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Publisher: Oxford University Press   (Total: 396 journals)

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Showing 1 - 200 of 396 Journals sorted alphabetically
ACS Symposium Series     Full-text available via subscription   (SJR: 0.189, CiteScore: 0)
Acta Biochimica et Biophysica Sinica     Hybrid Journal   (Followers: 5, SJR: 0.79, CiteScore: 2)
Adaptation     Hybrid Journal   (Followers: 9, SJR: 0.143, CiteScore: 0)
Advances in Nutrition     Hybrid Journal   (Followers: 50, SJR: 2.196, CiteScore: 5)
Aesthetic Surgery J.     Hybrid Journal   (Followers: 6, SJR: 1.434, CiteScore: 1)
African Affairs     Hybrid Journal   (Followers: 65, SJR: 1.869, CiteScore: 2)
Age and Ageing     Hybrid Journal   (Followers: 90, SJR: 1.989, CiteScore: 4)
Alcohol and Alcoholism     Hybrid Journal   (Followers: 18, SJR: 1.376, CiteScore: 3)
American Entomologist     Full-text available via subscription   (Followers: 7)
American Historical Review     Hybrid Journal   (Followers: 156, SJR: 0.467, CiteScore: 1)
American J. of Agricultural Economics     Hybrid Journal   (Followers: 42, SJR: 2.113, CiteScore: 3)
American J. of Clinical Nutrition     Hybrid Journal   (Followers: 159, SJR: 3.438, CiteScore: 6)
American J. of Epidemiology     Hybrid Journal   (Followers: 181, SJR: 2.713, CiteScore: 3)
American J. of Hypertension     Hybrid Journal   (Followers: 25, SJR: 1.322, CiteScore: 3)
American J. of Jurisprudence     Hybrid Journal   (Followers: 19, SJR: 0.281, CiteScore: 1)
American J. of Legal History     Full-text available via subscription   (Followers: 8, SJR: 0.116, CiteScore: 0)
American Law and Economics Review     Hybrid Journal   (Followers: 27, SJR: 1.053, CiteScore: 1)
American Literary History     Hybrid Journal   (Followers: 16, SJR: 0.391, CiteScore: 0)
Analysis     Hybrid Journal   (Followers: 22, SJR: 1.038, CiteScore: 1)
Animal Frontiers     Hybrid Journal   (Followers: 1)
Annals of Behavioral Medicine     Hybrid Journal   (Followers: 15, SJR: 1.423, CiteScore: 3)
Annals of Botany     Hybrid Journal   (Followers: 36, SJR: 1.721, CiteScore: 4)
Annals of Oncology     Hybrid Journal   (Followers: 45, SJR: 5.599, CiteScore: 9)
Annals of the Entomological Society of America     Full-text available via subscription   (Followers: 10, SJR: 0.722, CiteScore: 1)
Annals of Work Exposures and Health     Hybrid Journal   (Followers: 32, SJR: 0.728, CiteScore: 2)
AoB Plants     Open Access   (Followers: 4, SJR: 1.28, CiteScore: 3)
Applied Economic Perspectives and Policy     Hybrid Journal   (Followers: 18, SJR: 0.858, CiteScore: 2)
Applied Linguistics     Hybrid Journal   (Followers: 56, SJR: 2.987, CiteScore: 3)
Applied Mathematics Research eXpress     Hybrid Journal   (Followers: 1, SJR: 1.241, CiteScore: 1)
Arbitration Intl.     Full-text available via subscription   (Followers: 20)
Arbitration Law Reports and Review     Hybrid Journal   (Followers: 14)
Archives of Clinical Neuropsychology     Hybrid Journal   (Followers: 30, SJR: 0.731, CiteScore: 2)
Aristotelian Society Supplementary Volume     Hybrid Journal   (Followers: 3)
Arthropod Management Tests     Hybrid Journal   (Followers: 2)
Astronomy & Geophysics     Hybrid Journal   (Followers: 43, SJR: 0.146, CiteScore: 0)
Behavioral Ecology     Hybrid Journal   (Followers: 52, SJR: 1.871, CiteScore: 3)
Bioinformatics     Hybrid Journal   (Followers: 312, SJR: 6.14, CiteScore: 8)
Biology Methods and Protocols     Hybrid Journal  
Biology of Reproduction     Full-text available via subscription   (Followers: 9, SJR: 1.446, CiteScore: 3)
Biometrika     Hybrid Journal   (Followers: 20, SJR: 3.485, CiteScore: 2)
BioScience     Hybrid Journal   (Followers: 29, SJR: 2.754, CiteScore: 4)
Bioscience Horizons : The National Undergraduate Research J.     Open Access   (Followers: 1, SJR: 0.146, CiteScore: 0)
Biostatistics     Hybrid Journal   (Followers: 17, SJR: 1.553, CiteScore: 2)
BJA : British J. of Anaesthesia     Hybrid Journal   (Followers: 169, SJR: 2.115, CiteScore: 3)
BJA Education     Hybrid Journal   (Followers: 65)
Brain     Hybrid Journal   (Followers: 68, SJR: 5.858, CiteScore: 7)
Briefings in Bioinformatics     Hybrid Journal   (Followers: 49, SJR: 2.505, CiteScore: 5)
Briefings in Functional Genomics     Hybrid Journal   (Followers: 3, SJR: 2.15, CiteScore: 3)
British J. for the Philosophy of Science     Hybrid Journal   (Followers: 35, SJR: 2.161, CiteScore: 2)
British J. of Aesthetics     Hybrid Journal   (Followers: 25, SJR: 0.508, CiteScore: 1)
British J. of Criminology     Hybrid Journal   (Followers: 587, SJR: 1.828, CiteScore: 3)
British J. of Social Work     Hybrid Journal   (Followers: 87, SJR: 1.019, CiteScore: 2)
British Medical Bulletin     Hybrid Journal   (Followers: 6, SJR: 1.355, CiteScore: 3)
British Yearbook of Intl. Law     Hybrid Journal   (Followers: 32)
Bulletin of the London Mathematical Society     Hybrid Journal   (Followers: 4, SJR: 1.376, CiteScore: 1)
Cambridge J. of Economics     Hybrid Journal   (Followers: 65, SJR: 0.764, CiteScore: 2)
Cambridge J. of Regions, Economy and Society     Hybrid Journal   (Followers: 11, SJR: 2.438, CiteScore: 4)
Cambridge Quarterly     Hybrid Journal   (Followers: 9, SJR: 0.104, CiteScore: 0)
Capital Markets Law J.     Hybrid Journal   (Followers: 2, SJR: 0.222, CiteScore: 0)
Carcinogenesis     Hybrid Journal   (Followers: 2, SJR: 2.135, CiteScore: 5)
Cardiovascular Research     Hybrid Journal   (Followers: 14, SJR: 3.002, CiteScore: 5)
Cerebral Cortex     Hybrid Journal   (Followers: 46, SJR: 3.892, CiteScore: 6)
CESifo Economic Studies     Hybrid Journal   (Followers: 18, SJR: 0.483, CiteScore: 1)
Chemical Senses     Hybrid Journal   (Followers: 1, SJR: 1.42, CiteScore: 3)
Children and Schools     Hybrid Journal   (Followers: 5, SJR: 0.246, CiteScore: 0)
Chinese J. of Comparative Law     Hybrid Journal   (Followers: 4, SJR: 0.412, CiteScore: 0)
Chinese J. of Intl. Law     Hybrid Journal   (Followers: 22, SJR: 0.329, CiteScore: 0)
Chinese J. of Intl. Politics     Hybrid Journal   (Followers: 10, SJR: 1.392, CiteScore: 2)
Christian Bioethics: Non-Ecumenical Studies in Medical Morality     Hybrid Journal   (Followers: 10, SJR: 0.183, CiteScore: 0)
Classical Receptions J.     Hybrid Journal   (Followers: 27, SJR: 0.123, CiteScore: 0)
Clean Energy     Open Access   (Followers: 1)
Clinical Infectious Diseases     Hybrid Journal   (Followers: 66, SJR: 5.051, CiteScore: 5)
Communication Theory     Hybrid Journal   (Followers: 23, SJR: 2.424, CiteScore: 3)
Communication, Culture & Critique     Hybrid Journal   (Followers: 27, SJR: 0.222, CiteScore: 1)
Community Development J.     Hybrid Journal   (Followers: 27, SJR: 0.268, CiteScore: 1)
Computer J.     Hybrid Journal   (Followers: 9, SJR: 0.319, CiteScore: 1)
Conservation Physiology     Open Access   (Followers: 2, SJR: 1.818, CiteScore: 3)
Contemporary Women's Writing     Hybrid Journal   (Followers: 9, SJR: 0.121, CiteScore: 0)
Contributions to Political Economy     Hybrid Journal   (Followers: 5, SJR: 0.906, CiteScore: 1)
Critical Values     Full-text available via subscription  
Current Developments in Nutrition     Open Access   (Followers: 2)
Current Legal Problems     Hybrid Journal   (Followers: 29)
Current Zoology     Full-text available via subscription   (Followers: 3, SJR: 1.164, CiteScore: 2)
Database : The J. of Biological Databases and Curation     Open Access   (Followers: 8, SJR: 1.791, CiteScore: 3)
Digital Scholarship in the Humanities     Hybrid Journal   (Followers: 14, SJR: 0.259, CiteScore: 1)
Diplomatic History     Hybrid Journal   (Followers: 20, SJR: 0.45, CiteScore: 1)
DNA Research     Open Access   (Followers: 5, SJR: 2.866, CiteScore: 6)
Dynamics and Statistics of the Climate System     Open Access   (Followers: 4)
Early Music     Hybrid Journal   (Followers: 16, SJR: 0.139, CiteScore: 0)
Economic Policy     Hybrid Journal   (Followers: 41, SJR: 3.584, CiteScore: 3)
ELT J.     Hybrid Journal   (Followers: 24, SJR: 0.942, CiteScore: 1)
English Historical Review     Hybrid Journal   (Followers: 54, SJR: 0.612, CiteScore: 1)
English: J. of the English Association     Hybrid Journal   (Followers: 14, SJR: 0.1, CiteScore: 0)
Environmental Entomology     Full-text available via subscription   (Followers: 11, SJR: 0.818, CiteScore: 2)
Environmental Epigenetics     Open Access   (Followers: 3)
Environmental History     Hybrid Journal   (Followers: 27, SJR: 0.408, CiteScore: 1)
EP-Europace     Hybrid Journal   (Followers: 2, SJR: 2.748, CiteScore: 4)
Epidemiologic Reviews     Hybrid Journal   (Followers: 9, SJR: 4.505, CiteScore: 8)
ESHRE Monographs     Hybrid Journal  
Essays in Criticism     Hybrid Journal   (Followers: 17, SJR: 0.113, CiteScore: 0)
European Heart J.     Hybrid Journal   (Followers: 57, SJR: 9.315, CiteScore: 9)
European Heart J. - Cardiovascular Imaging     Hybrid Journal   (Followers: 9, SJR: 3.625, CiteScore: 3)
European Heart J. - Cardiovascular Pharmacotherapy     Full-text available via subscription   (Followers: 1)
European Heart J. - Quality of Care and Clinical Outcomes     Hybrid Journal  
European Heart J. : Case Reports     Open Access  
European Heart J. Supplements     Hybrid Journal   (Followers: 8, SJR: 0.223, CiteScore: 0)
European J. of Cardio-Thoracic Surgery     Hybrid Journal   (Followers: 9, SJR: 1.681, CiteScore: 2)
European J. of Intl. Law     Hybrid Journal   (Followers: 187, SJR: 0.694, CiteScore: 1)
European J. of Orthodontics     Hybrid Journal   (Followers: 4, SJR: 1.279, CiteScore: 2)
European J. of Public Health     Hybrid Journal   (Followers: 20, SJR: 1.36, CiteScore: 2)
European Review of Agricultural Economics     Hybrid Journal   (Followers: 10, SJR: 1.172, CiteScore: 2)
European Review of Economic History     Hybrid Journal   (Followers: 30, SJR: 0.702, CiteScore: 1)
European Sociological Review     Hybrid Journal   (Followers: 42, SJR: 2.728, CiteScore: 3)
Evolution, Medicine, and Public Health     Open Access   (Followers: 12)
Family Practice     Hybrid Journal   (Followers: 16, SJR: 1.018, CiteScore: 2)
Fems Microbiology Ecology     Hybrid Journal   (Followers: 13, SJR: 1.492, CiteScore: 4)
Fems Microbiology Letters     Hybrid Journal   (Followers: 27, SJR: 0.79, CiteScore: 2)
Fems Microbiology Reviews     Hybrid Journal   (Followers: 31, SJR: 7.063, CiteScore: 13)
Fems Yeast Research     Hybrid Journal   (Followers: 14, SJR: 1.308, CiteScore: 3)
Food Quality and Safety     Open Access   (Followers: 1)
Foreign Policy Analysis     Hybrid Journal   (Followers: 24, SJR: 1.425, CiteScore: 1)
Forest Science     Hybrid Journal   (Followers: 7, SJR: 0.89, CiteScore: 2)
Forestry: An Intl. J. of Forest Research     Hybrid Journal   (Followers: 16, SJR: 1.133, CiteScore: 3)
Forum for Modern Language Studies     Hybrid Journal   (Followers: 6, SJR: 0.104, CiteScore: 0)
French History     Hybrid Journal   (Followers: 33, SJR: 0.118, CiteScore: 0)
French Studies     Hybrid Journal   (Followers: 20, SJR: 0.148, CiteScore: 0)
French Studies Bulletin     Hybrid Journal   (Followers: 10, SJR: 0.152, CiteScore: 0)
Gastroenterology Report     Open Access   (Followers: 2)
Genome Biology and Evolution     Open Access   (Followers: 13, SJR: 2.578, CiteScore: 4)
Geophysical J. Intl.     Hybrid Journal   (Followers: 35, SJR: 1.506, CiteScore: 3)
German History     Hybrid Journal   (Followers: 23, SJR: 0.161, CiteScore: 0)
GigaScience     Open Access   (Followers: 4, SJR: 5.022, CiteScore: 7)
Global Summitry     Hybrid Journal   (Followers: 1)
Glycobiology     Hybrid Journal   (Followers: 13, SJR: 1.493, CiteScore: 3)
Health and Social Work     Hybrid Journal   (Followers: 56, SJR: 0.388, CiteScore: 1)
Health Education Research     Hybrid Journal   (Followers: 15, SJR: 0.854, CiteScore: 2)
Health Policy and Planning     Hybrid Journal   (Followers: 25, SJR: 1.512, CiteScore: 2)
Health Promotion Intl.     Hybrid Journal   (Followers: 22, SJR: 0.812, CiteScore: 2)
History Workshop J.     Hybrid Journal   (Followers: 31, SJR: 1.278, CiteScore: 1)
Holocaust and Genocide Studies     Hybrid Journal   (Followers: 28, SJR: 0.105, CiteScore: 0)
Human Communication Research     Hybrid Journal   (Followers: 15, SJR: 2.146, CiteScore: 3)
Human Molecular Genetics     Hybrid Journal   (Followers: 8, SJR: 3.555, CiteScore: 5)
Human Reproduction     Hybrid Journal   (Followers: 72, SJR: 2.643, CiteScore: 5)
Human Reproduction Open     Open Access  
Human Reproduction Update     Hybrid Journal   (Followers: 18, SJR: 5.317, CiteScore: 10)
Human Rights Law Review     Hybrid Journal   (Followers: 58, SJR: 0.756, CiteScore: 1)
ICES J. of Marine Science: J. du Conseil     Hybrid Journal   (Followers: 53, SJR: 1.591, CiteScore: 3)
ICSID Review     Hybrid Journal   (Followers: 11)
ILAR J.     Hybrid Journal   (Followers: 2, SJR: 1.732, CiteScore: 4)
IMA J. of Applied Mathematics     Hybrid Journal   (SJR: 0.679, CiteScore: 1)
IMA J. of Management Mathematics     Hybrid Journal   (SJR: 0.538, CiteScore: 1)
IMA J. of Mathematical Control and Information     Hybrid Journal   (Followers: 2, SJR: 0.496, CiteScore: 1)
IMA J. of Numerical Analysis - advance access     Hybrid Journal   (SJR: 1.987, CiteScore: 2)
Industrial and Corporate Change     Hybrid Journal   (Followers: 10, SJR: 1.792, CiteScore: 2)
Industrial Law J.     Hybrid Journal   (Followers: 36, SJR: 0.249, CiteScore: 1)
Inflammatory Bowel Diseases     Hybrid Journal   (Followers: 43, SJR: 2.511, CiteScore: 4)
Information and Inference     Free  
Integrative and Comparative Biology     Hybrid Journal   (Followers: 8, SJR: 1.319, CiteScore: 2)
Interacting with Computers     Hybrid Journal   (Followers: 11, SJR: 0.292, CiteScore: 1)
Interactive CardioVascular and Thoracic Surgery     Hybrid Journal   (Followers: 7, SJR: 0.762, CiteScore: 1)
Intl. Affairs     Hybrid Journal   (Followers: 62, SJR: 1.505, CiteScore: 3)
Intl. Data Privacy Law     Hybrid Journal   (Followers: 25)
Intl. Health     Hybrid Journal   (Followers: 6, SJR: 0.851, CiteScore: 2)
Intl. Immunology     Hybrid Journal   (Followers: 3, SJR: 2.167, CiteScore: 4)
Intl. J. for Quality in Health Care     Hybrid Journal   (Followers: 36, SJR: 1.348, CiteScore: 2)
Intl. J. of Constitutional Law     Hybrid Journal   (Followers: 63, SJR: 0.601, CiteScore: 1)
Intl. J. of Epidemiology     Hybrid Journal   (Followers: 238, SJR: 3.969, CiteScore: 5)
Intl. J. of Law and Information Technology     Hybrid Journal   (Followers: 5, SJR: 0.202, CiteScore: 1)
Intl. J. of Law, Policy and the Family     Hybrid Journal   (Followers: 24, SJR: 0.223, CiteScore: 1)
Intl. J. of Lexicography     Hybrid Journal   (Followers: 10, SJR: 0.285, CiteScore: 1)
Intl. J. of Low-Carbon Technologies     Open Access   (Followers: 1, SJR: 0.403, CiteScore: 1)
Intl. J. of Neuropsychopharmacology     Open Access   (Followers: 3, SJR: 1.808, CiteScore: 4)
Intl. J. of Public Opinion Research     Hybrid Journal   (Followers: 11, SJR: 1.545, CiteScore: 1)
Intl. J. of Refugee Law     Hybrid Journal   (Followers: 38, SJR: 0.389, CiteScore: 1)
Intl. J. of Transitional Justice     Hybrid Journal   (Followers: 11, SJR: 0.724, CiteScore: 2)
Intl. Mathematics Research Notices     Hybrid Journal   (Followers: 1, SJR: 2.168, CiteScore: 1)
Intl. Political Sociology     Hybrid Journal   (Followers: 39, SJR: 1.465, CiteScore: 3)
Intl. Relations of the Asia-Pacific     Hybrid Journal   (Followers: 23, SJR: 0.401, CiteScore: 1)
Intl. Studies Perspectives     Hybrid Journal   (Followers: 9, SJR: 0.983, CiteScore: 1)
Intl. Studies Quarterly     Hybrid Journal   (Followers: 47, SJR: 2.581, CiteScore: 2)
Intl. Studies Review     Hybrid Journal   (Followers: 25, SJR: 1.201, CiteScore: 1)
ISLE: Interdisciplinary Studies in Literature and Environment     Hybrid Journal   (Followers: 2, SJR: 0.15, CiteScore: 0)
ITNOW     Hybrid Journal   (Followers: 1, SJR: 0.103, CiteScore: 0)
J. of African Economies     Hybrid Journal   (Followers: 17, SJR: 0.533, CiteScore: 1)
J. of American History     Hybrid Journal   (Followers: 46, SJR: 0.297, CiteScore: 1)
J. of Analytical Toxicology     Hybrid Journal   (Followers: 14, SJR: 1.065, CiteScore: 2)
J. of Antimicrobial Chemotherapy     Hybrid Journal   (Followers: 15, SJR: 2.419, CiteScore: 4)
J. of Antitrust Enforcement     Hybrid Journal   (Followers: 1)
J. of Applied Poultry Research     Hybrid Journal   (Followers: 5, SJR: 0.585, CiteScore: 1)
J. of Biochemistry     Hybrid Journal   (Followers: 41, SJR: 1.226, CiteScore: 2)
J. of Burn Care & Research     Hybrid Journal   (Followers: 10, SJR: 0.768, CiteScore: 2)
J. of Chromatographic Science     Hybrid Journal   (Followers: 18, SJR: 0.36, CiteScore: 1)
J. of Church and State     Hybrid Journal   (Followers: 11, SJR: 0.139, CiteScore: 0)
J. of Communication     Hybrid Journal   (Followers: 55, SJR: 4.411, CiteScore: 5)
J. of Competition Law and Economics     Hybrid Journal   (Followers: 37, SJR: 0.33, CiteScore: 0)
J. of Complex Networks     Hybrid Journal   (Followers: 2, SJR: 1.05, CiteScore: 4)
J. of Computer-Mediated Communication     Open Access   (Followers: 29, SJR: 2.961, CiteScore: 6)
J. of Conflict and Security Law     Hybrid Journal   (Followers: 12, SJR: 0.402, CiteScore: 0)
J. of Consumer Research     Full-text available via subscription   (Followers: 46, SJR: 5.856, CiteScore: 5)
J. of Crohn's and Colitis     Hybrid Journal   (Followers: 8, SJR: 2.728, CiteScore: 5)

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Journal Cover
Journal of Infectious Diseases
Journal Prestige (SJR): 3.302
Citation Impact (citeScore): 4
Number of Followers: 42  
 
  Hybrid Journal Hybrid journal (It can contain Open Access articles)
ISSN (Print) 0022-1899 - ISSN (Online) 1537-6613
Published by Oxford University Press Homepage  [396 journals]
  • Marburg and Ebola Viruses – Marking 50 Years Since Their Discovery
    • Authors: Becker S; Feldmann H, Geisbert T, et al.
      Abstract: In 1967, a mysterious infectious disease was described in patients at the University Hospital in Marburg, Germany. Most patients had come into contact with a shipment of African green monkeys from Uganda. Additional patients were noted in Frankfurt, Germany and Belgrade, now Serbia. The etiological agent was identified as a virus and named after the city of Marburg – Marburg virus. Nine years later, a similar clinical infectious syndrome was described in patients in rural areas in southern Sudan (now South Sudan) and northern Zaire (now the Democratic Republic of Congo, DRC). The pathogen was identified as a virus similar to Marburg virus and named Ebola virus after a river in the northern DRC. Today we have a family of viruses, Filoviridae, comprising the genera Marburgvirus (single species), Ebolavirus (five species), and Cuevavirus (single species; no virus isolates) and a few unclassified sequences from bats.
      PubDate: Thu, 22 Nov 2018 00:00:00 GMT
      DOI: 10.1093/infdis/jiy674
      Issue No: Vol. 218, No. suppl_5 (2018)
       
  • Contribution of Environment Sample-Based Detection to Ebola Outbreak
           Management
    • Authors: Kapetshi J; Fausther-Bovendo H, Corbett C, et al.
      Abstract: Detection of chains of transmission is critical to interrupt Ebola virus (EBOV) outbreaks. For >25 years, quantitative reverse transcription polymerase chain reaction performed on biological fluids has been the reference standard for EBOV detection and identification. In the current study, we investigated the use of environmental sampling to detect EBOV shed from probable case patients buried without the collection of bodily fluids. During the 2012 Bundibugyo virus (BDBV) outbreak in the Democratic Republic of the Congo, environmental samples were screened for BDBV RNA by means of real-time polymerase chain reaction. Low levels of BDBV genomic RNA were detected in a hospital and in a house. Detection of BDBV RNA in the house led to the identification of the last chain of transmission still active, which resulted in the safe burial of the person with the last laboratory-confirmed case of this outbreak. Overall, environmental sampling can fill specific gaps to help confirm EBOV positivity and therefore be of value in outbreak management.
      PubDate: Tue, 16 Oct 2018 00:00:00 GMT
      DOI: 10.1093/infdis/jiy366
      Issue No: Vol. 218, No. suppl_5 (2018)
       
  • The Economic and Social Burden of the 2014 Ebola Outbreak in West Africa
    • Authors: Huber C; Finelli L, Stevens W.
      Abstract: BackgroundThe 2014 Ebola virus disease (EVD) outbreak in West Africa was more devastating than all previous EVD outbreaks combined; however, many estimates of its economic burden did not capture its significant social costs. This study aimed to review all currently available estimates, identify social components missed by these estimates, and generate a comprehensive cost of the 2014 EVD outbreak.MethodsWe conducted a systematic review of the grey (reports produced by nonprofit or nongovernmental organizations, government, or industry) and published literature to identify current estimates of the burden of the outbreak. Based on the findings of this review, we identified 6 key areas absent or underestimated from previous estimates and calculated the underestimated social costs using estimates from the literature and extrapolation.ResultsCurrent estimates of the economic burden of the outbreak range from $2.8 to $32.6 billion in lost gross domestic product. We estimated the comprehensive economic and social burden from the 2014 EVD outbreak to be $53.19 billion (2014 USD). The most significant component, $18.8 billion, was deaths from non-Ebola causes.ConclusionsA more complete understanding of the burden of the 2014 EVD outbreak underscores the value of interventions that can mitigate or reduce the severity of future outbreaks.
      PubDate: Sat, 13 Oct 2018 00:00:00 GMT
      DOI: 10.1093/infdis/jiy213
      Issue No: Vol. 218, No. suppl_5 (2018)
       
  • Role of Transmembrane Protein 16F in the Incorporation of
           Phosphatidylserine Into Budding Ebola Virus Virions
    • Authors: Younan P; Iampietro M, Santos R, et al.
      Abstract: Viral apoptotic mimicry, which is defined by exposure of phosphatidylserine (PtdSer) into the outer leaflet of budding enveloped viruses, increases viral tropism, infectivity and promotes immune evasion. Here, we report that the calcium (Ca2+)–dependent scramblase, transmembrane protein 16F (TMEM16F), is responsible for the incorporation of PtdSer into virion membranes during Ebola virus infection. Infection of Huh7 cells with Ebola virus resulted in a pronounced increase in plasma membrane-associated PtdSer, which was demonstrated to be dependent on TMEM16F function. Analysis of virions using imaging flow cytometry revealed that short hairpin RNA-mediated down-regulation of TMEM16F function directly reduced virion-associated PtdSer. Taken together, these studies demonstrate that TMEM16F is a central cellular factor in the exposure of PtdSer in the outer leaflet of viral membranes.
      PubDate: Fri, 05 Oct 2018 00:00:00 GMT
      DOI: 10.1093/infdis/jiy485
      Issue No: Vol. 218, No. suppl_5 (2018)
       
  • Disruption of Phosphatidylserine Synthesis or Trafficking Reduces
           Infectivity of Ebola Virus
    • Authors: Younan P; Iampietro M, Santos R, et al.
      Abstract: The outer leaflet of the viral membrane of Ebola virus (EBOV) virions is enriched with phosphatidylserine (PtdSer), which is thought to play a central role in viral tropism, entry, and virus-associated immune evasion. We investigated the effects of inhibiting synthesis and/or export of PtdSer to the cell surface of infected cells on viral infectivity. Knockdown of both PtdSer synthase enzymes, PTDSS1 and PTDSS2, effectively decreased viral production. Decreased PtdSer expression resulted in an accumulation of virions at the plasma membrane and adjacent of intracellular organelles, suggesting that virion budding is impaired. The addition of inhibitors that block normal cellular trafficking of PtdSer to the plasma membrane resulted in a similar accumulation of virions and reduced viral replication. These findings demonstrate that plasma membrane-associated PtdSer is required for efficient EBOV budding, increasing EBOV infectivity, and could constitute a potential therapeutic target for the development of future countermeasures against EBOV.
      PubDate: Thu, 04 Oct 2018 00:00:00 GMT
      DOI: 10.1093/infdis/jiy489
      Issue No: Vol. 218, No. suppl_5 (2018)
       
  • Mannoside Glycolipid Conjugates Display Antiviral Activity Against Ebola
           Virus
    • Authors: Reynard O; Schaeffer E, Volchkova V, et al.
      Abstract: The West African outbreak of Ebola virus (EBOV) infection during 2013–2016 highlighted the need for development of field-applicable therapeutic drugs for this infection. Here we report that mannoside glycolipid conjugates (MGCs) consisting of a trimannose head and a lipophilic chain assembled by a linker inhibit EBOV infection not only of human monocyte–derived dendritic cells and macrophages, but also of a number of susceptible cells. Analysis of the mode of action leads us to conclude that MGCs act directly on cells, notably by preventing virus endocytosis.
      PubDate: Mon, 17 Sep 2018 00:00:00 GMT
      DOI: 10.1093/infdis/jiy464
      Issue No: Vol. 218, No. suppl_5 (2018)
       
  • Distinct Biological Phenotypes of Marburg and Ravn Virus Infection in
           Macaques
    • Authors: Nicholas V; Rosenke R, Feldmann F, et al.
      Abstract: Filoviruses are among the most pathogenic infectious agents known to human, with high destructive potential, as evidenced by the recent Ebola virus epidemic in West Africa. As members of the filovirus family, marburgviruses have caused similar devastating outbreaks, albeit with lower case numbers. In this study we compare the pathogenesis of Ravn virus (RAVV) and Marburg virus (MARV) strains Angola, Musoke, and Ozolin in rhesus and cynomolgus macaques, the 2 nonhuman primate species most commonly used in filovirus research. Our results reveal the most pathogenic MARV strain to be Angola, followed by Musoke, whereas Ozolin is the least pathogenic. We also demonstrate that RAVV is highly pathogenic in cynomolgus macaques but less pathogenic in rhesus macaques. Our results demonstrate a preferential infection of endothelial cells by MARVs; in addition, analysis of tissue samples suggests that lymphocyte and hepatocyte apoptosis might play a role in MARV pathogenicity. This information expands our knowledge about pathogenicity and virulence of marburgviruses.
      PubDate: Wed, 12 Sep 2018 00:00:00 GMT
      DOI: 10.1093/infdis/jiy456
      Issue No: Vol. 218, No. suppl_5 (2018)
       
  • Infection Rates and Risk Factors for Infection Among Health Workers During
           Ebola and Marburg Virus Outbreaks: A Systematic Review
    • Authors: Selvaraj S; Lee K, Harrell M, et al.
      Abstract: BackgroundInfection in health workers (HWs) has characterized outbreaks of Ebola virus disease (EVD) and Marburg virus disease (MVD). We conducted a systematic review to investigate infection and mortality rates and common exposure risks in HWs in EVD and MVD outbreaks.MethodsWe searched the EMBASE and PubMed databases to identify articles posted before 27 December 2017, with no language restrictions. Data on the number, frequency, and mortality of HW infection and exposure risks were extracted.ResultsNinety-four articles related to 22 outbreaks were included. HW infections composed 2%–100% of cases in EVD and 5%–50% of cases in MVD outbreaks. Among exposed HWs, 0.6%–92% developed EVD, and 1%–10% developed MVD. HW infection rates were consistent through outbreaks. The most common exposure risk situations were inadequate personal protective equipment and exposure to patients with unrecognized EVD/MVD. Similar risks were reported in past EVD/MVD outbreaks and in the recent outbreak in West Africa.ConclusionsMany outbreaks reported high proportions of infected HWs. Similar HW infection rates and exposure risk factors in both past and recent EVD and MVD outbreaks emphasize the need to improve the implementation of appropriate infection control measures consistently across all healthcare settings.
      PubDate: Fri, 07 Sep 2018 00:00:00 GMT
      DOI: 10.1093/infdis/jiy435
      Issue No: Vol. 218, No. suppl_5 (2018)
       
  • Natural History and Pathogenesis of Wild-Type Marburg Virus Infection in
           STAT2 Knockout Hamsters
    • Authors: Atkins C; Miao J, Kalveram B, et al.
      Abstract: Marburg virus (MARV; family Filoviridae) causes sporadic outbreaks of Marburg hemorrhagic fever in sub-Saharan Africa with case fatality rates reaching 90%. Wild-type filoviruses, including MARV and the closely related Ebola virus, are unable to suppress the type I interferon response in rodents, and therefore require adaptation of the viruses to cause disease in immunocompetent animals. In the current study, we demonstrate that STAT2 knockout Syrian hamsters are susceptible to infection with different wild-type MARV variants. MARV Musoke causes a robust and systemic infection resulting in lethal disease. Histopathological findings share features similar to those observed in human patients and other animal models of filovirus infection. Reverse-transcription polymerase chain reaction analysis of host transcripts shows a dysregulation of the innate immune response. Our results demonstrate that the STAT2 knockout hamster represents a novel small animal model of severe MARV infection and disease without the requirement for virus adaptation.
      PubDate: Thu, 06 Sep 2018 00:00:00 GMT
      DOI: 10.1093/infdis/jiy457
      Issue No: Vol. 218, No. suppl_5 (2018)
       
  • Ebola Virus VP40 Modulates Cell Cycle and Biogenesis of Extracellular
           Vesicles
    • Authors: Pleet M; Erickson J, DeMarino C, et al.
      Abstract: BackgroundEbola virus (EBOV) mainly targets myeloid cells; however, extensive death of T cells is often observed in lethal infections. We have previously shown that EBOV VP40 in exosomes causes recipient immune cell death.MethodsUsing VP40-producing clones, we analyzed donor cell cycle, extracellular vesicle (EV) biogenesis, and recipient immune cell death. Transcription of cyclin D1 and nuclear localization of VP40 were examined via kinase and chromatin immunoprecipitation assays. Extracellular vesicle contents were characterized by mass spectrometry, cytokine array, and western blot. Biosafety level-4 facilities were used for wild-type Ebola virus infection studies.ResultsVP40 EVs induced apoptosis in recipient T cells and monocytes. VP40 clones were accelerated in growth due to cyclin D1 upregulation, and nuclear VP40 was found bound to the cyclin D1 promoter. Accelerated cell cycling was related to EV biogenesis, resulting in fewer but larger EVs. VP40 EV contents were enriched in ribonucleic acid-binding proteins and cytokines (interleukin-15, transforming growth factor-β1, and interferon-γ). Finally, EBOV-infected cell and animal EVs contained VP40, nucleoprotein, and glycoprotein.ConclusionsNuclear VP40 upregulates cyclin D1 levels, resulting in dysregulated cell cycle and EV biogenesis. Packaging of cytokines and EBOV proteins into EVs from infected cells may be responsible for the decimation of immune cells during EBOV pathogenesis.
      PubDate: Thu, 30 Aug 2018 00:00:00 GMT
      DOI: 10.1093/infdis/jiy472
      Issue No: Vol. 218, No. suppl_5 (2018)
       
  • Marburg Virus Viral Protein 35 Inhibits Protein Kinase R Activation in a
           Cell Type–Specific Manner
    • Authors: Hume A; Mühlberger E.
      Abstract: Protein kinase R (PKR) is a key antiviral protein involved in sensing and restricting viral infections. Here we analyzed the ability of Marburg virus (MARV) viral protein 35 (VP35) to inhibit PKR activation in human and bat cells. Similar to the related Ebola and Lloviu viruses, MARV VP35 was able to inhibit PKR activation in 293T cells. In contrast, we found that MARV VP35 did not inhibit human or bat PKR activation in human glioblastoma U-251-MG cells or a Rousettus aegyptiacus cell line. Additional experiments revealed that PACT, a known PKR regulator, was insufficient to rescue the ability of VP35 to inhibit PKR activation in these cells. Taken together, this study indicates that the ability of VP35 to inhibit PKR is cell type specific, potentially explaining discrepancies between the ability of filoviruses to potently block innate immune responses, and the high levels of interferon and interferon-stimulated genes observed in filovirus patients.
      PubDate: Tue, 28 Aug 2018 00:00:00 GMT
      DOI: 10.1093/infdis/jiy473
      Issue No: Vol. 218, No. suppl_5 (2018)
       
  • Protein Phosphatase 1–Targeting Small-Molecule C31 Inhibits Ebola
           Virus Replication
    • Authors: Ammosova T; Pietzsch C, Saygideğer Y, et al.
      Abstract: BackgroundEbola virus (EBOV) infection causes severe hemorrhagic fever. EBOV transcription is controlled by host protein phosphatase 1 (PP1), which dephosphorylates VP30 protein. We previously developed 1E7-03, a compound targeting a noncatalytic site of PP1 that induced VP30 phosphorylation and inhibited EBOV transcription. Here, we attempted to further improve 1E7-03, which was not stable in murine serum.ResultsHigh-throughput screening with EBOV–green fluorescent protein was conducted on 72 1E7-03 analogs and identified 6 best inhibitory and the least toxic compounds. A parallel in silico screening of compounds from the ZINC database by docking to PP1 identified the best-binding compound C31, which was also present among the top 6 compounds found in the viral screen. C31 showed the best EBOV inhibitory activity among the top 6 compounds and also inhibited EBOV minigenome. C31 bound to the PP1 C-terminal groove in vitro and increased VP30 phosphorylation in cultured cells. C31 demonstrated improved stability in mouse plasma and cell permeability, compared with 1E7-03. It was also detected for 24 hours after injection in mice.ConclusionC31 represents a novel PP1-targeting EBOV inhibitor with improved pharmacological properties that can be further evaluated for future antifiloviral therapy.
      PubDate: Tue, 28 Aug 2018 00:00:00 GMT
      DOI: 10.1093/infdis/jiy422
      Issue No: Vol. 218, No. suppl_5 (2018)
       
  • Budding of Ebola Virus Particles Requires the Rab11-Dependent Endocytic
           Recycling Pathway
    • Authors: Nanbo A; Ohba Y.
      Abstract: The Ebola virus-encoded major matrix protein VP40 traffics to the plasma membrane, which leads to the formation of filamentous viral particles and subsequent viral egress. However, the cellular machineries underlying this process are not fully understood. In the present study, we have assessed the role of host endocytic recycling in Ebola virus particle formation. We found that a small GTPase Rab11, which regulates recycling of molecules among the trans-Golgi network, recycling endosomes, and the plasma membrane, was incorporated in Ebola virus-like particles. Although Rab11 predominantly localized in the perinuclear region, it distributed diffusely in the cytoplasm and partly localized in the periphery of the cells transiently expressing VP40. In contrast, Rab11 exhibited a perinuclear distribution when 2 VP40 derivatives that lack ability to traffic to the plasma membrane were expressed. Finally, expression of a dominant-negative form of Rab11 or knockdown of Rab11 inhibited both VP40-induced clusters at the plasma membrane and release of viral-like particles. Taken together, our findings demonstrate that Ebola virus exploits host endocytic recycling machinery to facilitate the trafficking of VP40 to the cell surface and the subsequent release of viral-like particles for its establishment of efficient viral egress.
      PubDate: Thu, 23 Aug 2018 00:00:00 GMT
      DOI: 10.1093/infdis/jiy460
      Issue No: Vol. 218, No. suppl_5 (2018)
       
  • Comparative Transcriptomics in Ebola Makona-Infected Ferrets, Nonhuman
           Primates, and Humans
    • Authors: Cross R; Speranza E, Borisevich V, et al.
      Abstract: The domestic ferret is a uniformly lethal model of infection for 3 species of Ebolavirus known to be pathogenic in humans. Reagents to systematically analyze the ferret host response to infection are lacking; however, the recent publication of a draft ferret genome has opened the potential for transcriptional analysis of ferret models of disease. In this work, we present comparative analysis of longitudinally sampled blood taken from ferrets and nonhuman primates infected with lethal doses of the Makona variant of Zaire ebolavirus. Strong induction of proinflammatory and prothrombotic signaling programs were present in both ferrets and nonhuman primates, and both transcriptomes were similar to previously published datasets of fatal cases of human Ebola virus infection.
      PubDate: Thu, 23 Aug 2018 00:00:00 GMT
      DOI: 10.1093/infdis/jiy455
      Issue No: Vol. 218, No. suppl_5 (2018)
       
  • A Fluorescently Labeled Marburg Virus Glycoprotein as a New Tool to Study
           Viral Transport and Assembly
    • Authors: Mittler E; Schudt G, Halwe S, et al.
      Abstract: The single surface glycoprotein (GP) of filoviruses is indispensable for recognition of its cellular receptor and infection of target cells. To study the intracellular trafficking of GP by using live-cell imaging, the mucin-like domain of Marburg virus (MARV) GP was replaced by the fluorophore mCherry (GP∆MLD_mCherry). Intracellular distribution, surface transport, and recruitment of GP∆MLD_mCherry into virus-like particles were similar to observations for wild-type GP. Using reverse genetics, we generated a recombinant MARV expressing GP∆MLD_mCherry (recMARV MARVGP∆MLD_mCherry). Time-lapse microscopy of recMARV MARVGP∆MLD_mCherry–infected cells revealed that GP∆MLD_mCherry–positive vesicles were transported to the cell surface in a tubulin-dependent manner. Moreover, dual-color live-cell imaging revealed cotransport of GPΔMLD_mCherry and VP40 and their colocalization at the plasma membrane. In this proof-of-concept study we showed that the newly developed GP∆MLD_mCherry is a promising tool to elucidate intracellular trafficking and assembly pathways of MARV.
      PubDate: Wed, 22 Aug 2018 00:00:00 GMT
      DOI: 10.1093/infdis/jiy424
      Issue No: Vol. 218, No. suppl_5 (2018)
       
  • Vaccine-Mediated Induction of an Ebolavirus Cross-Species Antibody Binding
           to Conserved Epitopes on the Glycoprotein Heptad Repeat
           2/Membrane-Proximal External Junction
    • Authors: Cagigi A; Ploquin A, Niezold T, et al.
      Abstract: The membrane-proximal external regions (MPER) of the human immunodeficiency virus envelope glycoprotein (GP) generate broadly reactive antibody responses and are the focus of vaccine development efforts. The conservation of amino acids within filovirus GP heptad repeat region (HR)2/MPER suggests that it may also represent a target for a pan-filovirus vaccine. We immunized a cynomolgus macaque against Ebola virus (EBOV) using a deoxyribonucleic acid/adenovirus 5 prime/boost strategy, sequenced memory B-cell receptors, and tested the antibodies for functional activity against EBOV GP. Antibody ma-C10 bound to GP with an affinity of 48 nM and was capable of inducing antibody-dependent cellular cytotoxicity. Three-dimensional reconstruction of single-particle, negative-stained, electron microscopy showed that ma-C10 bound to the HR2/MPER, and enzyme-linked immunosorbent assay reveals it binds to residues 621–631. More importantly, ma-C10 was found to bind to the GP of the 3 most clinically relevant Ebolavirus species, suggesting that a cross-species immunogen strategy targeting the residues in this region may be a feasible approach for producing a pan-filovirus vaccine.
      PubDate: Wed, 22 Aug 2018 00:00:00 GMT
      DOI: 10.1093/infdis/jiy450
      Issue No: Vol. 218, No. suppl_5 (2018)
       
  • Kinetics of Soluble Mediators of the Host Response in Ebola Virus Disease
    • Authors: Kerber R; Krumkamp R, Korva M, et al.
      Abstract: BackgroundThe pathophysiology of Ebola virus disease (EVD) is still poorly understood. This study aimed at identifying soluble biomarkers that inform on disease mechanisms.MethodsFifty-four soluble mediators of the immune, coagulation, and endothelial system were measured in baseline and follow-up samples from hospitalized patients with EVD, using Luminex technology. Cross-sectional expression levels and changes over time were correlated with outcome.ResultsLevels of circulating proinflammatory cytokines and chemokines, as well as markers of endothelial dysfunction and coagulopathy, were elevated on admission to hospital in patients who died from EVD as compared to survivors. These markers further increased in patients who died and/or decreased over time in survivors. In contrast, markers of gut integrity and T-cell response were higher in survivors and increased until discharge.ConclusionsInflammatory response, endothelial integrity, gastric tissue protection, and T cell immunity play a role in EVD pathophysiology.
      PubDate: Wed, 08 Aug 2018 00:00:00 GMT
      DOI: 10.1093/infdis/jiy429
      Issue No: Vol. 218, No. suppl_5 (2018)
       
  • Pathogenicity of Ebola and Marburg Viruses Is Associated With Differential
           Activation of the Myeloid Compartment in Humanized Triple Knockout-Bone
           Marrow, Liver, and Thymus Mice
    • Authors: Lavender K; Williamson B, Saturday G, et al.
      Abstract: Ebola virus (EBOV) and Marburg virus (MARV) outbreaks are highly lethal, and infection results in a hemorrhagic fever with complex etiology. These zoonotic viruses dysregulate the immune system to cause disease, in part by replicating within myeloid cells that would normally innately control viral infection and shape the adaptive immune response. We used triple knockout (TKO)-bone marrow, liver, thymus (BLT) humanized mice to recapitulate the early in vivo human immune response to filovirus infection. Disease severity in TKO-BLT mice was dissimilar between EBOV and MARV with greater severity observed during EBOV infection. Disease severity was related to increased Kupffer cell infection in the liver, higher levels of myeloid dysfunction, and skewing of macrophage subtypes in EBOV compared with MARV-infected mice. Overall, the TKO-BLT model provided a practical in vivo platform to study the human immune response to filovirus infection and generated a better understanding of how these viruses modulate specific components of the immune system.
      PubDate: Mon, 06 Aug 2018 00:00:00 GMT
      DOI: 10.1093/infdis/jiy269
      Issue No: Vol. 218, No. suppl_5 (2018)
       
  • Long-Range Polymerase Chain Reaction Method for Sequencing the Ebola Virus
           Genome From Ecological and Clinical Samples
    • Authors: Seifert S; Schulz J, Matson M, et al.
      Abstract: Sequencing viral genomes during an outbreak can facilitate response and containment efforts. In this study, we describe a reverse transcription long-range polymerase chain reaction for efficient amplification and sequencing of the Ebola virus (EBOV) genome in 2 seminested reactions. We demonstrate that our method remains robust with complex biological samples by amplifying and sequencing the EBOV genome from EBOV-infected nonhuman primates (NHPs). We further demonstrate that we are able to recover viral genomes from starting concentrations as low as 103 50% tissue culture infective dose (TCID50)/mL, suggesting that this method can be employed to sequence EBOV genomes from ecologically or clinically derived samples.
      PubDate: Thu, 02 Aug 2018 00:00:00 GMT
      DOI: 10.1093/infdis/jiy290
      Issue No: Vol. 218, No. suppl_5 (2018)
       
  • Ebola Virus Shed Glycoprotein Triggers Differentiation, Infection, and
           Death of Monocytes Through Toll-Like Receptor 4 Activation
    • Authors: Iampietro M; Santos R, Lubaki N, et al.
      Abstract: A better understanding of the mechanisms used by Ebola virus to disable the host immune system and spread the infection are of great importance for development of new therapeutic strategies. We demonstrate that treatment of monocytic cells with Ebola virus shed glycoprotein (GP) promotes their differentiation resulting in increased infection and cell death. The effects were inhibited by blocking Toll-like receptor 4 pathway. In addition, high levels of shed GP were detected in supernatants of cells treated with Ebola vaccines. This study highlights the role of shed GP in Ebola pathogenesis and also in adverse effects associated with Ebola vaccines.
      PubDate: Tue, 31 Jul 2018 00:00:00 GMT
      DOI: 10.1093/infdis/jiy406
      Issue No: Vol. 218, No. suppl_5 (2018)
       
  • Ebolavirus Chimerization for the Development of a Mouse Model for
           Screening of Bundibugyo-Specific Antibodies
    • Authors: Ilinykh P; Graber J, Kuzmina N, et al.
      Abstract: Screening of monoclonal antibodies against ebolaviruses requires small-animal models. Wild-type mice require adaptation of ebolaviruses, whereas immunodeficient mice are still resistant to nonadapted Bundibugyo ebolavirus. Swapping of Ebola virus glycoprotein with that from Bundibugyo virus resulted in a replication-competent chimeric virus, which caused 100% lethal infection in STAT1 knockout mice. Monoclonal antibody BDBV223 isolated from a human survivor of Bundibugyo virus infection protected mice from challenge with the chimeric virus. These data demonstrate the suitability of the approach for in vivo screening of antibodies and suggest the greater contribution of internal Ebola proteins in pathogenesis compared to Bundibugyo virus proteins.
      PubDate: Sat, 28 Jul 2018 00:00:00 GMT
      DOI: 10.1093/infdis/jiy423
      Issue No: Vol. 218, No. suppl_5 (2018)
       
  • The Induction of IL-1β Secretion Through the NLRP3 Inflammasome
           During Ebola Virus Infection
    • Authors: Halfmann P; Hill-Batorski L, Kawaoka Y.
      Abstract: The inflammasome is part of the innate immune system that regulates the secretion of proinflammatory cytokines such as interleukin-1β (IL-1β). Ebola virus (EBOV) infection of monocytes and macrophages (primary target cells early during infection) leads to the production of proinflammatory cytokines; however, the mechanism behind the activation and release of these cytokines is not fully understood. Here, we demonstrate that EBOV infection leads to the activation of the NLRP3 inflammasome and the subsequent secretion of IL-1β and IL-18. This process is dependent on protease caspase-1, a component of the NLRP3 inflammasome complex, but is independent of virus replication. These findings may lead to the development of novel drugs that impede the pathogenesis of EBOV infection.
      PubDate: Fri, 27 Jul 2018 00:00:00 GMT
      DOI: 10.1093/infdis/jiy433
      Issue No: Vol. 218, No. suppl_5 (2018)
       
  • Generation and Optimization of a Green Fluorescent Protein-Expressing
           Transcription and Replication-Competent Virus-Like Particle System for
           Ebola Virus
    • Authors: Schmidt M; Tews B, Groseth A, et al.
      Abstract: Work with infectious Ebola virus is restricted to biosafety level (BSL) 4 laboratories. To overcome this limitation, life cycle modeling systems, which recapitulate part or all of the virus life cycle under BSL-1 or -2 conditions, have been developed. The tetracistronic transcription and replication-competent virus-like particle (trVLP) system is currently the most advanced of these systems and is particularly useful for drug screening. However, previous versions have used luciferase reporters, limiting the types of screening assays that can be performed. Here we describe the generation and optimization of a green fluorescent protein-expressing tetracistronic trVLP system, enabling high-content imaging and flow cytometry approaches.Summary: Transcription and replication-competent virus-like particle (trVLP) systems are powerful tools to model the life cycle of highly pathogenic Ebola viruses. Here we describe the generation of a novel, GFP-based trVLP system that allows high content imaging and flow cytometry approaches.
      PubDate: Wed, 25 Jul 2018 00:00:00 GMT
      DOI: 10.1093/infdis/jiy405
      Issue No: Vol. 218, No. suppl_5 (2018)
       
  • Human Polyclonal Antibodies Produced by Transchromosomal Cattle Provide
           Partial Protection Against Lethal Zaire Ebolavirus Challenge in Rhesus
           Macaques
    • Authors: Rosenke K; Bounds C, Hanley P, et al.
      Abstract: Antibody therapy has been used to treat a variety of diseases and the success of ZMapp and other monoclonal antibody-based therapies during the 2014–2016 West African Ebola outbreak has shown this countermeasure can be a successful therapy for Ebola hemorrhagic fever. This study utilized transchromosomal bovines (TcB) vaccinated with a DNA plasmid encoding Ebola virus glycoprotein sequence to produce human polyclonal antibodies directed against Ebola virus glycoprotein. When administered 1 day postinfection, these TcB polyclonal antibodies provided partial protection and resulted in a 50% survival rate following a lethal challenge of Ebola virus Makona in rhesus macaques.
      PubDate: Wed, 25 Jul 2018 00:00:00 GMT
      DOI: 10.1093/infdis/jiy430
      Issue No: Vol. 218, No. suppl_5 (2018)
       
  • New Insights Into Marburg Virus Disease Pathogenesis in the Rhesus Macaque
           Model
    • Authors: Cooper T; Sword J, Johnson J, et al.
      Abstract: Previously, several studies have been performed to delineate the development and progression of Marburg virus infection in nonhuman primates (NHPs), primarily to clarify the mechanisms of severe (fatal) disease. After the 2013–2016 Ebola virus disease (EVD) epidemic in Western Africa, there has been a reassessment of the available filovirus animal models and the utility of these to faithfully recapitulate human disease. The high lethality of the NHP models has raised doubts as to their ability to provide meaningful data for the full spectrum of disease observed in humans. Of particular interest are the etiologic and pathophysiologic mechanisms underlying postconvalescent sequelae observed in human survivors of EVD and Marburg virus disease (MVD). In the current study, we evaluated the lesions of MVD in NHPs; however, in contrast to previous studies, we focused on the potential for development of sequelae similar to those reported in human survivors of MVD and EVD. We found that during acute MVD in the macaque model, there is frequent inflammation of peripheral nerves, autonomic ganglia, and the iris of the eye. Furthermore, we demonstrate viral infection of the ocular ciliary body and retina, testis, epididymis, ovary, oviduct, uterine endometrium, prostate, and mammary gland. These findings are relevant for both development of postconvalescent sequelae and the natural transmission of virus.
      PubDate: Thu, 19 Jul 2018 00:00:00 GMT
      DOI: 10.1093/infdis/jiy367
      Issue No: Vol. 218, No. suppl_5 (2018)
       
  • The Genetic Adjuvants Interleukin-12 and Granulocyte-Macrophage Colony
           Stimulating Factor Enhance the Immunogenicity of an Ebola Virus
           Deoxyribonucleic Acid Vaccine in Mice
    • Authors: Suschak J; Bagley K, Shoemaker C, et al.
      Abstract: In previous studies, we showed that deoxyribonucleic acid (DNA) vaccines expressing codon-optimized filovirus envelope glycoprotein genes protect mice and nonhuman primates from viral challenge when delivered by intramuscular (IM) electroporation (EP). To determine whether we could achieve equivalent immunogenicity and protective efficacy by a simplified delivery method, we generated DNA vaccine plasmids expressing genetic adjuvants to potentiate immune responses. We tested the Th1-inducing cytokine interleukin-12 and the granulocyte growth factor granulocyte-macrophage colony stimulating factor, both of which have demonstrated significant adjuvant effect when included in clinical DNA vaccine formulations. In addition, because interferon (IFN)-αβ is required for DNA vaccine-induced immunity, we tested inclusion of a potent stimulator of the IFN-αβ pathway. Our data suggest that IM vaccination of mice with plasmid DNA encoding genetic adjuvants enhances vaccine immunogenicity, resulting in increased anti-Ebola virus (EBOV) immunoglobulin G and T-cell responses. Codelivery of genetic adjuvants also improved EBOV neutralizing capability compared with vaccine alone. Finally, IM vaccination with plasmid EBOV and genetic adjuvants provided complete protection against EBOV challenge. Overall, our data suggest that codelivery of genetic adjuvants with filovirus DNA vaccines using IM delivery can provide comparable efficacy to the same DNA vaccines when delivered using IM-EP devices.
      PubDate: Thu, 19 Jul 2018 00:00:00 GMT
      DOI: 10.1093/infdis/jiy378
      Issue No: Vol. 218, No. suppl_5 (2018)
       
  • The Past Need Not Be Prologue: Recommendations for Testing and Positioning
           the Most-Promising Medical Countermeasures for the Next Outbreak of Ebola
           Virus Infection
    • Authors: Davey R; Jr, Dodd L, Proschan M, et al.
      Abstract: BackgroundThe 2013–2016 outbreak of Ebola virus disease (EVD) in West Africa led to unprecedented morbidity and mortality. Although different classes of putative antiviral agents with supportive preclinical data were available for testing, and although several attempts to perform meaningful evaluation of these agents were undertaken during the epidemic, different research methods, a lack of appropriate controls in most studies, and formidable logistical challenges to completion of studies under field conditions hampered the success of these efforts. Ultimately only 1 randomized, placebo-controlled clinical trial (PREVAIL II) was performed in this setting, and, owing to a decrease in the number of new cases available for study, it, too, ended prior to reaching definitive results. Retrospective review of the lessons learned from this outbreak argues strongly for the need for much better preparedness in terms of selecting the trial design and drug(s) for use during the next outbreak.MethodsUsing recent data provided by representatives from the pharmaceutical industry, clinical and laboratory subject matter experts from the National Institute of Allergy and Infectious Diseases, other US government agencies, and academic partners were consulted regarding the current state of knowledge about several lead compounds with putative activity against EVD. Consensus was sought on recommendations concerning the most promising treatment strategies against EVD that should be studied in the context of a randomized clinical trial during the next outbreak.ResultsFour compounds from 2 different classes (monoclonal antibody [mAb] cocktails and direct-acting antiviral agents [DAAs]) were highlighted as lead candidates, limitations in the current knowledge base about these drug classes were reviewed, and recommendations about the optimal clinical research design for studying combinations of these different agents were made.ConclusionsAlthough achieving the desired sample size could be challenging, a randomized, controlled clinical trial based on a combination strategy of a mAb with a DAA was recommended as the most appropriate clinical trial design to be undertaken during the next outbreak of EVD.
      PubDate: Wed, 18 Jul 2018 00:00:00 GMT
      DOI: 10.1093/infdis/jiy334
      Issue No: Vol. 218, No. suppl_5 (2018)
       
  • In Vitro and In Vivo Activity of Amiodarone Against Ebola Virus
    • Authors: Dyall J; Johnson J, Hart B, et al.
      Abstract: At the onset of the 2013–2016 epidemic of Ebola virus disease (EVD), no vaccine or antiviral medication was approved for treatment. Therefore, considerable efforts were directed towards the concept of drug repurposing or repositioning. Amiodarone, an approved multi-ion channel blocker for the treatment of cardiac arrhythmia, was reported to inhibit filovirus entry in vitro. Compassionate use of amiodarone in EVD patients indicated a possible survival benefit. In support of further clinical testing, we confirmed anti-Ebola virus activity of amiodarone in different cell types. Despite promising in vitro results, amiodarone failed to protect guinea pigs from a lethal dose of Ebola virus.
      PubDate: Mon, 16 Jul 2018 00:00:00 GMT
      DOI: 10.1093/infdis/jiy345
      Issue No: Vol. 218, No. suppl_5 (2018)
       
  • Fully Human Immunoglobulin G From Transchromosomic Bovines Treats Nonhuman
           Primates Infected With Ebola Virus Makona Isolate
    • Authors: Luke T; Bennett R, Gerhardt D, et al.
      Abstract: Transchromosomic bovines (Tc-bovines) adaptively produce fully human polyclonal immunoglobulin (Ig)G antibodies after exposure to immunogenic antigen(s). The National Interagency Confederation for Biological Research and collaborators rapidly produced and then evaluated anti-Ebola virus IgG immunoglobulins (collectively termed SAB-139) purified from Tc-bovine plasma after sequential hyperimmunization with an Ebola virus Makona isolate glycoprotein nanoparticle vaccine. SAB-139 was characterized by several in vitro production, research, and clinical level assays using wild-type Makona-C05 or recombinant virus/antigens from different Ebola virus variants. SAB-139 potently activates natural killer cells, monocytes, and peripheral blood mononuclear cells and has high-binding avidity demonstrated by surface plasmon resonance. SAB-139 has similar concentrations of galactose-α-1,3-galactose carbohydrates compared with human-derived intravenous Ig, and the IgG1 subclass antibody is predominant. All rhesus macaques infected with Ebola virus/H.sapiens-tc/GIN/2014/Makona-C05 and treated with sufficient SAB-139 at 1 day (n = 6) or 3 days (n = 6) postinfection survived versus 0% of controls. This study demonstrates that Tc-bovines can produce pathogen-specific human Ig to prevent and/or treat patients when an emerging infectious disease either threatens to or becomes an epidemic.
      PubDate: Mon, 16 Jul 2018 00:00:00 GMT
      DOI: 10.1093/infdis/jiy377
      Issue No: Vol. 218, No. suppl_5 (2018)
       
  • Single-Nucleotide Polymorphisms in Human NPC1 Influence Filovirus Entry
           Into Cells
    • Authors: Kondoh T; Letko M, Munster V, et al.
      Abstract: Niemann-Pick C1 (NPC1), a host receptor involved in the envelope glycoprotein (GP)–mediated entry of filoviruses into cells, is believed to be a major determinant of cell susceptibility to filovirus infection. It is known that proteolytically digested Ebola virus (EBOV) GP interacts with 2 protruding loops in domain C of NPC1. Using previously published structural data and the National Center for Biotechnology Information Single-Nucleotide Polymorphism (SNP) database, we identified 10 naturally occurring missense SNPs in human NPC1. To investigate whether these SNPs affect cell susceptibility to filovirus infection, we generated Vero E6 cell lines stably expressing NPC1 with SNP substitutions and compared their susceptibility to vesicular stomatitis virus pseudotyped with filovirus GPs and infectious EBOV. We found that some of the substitutions resulted in reduced susceptibility to filoviruses, as indicated by the lower titers and smaller plaque/focus sizes of the viruses. Our data suggest that human NPC1 SNPs may likely affect host susceptibility to filoviruses.
      PubDate: Sat, 14 Jul 2018 00:00:00 GMT
      DOI: 10.1093/infdis/jiy248
      Issue No: Vol. 218, No. suppl_5 (2018)
       
  • Vaccine Generation of Protective Ebola Antibodies and Identification of
           Conserved B-Cell Signatures
    • Authors: Cagigi A; Misasi J, Ploquin A, et al.
      Abstract: We recently identified a single potently neutralizing monoclonal antibody (mAb), mAb114, isolated from a human survivor of natural Zaire ebolavirus (EBOV) infection, which fully protects nonhuman primates (NHPs) against lethal EBOV challenge. To evaluate the ability of vaccination to generate mAbs such as mAb114, we cloned antibodies from NHPs vaccinated with vectors encoding the EBOV glycoprotein (GP). We identified 14 unique mAbs with potent binding to GP, 4 of which were neutralized and had the functional characteristics of mAb114. These vaccine-induced macaque mAbs share many sequence similarities with mAb114 and use the same mAb114 VH gene (ie, IGHV3-13) when classified using the macaque IMGT database. The antigen-specific VH-gene repertoire present after each immunization indicated that IGHV3-13 mAbs populate an EBOV-specific B-cell repertoire that appears to become more prominent with subsequent boosting. These findings will support structure-based vaccine design aimed at enhanced induction of antibodies such as mAb114.
      PubDate: Thu, 12 Jul 2018 00:00:00 GMT
      DOI: 10.1093/infdis/jiy333
      Issue No: Vol. 218, No. suppl_5 (2018)
       
  • T-Cell Receptor Diversity and the Control of T-Cell Homeostasis Mark Ebola
           Virus Disease Survival in Humans
    • Authors: Speranza E; Ruibal P, Port J, et al.
      Abstract: Differences in T-cell phenotype, particularly the expression of markers of T-cell homeostasis, have been observed in fatal and nonfatal Ebola virus disease (EVD). However, the relationship between these markers with T-cell function and virus clearance during EVD is poorly understood. To gain biological insight into the role of T cells during EVD, combined transcriptomics and T-cell receptor sequencing was used to profile blood samples from fatal and nonfatal EVD patients from the recent West African EVD epidemic. Fatal EVD was characterized by strong T-cell activation and increased abundance of T-cell inhibitory molecules. However, the early T-cell response was oligoclonal and did not result in viral clearance. In contrast, survivors mounted highly diverse T-cell responses, maintained low levels of T-cell inhibitors, and cleared Ebola virus. Our findings highlight the importance of T-cell immunity in surviving EVD and strengthen the foundation for further research on targeting of the dendritic cell-T cell interface for postexposure immunotherapy.
      PubDate: Fri, 06 Jul 2018 00:00:00 GMT
      DOI: 10.1093/infdis/jiy352
      Issue No: Vol. 218, No. suppl_5 (2018)
       
  • Serological Evidence for the Circulation of Ebolaviruses in Pigs From
           Sierra Leone
    • Authors: Fischer K; Jabaty J, Suluku R, et al.
      Abstract: Many human ebolavirus outbreaks have been linked to contact with wildlife including nonhuman primates and bats, which are assumed to serve as host species. However, it is largely unknown to what extent other animal species, particularly livestock, are involved in the transmission cycle or act as additional hosts for filoviruses. Pigs were identified as a susceptible host for Reston virus with subsequent transmission to humans reported in the Philippines. To date, there is no evidence of natural Ebola virus (EBOV) infection in pigs, although pigs were shown to be susceptible to EBOV infection under experimental settings. To investigate the potential role of pigs in the ecology of EBOV, we analyzed 400 porcine serum samples from Sierra Leone for the presence of ebolavirus-specific antibodies. Three samples reacted with ebolavirus nucleoproteins but had no neutralizing antibodies. Our results (1) suggest the circulation of ebolaviruses in swine in Sierra Leone that are antigenically related but not identical to EBOV and (2) could represent undiscovered ebolaviruses with unknown pathogenic and/or zoonotic potential.
      PubDate: Thu, 05 Jul 2018 00:00:00 GMT
      DOI: 10.1093/infdis/jiy330
      Issue No: Vol. 218, No. suppl_5 (2018)
       
  • Efficacy of Human Monoclonal Antibody Monotherapy Against Bundibugyo Virus
           Infection in Nonhuman Primates
    • Authors: Gilchuk P; Mire C, Geisbert J, et al.
      Abstract: BackgroundThe 2013–2016 Ebola virus disease (EVD) epidemics in West Africa highlighted a need for effective therapeutics for treatment of the disease caused by filoviruses. Monoclonal antibodies (mAbs) are promising therapeutic candidates for prophylaxis or treatment of virus infections. Data about efficacy of human mAb monotherapy against filovirus infections in preclinical nonhuman primate models are limited.MethodsPreviously, we described a large panel of human mAbs derived from the circulating memory B cells from Bundibugyo virus (BDBV) infection survivors that bind to the surface glycoprotein (GP) of the virus. We tested one of these neutralizing mAbs that recognized the glycan cap of the GP, designated mAb BDBV289, as monotherapy in rhesus macaques.ResultsWe found that recombinant mAb BDBV289-N could confer up to 100% protection to BDBV-infected rhesus macaques when treatment was initiated as late as 8 days after virus challenge. Protection was associated with survival and decreased viremia levels in the blood of treated animals.ConclusionsThese findings define the efficacy of monotherapy of lethal BDBV infection with a glycan cap–specific mAb and identify a candidate mAb therapeutic molecule that could be included in antibody cocktails for prevention or treatment of ebolavirus infections.
      PubDate: Thu, 05 Jul 2018 00:00:00 GMT
      DOI: 10.1093/infdis/jiy295
      Issue No: Vol. 218, No. suppl_5 (2018)
       
  • Compatibility of Maximum-Containment Virus–Inactivation Protocols With
           Identification of Bacterial Coinfections by Matrix-Assisted Laser
           Desorption/Ionization Time-of-Flight Mass Spectrometry
    • Authors: Matson M; Stock F, Shupert W, et al.
      Abstract: Diagnostics and research analyses involving samples containing maximum-containment viruses present unique challenges, and inactivation protocols compatible with downstream testing are needed. Our aim was to identify a validated viral inactivation protocol compatible with bacterial identification by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS). We assessed a panel of bacteria with 6 validated maximum-containment virus–inactivation protocols and report that inactivation with TRIzol or γ-irradiation is compatible with MALDI-TOF MS. The availability, simplicity, and rapidity of TRIzol inactivation make this method the more suitable choice.
      PubDate: Wed, 04 Jul 2018 00:00:00 GMT
      DOI: 10.1093/infdis/jiy292
      Issue No: Vol. 218, No. suppl_5 (2018)
       
  • The Calcium Channel Blocker Bepridil Demonstrates Efficacy in the Murine
           Model of Marburg Virus Disease
    • Authors: DeWald L; Dyall J, Sword J, et al.
      Abstract: No therapeutics are approved for the treatment of filovirus infections. Bepridil, a calcium channel blocker developed for treating angina, was identified as a potent inhibitor of filoviruses in vitro, including Ebola and Marburg viruses, and Ebola virus in vivo. We evaluated the efficacy of bepridil in a lethal mouse model of Marburg virus disease. A dose of 12 mg/kg bepridil once or twice daily resulted in 80% or 90% survival, respectively. These data confirm bepridil’s broad-spectrum anti-filovirus activity warranting further investigation of bepridil, or improved compounds with a similar mechanism, as a pan-filovirus therapeutic agent.
      PubDate: Wed, 04 Jul 2018 00:00:00 GMT
      DOI: 10.1093/infdis/jiy332
      Issue No: Vol. 218, No. suppl_5 (2018)
       
  • Postexposure Protective Efficacy of T-705 (Favipiravir) Against Sudan
           Virus Infection in Guinea Pigs
    • Authors: Rahim M; Zhang Z, He S, et al.
      Abstract: Filoviruses such as Ebola virus (EBOV), Marburg virus (MARV), and Sudan virus (SUDV) cause deadly viral hemorrhagic fever in humans, with high case-fatality rates; however, no licensed therapeutic agent or vaccine has been clinically approved to treat or prevent infection. T-705 (favipiravir) is a novel antiviral drug that has been approved for the treatment of influenza in Japan. T-705 exhibits broad-spectrum antiviral activity against different viruses, including MARV and EBOV, and here, we are the first to report the in vitro and in vivo antiviral activity of T-705 against SUDV. T-705 treatment reduced SUDV replication in Vero E6 cells. Subcutaneous administration of T-705, beginning 1–4 days after infection and continuing for 7 days, significantly protected SUDV-infected guinea pigs, with a survival rate of 83%–100%. Viral RNA replication and infectious virus production were also significantly reduced in the blood, spleen, liver, lungs, and kidney. Moreover, early administration of low-dose T-705 and late administration (at 5 days after infection) of higher-dose T-705 also showed partial protection. Overall, our study is the first to demonstrate the antiviral activity of T-705 against SUDV, suggesting that T-705 may be a potential drug candidate for use during outbreaks.
      PubDate: Mon, 02 Jul 2018 00:00:00 GMT
      DOI: 10.1093/infdis/jiy303
      Issue No: Vol. 218, No. suppl_5 (2018)
       
  • Marburg and Ravn Viruses Fail to Cause Disease in the Domestic Ferret
           (Mustela putorius furo)
    • Authors: Cross R; Mire C, Agans K, et al.
      Abstract: The domestic ferret was recently described as a uniformly lethal model for 3 species of Ebolavirus. More importantly, this new model utilizes nonadapted wild-type Ebolaviruses. Here, in a proof-of-concept study, we infected ferrets with different variants of the closely related Marburg and Ravn viruses using different doses and routes of exposure. Although ferrets produced a neutralizing humoral response to challenge, we did not observe disease or viremia in any animal. The lack of disease in ferrets underscores the notion that differential mechanisms to immunity among filoviruses exist and may provide a model to better understand how differences contribute to disease.
      PubDate: Thu, 28 Jun 2018 00:00:00 GMT
      DOI: 10.1093/infdis/jiy268
      Issue No: Vol. 218, No. suppl_5 (2018)
       
  • Autophagy-Associated Proteins Control Ebola Virus Internalization Into
           Host Cells
    • Authors: Shtanko O; Reyes A, Jackson W, et al.
      Abstract: Ebola virus (EBOV) enters host cells by macropinocytosis, a poorly understood process. Recent studies have suggested that cell factors involved in autophagy, an evolutionally conserved pathway leading to the lysosomal degradation of protein aggregates and organelles during cellular stress, also have roles in macropinocytosis. Here, we demonstrate that autophagy-associated proteins are required for trafficking of EBOV into the cell body. Depleting cells of beclin 1, autophagy-related protein 7, or microtubule-associated protein 1A/B light chain 3B (LC3B) abolished EBOV uptake, owing to a block in vesicle formation at the cell surface. Both LC3B-I and LC3B-II interacted with macropinocytic structures. Our work indicates that, although various forms of LC3B possess an inherent ability to associate with forming macropinosomes, LC3B-II is critical for internalization of macropinocytic vesicles and, therefore, EBOV from the cell surface.
      PubDate: Wed, 27 Jun 2018 00:00:00 GMT
      DOI: 10.1093/infdis/jiy294
      Issue No: Vol. 218, No. suppl_5 (2018)
       
  • Efficacy of Ebola Glycoprotein-Specific Equine Polyclonal Antibody Product
           Against Lethal Ebola Virus Infection in Guinea Pigs
    • Authors: Chan M; Holtsberg F, Vu H, et al.
      Abstract: BackgroundFiloviruses including Ebola, Sudan, and other species are emerging zoonotic pathogens representing a significant public health concern with high outbreak potential, and they remain a potential bioterrorism-related threat. We have developed a despeciated equine Ebola polyclonal antibody (E-EIG) postexposure treatment against Ebola virus (EBOV) and evaluated its efficacy in the guinea pig model of EBOV infection.MethodsGuinea pigs were infected with guinea pig-adapted EBOV (Mayinga strain) and treated with various dose levels of E-EIG (20–100 mg/kg) twice daily for 6 days starting at 24 h postinfection. The E-EIG was also assessed for neutralization activity against related filoviruses including EBOV strains Mayinga, Kikwit, and Makona and the Bundibugyo and Taï Forest ebolavirus species.ResultsTreatment with E-EIG conferred 83% to 100% protection in guinea pigs. The results demonstrated a comparable neutralization activity (range, 1:512–1:896) of E-EIG against all tested strains, suggesting the potential for cross-protection with the polyclonal antibody therapeutic.ConclusionsThis study showed that equine-derived polyclonal antibodies are efficacious against lethal EBOV disease in a relevant animal model. Furthermore, the studies support the utility of the equine antibody platform for the rapid production of a therapeutic product in the event of an outbreak by a filovirus or other zoonotic pathogen.
      PubDate: Wed, 27 Jun 2018 00:00:00 GMT
      DOI: 10.1093/infdis/jiy329
      Issue No: Vol. 218, No. suppl_5 (2018)
       
  • Role of Antibodies in Protection Against Ebola Virus in Nonhuman Primates
           Immunized With Three Vaccine Platforms
    • Authors: Warfield K; Howell K, Vu H, et al.
      Abstract: BackgroundSeveral vaccine platforms have been successfully evaluated for prevention of Ebola virus (EBOV) disease (EVD) in nonhuman primates and humans. Despite remarkable efficacy by multiple vaccines, the immunological correlates of protection against EVD are incompletely understood.MethodsWe systematically evaluated the antibody response to various EBOV proteins in 79 nonhuman primates vaccinated with various EBOV vaccine platforms. We evaluated the serum immunoglobulin (Ig)G titers against EBOV glycoprotein (GP), the ability of the vaccine-induced antibodies to bind GP at acidic pH or to displace ZMapp, and virus neutralization titers. The correlation of these outcomes with survival from EVD was evaluated by appropriate statistical methods.ResultsIrrespective of the vaccine platform, protection from EVD strongly correlated with anti-GP IgG titers. The GP-directed antibody levels required for protection in animals vaccinated with virus-like particles (VLPs) lacking nucleoprotein (NP) was significantly higher than animals immunized with NP-containing VLPs or adenovirus-expressed GP, platforms that induce strong T-cell responses. Furthermore, protective immune responses correlated with anti-GP antibody binding strength at acidic pH, neutralization of GP-expressing pseudovirions, and the ability to displace ZMapp components from GP.ConclusionsThese findings suggest key quantitative and qualitative attributes of antibody response to EVD vaccines as potential correlates of protection.
      PubDate: Mon, 25 Jun 2018 00:00:00 GMT
      DOI: 10.1093/infdis/jiy316
      Issue No: Vol. 218, No. suppl_5 (2018)
       
  • Broad Neutralizing Activity Against Ebolaviruses Lacking the Mucin-Like
           Domain in Convalescent Plasma Specimens From Patients With Ebola Virus
           Disease
    • Authors: Luczkowiak J; Lasala F, Mora-Rillo M, et al.
      Abstract: BackgroundIn Ebola virus (EBOV) infection, the specific neutralizing activity of convalescent plasma against other members of the Ebolavirus genus has not been extensively analyzed.MethodsWe measured the neutralizing activity in plasma from 3 survivors of the recent outbreak due to the Makona variant of EBOV and tested its neutralizing potency against other variants of EBOV (ie, Mayinga and Kikwit) and against Sudan virus (SUDV), Bundibugyo virus (BDBV), and Reston virus (RESTV), using a glycoprotein (GP)–pseudotyped lentiviral system both with full-length GP and in vitro–cleaved GP (GPCL).ResultsConvalescent plasma specimens from survivors of EBOV infection showed low neutralizing activity against full-length GPs of SUDV, BDBV, RESTV, and EBOV variants Mayinga and Kikwit. However, broad and potent neutralizing activity was observed against the GPCL forms of SUDV, BDBV, and RESTV.DiscussionRemoval of the mucin-like domain and glycan cap from the GP of members of the Ebolavirus genus presumably exposes conserved epitopes in or in the vicinity of the receptor binding site and internal fusion loop that are readily amenable to neutralization. These types of broad neutralizing antibodies could be induced by using immunogens mimicking GPCL.
      PubDate: Mon, 25 Jun 2018 00:00:00 GMT
      DOI: 10.1093/infdis/jiy302
      Issue No: Vol. 218, No. suppl_5 (2018)
       
  • Postexposure Efficacy of Recombinant Vesicular Stomatitis Virus Vectors
           Against High and Low Doses of Marburg Virus Variant Angola in Nonhuman
           Primates
    • Authors: Woolsey C; Geisbert J, Matassov D, et al.
      Abstract: A recombinant vesicular stomatitis virus (rVSV) expressing the Marburg virus (MARV) Musoke variant glycoprotein fully protects macaques against 2 MARV variants and Ravn virus as a preventive vaccine and MARV variant Musoke as a postexposure treatment. To evaluate postexposure efficacy against the most pathogenic MARV variant, Angola, we engineered rVSVs expressing homologous Angola glycoprotein. Macaques were challenged with high or low doses of variant Angola and treated 20–30 minutes after exposure. A total of 25% and 60%–75% of treated macaques survived the high-dose and low-dose challenges, respectively. The more rapid disease progression of variant Angola versus variant Musoke may account for the incomplete protection observed.
      PubDate: Mon, 25 Jun 2018 00:00:00 GMT
      DOI: 10.1093/infdis/jiy293
      Issue No: Vol. 218, No. suppl_5 (2018)
       
  • Antibody Repertoire of Human Polyclonal Antibodies Against Ebola Virus
           Glycoprotein Generated After Deoxyribonucleic Acid and Protein Vaccination
           of Transchromosomal Bovines
    • Authors: Fuentes S; Ravichandran S, Khurana S.
      Abstract: Several Ebola vaccines and therapeutics are under clinical development. However, limited knowledge exists on the quality of antibody response generated by different Ebola vaccines. In this study, antibody repertoire induced by vaccination of transchromosomal bovine (TcB) with Ebola virus (EBOV) glycoprotein ([GP]; recombinant GP [rGP]) encoded by either deoxyribonucleic acid (DNA) or nanoparticle-based vaccine platform was analyzed using EBOV genome fragment phage display library and surface plasmon resonance (SPR)-based real-time kinetics assay to measure antibody affinity maturation to both native and partially denatured Ebola GP as well as GP containing the receptor binding domain but lacking the mucin-like domain. Immunoglobulin (IgG) obtained from rGP nanoparticle-vaccinated TcB demonstrated ~4-fold higher binding affinity compared with DNA-vaccinated TcB-induced IgG against the native rGP’s. The rGP nanoparticle vaccine generated a more robust and diverse antibody immune response to the native EBOV-GP compared with the DNA vaccine, which may explain the protective efficacy observed for these antibody preparations.
      PubDate: Mon, 25 Jun 2018 00:00:00 GMT
      DOI: 10.1093/infdis/jiy325
      Issue No: Vol. 218, No. suppl_5 (2018)
       
  • Identification of Combinations of Approved Drugs With Synergistic Activity
           Against Ebola Virus in Cell Cultures
    • Authors: Dyall J; Nelson E, DeWald L, et al.
      Abstract: BackgroundA need to develop therapeutics to treat Ebola virus disease patients in remote and resource-challenged settings remains in the wake of the 2013–2016 epidemic in West Africa. Toward this goal, we screened drugs under consideration as treatment options and other drugs of interest, most being small molecules approved by the Food and Drug Administration. Drugs demonstrating in vitro antiviral activity were advanced for evaluation in combinations because of advantages often provided by drug cocktails.MethodsDrugs were screened for blockade of Ebola virus infection in cultured cells. Twelve drugs were tested in all (78 pair-wise) combinations, and 3 were tested in a subset of combinations.ResultsMultiple synergistic drug pairs emerged, with the majority comprising 2 entry inhibitors. For the pairs of entry inhibitors studied, synergy was demonstrated at the level of virus entry into host cells. Highly synergistic pairs included aripiprazole/piperacetazine, sertraline/toremifene, sertraline/bepridil, and amodiaquine/clomiphene.ConclusionsOur study shows the feasibility of identifying pairs of approved drugs that synergistically block Ebola virus infection in cell cultures. We discuss our findings in terms of the theoretic ability of these or alternate combinations to reach therapeutic levels. Future research will assess selected combinations in small-animal models of Ebola virus disease.
      PubDate: Mon, 25 Jun 2018 00:00:00 GMT
      DOI: 10.1093/infdis/jiy304
      Issue No: Vol. 218, No. suppl_5 (2018)
       
  • Analysis of a Putative Late Domain Using an Ebola Virus Transcription and
           Replication-Competent Virus-Like Particle System
    • Authors: Wendt L; Kämper L, Schmidt M, et al.
      Abstract: The Ebola virus (EBOV) matrix protein VP40 drives budding of virions and encodes 2 overlapping late domain motifs at amino acid positions 7–13 (PTAPPEY). However, these motifs are not absolutely essential for replication in cell culture, and recently a potential third late domain motif (YPx(6)I) was proposed at amino acid positions 18–26 of VP40. To analyze the importance of this motif in viral budding, we used a transcription and replication-competent virus-like particle system. Using this system, we show that this motif does not contribute to EBOV budding or particle propagation.
      PubDate: Wed, 20 Jun 2018 00:00:00 GMT
      DOI: 10.1093/infdis/jiy247
      Issue No: Vol. 218, No. suppl_5 (2018)
       
  • Suspected Exposure to Filoviruses Among People Contacting Wildlife in
           Southwestern Uganda
    • Authors: Smiley Evans T; Tutaryebwa L, Gilardi K, et al.
      Abstract: BackgroundHuman and filovirus host interactions remain poorly understood in areas where Ebola hemorrhagic fever outbreaks are likely to occur. In the Bwindi region of Uganda, a hot spot of mammalian biodiversity in Africa, human livelihoods are intimately connected with wildlife, creating potential for exposure to filoviruses.MethodsWe tested samples from 331 febrile patients presenting to healthcare facilities near Bwindi Impenetrable Forest, Uganda, by polymerase chain reaction (PCR) analysis and Western blot, using recombinant glycoprotein antigens for Ebola virus (EBOV), Sudan virus (SUDV), Bundibugyo virus (BDBV), and Marburg virus. Behavioral data on contact with wildlife were collected to examine risk factors for filovirus seropositivity.ResultsAll patients were negative for active filovirus infection, by PCR analysis. However, patients were seroreactive to SUDV (4.7%), EBOV (5.3%), and BDBV (8.9%), indicating previous exposure. Touching duikers was the most significant risk factor associated with EBOV seropositivity, while hunting primates and touching and/or eating cane rats were significant risk factors for SUDV seropositivity.ConclusionsPeople in southwestern Uganda have suspected previous exposure to filoviruses, particularly those with a history of wildlife contact. Circulation of filoviruses in wild animals and subsequent spillover into humans could be more common than previously reported.
      PubDate: Mon, 18 Jun 2018 00:00:00 GMT
      DOI: 10.1093/infdis/jiy251
      Issue No: Vol. 218, No. suppl_5 (2018)
       
  • Ebola Virus Transmission Caused by Persistently Infected Survivors of the
           2014–2016 Outbreak in West Africa
    • Authors: Subissi L; Keita M, Mesfin S, et al.
      Abstract: The 2014–2016 Ebola virus (EBOV) disease outbreak affected over 29000 people and left behind the biggest cohort (over 17000 individuals) of Ebola survivors in history. Although the persistence of EBOV in body fluids of survivors was reported before the recent outbreak, new evidence revealed that the virus can be detected up to 18 months in the semen, which represents the biggest risk of Ebola resurgence in affected communities. In this study, we review the knowledge on the Ebola flare-ups that occurred after the peak of the 2014–2016 Ebola epidemic in West Africa.
      PubDate: Mon, 18 Jun 2018 00:00:00 GMT
      DOI: 10.1093/infdis/jiy280
      Issue No: Vol. 218, No. suppl_5 (2018)
       
  • Seroprevalence of Filovirus Infection of Rousettus aegyptiacus Bats in
           Zambia
    • Authors: Changula K; Kajihara M, Mori-Kajihara A, et al.
      Abstract: Bats are suspected to play important roles in the ecology of filoviruses, including ebolaviruses and marburgviruses. A cave-dwelling fruit bat, Rousettus aegyptiacus, has been shown to be a reservoir of marburgviruses. Using an enzyme-linked immunosorbent assay with the viral glycoprotein antigen, we detected immunoglobulin G antibodies specific to multiple filoviruses in 158 of 290 serum samples of R aegyptiacus bats captured in Zambia during the years 2014–2017. In particular, 43.8% of the bats were seropositive to marburgvirus, supporting the notion that this bat species continuously maintains marburgviruses as a reservoir. Of note, distinct peaks of seropositive rates were repeatedly observed at the beginning of rainy seasons, suggesting seasonality of the presence of newly infected individuals in this bat population. These data highlight the need for continued monitoring of filovirus infection in this bat species even in countries where filovirus diseases have not been reported.
      PubDate: Fri, 08 Jun 2018 00:00:00 GMT
      DOI: 10.1093/infdis/jiy266
      Issue No: Vol. 218, No. suppl_5 (2018)
       
  • Marburg and Ravn Virus Infections Do Not Cause Observable Disease in
           Ferrets
    • Authors: Wong G; Zhang Z, He S, et al.
      Abstract: Ferrets are used for studying infections with wild-type Ebola virus isolates. Here, we investigated whether these animals are also susceptible to wild-type isolates of Marburg virus (MARV). Ferrets were challenged intramuscularly or intranasally with MARV strain Angola and monitored for 3 weeks. Unexpectedly, the animals neither showed observable signs of disease nor died of infection, and viremia was not detected after challenge. All animals were seropositive for MARV-specific immunoglobulin antibodies. Confirmatory studies with MARV strain Musoke and Ravn virus yielded the same outcomes. Therefore, ferrets may be of limited usefulness for studying the pathogenesis of MARV and Ravn virus infections.
      PubDate: Fri, 08 Jun 2018 00:00:00 GMT
      DOI: 10.1093/infdis/jiy245
      Issue No: Vol. 218, No. suppl_5 (2018)
       
  • Intradermal Vaccination With Adjuvanted Ebola Virus Soluble Glycoprotein
           Subunit Vaccine by Microneedle Patches Protects Mice Against Lethal Ebola
           Virus Challenge
    • Authors: Liu Y; Ye L, Lin F, et al.
      Abstract: In this study, we investigated immune responses induced by purified Ebola virus (EBOV) soluble glycoprotein (sGP) subunit vaccines via intradermal immunization with microneedle (MN) patches in comparison with intramuscular (IM) injection in mice. Our results showed that MN delivery of EBOV sGP was superior to IM injection in eliciting higher levels and longer lasting antibody responses against EBOV sGP and GP antigens. Moreover, sGP-specific immune responses induced by MN or IM immunizations were effectively augmented by formulating sGP with a saponin-based adjuvant, and they were shown to confer complete protection of mice against lethal mouse-adapted EBOV (MA-EBOV) challenge. In comparison, mice that received sGP without adjuvant by MN or IM immunizations succumbed to lethal MA-EBOV challenge. These results show that immunization with EBOV sGP subunit vaccines with adjuvant by MN patches, which have been shown to provide improved safety and thermal stability, is a promising approach to protect against EBOV infection.
      PubDate: Fri, 08 Jun 2018 00:00:00 GMT
      DOI: 10.1093/infdis/jiy267
      Issue No: Vol. 218, No. suppl_5 (2018)
       
  • Monoclonal Antibody Cocktail Protects Hamsters From Lethal Marburg Virus
           Infection
    • Authors: Marzi A; Haddock E, Kajihara M, et al.
      Abstract: Marburg virus (MARV), family Filoviridae, causes Marburg hemorrhagic fever (MHF) in humans and nonhuman primates with case fatality rates of up to 90%. There is no approved therapeutic for MHF, yet several experimental approaches have been evaluated in preclinical studies including small interfering RNA and monoclonal antibody (mAb) treatment. In this study we attempted to improve the therapeutic efficacy of the neutralizing mAb M4 by combining treatment with 1 or 2 of blocking but nonneutralizing mAbs 126-15 and 127-8. We found that single-dose treatment early after infection with the neutralizing mAb M4 or any of the mAb combinations resulted in similar protection in the MARV hamster model. However, a single-dose treatment with the cocktail of all 3 mAbs provided the best protection in delayed treatment, with 67%–100% of the animals surviving a lethal challenge depending on the time of treatment. This study identified a new promising mAb cocktail as a therapeutic option for MHF.
      PubDate: Fri, 08 Jun 2018 00:00:00 GMT
      DOI: 10.1093/infdis/jiy235
      Issue No: Vol. 218, No. suppl_5 (2018)
       
  • The Effect of Plasmodium on the Outcome of Ebola Virus Infection in a
           Mouse Model
    • Authors: Rosenke K; Mercado-Hernandez R, Cronin J, et al.
      Abstract: Following the Ebola virus epidemic in West Africa, several studies investigated whether there was an effect of Plasmodium coinfection on survival in Ebola virus (EBOV) disease patients. Different effects of coinfection were found in different patient cohorts. To determine whether an effect of Plasmodium coinfection on EBOV survival may exist, we modeled coinfection of Plasmodium yoelii and mouse-adapted EBOV (MA-EBOV) in CD1 mice. Subsequent infection with MA-EBOV at different time points after P. yoelii infection did not have any significant effect on survival.
      PubDate: Thu, 07 Jun 2018 00:00:00 GMT
      DOI: 10.1093/infdis/jiy236
      Issue No: Vol. 218, No. suppl_5 (2018)
       
  • Ebola Virus Infection in Commonly Used Laboratory Mouse Strains
    • Authors: Haddock E; Feldmann H, Marzi A.
      Abstract: The mouse model for Ebola virus (EBOV) is an established and often used animal model for countermeasure development. Although it has its limitations, it recapitulates certain key features of human EBOV disease and principally shows uniform lethality. However, in the recent past, several studies reported surviving animals when evaluating treatment or vaccine approaches. Therefore, we analyzed the severity of disease and lethality of mouse-adapted (MA-) EBOV infection in 6 different mouse strains. We identified outbred CD-1 mice to be the only strain tested resulting in uniform lethality when infected with different doses of MA-EBOV or reverse genetics–generated MA-EBOV. In contrast, infection of different inbred mouse strains resulted in partial survival depending on virus and dose. Of these inbred strains, 129 mice provided the most consistent model. Our study provides a helpful dataset when planning EBOV mouse studies for countermeasure efficacy testing and highlights the limitations of certain mouse strains as EBOV models.
      PubDate: Thu, 07 Jun 2018 00:00:00 GMT
      DOI: 10.1093/infdis/jiy208
      Issue No: Vol. 218, No. suppl_5 (2018)
       
  • The Makona Variant of Ebola Virus Is Highly Lethal to Immunocompromised
           Mice and Immunocompetent Ferrets
    • Authors: Wong G; Leung A, He S, et al.
      Abstract: During 2013–2016, a novel isolate of Ebola virus (EBOV-Makona) caused an epidemic in West Africa. The virus was distinct from known EBOV strains (EBOV-Kikwit and EBOV-Mayinga), which were responsible for previous outbreaks in Central Africa. To investigate the pathogenicity of EBOV-Makona, we engineered and rescued an early isolate (H.sapiens-wt/GIN/2014/Makona-Gueckedou-C07, called rgEBOV-C07) using an updated reverse-genetics system. rgEBOV-C07 was found to be highly pathogenic in both the knockout mouse and ferret models, with median lethal dose values of 0.078 and 0.015 plaque-forming units, respectively. Therefore, these animals are appropriate for screening potential countermeasures against EBOV-Makona without the need for species adaptation.
      PubDate: Thu, 07 Jun 2018 00:00:00 GMT
      DOI: 10.1093/infdis/jiy141
      Issue No: Vol. 218, No. suppl_5 (2018)
       
  • Development of Clinical-Stage Human Monoclonal Antibodies That Treat
           Advanced Ebola Virus Disease in Nonhuman Primates
    • Authors: Pascal K; Dudgeon D, Trefry J, et al.
      Abstract: BackgroundFor most classes of drugs, rapid development of therapeutics to treat emerging infections is challenged by the timelines needed to identify compounds with the desired efficacy, safety, and pharmacokinetic profiles. Fully human monoclonal antibodies (mAbs) provide an attractive method to overcome many of these hurdles to rapidly produce therapeutics for emerging diseases.MethodsIn this study, we deployed a platform to generate, test, and develop fully human antibodies to Zaire ebolavirus. We obtained specific anti-Ebola virus (EBOV) antibodies by immunizing VelocImmune mice that use human immunoglobulin variable regions in their humoral responses.ResultsOf the antibody clones isolated, 3 were selected as best at neutralizing EBOV and triggering FcγRIIIa. Binding studies and negative-stain electron microscopy revealed that the 3 selected antibodies bind to non-overlapping epitopes, including a potentially new protective epitope not targeted by other antibody-based treatments. When combined, a single dose of a cocktail of the 3 antibodies protected nonhuman primates (NHPs) from EBOV disease even after disease symptoms were apparent.ConclusionsThis antibody cocktail provides complementary mechanisms of actions, incorporates novel specificities, and demonstrates high-level postexposure protection from lethal EBOV disease in NHPs. It is now undergoing testing in normal healthy volunteers in preparation for potential use in future Ebola epidemics.
      PubDate: Thu, 31 May 2018 00:00:00 GMT
      DOI: 10.1093/infdis/jiy285
      Issue No: Vol. 218, No. suppl_5 (2018)
       
 
 
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