in Goderich (Freetown, Sierra Leone) during the 2014 to 2016 EBOV epidemic in Western Africa, we analyzed the pathway-focused gene expression profile of secreted proteins involved in the immune response and the levels of specific anti-EBOV IgM and IgG from the time of admission till discharge or death. We observed a dysregulated inflammatory response in fatal patients as compared to survivors, mainly consisting of the upregulation of inflammatory mediators, whose extent directly correlated with viremia levels. The upregulation persisted and intensified during the late phase of infection. Relevant differences were also found in humoral immunity, as an earlier and more robust EBOV antibody response was observed in survivor patients.

scholarly journals Peripheral Neuronopathy Associated With Ebola Virus Infection in Rhesus Macaques: A Possible Cause of Neurological Signs and Symptoms in Human Ebola Patients

2020 ◽  
Vol 222 (10) ◽  
pp. 1745-1755
Author(s):  
David X Liu ◽  
Donna L Perry ◽  
Timothy K Cooper ◽  
Louis M Huzella ◽  
Randy J Hart ◽  
...  
Keyword(s):  
Ebola Virus ◽  
Neuronal Degeneration ◽  
Virus Disease ◽  
Rhesus Macaques ◽  
Signs And Symptoms ◽  
Ebola Virus Disease ◽  
Target Cells ◽  
Neurological Signs ◽  
Enteric Ganglia ◽  
Transmission Electron

Abstract 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 ganglia. By immunohistochemistry, RNAscope in situ hybridization, transmission electron microscopy, and confocal microscopy, we confirmed that CD68+ macrophages are the target cells for EBOV in affected ganglia. Further, we demonstrated that EBOV can induce satellite cell and neuronal apoptosis and microglial activation in infected ganglia. Our results demonstrate that EBOV can infect peripheral ganglia and results in ganglionopathy in rhesus macaques, which may contribute to the neurological signs and symptoms observed in acute and convalescent Ebola virus disease in human patients.

scholarly journals 411. Does an Early Cytokine Response During Ebola Virus Disease Improve the Duration of Survival in Rhesus Macaques?

2019 ◽  
Vol 6 (Supplement_2) ◽  
pp. S208-S208
Author(s):  
Paul W Blair ◽  
Karen A O Martins ◽  
Keshtkar-Jahromi Maryam ◽  
Mark G Kortepeter ◽  
Keebaugh Michael ◽  
...  
Keyword(s):  
Ebola Virus ◽  
Cox Regression ◽  
Virus Disease ◽  
Rhesus Macaques ◽  
Early Death ◽  
Ebola Virus Disease ◽  
Cytokine Release ◽  
Time To Death ◽  
Post Exposure ◽  
Increased Risk

Abstract Background Ebola virus disease results in a severe cytokine release resulting in organ failure and disseminated intravascular coagulation, often leading to death. An early post-exposure immune response may improve outcomes but that remains poorly characterized. Therefore, we evaluated select serum cytokine markers of immune activation in nonhuman primates (NHPs) for their association with duration of survival. Methods This was a post-hoc analysis of an interventional supportive care NHP study in which 13 rhesus macaques were inoculated intramuscularly with a target dose of 1000 PFU Zaire ebolavirus (Kikwit). We measured cytokines with a Luminex MAGPIX panel at baseline and daily starting day 3 post-exposure until euthanasia. Based on human clinical data, 10 cytokines and proteins were included in our analysis: IL-1ra, IL-6, IL-10, GM-CSF, MCP-1, MIP-1α, MIP-1β, IFN-γ, TNF-α, and C-reactive protein levels. After NHPs were divided into two groups by k-means clustering, we developed Kaplan–Meier curves for time to death (Figure 1). We visually explored Pearson’s correlation and kinetics of serum cytokines and log10viral load (Figure 1; Figure 2). We fitted cox regression models with each cytokine to evaluate the risk of early disease for each cytokine log10 level or log2-fold change. We performed a sensitivity analysis for MIP-1β centering the data at dpe 0. Results Among NHPs with temperature data, 83% (N = 10) developed fevers (>3 SD baseline) from dpe 3 to 4.The macrophage markerMIP-1β was associated with an increased risk of early death (per log10pg/mL increase, HR= 52.83 at dpe 3, adjusted P = 0.045). Surprisingly, this association was also observed at dpe 0 (HR= 36.88 at dpe 0, adjusted P = 0.044). Other cytokine levels or changes were not associated with an increased hazard of death. Conclusion Our findings did not support a role for early systemic cytokine release in improving survival. However, elevated baseline levels of the MIP-1β may predispose NHPs to early death from EVD. This finding could represent a target for therapeutic strategies and should be further researched. Disclosures All authors: No reported disclosures.

scholarly journals Development of an antibody cocktail for treatment of Sudan virus infection

2020 ◽  
Vol 117 (7) ◽  
pp. 3768-3778 ◽  
Author(s):  
Andrew S. Herbert ◽  
Jeffery W. Froude ◽  
Ramon A. Ortiz ◽  
Ana I. Kuehne ◽  
Danielle E. Dorosky ◽  
...  
Keyword(s):  
Treatment Option ◽  
Ebola Virus ◽  
Protective Efficacy ◽  
Rhesus Macaques ◽  
Macaque Model ◽  
Mammalian Expression ◽  
Significant Difference ◽  
Antibody Cocktail

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 evaluations. Neutralizing activity, competitive binding groups, and epitope specificity of SUDV mAbs were defined before assessing protective efficacy of individual mAbs using a mouse model of SUDV infection. Of the mAbs tested, GP base-binding mAbs were more potent neutralizers and more protective than glycan cap- or mucin-like domain-binding mAbs. No significant difference was observed between plant and mammalian mAbs in any of our in vitro or in vivo evaluations. Based on in vitro and rodent testing, a combination of two SUDV-specific mAbs, one base binding (16F6) and one glycan cap binding (X10H2), was down-selected for assessment in a macaque model of SUDV infection. This cocktail, RIID F6-H2, provided protection from SUDV infection in rhesus macaques when administered at 50 mg/kg on days 4 and 6 postinfection. RIID F6-H2 is an effective postexposure SUDV therapy and provides a potential treatment option for managing human SUDV infection.

scholarly journals ICU-like Care of Nonhuman Primates with Ebola Virus Disease

2020 ◽  
Author(s):  
Paul W Blair ◽  
Mark G Kortepeter ◽  
Lydia G Downey ◽  
Cristian S Madar ◽  
Isaac L Downs ◽  
...  
Keyword(s):  
Supportive Care ◽  
Ebola Virus ◽  
Clinical Laboratory ◽  
Virus Disease ◽  
Rhesus Macaques ◽  
Kidney Injury ◽  
Ebola Virus Disease ◽  
Observational Research ◽  
Control Group ◽  
Survival Difference

Abstract Background Ebola virus disease (EVD) supportive care strategies are largely guided by retrospective observational research. This study investigated the effect of EVD supportive care algorithms on duration of survival in a controlled nonhuman primate (NHP) model. Methods Fourteen rhesus macaques were challenged intramuscularly (IM) with a target dose of 1000 PFU Zaire ebolavirus (Kikwit). NHPs were allocated to intensive care unit (ICU)-like algorithms (n=7), intravenous fluids (IVF) plus levofloxacin (n=2), or a control group (n=5). The primary outcome measure was duration of survival, and secondary outcomes included changes in clinical laboratory values. Results Duration of survival was not significantly different between the pooled ICU-like algorithm and control groups (8.2 vs 6.9 days of survival, hazard ratio 0.50, p = 0.25). Norepinephrine was effective in transiently maintaining baseline blood pressure. NHPs treated with ICU-like algorithms had delayed onset of liver and kidney injury. Conclusions While an obvious survival difference was not observed with ICU-like care, clinical observations from this model may aid in EVD supportive care NHP model refinement.

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