scholarly journals Equine-Origin Immunoglobulin Fragments Protect Nonhuman Primates from Ebola Virus Disease

2018 ◽  
Vol 93 (5) ◽  
Author(s):  
Hualei Wang ◽  
Gary Wong ◽  
Wenjun Zhu ◽  
Shihua He ◽  
Yongkun Zhao ◽  
...  
Keyword(s):  
Large Scale ◽  
Nonhuman Primates ◽  
Ebola Virus ◽  
Virus Disease ◽  
Hemorrhagic Fever ◽  
West African ◽  
Clinical Testing ◽  
The Past ◽  
Over 40 Years

ABSTRACT Ebola virus (EBOV) infections result in aggressive hemorrhagic fever in humans, with fatality rates reaching 90% and with no licensed specific therapeutics to treat ill patients. Advances over the past 5 years have firmly established monoclonal antibody (MAb)-based products as the most promising therapeutics for treating EBOV infections, but production is costly and quantities are limited; therefore, MAbs are not the best candidates for mass use in the case of an epidemic. To address this need, we generated EBOV-specific polyclonal F(ab′)2 fragments from horses hyperimmunized with an EBOV vaccine. The F(ab′)2 was found to potently neutralize West African and Central African EBOV in vitro. Treatment of nonhuman primates (NHPs) with seven doses of 100 mg/kg F(ab′)2 beginning 3 or 5 days postinfection (dpi) resulted in a 100% survival rate. Notably, NHPs for which treatment was initiated at 5 dpi were already highly viremic, with observable signs of EBOV disease, which demonstrated that F(ab′)2 was still effective as a therapeutic agent even in symptomatic subjects. These results show that F(ab′)2 should be advanced for clinical testing in preparation for future EBOV outbreaks and epidemics. IMPORTANCE EBOV is one of the deadliest viruses to humans. It has been over 40 years since EBOV was first reported, but no cure is available. Research breakthroughs over the past 5 years have shown that MAbs constitute an effective therapy for EBOV infections. However, MAbs are expensive and difficult to produce in large amounts and therefore may only play a limited role during an epidemic. A cheaper alternative is required, especially since EBOV is endemic in several third world countries with limited medical resources. Here, we used a standard protocol to produce large amounts of antiserum F(ab′)2 fragments from horses vaccinated with an EBOV vaccine, and we tested the protectiveness in monkeys. We showed that F(ab′)2 was effective in 100% of monkeys even after the animals were visibly ill with EBOV disease. Thus, F(ab′)2 could be a very good option for large-scale treatments of patients and should be advanced to clinical testing.

scholarly journals Macaque Monoclonal Antibodies Targeting Novel Conserved Epitopes within Filovirus Glycoprotein

2015 ◽  
Vol 90 (1) ◽  
pp. 279-291 ◽  
Author(s):  
Zhen-Yong Keck ◽  
Sven G. Enterlein ◽  
Katie A. Howell ◽  
Hong Vu ◽  
Sergey Shulenin ◽  
...  
Keyword(s):  
Monoclonal Antibodies ◽  
Nonhuman Primates ◽  
Ebola Virus ◽  
Virus Disease ◽  
Protective Efficacy ◽  
Hemorrhagic Fever ◽  
Marburg Virus ◽  
Human Pathogens ◽  
Content Type ◽  
The Core

ABSTRACTFiloviruses cause highly lethal viral hemorrhagic fever in humans and nonhuman primates. Current immunotherapeutic options for filoviruses are mostly specific to Ebola virus (EBOV), although other members ofFiloviridaesuch as Sudan virus (SUDV), Bundibugyo virus (BDBV), and Marburg virus (MARV) have also caused sizeable human outbreaks. Here we report a set of pan-ebolavirus and pan-filovirus monoclonal antibodies (MAbs) derived from cynomolgus macaques immunized repeatedly with a mixture of engineered glycoproteins (GPs) and virus-like particles (VLPs) for three different filovirus species. The antibodies recognize novel neutralizing and nonneutralizing epitopes on the filovirus glycoprotein, including conserved conformational epitopes within the core regions of the GP1 subunit and a novel linear epitope within the glycan cap. We further report the first filovirus antibody binding to a highly conserved epitope within the fusion loop of ebolavirus and marburgvirus species. One of the antibodies binding to the core GP1 region of all ebolavirus species and with lower affinity to MARV GP cross neutralized both SUDV and EBOV, the most divergent ebolavirus species. In a mouse model of EBOV infection, this antibody provided 100% protection when administered in two doses and partial, but significant, protection when given once at the peak of viremia 3 days postinfection. Furthermore, we describe novel cocktails of antibodies with enhanced protective efficacy compared to individual MAbs. In summary, the present work describes multiple novel, cross-reactive filovirus epitopes and innovative combination concepts that challenge the current therapeutic models.IMPORTANCEFiloviruses are among the most deadly human pathogens. The 2014-2015 outbreak of Ebola virus disease (EVD) led to more than 27,000 cases and 11,000 fatalities. While there are five species ofEbolavirusand several strains of marburgvirus, the current immunotherapeutics primarily target Ebola virus. Since the nature of future outbreaks cannot be predicted, there is an urgent need for therapeutics with broad protective efficacy against multiple filoviruses. Here we describe a set of monoclonal antibodies cross-reactive with multiple filovirus species. These antibodies target novel conserved epitopes within the envelope glycoprotein and exhibit protective efficacy in mice. We further present novel concepts for combination of cross-reactive antibodies against multiple epitopes that show enhanced efficacy compared to monotherapy and provide complete protection in mice. These findings set the stage for further evaluation of these antibodies in nonhuman primates and development of effective pan-filovirus immunotherapeutics for use in future outbreaks.

scholarly journals IN VITRO DIAGNOSIS FOR EBOLA VIRUS DISEASE. A COMPARISON OF CURRENT TECHNIQUES AND DIAGNOSTIC ASSAYS

2019 ◽  
Vol 1 (3) ◽  
pp. 105-116
Author(s):  
A. O. Sementsova ◽  
V. G. Dedkov ◽  
V. A. Ternovoy ◽  
E. V. Chub ◽  
S. A. Pyankov ◽  
...  
Keyword(s):  
Ebola Virus ◽  
Clinical Symptoms ◽  
Virus Disease ◽  
Hemorrhagic Fever ◽  
Multiple Organ ◽  
Ebola Virus Disease ◽  
Diagnostic Assays ◽  
Natural Foci ◽  
Forested Areas

Ebola virus disease is dangerous viral infection, occurring in the form of hemorrhagic fever, characterized by acute clinical symptoms and high mortality rate due to multiple organ failure. Ebola virus natural foci are located in forested areas of the central and western parts of Africa. It was believed for many years, the incidence of Ebola virus disease has been sporadic and the burden of it is true only in endemic areas. However, the unprecedented Ebola epidemic caused by Zaire virus in 2013 — 2016, has significantly changed our understanding of this disease and the patterns of its distribution. We have also identified weaknesses in the organization of anti-epidemic measures, the effectiveness of which was not very effective at the onset of the epidemic, in particular due to weak development of in vitro diagnostics (IVD). However, during the elimination of the epidemic in West Africa, anti-epidemic system has been modified substantially, largely due to quickly developed IVD kits. This review is devoted to analysis of trends in IVD for Ebola virus disease based on the experience obtained in the course of the West-African epidemic in 2013 — 2016.

scholarly journals Ebolavirus Entry: From Molecular Characterization to Drug Discovery

2019 ◽  
Author(s):  
Cristiano Salata ◽  
Arianna Calistri ◽  
Gualtiero Alvisi ◽  
Michele Celestino ◽  
Cristina Parolin ◽  
...  
Keyword(s):  
Life Cycle ◽  
Viral Entry ◽  
Large Scale ◽  
Ebola Virus ◽  
Virus Disease ◽  
Drug Repurposing ◽  
In Vitro Study ◽  
Rational Drug Design ◽  
Global Public Health

Ebola Virus Disease (EVD) is one of the most lethal transmissible infections characterized by a high fatality rate, and caused by members of the Filoviridae family. The recent large outbreak of EVD in West Africa (2013-2016), highlighted the worldwide danger of this disease and its impact on global public health and economy. The development of highly needed anti-Filoviridae antivirals has been so far hampered by the shortage of tools to study their life cycle in vitro, and therefore screen for potential active compounds outside a biosafety level-4 (BSL-4) containment. Importantly, the development of surrogate models to in vitro study of Filoviridae entry in a BSL-2 setting, such as viral pseudotypes and Ebola virus like particles, tremendously boosted both our knowledge on viral life cycle and the identification of promising anti-Filoviridae compounds interfering with viral entry. In this context, the combination of such surrogate systems with large-scale small molecule compounds and haploid genetic screenings, as well as rational drug design and drug repurposing approaches will prove priceless in our quest for the development of a treatment for EVD.

scholarly journals Identification and characterization of defective viral genomes in Ebola virus infected rhesus macaques

2021 ◽  
Author(s):  
Rebecca I. Johnson ◽  
Beata Boczkowska ◽  
Kendra Alfson ◽  
Taylor Weary ◽  
Heather Menzie ◽  
...  
Keyword(s):  
Nonhuman Primates ◽  
Ebola Virus ◽  
Sequence Data ◽  
Rna Virus ◽  
Hemorrhagic Fever ◽  
Marburg Virus ◽  
Immunostimulatory Activity ◽  
Viral Genomes

Ebola virus (EBOV), of the family Filoviridae, is an RNA virus that can cause hemorrhagic fever with a high mortality rate. Defective viral genomes (DVGs) are truncated genomes that have been observed during multiple RNA virus infections, including  in vitro EBOV infection, and have previously been associated with viral persistence and immunostimulatory activity. As DVGs have been detected in cells persistently infected with EBOV, we hypothesized that DVGs may also accumulate during viral replication in filovirus-infected hosts. Therefore, we interrogated sequence data from serum and tissues using a bioinformatics tool in order to identify the presence of DVGs in nonhuman primates (NHPs) infected with EBOV, Sudan virus (SUDV) or Marburg virus (MARV). Multiple 5’ copy-back DVGs (cbDVGs) were detected in NHP serum during the acute phase of filovirus infection. While the relative abundance of total DVGs in most animals was low, serum collected during acute EBOV and SUDV infections, but not MARV infection, contained a higher proportion of short trailer sequence cbDVGs than the challenge stock. This indicated an accumulation of these DVGs throughout infection, potentially due to the preferential replication of short DVGs over the longer viral genome. Using RT-PCR and deep sequencing, we also confirmed the presence of 5’ cbDVGs in EBOV-infected NHP testes, which is of interest due to EBOV persistence in semen of male survivors of infection. This work suggests that DVGs play a role in EBOV infection in vivo and further study will lead to a better understanding of EBOV pathogenesis. Importance The study of filovirus pathogenesis is critical for understanding the consequences of infection and the development of strategies to ameliorate future outbreaks. Defective viral genomes (DVGs) have been detected during EBOV infections in vitro , however their presence in in vivo infections remains unknown. In this study, DVGs were detected in samples collected from EBOV- and SUDV-infected nonhuman primates (NHPs). The accumulation of these DVGs in the trailer region of the genome during infection indicates a potential role in EBOV and SUDV pathogenesis. In particular, the presence of DVGs in the testes of infected NHPs requires further investigation as it may be linked to the establishment of persistence.

scholarly journals Ebola Virus Entry: From Molecular Characterization to Drug Discovery

Viruses ◽  
2019 ◽  
Vol 11 (3) ◽  
pp. 274 ◽  
Author(s):  
Cristiano Salata ◽  
Arianna Calistri ◽  
Gualtiero Alvisi ◽  
Michele Celestino ◽  
Cristina Parolin ◽  
...  
Keyword(s):  
Life Cycle ◽  
Viral Entry ◽  
Large Scale ◽  
Ebola Virus ◽  
Virus Disease ◽  
Virus Entry ◽  
Drug Repurposing ◽  
Rational Drug Design ◽  
Global Public Health

Ebola Virus Disease (EVD) is one of the most lethal transmissible infections, characterized by a high fatality rate, and caused by a member of the Filoviridae family. The recent large outbreak of EVD in Western Africa (2013–2016) highlighted the worldwide threat represented by the disease and its impact on global public health and the economy. The development of highly needed anti-Ebola virus antivirals has been so far hampered by the shortage of tools to study their life cycle in vitro, allowing to screen for potential active compounds outside a biosafety level-4 (BSL-4) containment. Importantly, the development of surrogate models to study Ebola virus entry in a BSL-2 setting, such as viral pseudotypes and Ebola virus-like particles, tremendously boosted both our knowledge of the viral life cycle and the identification of promising antiviral compounds interfering with viral entry. In this context, the combination of such surrogate systems with large-scale small molecule compounds and haploid genetic screenings, as well as rational drug design and drug repurposing approaches will prove priceless in our quest for the development of a treatment for EVD.

scholarly journals A Mathematical Model of Contact Tracing during the 2014–2016 West African Ebola Outbreak

Mathematics ◽  
2021 ◽  
Vol 9 (6) ◽  
pp. 608
Author(s):  
Danielle Burton ◽  
Suzanne Lenhart ◽  
Christina J. Edholm ◽  
Benjamin Levy ◽  
Michael L. Washington ◽  
...  
Keyword(s):  
Mathematical Model ◽  
Disease Management ◽  
Ebola Virus ◽  
Virus Disease ◽  
Infected Individual ◽  
Vital Role ◽  
West African ◽  
Contact Tracing ◽  
The Novel ◽  
Using Data

The 2014–2016 West African outbreak of Ebola Virus Disease (EVD) was the largest and most deadly to date. Contact tracing, following up those who may have been infected through contact with an infected individual to prevent secondary spread, plays a vital role in controlling such outbreaks. Our aim in this work was to mechanistically represent the contact tracing process to illustrate potential areas of improvement in managing contact tracing efforts. We also explored the role contact tracing played in eventually ending the outbreak. We present a system of ordinary differential equations to model contact tracing in Sierra Leonne during the outbreak. Using data on cumulative cases and deaths, we estimate most of the parameters in our model. We include the novel features of counting the total number of people being traced and tying this directly to the number of tracers doing this work. Our work highlights the importance of incorporating changing behavior into one’s model as needed when indicated by the data and reported trends. Our results show that a larger contact tracing program would have reduced the death toll of the outbreak. Counting the total number of people being traced and including changes in behavior in our model led to better understanding of disease management.

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