#Equine-origin #immunoglobulin fragments protects nonhuman #primates from #Ebola virus disease (J Virol., abstract)

[Source: Journal of Virology, full page: (LINK). Abstract, edited.]

Equine-origin immunoglobulin fragments protects nonhuman primates from Ebola virus disease

Hualei Wang, Gary Wong, Wenjun Zhu, Shihua He, Yongkun Zhao, Feihu Yan, Md Niaz Rahim, Yuhai Bi, Zirui Zhang, Keding Cheng, Hongli Jin, Zengguo Cao, Xuexing Zheng, Weiwei Gai,Jieying Bai, Weijin Chen, Yong Zou, Yuwei Gao, George F Gao, Songtao Yang, Xianzhu Xia, Xiangguo Qiu

DOI: 10.1128/JVI.01548-18

 

ABSTRACT

Ebola virus (EBOV) infections result in aggressive hemorrhagic fever in humans with fatality rates reaching 90%, 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, quantities are limited, and thus mAbs are not the best candidates for mass use in the case of an epidemic. To address this need, we generated EBOV-specific polyclonal immunoglobulin fragments F(ab’)2 from horses hyperimmunized with an EBOV vaccine. The F(ab’)2 was found to potently neutralize West and Central African EBOV in vitro. Treatment of nonhuman primates (NHPs) with seven doses of 100mg/kg F(ab’)2 beginning at 3 or 5 days post-infection (dpi) resulted in 100% survival. Notably, NHPs that initiated treatment at 5 dpi were already highly viremic with observable signs of EBOV disease, demonstrating that F(ab’)2 was still effective as a therapeutic even in symptomatic patients. These results show that F(ab’)2 should be accelerated for clinical testing in preparation of future EBOV outbreaks and epidemics.

 

IMPORTANCE

Ebola is one of the deadliest viruses to humans. It has been over 40 years since Ebola was first reported, but no cure is available. Research breakthroughs over the last 5 years have shown that monoclonal antibodies (mAbs) constitute an effective therapy for Ebola. However, mAbs are expensive, difficult to produce in large amounts and therefore may only play a limited role during an epidemic. A cheaper alternative is required, especially since Ebola is endemic in several third-world countries with limited medical resources. Here, we used a standard protocol to produce large amounts of antisera fragments (F(ab’)2) from horses vaccinated with an Ebola vaccine, and tested its protectiveness in monkeys. We showed that F(ab’)2 was effective in 100% of monkeys even after these animals were visibly ill with Ebola. Thus, F(ab’)2 could be a very good option for large-scale treatments of patients and should be advanced to clinical testing.

© Crown copyright 2018. This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International license.

Keywords: Ebola; Serotherapy; Animal models.

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Contemporary anti- #Ebola #drug #discovery approaches and platforms (ACS Infect Dis., abstract)

[Source: US National Library of Medicine, full page: (LINK). Abstract, edited.]

ACS Infect Dis. 2018 Dec 5. doi: 10.1021/acsinfecdis.8b00285. [Epub ahead of print]

Contemporary anti-Ebola drug discovery approaches and platforms.

Schneider-Futschik EK, Hoyer D, Khromykh A, Baell JB, Marsh G, Baker MA, Li J, Velkov T.

 

Abstract

The Ebola virus has a grave potential to destabilise civil society as we know it. The past few deadly Ebola outbreaks were unprecedented in size: the virus spread from the epicentres of Guinea, Sierra Leone, Nigeria and Liberia. The 2014-15 Ebola West Africa outbreak was associated with almost 30,000 suspected or confirmed cases and over 11,000 documented deaths. There is a general acceptance within the World Health Organisation (WHO) and the Ebola outbreak response community that future outbreaks will become increasingly more frequent and more likely to involve inter-continental transmission. The magnitude of the recent outbreaks demonstrated in dramatic fashion the shortcomings of our mass casualty disease response capabilities and lack of therapeutic modalities for supporting Ebola outbreak prevention and control. Currently, there are no approved drugs in sight although vaccines for human Ebola virus infection are in the trial phases. Treatment is limited to pain management and supportive care to counter dehydration and lack of oxygen. This underscores the critical need for effective anti-viral drugs that specifically target this deadly disease. This review examines the current approaches for the discovery of anti-Ebola small molecule or biological therapeutics, their viral targets, mode of action and contemporary platforms, which collectively form the backbone of the anti-Ebola drug discovery pipeline.

PMID: 30516045 DOI: 10.1021/acsinfecdis.8b00285

Keywords: Ebola; Antivirals.

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Role of the #Ebola #membrane in the protection conferred by the three- #mAb cocktail #MIL77 (Sci Rep., abstract)

[Source: US National Library of Medicine, full page: (LINK). Abstract, edited.]

Sci Rep. 2018 Dec 4;8(1):17628. doi: 10.1038/s41598-018-35964-6.

Role of the Ebola membrane in the protection conferred by the three-mAb cocktail MIL77.

Cao P1, Bai H2, Wang X3, Che J4.

Author information: 1 Center for Drug Evaluation, CFDA, Beijing, People’s Republic of China. 2 Phase I Clinical Trial Center, Beijing Shijitan Hospital of Capital Medical University, Beijing, People’s Republic of China. 3 Phase I Clinical Trial Center, Beijing Shijitan Hospital of Capital Medical University, Beijing, People’s Republic of China. wangxh@bjsjth.cn. 4 State Key Laboratory of Toxicology and Medical Countermeasures, Institute of Pharmacology and Toxicology, Beijing, People’s Republic of China. chejinjing80@126.com.

 

Abstract

MIL77, which has a higher manufacturing capacity than ZMapp, comprises MIL77-1, MIL77-2, and MIL77-3. The mechanisms by which these antibodies inhibit glycoprotein are unclear. Infection by viruses with lipid-bilayer envelopes occurs via the fusion of the viral membrane with the membrane of the target cell. Therefore, the interaction between the antibodies and the EBOV membrane is crucial. We examined the interactions between MIL77 and the viral membrane using SPR. MIL77-1 selectively binds to viral membranes, while MIL77-2 and MIL77-3 do not. MIL77-1’s ability to screen the more rigid domains of the membranes results in a locally increased concentration of the drug at the fusion site. Although MIL77-2 recognizes an epitope of GP, it is not necessary in the MIL77 cocktail. These results highlight the importance of EBOV membrane interactions in improving the efficiency of a neutralizing antibody. Furthermore, the viral membrane may be an important target of antibodies against EBOV.

PMID: 30514891 DOI: 10.1038/s41598-018-35964-6 Free full text

Keywords: Ebola; Monoclonal antibodies.

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#Persistence and #Sexual #Transmission of #Filoviruses (Viruses, abstract)

[Source: US National Library of Medicine, full page: (LINK). Abstract, edited.]

Viruses. 2018 Dec 2;10(12). pii: E683. doi: 10.3390/v10120683.

Persistence and Sexual Transmission of Filoviruses.

Schindell BG1, Webb AL2, Kindrachuk J3.

Author information: 1 Laboratory of Emerging and Re-Emerging Viruses, Department of Medical Microbiology and Infectious Diseases, University of Manitoba, Winnipeg, MB R3E 0J9, Canada. schindeb@myumanitoba.ca. 2 Laboratory of Emerging and Re-Emerging Viruses, Department of Medical Microbiology and Infectious Diseases, University of Manitoba, Winnipeg, MB R3E 0J9, Canada. webba2@myumanitoba.ca. 3 Laboratory of Emerging and Re-Emerging Viruses, Department of Medical Microbiology and Infectious Diseases, University of Manitoba, Winnipeg, MB R3E 0J9, Canada. Jason.Kindrachuk@umanitoba.ca.

 

Abstract

There is an increasing frequency of reports regarding the persistence of the Ebola virus (EBOV) in Ebola virus disease (EVD) survivors. During the 2014⁻2016 West African EVD epidemic, sporadic transmission events resulted in the initiation of new chains of human-to-human transmission. Multiple reports strongly suggest that these re-emergences were linked to persistent EBOV infections and included sexual transmission from EVD survivors. Asymptomatic infection and long-term viral persistence in EVD survivors could result in incidental introductions of the Ebola virus in new geographic regions and raise important national and local public health concerns. Alarmingly, although the persistence of filoviruses and their potential for sexual transmission have been documented since the emergence of such viruses in 1967, there is limited knowledge regarding the events that result in filovirus transmission to, and persistence within, the male reproductive tract. Asymptomatic infection and long-term viral persistence in male EVD survivors could lead to incidental transfer of EBOV to new geographic regions, thereby generating widespread outbreaks that constitute a significant threat to national and global public health. Here, we review filovirus testicular persistence and discuss the current state of knowledge regarding the rates of persistence in male survivors, and mechanisms underlying reproductive tract localization and sexual transmission.

KEYWORDS: Ebola virus; blood-testis barrier; emerging virus; filovirus; outbreak; persistence; public health; sexual transmission; testis

PMID: 30513823 DOI: 10.3390/v10120683 Free full text

Keywords: Filovirus; Ebola; Marburg.

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#ANTIBODY-MEDIATED PROTECTIVE MECHANISMS INDUCED BY A TRIVALENT #PARAINFLUENZA-VECTORED #EBOLAVIRUS #VACCINE (J Virol., abstract)

[Source: Journal of Virology, full page: (LINK). Abstract, edited.]

ANTIBODY-MEDIATED PROTECTIVE MECHANISMS INDUCED BY A TRIVALENT PARAINFLUENZA-VECTORED EBOLAVIRUS VACCINE

J. Brian Kimble, Delphine C. Malherbe, Michelle Meyer, Bronwyn M. Gunn, Marcus M. Karim, Philipp A. Ilinykh, Mathieu Iampietro, Khaled S. Mohamed, Surendra Negi, Pavlo Gilchuk,Kai Huang, Yuri I. Wolf, Werner Braun, James E. Crowe, Jr., Galit Alter, Alexander Bukreyev

DOI: 10.1128/JVI.01845-18

 

ABSTRACT

Ebolaviruses Zaire (EBOV), Bundibugyo (BDBV) and Sudan (SUDV) cause human disease with high case fatality rates. Experimental monovalent vaccines, which all utilize the sole envelope glycoprotein (GP), do not protect against heterologous ebolaviruses. Human parainfluenza virus type 3-vectored vaccines offer benefits including needle-free administration and induction of mucosal responses in the respiratory tract. Multiple approaches were taken to induce a broad protection against the three ebolaviruses. While GP consensus-based antigens failed to elicit neutralizing antibodies, polyvalent immunization induced neutralizing responses to all three ebolaviruses and protected animals from death and disease caused by EBOV, SUDV and BDBV. As immunization with a cocktail of antigenically-related antigens can skew the responses and change the epitope hierarchy, we performed comparative analysis of antibody repertoire and Fc-mediated protective mechanisms in animals immunized with monovalent versus polyvalent vaccines. Compared to the monovalent vaccines, sera from trivalent vaccinated guinea pigs bound and neutralized EBOV and SUDV at equivalent levels and BDBV at only slightly reduced level. Peptide microarrays revealed a preponderance of binding to amino acids 389–403, 397-415 and 477-493, representing three linear epitopes in the mucin-like domain known to induce a protective antibody response. Competition binding assays with monoclonal antibodies isolated from human ebolavirus survivors demonstrated that the immune sera block binding of antibodies specific for the GP glycan cap, GP1-GP2 interface, the mucin-like domain, and the membrane-proximal external region. Thus, cocktail administration of three ebolavirus vaccines induces a desirable broad antibody response, without skewing of the response toward preferential recognition of a single virus.

 

IMPORTANCE

Symptoms of the disease caused by ebolaviruses Ebola, Bundibugyo and Sudan are similar, and their endemic areas overlap. However, because of the limited antigenic relatedness of ebolavirus glycoprotein (GP) used in all candidate vaccines against these viruses, they protect only against homologous but not heterologous ebolaviruses. Therefore, a broadly specific pan-ebolavirus vaccine is required, which might be achieved by administration of a cocktail of vaccines. The effects of cocktail administration of ebolavirus vaccines on the antibody repertoire remain unknown. Here in-depth analysis of the antibody responses to cocktail administration of human parainfluenza type 3-vectored vaccines against individual ebolaviruses was performed, which included analysis of binding to GP, neutralization of individual ebolaviruses, epitope specificity, Fc-mediated functions, and protection against the three ebolaviruses. The results demonstrated potent and balanced responses against individual ebolaviruses and no significant reduction of the responses, compared to that induced by individual vaccines.

Copyright © 2018 American Society for Microbiology. All Rights Reserved.

Keywords: Ebolavirus; Ebola; Sudan Virus; Bundibugyo Virus; Vaccines.

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#Ebola Virus #Infection Associated with #Transmission from #Survivors (Emerg Infect Dis., abstract)

[Source: US Centers for Disease Control and Prevention (CDC), Emerging Infectious Diseases Journal, full page: (LINK). Abstract, edited.]

Volume 25, Number 2—February 2019 / Synopsis

Ebola Virus Infection Associated with Transmission from Survivors

Saskia Den Boon1  , Barbara J. Marston1, Tolbert G. Nyenswah, Amara Jambai, Moumie Barry, Sakoba Keita, Kara Durski, Schabbethai S. Senesie, Devin Perkins, Anita Shah, Hugh H. Green, Esther L. Hamblion, Margaret Lamunu, Alex Gasasira, Nuha O. Mahmoud, Mamadou H. Djingarey, Oliver Morgan, Ian Crozier, and Christopher Dye

Author affiliations: World Health Organization, Geneva, Switzerland (S. Den Boon, K. Durski, D. Perkins, A. Shah, O. Morgan, I. Crozier, C. Dye); Centers for Disease Control and Prevention, Atlanta, Georgia, USA (B.J. Marston, S.S. Senesie, H.H. Green, O. Morgan); National Public Health Institute, Monrovia, Liberia (T.G. Nyenswah); Ministry of Health and Sanitation, Freetown, Sierra Leone (A. Jambai); Ministry of Health, Conakry, Guinea (M. Barry, S. Keita); World Health Organization, Monrovia, Liberia (E.L. Hamblion, A. Gasasira, N.O. Mahmoud); World Health Organization, Freetown, Sierra Leone (M. Lamunu); World Health Organization, Conakry (M.H. Djingarey); University of Oxford, Oxford, UK (C. Dye)

 

Abstract

Ebola virus (EBOV) can persist in immunologically protected body sites in survivors of Ebola virus disease, creating the potential to initiate new chains of transmission. From the outbreak in West Africa during 2014–2016, we identified 13 possible events of viral persistence–derived transmission of EBOV (VPDTe) and applied predefined criteria to classify transmission events based on the strength of evidence for VPDTe and source and route of transmission. For 8 events, a recipient case was identified; possible source cases were identified for 5 of these 8. For 5 events, a recipient case or chain of transmission could not be confidently determined. Five events met our criteria for sexual transmission (male-to-female). One VPDTe event led to at least 4 generations of cases; transmission was limited after the other events. VPDTe has increased the importance of Ebola survivor services and sustained surveillance and response capacity in regions with previously widespread transmission.

Keywords: Ebola.

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#Ebola and #War in the #DRC – Avoiding #Failure and Thinking Ahead (JAMA, summary)

[Source: Journal of the American Medical Association (JAMA), full page: (LINK). Summary, edited.]

Viewpoint / November 29, 2018

Ebola and War in the Democratic Republic of CongoAvoiding Failure and Thinking Ahead

Lawrence O. Gostin, JD1; Matthew M. Kavanagh, PhD1; Elizabeth Cameron, PhD2

Author Affiliations: 1 O’Neill Institute for National and Global Health Law, Georgetown University Law Center, Washington, DC; 2 Nuclear Threat Initiative, Washington, DC

JAMA. Published online November 29, 2018. doi:10.1001/jama.2018.19743

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The Ebola epidemic in the Democratic Republic of Congo (DRC) is exceptionally dangerous, occurring within active armed conflict and geopolitical volatility, including a million displaced persons. With 421 cases, 240 deaths, and the numbers increasing, this Ebola outbreak is the second deadliest in history.1 Recent spread to Butembo, home to 1.2 million people, raised concerns. The DRC, World Health Organization (WHO), and partners are leading a vigorous international response, yet despite deploying an experimental vaccine, cases doubled in October 2018 and many cases had unknown origin.

(…)

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Corresponding Author: Lawrence O. Gostin, JD, O’Neill Institute for National and Global Health Law, Georgetown University Law Center, 600 New Jersey Ave, NW, Washington, DC 20001 (gostin@law.georgetown.edu).

Published Online: November 29, 2018. doi:10.1001/jama.2018.19743

Conflict of Interest Disclosures: Dr Cameron reports grants from Open Philanthropy Project, Bill & Melinda Gates Foundation, and Global Affairs Canada. No other disclosures were reported.

Additional Contributions: In addition to the authors, the following participated in the expert consultation generating these recommendations: Sharon Abramowitz, Rutgers University; Deus Bazira,University of Maryland; Chris Beyrer, Jennifer Nuzzo, and Leonard Rubenstein,Johns Hopkins Bloomberg School of Public Health; Thomas Bollyky,Council on Foreign Relations; Lauren Carruth,American University; Victor Dzau,National Academy of Medicine; Katie Gottschalk,Georgetown University O’Neill Institute for National and Global Health; Charles Holmes, Rebecca Katz, Emily Mendenhall, and John Monahan,Georgetown University; Bonnie Jenkins,Brookings Institution; Jeremy Konyndyk,Center for Global Development; James Lawler,University of Nebraska; Nicole Lurie,Coalition for Epidemic Preparedness Initiatives; Dawn O’Connell,US Office for the Coalition for Epidemic Preparedness Innovations; Loyce Pace,Global Health Council; Carolyn Reynolds, PATH; Mesfin Teklu Tessema,International Rescue Committee; and Emira Woods,Institute for Policy Studies. We acknowledge experts from the Centers for Disease Control and Prevention and J. Stephen Morrison from the Center for Strategic and International Studies who provided important technical insights.

Keywords: DRC; Ebola; International cooperation; USA; Wars.

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