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1
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Roe MD, Hood G, Sterling SL, Yan L, Boré JA, Tipton T, Thompson C, Carroll MW, Laing ED. Performance of an envelope glycoprotein-based multiplex immunoassay for Ebola virus antibody detection in a cohort of Ebola virus disease survivors. J Virol Methods 2025; 331:115057. [PMID: 39461623 DOI: 10.1016/j.jviromet.2024.115057] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2024] [Revised: 10/18/2024] [Accepted: 10/23/2024] [Indexed: 10/29/2024]
Abstract
Serological surveillance in animal and human hosts can be a cost-effective strategy for orthoebolavirus detection, but is challenged by accurate estimates of seroprevalence, potential pauci-symptomatic disease presentation, and antigenic cross-reactivity. Here, we describe the use of an envelope glycoprotein (GP)-based multiplex microsphere immunoassay, consisting of nine filovirus GP antigens for the detection of anti-Ebola virus (EBOV) antibodies in a well-characterized cohort of Guinean Ebola virus disease (EVD) survivors and contacts from the 2013 - 2016 West African EVD outbreak. We examined sensitivity and specificity for the detection of anti-EBOV antibodies by GP expressed as recombinant trimeric ectodomains, yielding an assay performance of 95.96 % sensitivity and 98.61 % specificity. Additionally, agreement between the multiplex test and a whole virus ELISA and virus neutralization test showed strong correlations. The results demonstrate that this filovirus multiplex test is a sensitive tool for high-throughput serosurveillance.
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Affiliation(s)
- McKenna D Roe
- Department of Microbiology and Immunology, Uniformed Services University, Bethesda, MD, USA
| | - Grace Hood
- Centre for Human Genetics & Pandemic Sciences Institute, University of Oxford, Oxford, UK
| | - Spencer L Sterling
- Department of Microbiology and Immunology, Uniformed Services University, Bethesda, MD, USA; Henry M. Jackson for the Advancement of Military Medicine, Rockledge, MD, USA
| | - Lianying Yan
- Department of Microbiology and Immunology, Uniformed Services University, Bethesda, MD, USA; Henry M. Jackson for the Advancement of Military Medicine, Rockledge, MD, USA
| | - Joseph Akoi Boré
- Centre de Recherche et d'Analyse Biomédicale (CRAM), Macenta, Guinea
| | - Tom Tipton
- Centre for Human Genetics & Pandemic Sciences Institute, University of Oxford, Oxford, UK
| | - Craig Thompson
- Division of Biomedical Sciences, Warwick Medical School, University of Warwick, Warwick, UK
| | - Miles W Carroll
- Centre for Human Genetics & Pandemic Sciences Institute, University of Oxford, Oxford, UK
| | - Eric D Laing
- Department of Microbiology and Immunology, Uniformed Services University, Bethesda, MD, USA.
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2
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Santos RI, Bukreyev A. Protocol for quantification of intercellular connection transmission in ebolavirus infections using ImageJ. STAR Protoc 2024; 5:103363. [PMID: 39369387 PMCID: PMC11491943 DOI: 10.1016/j.xpro.2024.103363] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2024] [Revised: 07/14/2024] [Accepted: 09/13/2024] [Indexed: 10/08/2024] Open
Abstract
Previous work demonstrates that ebolaviruses can spread to neighboring cells through intercellular connections. Here, we present a protocol to quantify the intercellular spread of ebolaviruses via immunofluorescence. We describe steps for cell plating, Bundibugyo virus infection, and adding a neutralizing antibody. We detail procedures for quantitative microscopy assay using ebolavirus immunodetection. Strong virus accumulation around the plasma membrane leads to high fluorescence signal preventing quantification of viral spread based on signal intensity. This protocol minimizes the impact of this bias. For complete details on the use and execution of this protocol, please refer to Santos et al.1.
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Affiliation(s)
- Rodrigo I Santos
- Department of Pathology, University of Texas Medical Branch, Galveston, TX, USA; Galveston National Laboratory, Galveston, TX, USA.
| | - Alexander Bukreyev
- Department of Pathology, University of Texas Medical Branch, Galveston, TX, USA; Galveston National Laboratory, Galveston, TX, USA
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3
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Wiśniewski M, Babirye P, Musubika C, Papakonstantinou E, Kirimunda S, Łaźniewski M, Szczepińska T, Joloba ML, Eliopoulos E, Bongcam-Rudloff E, Vlachakis D, Kumar Halder A, Plewczyński D, Wayengera M. Use of in silico approaches, synthesis and profiling of Pan-filovirus GP-1,2 preprotein specific antibodies. Brief Funct Genomics 2024; 23:765-774. [PMID: 38605526 DOI: 10.1093/bfgp/elae012] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2023] [Revised: 03/15/2024] [Accepted: 03/22/2024] [Indexed: 04/13/2024] Open
Abstract
Intermolecular interactions of protein-protein complexes play a principal role in the process of discovering new substances used in the diagnosis and treatment of many diseases. Among such complexes of proteins, we have to mention antibodies; they interact with specific antigens of two genera of single-stranded RNA viruses belonging to the family Filoviridae-Ebolavirus and Marburgvirus; both cause rare but fatal viral hemorrhagic fever in Africa, with pandemic potential. In this research, we conduct studies aimed at the design and evaluation of antibodies targeting the filovirus glycoprotein precursor GP-1,2 to develop potential targets for the pan-filovirus easy-to-use rapid diagnostic tests. The in silico research using the available 3D structure of the natural antibody-antigen complex was carried out to determine the stability of individual protein segments in the process of its formation and maintenance. The computed free binding energy of the complex and its decomposition for all amino acids allowed us to define the residues that play an essential role in the structure and indicated the spots where potential antibodies can be improved. Following that, the study involved targeting six epitopes of the filovirus GP1,2 with two polyclonal antibodies (pABs) and 14 monoclonal antibodies (mABs). The evaluation conducted using Enzyme Immunoassays tested 62 different sandwich combinations of monoclonal antibodies (mAbs), identifying 10 combinations that successfully captured the recombinant GP1,2 (rGP). Among these combinations, the sandwich option (3G2G12* - (rGP) - 2D8F11) exhibited the highest propensity for capturing the rGP antigen.
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Affiliation(s)
- Maciej Wiśniewski
- Laboratory of Functional and Structural Genomics, Centre of New Technologies, University of Warsaw, Banacha 2c, 02-097, Warsaw, Poland
| | - Peace Babirye
- Department of Immunology and Molecular Biology, School of Biomedical Sciences, College of Health Sciences, Makerere University, Old Mulago Hill Road P.O. Box 7072, Kampala, Uganda
| | - Carol Musubika
- Department of Immunology and Molecular Biology, School of Biomedical Sciences, College of Health Sciences, Makerere University, Old Mulago Hill Road P.O. Box 7072, Kampala, Uganda
| | - Eleni Papakonstantinou
- Genetics Laboratory, Biotechnology Department, School of Applied Biology and Biotechnology,Agricultural University of Athens, Iera Odos 7511855 Athens, Greece
| | - Samuel Kirimunda
- Department of Immunology and Molecular Biology, School of Biomedical Sciences, College of Health Sciences, Makerere University, Old Mulago Hill Road P.O. Box 7072, Kampala, Uganda
| | - Michal Łaźniewski
- Laboratory of Functional and Structural Genomics, Centre of New Technologies, University of Warsaw, Banacha 2c, 02-097, Warsaw, Poland
| | - Teresa Szczepińska
- Laboratory of Functional and Structural Genomics, Centre of New Technologies, University of Warsaw, Banacha 2c, 02-097, Warsaw, Poland
| | - Moses L Joloba
- Department of Immunology and Molecular Biology, School of Biomedical Sciences, College of Health Sciences, Makerere University, Old Mulago Hill Road P.O. Box 7072, Kampala, Uganda
| | - Elias Eliopoulos
- Genetics Laboratory, Biotechnology Department, School of Applied Biology and Biotechnology,Agricultural University of Athens, Iera Odos 7511855 Athens, Greece
| | - Erik Bongcam-Rudloff
- Department of Animal Breeding and Genetics, Bioinformatics section, Swedish University for Agricultural Sciences, Ulls väg 26, PO Box 7023, S-750 07 Uppsala, Sweden
| | - Dimitrios Vlachakis
- Genetics Laboratory, Biotechnology Department, School of Applied Biology and Biotechnology, Agricultural University of Athens, Iera Odos 7511855 Athens, Greece
| | - Anup Kumar Halder
- Laboratory of Functional and Structural Genomics, Centre of New Technologies, University of Warsaw, Banacha 2c, 02-097, Warsaw, Poland
- Laboratory of Bioinformatics and Computational Genomics, Faculty of Mathematics and Information Science, Warsaw University of Technology, Koszykowa 75, 00-662, Warsaw, Poland
| | - Dariusz Plewczyński
- Laboratory of Functional and Structural Genomics, Centre of New Technologies, University of Warsaw, Banacha 2c, 02-097, Warsaw, Poland
- Laboratory of Bioinformatics and Computational Genomics, Faculty of Mathematics and Information Science, Warsaw University of Technology, Koszykowa 75, 00-662, Warsaw, Poland
| | - Misaki Wayengera
- Department of Immunology and Molecular Biology, School of Biomedical Sciences, College of Health Sciences, Makerere University, Old Mulago Hill Road P.O. Box 7072, Kampala, Uganda
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4
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Bu F, Ye G, Morsheimer K, Mendoza A, Turner-Hubbard H, Herbst M, Spiller B, Wadzinski BE, Eaton B, Anantpadma M, Yang G, Liu B, Davey R, Li F. Discovery of Nanosota-EB1 and -EB2 as Novel Nanobody Inhibitors Against Ebola Virus Infection. PLoS Pathog 2024; 20:e1012817. [PMID: 39715280 PMCID: PMC11723632 DOI: 10.1371/journal.ppat.1012817] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2024] [Revised: 01/10/2025] [Accepted: 12/09/2024] [Indexed: 12/25/2024] Open
Abstract
The Ebola filovirus (EBOV) poses a serious threat to global health and national security. Nanobodies, a type of single-domain antibody, have demonstrated promising therapeutic potential. We identified two anti-EBOV nanobodies, Nanosota-EB1 and Nanosota-EB2, which specifically target the EBOV glycoprotein (GP). Cryo-EM and biochemical data revealed that Nanosota-EB1 binds to the glycan cap of GP1, preventing its protease cleavage, while Nanosota-EB2 binds to critical membrane-fusion elements in GP2, stabilizing it in the pre-fusion state. Nanosota-EB2 is a potent neutralizer of EBOV infection in vitro and offers excellent protection in a mouse model of EBOV challenge, while Nanosota-EB1 provides moderate neutralization and protection. Nanosota-EB1 and Nanosota-EB2 are the first nanobodies shown to inhibit authentic EBOV. Combined with our newly developed structure-guided in vitro evolution approach, they lay the foundation for nanobody-based therapies against EBOV and other viruses within the ebolavirus genus.
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Affiliation(s)
- Fan Bu
- Department of Pharmacology, University of Minnesota Medical School, Minneapolis, Minnesota, United States of America
- Center for Emerging Viruses, University of Minnesota, Minneapolis, Minnesota, United States of America
| | - Gang Ye
- Department of Pharmacology, University of Minnesota Medical School, Minneapolis, Minnesota, United States of America
- Center for Emerging Viruses, University of Minnesota, Minneapolis, Minnesota, United States of America
| | - Kimberly Morsheimer
- National Emerging Infectious Diseases Laboratories, Boston University, Boston, Massachusetts, United States of America
- Department of Virology, Immunology, and Microbiology, Boston University School of Medicine, Boston, Massachusetts, United States of America
| | - Alise Mendoza
- Department of Pharmacology, University of Minnesota Medical School, Minneapolis, Minnesota, United States of America
- Center for Emerging Viruses, University of Minnesota, Minneapolis, Minnesota, United States of America
| | - Hailey Turner-Hubbard
- Department of Pharmacology, University of Minnesota Medical School, Minneapolis, Minnesota, United States of America
- Center for Emerging Viruses, University of Minnesota, Minneapolis, Minnesota, United States of America
| | - Morgan Herbst
- Department of Pharmacology, University of Minnesota Medical School, Minneapolis, Minnesota, United States of America
- Center for Emerging Viruses, University of Minnesota, Minneapolis, Minnesota, United States of America
| | - Benjamin Spiller
- Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, Tennessee, United States of America
| | - Brian E. Wadzinski
- Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, Tennessee, United States of America
| | - Brett Eaton
- Integrated Research Facility at Fort Detrick, Division of Clinical Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Frederick, Maryland, United States of America
| | - Manu Anantpadma
- Integrated Research Facility at Fort Detrick, Division of Clinical Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Frederick, Maryland, United States of America
| | - Ge Yang
- Hormel Institute, University of Minnesota, Austin, Minnesota, United States of America
| | - Bin Liu
- Hormel Institute, University of Minnesota, Austin, Minnesota, United States of America
| | - Robert Davey
- National Emerging Infectious Diseases Laboratories, Boston University, Boston, Massachusetts, United States of America
- Department of Virology, Immunology, and Microbiology, Boston University School of Medicine, Boston, Massachusetts, United States of America
| | - Fang Li
- Department of Pharmacology, University of Minnesota Medical School, Minneapolis, Minnesota, United States of America
- Center for Emerging Viruses, University of Minnesota, Minneapolis, Minnesota, United States of America
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5
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Prasad AN, Geisbert TW. A Glass-Half-Full Perspective on Negative Data in Ebolavirus Vaccine Studies. J Infect Dis 2024; 230:1057-1060. [PMID: 38488013 DOI: 10.1093/infdis/jiae109] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2024] [Accepted: 03/13/2024] [Indexed: 11/16/2024] Open
Affiliation(s)
- Abhishek N Prasad
- Galveston National Laboratory
- Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, Texas
| | - Thomas W Geisbert
- Galveston National Laboratory
- Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, Texas
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6
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Marzi A, Feldmann H. Filovirus vaccines as a response paradigm for emerging infectious diseases. NPJ Vaccines 2024; 9:186. [PMID: 39394249 PMCID: PMC11470150 DOI: 10.1038/s41541-024-00985-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2024] [Accepted: 09/25/2024] [Indexed: 10/13/2024] Open
Abstract
Nowadays, filovirus vaccine development may be seen as a paradigm for our response capabilities to emerging and re-emerging infectious diseases. Specifically, the West African Ebola virus disease (EVD) epidemic accelerated countermeasure licensure for several vaccine and therapeutic products. Those products have been successfully used to control EVD outbreaks in Central Africa over the past years. This positive development, however, has not yet reached beyond EVD. Therefore, it is pertinent to increase our efforts in the development of countermeasures for other human pathogenic members of the family Filoviridae as they continue to threaten public health in Sub-Saharan Africa. This review article summarizes the current filovirus vaccines in preclinical macaque studies and human clinical trials and discusses the most promising recent advancements.
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Affiliation(s)
- Andrea Marzi
- Laboratory of Virology, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rocky Mountain Laboratories, Hamilton, MT, USA.
| | - Heinz Feldmann
- Laboratory of Virology, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rocky Mountain Laboratories, Hamilton, MT, USA.
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7
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Kainulainen MH, Harmon JR, Karaaslan E, Kyondo J, Whitesell A, Twongyeirwe S, Malenfant JH, Baluku J, Kofman A, Bergeron É, Waltenburg MA, Nyakarahuka L, Balinandi S, Cossaboom CM, Choi MJ, Shoemaker TR, Montgomery JM, Spiropoulou CF. A public, cross-reactive glycoprotein epitope confounds Ebola virus serology. J Med Virol 2024; 96:e29946. [PMID: 39370872 PMCID: PMC11874798 DOI: 10.1002/jmv.29946] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2024] [Revised: 09/06/2024] [Accepted: 09/23/2024] [Indexed: 10/08/2024]
Abstract
Ebola disease (EBOD) in humans is a severe disease caused by at least four related viruses in the genus Orthoebolavirus, most often by the eponymous Ebola virus. Due to human-to-human transmission and incomplete success in treating cases despite promising therapeutic development, EBOD is a high priority in public health research. Yet despite almost 50 years since EBOD was first described, the sources of these viruses remain undefined and much remains to be understood about the disease epidemiology and virus emergence and spread. One important approach to improve our understanding is detection of antibodies that can reveal past human infections. However, serosurveys routinely describe seroprevalences that imply infection rates much higher than those clinically observed. Proposed hypotheses to explain this difference include existence of common but less pathogenic strains or relatives of these viruses, misidentification of EBOD as something else, and a higher proportion of subclinical infections than currently appreciated. The work presented here maps B-cell epitopes in the spike protein of Ebola virus and describes a single epitope that is cross-reactive with an antigen seemingly unrelated to orthoebolaviruses. Antibodies against this epitope appear to explain most of the unexpected reactivity towards the spike, arguing against common but unidentified infections in the population. Importantly, antibodies of cross-reactive donors from within and outside the known EBOD geographic range bound the same epitope. In light of this finding, it is plausible that epitope mapping enables broadly applicable specificity improvements in the field of serology.
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Affiliation(s)
- Markus H. Kainulainen
- Viral Special Pathogens Branch, Division of High-Consequence Pathogens and Pathology, Centers for Disease Control and Prevention, Atlanta, Georgia, USA
| | - Jessica R. Harmon
- Viral Special Pathogens Branch, Division of High-Consequence Pathogens and Pathology, Centers for Disease Control and Prevention, Atlanta, Georgia, USA
| | - Elif Karaaslan
- Viral Special Pathogens Branch, Division of High-Consequence Pathogens and Pathology, Centers for Disease Control and Prevention, Atlanta, Georgia, USA
| | - Jackson Kyondo
- VHF Diagnostics Laboratory, Department of Arbovirology, Emerging and Re-emerging Infectious Diseases, Uganda Virus Research Institute, Entebbe, Uganda
| | - Amy Whitesell
- Viral Special Pathogens Branch, Division of High-Consequence Pathogens and Pathology, Centers for Disease Control and Prevention, Atlanta, Georgia, USA
| | - Sam Twongyeirwe
- VHF Diagnostics Laboratory, Department of Arbovirology, Emerging and Re-emerging Infectious Diseases, Uganda Virus Research Institute, Entebbe, Uganda
| | - Jason H. Malenfant
- Viral Special Pathogens Branch, Division of High-Consequence Pathogens and Pathology, Centers for Disease Control and Prevention, Atlanta, Georgia, USA
| | - Jimmy Baluku
- VHF Diagnostics Laboratory, Department of Arbovirology, Emerging and Re-emerging Infectious Diseases, Uganda Virus Research Institute, Entebbe, Uganda
| | - Aaron Kofman
- Viral Special Pathogens Branch, Division of High-Consequence Pathogens and Pathology, Centers for Disease Control and Prevention, Atlanta, Georgia, USA
| | - Éric Bergeron
- Viral Special Pathogens Branch, Division of High-Consequence Pathogens and Pathology, Centers for Disease Control and Prevention, Atlanta, Georgia, USA
| | - Michelle A. Waltenburg
- Viral Special Pathogens Branch, Division of High-Consequence Pathogens and Pathology, Centers for Disease Control and Prevention, Atlanta, Georgia, USA
| | - Luke Nyakarahuka
- VHF Diagnostics Laboratory, Department of Arbovirology, Emerging and Re-emerging Infectious Diseases, Uganda Virus Research Institute, Entebbe, Uganda
- Department of Biosecurity, Ecosystems, and Veterinary Public Health, College of Veterinary Medicine, Animal Resources, and Biosecurity, Makerere University, Kampala, Uganda
| | - Stephen Balinandi
- VHF Diagnostics Laboratory, Department of Arbovirology, Emerging and Re-emerging Infectious Diseases, Uganda Virus Research Institute, Entebbe, Uganda
| | - Caitlin M. Cossaboom
- Viral Special Pathogens Branch, Division of High-Consequence Pathogens and Pathology, Centers for Disease Control and Prevention, Atlanta, Georgia, USA
| | - Mary J. Choi
- Viral Special Pathogens Branch, Division of High-Consequence Pathogens and Pathology, Centers for Disease Control and Prevention, Atlanta, Georgia, USA
| | - Trevor R. Shoemaker
- Viral Special Pathogens Branch, Division of High-Consequence Pathogens and Pathology, Centers for Disease Control and Prevention, Atlanta, Georgia, USA
| | - Joel M. Montgomery
- Viral Special Pathogens Branch, Division of High-Consequence Pathogens and Pathology, Centers for Disease Control and Prevention, Atlanta, Georgia, USA
| | - Christina F. Spiropoulou
- Viral Special Pathogens Branch, Division of High-Consequence Pathogens and Pathology, Centers for Disease Control and Prevention, Atlanta, Georgia, USA
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8
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Kandathil AJ, Blair PW, Lu J, Anantharam R, Kobba K, Robinson ML, Alharthi S, Ndawula EC, Dumler JS, Kakooza F, Lamorde M, Thomas DL, Salzberg SL, Manabe YC. Metagenomic next generation sequencing of plasma RNA for diagnosis of unexplained, acute febrile illness in Uganda. PLoS Negl Trop Dis 2024; 18:e0012451. [PMID: 39298515 PMCID: PMC11460704 DOI: 10.1371/journal.pntd.0012451] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2024] [Revised: 10/08/2024] [Accepted: 08/11/2024] [Indexed: 09/21/2024] Open
Abstract
Metagenomic next generation metagenomic sequencing (mNGS) has proven to be a useful tool in the diagnosis and identification of novel human pathogens and pathogens not identified on routine clinical microbiologic tests. In this study, we applied mNGS to characterize plasma RNA isolated from 42 study participants with unexplained acute febrile illness (AFI) admitted to tertiary referral hospitals in Mubende and Arua, Uganda. Study participants were selected based on clinical criteria suggestive of viral infection (i.e., thrombocytopenia, leukopenia). The study population had a median age of 28 years (IQR:24 to 38.5) and median platelet count of 114 x103 cells/mm3 (IQR:66,500 to 189,800). An average of 25 million 100 bp reads were generated per sample. We identified strong signals from diverse virus, bacteria, fungi, or parasites in 10 (23.8%) of the study participants. These included well recognized pathogens like Helicobacter pylori, human herpes virus-8, Plasmodium falciparum, Neisseria gonorrhoeae, and Rickettsia conorii. We further confirmed Rickettsia conorii infection, the cause of Mediterranean Spotted Fever (MSF), using PCR assays and Sanger sequencing. mNGS was a useful addition for detection of otherwise undetected pathogens and well-recognized non-pathogens. This is the first report to describe the molecular confirmation of a hospitalized case of MSF in sub-Saharan Africa (SSA). Further studies are needed to determine the utility of mNGS for disease surveillance in similar settings.
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Affiliation(s)
- Abraham J. Kandathil
- Division of Infectious Diseases, Johns Hopkins School of Medicine, Baltimore, Maryland, United States of America
| | - Paul W. Blair
- Division of Infectious Diseases, Johns Hopkins School of Medicine, Baltimore, Maryland, United States of America
- Department of Pathology, Uniformed Services University, Bethesda, Maryland, United States of America
| | - Jennifer Lu
- Center for Computational Biology, Johns Hopkins University, Baltimore, Maryland, United States of America
- Department of Biomedical Engineering, Johns Hopkins University, Baltimore, Maryland, United States of America
- Department of Pathology, Johns Hopkins School of Medicine, Baltimore, Maryland, United States of America
| | - Raghavendran Anantharam
- Division of Infectious Diseases, Johns Hopkins School of Medicine, Baltimore, Maryland, United States of America
| | - Kenneth Kobba
- Infectious Diseases Institute, Makerere University, Kampala, Uganda
| | - Matthew L. Robinson
- Division of Infectious Diseases, Johns Hopkins School of Medicine, Baltimore, Maryland, United States of America
| | - Sultanah Alharthi
- Department of Pathology, Uniformed Services University, Bethesda, Maryland, United States of America
| | - Edgar C. Ndawula
- Infectious Diseases Institute, Makerere University, Kampala, Uganda
| | - J. Stephen Dumler
- Department of Pathology, Uniformed Services University, Bethesda, Maryland, United States of America
- Department of Pathology, Johns Hopkins School of Medicine, Baltimore, Maryland, United States of America
| | - Francis Kakooza
- Infectious Diseases Institute, Makerere University, Kampala, Uganda
| | - Mohammed Lamorde
- Infectious Diseases Institute, Makerere University, Kampala, Uganda
| | - David L. Thomas
- Division of Infectious Diseases, Johns Hopkins School of Medicine, Baltimore, Maryland, United States of America
| | - Steven L. Salzberg
- Center for Computational Biology, Johns Hopkins University, Baltimore, Maryland, United States of America
- Department of Biomedical Engineering, Johns Hopkins University, Baltimore, Maryland, United States of America
- Departments of Computer Science and Biostatistics, Johns Hopkins University, Baltimore, Maryland, United States of America
| | - Yukari C. Manabe
- Division of Infectious Diseases, Johns Hopkins School of Medicine, Baltimore, Maryland, United States of America
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9
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Groseth A, Hoenen T. Novel filoviruses: indication of a global threat or cause to reassess our risk perception? NPJ VIRUSES 2024; 2:38. [PMID: 40295872 PMCID: PMC11721365 DOI: 10.1038/s44298-024-00050-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/04/2024] [Accepted: 08/06/2024] [Indexed: 04/30/2025]
Abstract
Filoviruses such as Ebola virus are widely known as causative agents of severe human disease, although apathogenic filoviruses also exist. There is now increasing evidence that filoviruses circulate in almost all parts of the world, where they are being discovered in an expanding range of sometimes unexpected host species. Here we summarize the current knowledge regarding these novel filoviruses, and open questions that need answering to assess and prepare for the risk they pose.
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Affiliation(s)
- Allison Groseth
- Institute for Molecular Virology and Cell Biology, Friedrich-Loeffler-Institut, Greifswald - Insel Riems, Greifswald, Germany
| | - Thomas Hoenen
- Institute for Molecular Virology and Cell Biology, Friedrich-Loeffler-Institut, Greifswald - Insel Riems, Greifswald, Germany.
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10
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Munyeku-Bazitama Y, Edidi-Atani F, Takada A. Non-Ebola Filoviruses: Potential Threats to Global Health Security. Viruses 2024; 16:1179. [PMID: 39205153 PMCID: PMC11359311 DOI: 10.3390/v16081179] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2024] [Revised: 07/19/2024] [Accepted: 07/21/2024] [Indexed: 09/04/2024] Open
Abstract
Filoviruses are negative-sense single-stranded RNA viruses often associated with severe and highly lethal hemorrhagic fever in humans and nonhuman primates, with case fatality rates as high as 90%. Of the known filoviruses, Ebola virus (EBOV), the prototype of the genus Orthoebolavirus, has been a major public health concern as it frequently causes outbreaks and was associated with an unprecedented outbreak in several Western African countries in 2013-2016, affecting 28,610 people, 11,308 of whom died. Thereafter, filovirus research mostly focused on EBOV, paying less attention to other equally deadly orthoebolaviruses (Sudan, Bundibugyo, and Taï Forest viruses) and orthomarburgviruses (Marburg and Ravn viruses). Some of these filoviruses have emerged in nonendemic areas, as exemplified by four Marburg disease outbreaks recorded in Guinea, Ghana, Tanzania, and Equatorial Guinea between 2021 and 2023. Similarly, the Sudan virus has reemerged in Uganda 10 years after the last recorded outbreak. Moreover, several novel bat-derived filoviruses have been discovered in the last 15 years (Lloviu virus, Bombali virus, Měnglà virus, and Dehong virus), most of which are poorly characterized but may display a wide host range. These novel viruses have the potential to cause outbreaks in humans. Several gaps are yet to be addressed regarding known and emerging filoviruses. These gaps include the virus ecology and pathogenicity, mechanisms of zoonotic transmission, host range and susceptibility, and the development of specific medical countermeasures. In this review, we summarize the current knowledge on non-Ebola filoviruses (Bombali virus, Bundibugyo virus, Reston virus, Sudan virus, Tai Forest virus, Marburg virus, Ravn virus, Lloviu virus, Měnglà virus, and Dehong virus) and suggest some strategies to accelerate specific countermeasure development.
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Affiliation(s)
- Yannick Munyeku-Bazitama
- Division of Global Epidemiology, International Institute for Zoonosis Control, Hokkaido University, Sapporo 001-0020, Japan; (Y.M.-B.); (F.E.-A.)
- Institut National de Recherche Biomédicale, Kinshasa P.O. Box 1197, Democratic Republic of the Congo
- Département de Biologie Médicale, Faculté de Médecine, Université de Kinshasa, Kinshasa P.O. Box 123, Democratic Republic of the Congo
| | - Francois Edidi-Atani
- Division of Global Epidemiology, International Institute for Zoonosis Control, Hokkaido University, Sapporo 001-0020, Japan; (Y.M.-B.); (F.E.-A.)
- Institut National de Recherche Biomédicale, Kinshasa P.O. Box 1197, Democratic Republic of the Congo
- Département de Biologie Médicale, Faculté de Médecine, Université de Kinshasa, Kinshasa P.O. Box 123, Democratic Republic of the Congo
| | - Ayato Takada
- Division of Global Epidemiology, International Institute for Zoonosis Control, Hokkaido University, Sapporo 001-0020, Japan; (Y.M.-B.); (F.E.-A.)
- International Collaboration Unit, International Institute for Zoonosis Control, Hokkaido University, Sapporo 001-0020, Japan
- One Health Research Center, Hokkaido University, Sapporo 001-0020, Japan
- Department of Disease Control, School of Veterinary Medicine, University of Zambia, Lusaka 10101, Zambia
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11
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Sizikova TE, Lebedev VN, Borisevich SV. [Comparative analysis of the taxonomic classification criteria for a number of groups of pathogenic DNA and RNA viruses based on genomic data]. Vopr Virusol 2024; 69:203-218. [PMID: 38996370 DOI: 10.36233/0507-4088-238] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2024] [Indexed: 07/14/2024]
Abstract
The basis for criteria of the taxonomic classification of DNA and RNA viruses based on data of the genomic sequencing are viewed in this review. The genomic sequences of viruses, which have genome represented by double-stranded DNA (orthopoxviruses as example), positive-sense single-stranded RNA (alphaviruses and flaviviruses as example), non-segmented negative-sense single-stranded RNA (filoviruses as example), segmented negative-sense single-stranded RNA (arenaviruses and phleboviruses as example) are analyzed. The levels of genetic variability that determine the assignment of compared viruses to taxa of various orders are established for each group of viruses.
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Affiliation(s)
- T E Sizikova
- 48th Central Scientific Research Institute of the Ministry of Defense of the Russian Federation
| | - V N Lebedev
- 48th Central Scientific Research Institute of the Ministry of Defense of the Russian Federation
| | - S V Borisevich
- 48th Central Scientific Research Institute of the Ministry of Defense of the Russian Federation
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12
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Donnellan FR, Rayaprolu V, Rijal P, O’Dowd V, Parvate A, Callaway H, Hariharan C, Parekh D, Hui S, Shaffer K, Avalos RD, Hastie K, Schimanski L, Müller-Kräuter H, Strecker T, Balaram A, Halfmann P, Saphire EO, Lightwood DJ, Townsend AR, Draper SJ. A broadly-neutralizing antibody against Ebolavirus glycoprotein that potentiates the breadth and neutralization potency of other antibodies. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.06.21.600001. [PMID: 38979279 PMCID: PMC11230233 DOI: 10.1101/2024.06.21.600001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 07/10/2024]
Abstract
Ebolavirus disease (EVD) is caused by multiple species of Ebolavirus. Monoclonal antibodies (mAbs) against the virus glycoprotein (GP) are the only class of therapeutic approved for treatment of EVD caused by Zaire ebolavirus (EBOV). Therefore, mAbs targeting multiple Ebolavirus species may represent the next generation of EVD therapeutics. Broadly reactive anti-GP mAbs were produced; among these, mAbs 11886 and 11883 were broadly neutralizing in vitro. A 3.0 Å cryo-electron microscopy structure of EBOV GP bound to both mAbs shows that 11886 binds a novel epitope bridging the glycan cap (GC), 310 pocket and GP2 N-terminus, whereas 11883 binds the receptor binding region (RBR) and GC. In vitro, 11886 synergized with a range of mAbs with epitope specificities spanning the RBR/GC, including 11883. Notably, 11886 increased the breadth of neutralization by partner mAbs against different Ebolavirus species. These data provide a strategic route to design improved mAb-based next-generation EVD therapeutics.
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Affiliation(s)
- Francesca R. Donnellan
- Department of Biochemistry, University of Oxford, Dorothy Crowfoot Hodgkin Building, Oxford, OX1 3QU, UK
- Kavli Institute for Nanoscience Discovery, Dorothy Crowfoot Hodgkin Building, University of Oxford, Oxford, OX1 3QU, UK
- The Jenner Institute, University of Oxford, Old Road Campus Research Building, Oxford, OX3 7DQ, UK
| | - Vamseedhar Rayaprolu
- Center for Vaccine Innovation, La Jolla Institute for Immunology, 9420 Athena Circle, La Jolla, CA 92037, USA
- Current affiliation: Pacific Northwest Cryo-EM Center, Oregon Health and Sciences University, Portland, OR 97201, USA
| | - Pramila Rijal
- Center for Translational Immunology, Chinese Academy of Medical Science Oxford Institute, Nuffield Department of Medicine, University of Oxford, OX3 7BN, UK
- MRC Translational Immune Discovery Unit, MRC Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, Headington, Oxford, OX3 9DS, UK
| | | | - Amar Parvate
- Center for Vaccine Innovation, La Jolla Institute for Immunology, 9420 Athena Circle, La Jolla, CA 92037, USA
- Current affiliation: Environmental Molecular Sciences Laboratory, Pacific Northwest National Laboratory, Richland, WA 99354, USA
| | - Heather Callaway
- Center for Vaccine Innovation, La Jolla Institute for Immunology, 9420 Athena Circle, La Jolla, CA 92037, USA
- Current affiliation: Chemistry & Biochemistry Building, Montana State University, Bozeman, MT 59717, USA
| | - Chitra Hariharan
- Center for Vaccine Innovation, La Jolla Institute for Immunology, 9420 Athena Circle, La Jolla, CA 92037, USA
| | - Dipti Parekh
- Center for Vaccine Innovation, La Jolla Institute for Immunology, 9420 Athena Circle, La Jolla, CA 92037, USA
| | - Sean Hui
- Center for Vaccine Innovation, La Jolla Institute for Immunology, 9420 Athena Circle, La Jolla, CA 92037, USA
- Current Affiliation: Department of Pathology & Immunology, Washington University School of Medicine. St. Louis MO 63110, USA
| | - Kelly Shaffer
- Center for Vaccine Innovation, La Jolla Institute for Immunology, 9420 Athena Circle, La Jolla, CA 92037, USA
- Department of Medicine. University of California San Diego. La Jolla, CA 92037, USA
| | - Ruben Diaz Avalos
- Center for Vaccine Innovation, La Jolla Institute for Immunology, 9420 Athena Circle, La Jolla, CA 92037, USA
| | - Kathryn Hastie
- Center for Vaccine Innovation, La Jolla Institute for Immunology, 9420 Athena Circle, La Jolla, CA 92037, USA
| | - Lisa Schimanski
- MRC Translational Immune Discovery Unit, MRC Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, Headington, Oxford, OX3 9DS, UK
| | - Helena Müller-Kräuter
- Institute of Virology, Philipps University Marburg, Hans-Meerwein-Straße 2, 35043 Marburg, Germany
| | - Thomas Strecker
- Institute of Virology, Philipps University Marburg, Hans-Meerwein-Straße 2, 35043 Marburg, Germany
| | - Ariane Balaram
- Influenza Research Institute, School of Veterinary Medicine, University of Wisconsin, Madison, WI, 53713, USA
| | - Peter Halfmann
- Influenza Research Institute, School of Veterinary Medicine, University of Wisconsin, Madison, WI, 53713, USA
| | - Erica Ollmann Saphire
- Center for Vaccine Innovation, La Jolla Institute for Immunology, 9420 Athena Circle, La Jolla, CA 92037, USA
- Department of Medicine. University of California San Diego. La Jolla, CA 92037, USA
| | | | - Alain R. Townsend
- Center for Translational Immunology, Chinese Academy of Medical Science Oxford Institute, Nuffield Department of Medicine, University of Oxford, OX3 7BN, UK
- MRC Translational Immune Discovery Unit, MRC Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, Headington, Oxford, OX3 9DS, UK
| | - Simon J. Draper
- Department of Biochemistry, University of Oxford, Dorothy Crowfoot Hodgkin Building, Oxford, OX1 3QU, UK
- Kavli Institute for Nanoscience Discovery, Dorothy Crowfoot Hodgkin Building, University of Oxford, Oxford, OX1 3QU, UK
- The Jenner Institute, University of Oxford, Old Road Campus Research Building, Oxford, OX3 7DQ, UK
- NIHR Oxford Biomedical Research Centre, Oxford, UK
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13
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Moso MA, Lim CK, Williams E, Marshall C, McCarthy J, Williamson DA. Prevention and post-exposure management of occupational exposure to Ebola virus. THE LANCET. INFECTIOUS DISEASES 2024; 24:e93-e105. [PMID: 37722397 DOI: 10.1016/s1473-3099(23)00376-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/08/2023] [Revised: 06/04/2023] [Accepted: 06/09/2023] [Indexed: 09/20/2023]
Abstract
There have been significant advances in the prevention and management of Ebola virus disease (EVD) caused by Zaire Ebola virus (ZEBOV), including the development of two effective vaccines, rVSV-ZEBOV and Ad26.ZEBOV/MVA-BN-Filo. In addition, ZEBOV monoclonal antibodies have become first-line therapy for EVD. However, the 2022-23 outbreak of Sudan Ebola virus (SUDV) in Uganda has highlighted the gap in current therapies and vaccines, whose efficacy is uncertain against non-ZEBOV species. Health-care and laboratory staff working in EVD treatment centres or Ebola virus diagnostic and research laboratories face unique risks relating to potential occupational exposure to Ebola viruses. Given the substantial morbidity and mortality associated with EVD, facilities should have strategies in place to manage occupational exposures, including consideration of post-exposure therapies. In this Review, we discuss currently available evidence for prevention and post-exposure prophylaxis of EVD, including therapies currently under evaluation for SUDV.
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Affiliation(s)
- Michael A Moso
- Victorian Infectious Diseases Reference Laboratory, The Peter Doherty Institute for Infection and Immunity, Melbourne, VIC, Australia; Department of Infectious Diseases, The University of Melbourne, The Peter Doherty Institute for Infection and Immunity, Melbourne, VIC, Australia; Victorian Infectious Diseases Service, The Royal Melbourne Hospital, The Peter Doherty Institute for Infection and Immunity, Melbourne, VIC, Australia.
| | - Chuan K Lim
- Victorian Infectious Diseases Reference Laboratory, The Peter Doherty Institute for Infection and Immunity, Melbourne, VIC, Australia
| | - Eloise Williams
- Victorian Infectious Diseases Reference Laboratory, The Peter Doherty Institute for Infection and Immunity, Melbourne, VIC, Australia
| | - Caroline Marshall
- Department of Infectious Diseases, The University of Melbourne, The Peter Doherty Institute for Infection and Immunity, Melbourne, VIC, Australia; Victorian Infectious Diseases Service, The Royal Melbourne Hospital, The Peter Doherty Institute for Infection and Immunity, Melbourne, VIC, Australia
| | - James McCarthy
- Department of Infectious Diseases, The University of Melbourne, The Peter Doherty Institute for Infection and Immunity, Melbourne, VIC, Australia; Victorian Infectious Diseases Service, The Royal Melbourne Hospital, The Peter Doherty Institute for Infection and Immunity, Melbourne, VIC, Australia
| | - Deborah A Williamson
- Victorian Infectious Diseases Reference Laboratory, The Peter Doherty Institute for Infection and Immunity, Melbourne, VIC, Australia; Department of Infectious Diseases, The University of Melbourne, The Peter Doherty Institute for Infection and Immunity, Melbourne, VIC, Australia
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14
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Lewis CE, Pinette MM, Lakin SM, Smith G, Fisher M, Moffat E, Embury-Hyatt C, Pickering BS. Experimental Infection of Bundibugyo Virus in Domestic Swine Leads to Viral Shedding with Evidence of Intraspecies Transmission. Transbound Emerg Dis 2024; 2024:5350769. [PMID: 40303058 PMCID: PMC12017203 DOI: 10.1155/2024/5350769] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2023] [Revised: 10/18/2023] [Accepted: 10/28/2023] [Indexed: 05/02/2025]
Abstract
The Ebolavirus genus contains several of the deadliest zoonotic viruses known. One of these, Bundibugyo virus (BDBV), has been the causative agent of two outbreaks of human disease that have resulted in 211 known cases with a case fatality rate of 33.6%. Although bats are routinely implicated as the possible reservoir species for the ebolaviruses, the source of infection for index cases in almost all outbreaks is unknown with only limited epidemiological evidence directly linking human cases to bats. This lack of evidence leaves open the possibility that maintenance of one or more of these viruses could involve multiple host species or more complex spillover dynamics. Domestic pigs have been found naturally infected with Reston virus (RESTV) and are experimentally susceptible to infection with Ebola virus (EBOV), two other members of the Ebolavirus genus. Infection of pigs resulted in shedding of infectious virus with subsequent transmission to naïve animals being documented, including transmission to humans for RESTV and to nonhuman primates for EBOV. The susceptibility and subsequent viral shedding and pathogenesis of domestic pigs to other ebolaviruses and the potential role this species may play in virus ecology, spillover dynamics, and human public health risk is unknown. For these reasons, we conducted a series of studies aimed at determining the susceptibility of domestic pigs to BDBV thereby demonstrating that pigs are not only susceptible to experimental infection but that the development of productive infection, tissue dissemination, and shedding of infectious virus can also occur while animals remain clinically normal. The role of pigs as a possible interim or amplifying host for ebolaviruses is a concern for both human public health and food security.
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Affiliation(s)
- Charles E. Lewis
- Department of Veterinary Microbiology and Preventive Medicine, College of Veterinary Medicine, Iowa State University, Ames, Iowa, USA
- Interdepartmental Microbiology Program, College of Agriculture and Life Sciences, Iowa State University, Ames, Iowa, USA
| | - Mathieu M. Pinette
- National Centre for Foreign Animal Diseases, Canadian Food Inspection Agency, Winnipeg, Manitoba, Canada
| | - Steven M. Lakin
- Scientific Liaison Services Section, Foreign Animal Disease Diagnostic Laboratory, National Veterinary Services Laboratories, Animal Plant Health Inspection Service, United States Department of Agriculture, Orient Point, New York, USA
| | - Greg Smith
- National Centre for Foreign Animal Diseases, Canadian Food Inspection Agency, Winnipeg, Manitoba, Canada
| | - Mathew Fisher
- National Centre for Foreign Animal Diseases, Canadian Food Inspection Agency, Winnipeg, Manitoba, Canada
| | - Estella Moffat
- National Centre for Foreign Animal Diseases, Canadian Food Inspection Agency, Winnipeg, Manitoba, Canada
| | - Carissa Embury-Hyatt
- National Centre for Foreign Animal Diseases, Canadian Food Inspection Agency, Winnipeg, Manitoba, Canada
| | - Brad S. Pickering
- Department of Veterinary Microbiology and Preventive Medicine, College of Veterinary Medicine, Iowa State University, Ames, Iowa, USA
- National Centre for Foreign Animal Diseases, Canadian Food Inspection Agency, Winnipeg, Manitoba, Canada
- Department of Medical Microbiology and Infectious Diseases, University of Manitoba, Winnipeg, Manitoba, Canada
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15
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Noonan-Shueh M, Aman MJ, Kailasan S. Production and Purification of Filovirus Glycoproteins. Methods Mol Biol 2024; 2762:17-25. [PMID: 38315357 DOI: 10.1007/978-1-0716-3666-4_2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2024]
Abstract
Ebola (EBOV) and Marburg (MARV) viruses cause hemorrhagic fever disease in humans and non-human primates (NHPs) with case-fatality rates as high as 90%. The 2013-2016 Ebola virus disease (EVD) outbreak led to over 28,000 cases and 11,000 deaths and took an enormous toll on the economy of West African nations, in the absence of any vaccine or therapeutic options. Like EVD, there have been at least 6 outbreaks of MVD with ~88% case-fatality and the most recent cases emerging in Equatorial Guinea in February 2023. These outbreaks have spurred an unprecedented global effort to develop vaccines and therapeutics for EVD and MVD and led to an approved vaccine (ERVEBO™) and two monoclonal antibody (mAb) therapeutics for EBOV. In contrast to EVD, therapeutic options against Marburg and another Ebola-relative Sudan virus (SUDV) are lacking. The filovirus glycoprotein (GP), which mediates host cell entry and fusion, is the primary target of neutralizing antibodies. In addition to its pre- and post-fusion trimeric states, the protein is highly glycosylated making production of pure and homogeneous trimers on a large scale, a requirement for subunit vaccine development, a challenge. In efforts to address this roadblock, we have developed a unique combination of structure-based design, selection of expression system, and purification methods to produce uniform and stable EBOV and MARV GP trimers at scales appropriate for vaccine production.
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16
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Dobbs KR, Lobb A, Dent AE. Ebola virus disease in children: epidemiology, pathogenesis, management, and prevention. Pediatr Res 2024; 95:488-495. [PMID: 37903937 DOI: 10.1038/s41390-023-02873-y] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/24/2023] [Revised: 10/06/2023] [Accepted: 10/12/2023] [Indexed: 11/01/2023]
Abstract
Ebola disease is a severe disease with extremely high case-fatality rates ranging from 28-100%. Observations made during the 2013-2016 West African epidemic improved our understanding of the clinical course of Ebola disease and accelerated the study of therapeutic and preventative strategies. The epidemic also highlighted the unique challenges associated with providing optimal care for children during Ebola disease outbreaks. In this review, we outline current understanding of Ebola disease epidemiology, pathogenesis, management, and prevention, highlighting data pertinent to the care of children. IMPACT: In this review, we summarize recent advancements in our understanding of Ebola disease epidemiology, clinical presentation, and therapeutic and preventative strategies. We highlight recent data pertinent to the care of children and pregnant women and identify research gaps for this important emerging viral infection in children.
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Affiliation(s)
- Katherine R Dobbs
- Case Western Reserve University School of Medicine, Cleveland, OH, USA.
- UH Rainbow Babies and Children's Hospital, Cleveland, OH, USA.
| | - Alyssa Lobb
- Case Western Reserve University School of Medicine, Cleveland, OH, USA
| | - Arlene E Dent
- Case Western Reserve University School of Medicine, Cleveland, OH, USA
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17
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Changula K, Kajihara M, Muramatsu S, Hiraoka K, Yamaguchi T, Yago Y, Kato D, Miyamoto H, Mori-Kajihara A, Shigeno A, Yoshida R, Henderson CW, Marzi A, Takada A. Development of an Immunochromatography Assay to Detect Marburg Virus and Ravn Virus. Viruses 2023; 15:2349. [PMID: 38140590 PMCID: PMC10747695 DOI: 10.3390/v15122349] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2023] [Revised: 11/24/2023] [Accepted: 11/27/2023] [Indexed: 12/24/2023] Open
Abstract
The recent outbreaks of Marburg virus disease (MVD) in Guinea, Ghana, Equatorial Guinea, and Tanzania, none of which had reported previous outbreaks, imply increasing risks of spillover of the causative viruses, Marburg virus (MARV) and Ravn virus (RAVV), from their natural host animals. These outbreaks have emphasized the need for the development of rapid diagnostic tests for this disease. Using monoclonal antibodies specific to the viral nucleoprotein, we developed an immunochromatography (IC) assay for the rapid diagnosis of MVD. The IC assay was found to be capable of detecting approximately 102-4 50% tissue culture infectious dose (TCID50)/test of MARV and RAVV in the infected culture supernatants. We further confirmed that the IC assay could detect the MARV and RAVV antigens in the serum samples from experimentally infected nonhuman primates. These results indicate that the IC assay to detect MARV can be a useful tool for the rapid point-of-care diagnosis of MVD.
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Affiliation(s)
- Katendi Changula
- Department of Paraclinical Studies, School of Veterinary Medicine, University of Zambia, Lusaka 10101, Zambia;
| | - Masahiro Kajihara
- Division of Global Epidemiology, International Institute for Zoonosis Control, Hokkaido University, Sapporo 001-0020, Japan; (M.K.); (H.M.); (A.M.-K.); (A.S.); (R.Y.)
| | - Shino Muramatsu
- DENKA Co., Ltd., Tokyo 103-8338, Japan; (S.M.); (K.H.); (T.Y.); (Y.Y.); (D.K.)
| | - Koji Hiraoka
- DENKA Co., Ltd., Tokyo 103-8338, Japan; (S.M.); (K.H.); (T.Y.); (Y.Y.); (D.K.)
| | - Toru Yamaguchi
- DENKA Co., Ltd., Tokyo 103-8338, Japan; (S.M.); (K.H.); (T.Y.); (Y.Y.); (D.K.)
| | - Yoko Yago
- DENKA Co., Ltd., Tokyo 103-8338, Japan; (S.M.); (K.H.); (T.Y.); (Y.Y.); (D.K.)
| | - Daisuke Kato
- DENKA Co., Ltd., Tokyo 103-8338, Japan; (S.M.); (K.H.); (T.Y.); (Y.Y.); (D.K.)
| | - Hiroko Miyamoto
- Division of Global Epidemiology, International Institute for Zoonosis Control, Hokkaido University, Sapporo 001-0020, Japan; (M.K.); (H.M.); (A.M.-K.); (A.S.); (R.Y.)
| | - Akina Mori-Kajihara
- Division of Global Epidemiology, International Institute for Zoonosis Control, Hokkaido University, Sapporo 001-0020, Japan; (M.K.); (H.M.); (A.M.-K.); (A.S.); (R.Y.)
| | - Asako Shigeno
- Division of Global Epidemiology, International Institute for Zoonosis Control, Hokkaido University, Sapporo 001-0020, Japan; (M.K.); (H.M.); (A.M.-K.); (A.S.); (R.Y.)
| | - Reiko Yoshida
- Division of Global Epidemiology, International Institute for Zoonosis Control, Hokkaido University, Sapporo 001-0020, Japan; (M.K.); (H.M.); (A.M.-K.); (A.S.); (R.Y.)
| | - Corey W. Henderson
- Laboratory of Virology, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Hamilton, MT 59840, USA
| | - Andrea Marzi
- Laboratory of Virology, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Hamilton, MT 59840, USA
| | - Ayato Takada
- Division of Global Epidemiology, International Institute for Zoonosis Control, Hokkaido University, Sapporo 001-0020, Japan; (M.K.); (H.M.); (A.M.-K.); (A.S.); (R.Y.)
- International Collaboration Unit, International Institute for Zoonosis Control, Hokkaido University, Sapporo 001-0020, Japan
- One Health Research Center, Hokkaido University, Sapporo 001-0020, Japan
- Department of Disease Control, School of Veterinary Medicine, University of Zambia, Lusaka 10101, Zambia
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18
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Woolsey C, Borisevich V, Agans KN, O’Toole R, Fenton KA, Harrison MB, Prasad AN, Deer DJ, Gerardi C, Morrison N, Cross RW, Eldridge JH, Matassov D, Geisbert TW. A Highly Attenuated Panfilovirus VesiculoVax Vaccine Rapidly Protects Nonhuman Primates Against Marburg Virus and 3 Species of Ebola Virus. J Infect Dis 2023; 228:S660-S670. [PMID: 37171813 PMCID: PMC11009496 DOI: 10.1093/infdis/jiad157] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2023] [Revised: 05/01/2023] [Accepted: 05/09/2023] [Indexed: 05/13/2023] Open
Abstract
BACKGROUND The family Filoviridae consists of several virus members known to cause significant mortality and disease in humans. Among these, Ebola virus (EBOV), Marburg virus (MARV), Sudan virus (SUDV), and Bundibugyo virus (BDBV) are considered the deadliest. The vaccine, Ervebo, was shown to rapidly protect humans against Ebola disease, but is indicated only for EBOV infections with limited cross-protection against other filoviruses. Whether multivalent formulations of similar recombinant vesicular stomatitis virus (rVSV)-based vaccines could likewise confer rapid protection is unclear. METHODS Here, we tested the ability of an attenuated, quadrivalent panfilovirus VesiculoVax vaccine (rVSV-Filo) to elicit fast-acting protection against MARV, EBOV, SUDV, and BDBV. Groups of cynomolgus monkeys were vaccinated 7 days before exposure to each of the 4 viral pathogens. All subjects (100%) immunized 1 week earlier survived MARV, SUDV, and BDBV challenge; 80% survived EBOV challenge. Survival correlated with lower viral load, higher glycoprotein-specific immunoglobulin G titers, and the expression of B-cell-, cytotoxic cell-, and antigen presentation-associated transcripts. CONCLUSIONS These results demonstrate multivalent VesiculoVax vaccines are suitable for filovirus outbreak management. The highly attenuated nature of the rVSV-Filo vaccine may be preferable to the Ervebo "delta G" platform, which induced adverse events in a subset of recipients.
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Affiliation(s)
- Courtney Woolsey
- Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, Texas, USA
- Galveston National Laboratory, University of Texas Medical Branch, Galveston, Texas, USA
| | - Viktoriya Borisevich
- Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, Texas, USA
- Galveston National Laboratory, University of Texas Medical Branch, Galveston, Texas, USA
| | - Krystle N Agans
- Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, Texas, USA
- Galveston National Laboratory, University of Texas Medical Branch, Galveston, Texas, USA
| | - Rachel O’Toole
- Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, Texas, USA
- Galveston National Laboratory, University of Texas Medical Branch, Galveston, Texas, USA
| | - Karla A Fenton
- Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, Texas, USA
- Galveston National Laboratory, University of Texas Medical Branch, Galveston, Texas, USA
| | - Mack B Harrison
- Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, Texas, USA
- Galveston National Laboratory, University of Texas Medical Branch, Galveston, Texas, USA
| | - Abhishek N Prasad
- Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, Texas, USA
- Galveston National Laboratory, University of Texas Medical Branch, Galveston, Texas, USA
| | - Daniel J Deer
- Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, Texas, USA
- Galveston National Laboratory, University of Texas Medical Branch, Galveston, Texas, USA
| | - Cheryl Gerardi
- Department of Viral Vaccine Development, Auro Vaccines, Pearl River, New York, USA
| | - Nneka Morrison
- Department of Viral Vaccine Development, Auro Vaccines, Pearl River, New York, USA
| | - Robert W Cross
- Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, Texas, USA
- Galveston National Laboratory, University of Texas Medical Branch, Galveston, Texas, USA
| | - John H Eldridge
- Department of Viral Vaccine Development, Auro Vaccines, Pearl River, New York, USA
| | - Demetrius Matassov
- Department of Viral Vaccine Development, Auro Vaccines, Pearl River, New York, USA
| | - Thomas W Geisbert
- Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, Texas, USA
- Galveston National Laboratory, University of Texas Medical Branch, Galveston, Texas, USA
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19
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Malherbe DC, Kimble JB, Atyeo C, Fischinger S, Meyer M, Cody SG, Hyde M, Alter G, Bukreyev A. A Single-Dose Intranasal Combination Panebolavirus Vaccine. J Infect Dis 2023; 228:S648-S659. [PMID: 37469133 PMCID: PMC10651208 DOI: 10.1093/infdis/jiad266] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2023] [Revised: 06/23/2023] [Accepted: 07/10/2023] [Indexed: 07/21/2023] Open
Abstract
BACKGROUND Ebolaviruses Ebola (EBOV), Sudan (SUDV), and Bundibugyo (BDBV) cause severe human disease, which may be accompanied by hemorrhagic syndrome, with high case fatality rates. Monovalent vaccines do not offer cross-protection against these viruses whose endemic areas overlap. Therefore, development of a panebolavirus vaccine is a priority. As a vaccine vector, human parainfluenza virus type 3 (HPIV3) has the advantages of needle-free administration and induction of both systemic and local mucosal antibody responses in the respiratory tract. METHODS To minimize the antivector immunity, genes encoding the HPIV3 envelope proteins F and HN were removed from the vaccine constructs, resulting in expression of only the ebolavirus envelope protein-glycoprotein. These second-generation vaccine constructs were used to develop a combination vaccine against EBOV, SUDV, and BDBV. RESULTS A single intranasal vaccination of guinea pigs or ferrets with the trivalent combination vaccine elicited humoral responses to each of the targeted ebolaviruses, including binding and neutralizing antibodies, as well as Fc-mediated effector functions. This vaccine protected animals from death and disease caused by lethal challenges with EBOV, SUDV, or BDBV. CONCLUSIONS The combination vaccine elicited protection that was comparable to that induced by the monovalent vaccines, thus demonstrating the value of this combination trivalent vaccine.
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Affiliation(s)
- Delphine C Malherbe
- Department of Pathology, University of Texas Medical Branch, Galveston, Texas, USA
- Galveston National Laboratory, Galveston, Texas, USA
| | - J Brian Kimble
- Department of Pathology, University of Texas Medical Branch, Galveston, Texas, USA
- Galveston National Laboratory, Galveston, Texas, USA
| | - Caroline Atyeo
- Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology, and Harvard, Cambridge, Massachusetts, USA
| | - Stephanie Fischinger
- Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology, and Harvard, Cambridge, Massachusetts, USA
| | - Michelle Meyer
- Department of Pathology, University of Texas Medical Branch, Galveston, Texas, USA
- Galveston National Laboratory, Galveston, Texas, USA
| | - S Gabrielle Cody
- Department of Pathology, University of Texas Medical Branch, Galveston, Texas, USA
| | - Matthew Hyde
- Galveston National Laboratory, Galveston, Texas, USA
| | - Galit Alter
- Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology, and Harvard, Cambridge, Massachusetts, USA
| | - Alexander Bukreyev
- Department of Pathology, University of Texas Medical Branch, Galveston, Texas, USA
- Galveston National Laboratory, Galveston, Texas, USA
- Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, Texas, USA
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20
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Santos RI, Ilinykh PA, Pietzsch CA, Ronk AJ, Huang K, Kuzmina NA, Zhou F, Crowe JE, Bukreyev A. Blocking of ebolavirus spread through intercellular connections by an MPER-specific antibody depends on BST2/tetherin. Cell Rep 2023; 42:113254. [PMID: 37858466 PMCID: PMC10664807 DOI: 10.1016/j.celrep.2023.113254] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2022] [Revised: 08/10/2023] [Accepted: 09/27/2023] [Indexed: 10/21/2023] Open
Abstract
Ebola virus (EBOV) and Bundibugyo virus (BDBV) belong to the family Filoviridae and cause a severe disease in humans. We previously isolated a large panel of monoclonal antibodies from B cells of human survivors from the 2007 Uganda BDBV outbreak, 16 survivors from the 2014 EBOV outbreak in the Democratic Republic of the Congo, and one survivor from the West African 2013-2016 EBOV epidemic. Here, we demonstrate that EBOV and BDBV are capable of spreading to neighboring cells through intercellular connections in a process that depends upon actin and T cell immunoglobulin and mucin 1 protein. We quantify spread through intercellular connections by immunofluorescence microscopy and flow cytometry. One of the antibodies, BDBV223, specific to the membrane-proximal external region, induces virus accumulation at the plasma membrane. The inhibiting activity of BDBV223 depends on BST2/tetherin.
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Affiliation(s)
- Rodrigo I Santos
- Department of Pathology, University of Texas Medical Branch, Galveston, TX, USA; Galveston National Laboratory, Galveston, TX, USA
| | - Philipp A Ilinykh
- Department of Pathology, University of Texas Medical Branch, Galveston, TX, USA; Galveston National Laboratory, Galveston, TX, USA
| | - Colette A Pietzsch
- Department of Pathology, University of Texas Medical Branch, Galveston, TX, USA; Galveston National Laboratory, Galveston, TX, USA
| | - Adam J Ronk
- Department of Pathology, University of Texas Medical Branch, Galveston, TX, USA; Galveston National Laboratory, Galveston, TX, USA
| | - Kai Huang
- Department of Pathology, University of Texas Medical Branch, Galveston, TX, USA; Galveston National Laboratory, Galveston, TX, USA
| | - Natalia A Kuzmina
- Department of Pathology, University of Texas Medical Branch, Galveston, TX, USA; Galveston National Laboratory, Galveston, TX, USA
| | - Fuchun Zhou
- Department of Pathology, University of Texas Medical Branch, Galveston, TX, USA; Galveston National Laboratory, Galveston, TX, USA
| | - James E Crowe
- Vanderbilt Vaccine Center, Vanderbilt University Medical Center, Nashville, TN, USA; Department of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, TN, USA; Department of Pediatrics, Vanderbilt University Medical Center, Nashville, TN, USA.
| | - Alexander Bukreyev
- Department of Pathology, University of Texas Medical Branch, Galveston, TX, USA; Galveston National Laboratory, Galveston, TX, USA; Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, TX, USA.
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21
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Balinandi S, Whitmer S, Mulei S, Nassuna C, Pimundu G, Muyigi T, Kainulainen M, Shedroff E, Krapiunaya I, Scholte F, Nyakarahuka L, Tumusiime A, Kyondo J, Baluku J, Kiconco J, Harris JR, Ario AR, Kagirita A, Bosa HK, Ssewanyana I, Nabadda S, Mwebesa HG, Aceng JR, Atwine D, Lutwama JJ, Shoemaker TR, Montgomery JM, Kaleebu P, Klena JD. Molecular characterization of the 2022 Sudan virus disease outbreak in Uganda. J Virol 2023; 97:e0059023. [PMID: 37750724 PMCID: PMC10617429 DOI: 10.1128/jvi.00590-23] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2023] [Accepted: 08/08/2023] [Indexed: 09/27/2023] Open
Abstract
IMPORTANCE Ebola disease (EBOD) is a public health threat with a high case fatality rate. Most EBOD outbreaks have occurred in remote locations, but the 2013-2016 Western Africa outbreak demonstrated how devastating EBOD can be when it reaches an urban population. Here, the 2022 Sudan virus disease (SVD) outbreak in Mubende District, Uganda, is summarized, and the genetic relatedness of the new variant is evaluated. The Mubende variant exhibited 96% amino acid similarity with historic SUDV sequences from the 1970s and a high degree of conservation throughout the outbreak, which was important for ongoing diagnostics and highly promising for future therapy development. Genetic differences between viruses identified during the Mubende SVD outbreak were linked with epidemiological data to better interpret viral spread and contact tracing chains. This methodology should be used to better integrate discrete epidemiological and sequence data for future viral outbreaks.
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Affiliation(s)
| | - Shannon Whitmer
- Viral Special Pathogens Branch, Centers for Disease Control and Prevention, Atlanta, Georgia, USA
| | - Sophia Mulei
- Uganda Virus Research Institute, Entebbe, Uganda
| | | | - Godfrey Pimundu
- Uganda National Health Laboratory Services, Ministry of Health, Kampala, Uganda
| | - Tonny Muyigi
- Uganda National Health Laboratory Services, Ministry of Health, Kampala, Uganda
| | - Markus Kainulainen
- Viral Special Pathogens Branch, Centers for Disease Control and Prevention, Atlanta, Georgia, USA
| | - Elizabeth Shedroff
- Viral Special Pathogens Branch, Centers for Disease Control and Prevention, Atlanta, Georgia, USA
| | - Inna Krapiunaya
- Viral Special Pathogens Branch, Centers for Disease Control and Prevention, Atlanta, Georgia, USA
| | - Florine Scholte
- Viral Special Pathogens Branch, Centers for Disease Control and Prevention, Atlanta, Georgia, USA
| | - Luke Nyakarahuka
- Uganda Virus Research Institute, Entebbe, Uganda
- College of Veterinary Medicine, Animal Resources and Biosecurity, Makerere University, Kampala, Uganda
| | | | | | - Jimmy Baluku
- Uganda Virus Research Institute, Entebbe, Uganda
| | | | | | - Alex R. Ario
- Uganda Public Health Fellowship Program, Kampala, Uganda
| | | | - Henry K. Bosa
- Ministry of Health, Kampala, Uganda
- Kellogg College, University of Oxford, Oxford, United Kingdom
| | - Isaac Ssewanyana
- Uganda National Health Laboratory Services, Ministry of Health, Kampala, Uganda
| | - Susan Nabadda
- Uganda National Health Laboratory Services, Ministry of Health, Kampala, Uganda
| | | | | | | | | | - Trevor R. Shoemaker
- Viral Special Pathogens Branch, Centers for Disease Control and Prevention, Atlanta, Georgia, USA
| | - Joel M. Montgomery
- Viral Special Pathogens Branch, Centers for Disease Control and Prevention, Atlanta, Georgia, USA
| | - Pontiano Kaleebu
- Uganda Virus Research Institute, Entebbe, Uganda
- MRC/UVRI & LSHTM Uganda Research Unit, Entebbe, Uganda
| | - John D. Klena
- Viral Special Pathogens Branch, Centers for Disease Control and Prevention, Atlanta, Georgia, USA
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22
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Dupuy LC, Spiropoulou CF, Towner JS, Spengler JR, Sullivan NJ, Montgomery JM. Filoviruses: Scientific Gaps and Prototype Pathogen Recommendation. J Infect Dis 2023; 228:S446-S459. [PMID: 37849404 PMCID: PMC11009505 DOI: 10.1093/infdis/jiad362] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/19/2023] Open
Abstract
Viruses in the family Filoviridae, including the commonly known Ebola (EBOV) and Marburg (MARV) viruses, can cause severe hemorrhagic fever in humans and nonhuman primates. Sporadic outbreaks of filovirus disease occur in sub-Saharan Africa with reported case fatality rates ranging from 25% to 90%. The high mortality and increasing frequency and magnitude of recent outbreaks along with the increased potential for spread from rural to urban areas highlight the importance of pandemic preparedness for these viruses. Despite their designation as high-priority pathogens, numerous scientific gaps exist in critical areas. In this review, these gaps and an assessment of potential prototype pathogen candidates are presented for this important virus family.
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Affiliation(s)
- Lesley C Dupuy
- Virology Branch, Division of Microbiology and Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA
| | - Christina F Spiropoulou
- Viral Special Pathogens Branch, Division of High Consequence Pathogens and Pathology, National Center for Emerging Zoonotic Infectious Diseases, Centers for Disease Control and Prevention, Atlanta, Georgia, USA
| | - Jonathan S Towner
- Viral Special Pathogens Branch, Division of High Consequence Pathogens and Pathology, National Center for Emerging Zoonotic Infectious Diseases, Centers for Disease Control and Prevention, Atlanta, Georgia, USA
| | - Jessica R Spengler
- Viral Special Pathogens Branch, Division of High Consequence Pathogens and Pathology, National Center for Emerging Zoonotic Infectious Diseases, Centers for Disease Control and Prevention, Atlanta, Georgia, USA
| | - Nancy J Sullivan
- National Emerging Infectious Diseases Laboratories, Boston University, Boston, Massachusetts, USA
| | - Joel M Montgomery
- Viral Special Pathogens Branch, Division of High Consequence Pathogens and Pathology, National Center for Emerging Zoonotic Infectious Diseases, Centers for Disease Control and Prevention, Atlanta, Georgia, USA
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23
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Chavez S, Koyfman A, Gottlieb M, Brady WJ, Carius BM, Liang SY, Long B. Ebola virus disease: A review for the emergency medicine clinician. Am J Emerg Med 2023; 70:30-40. [PMID: 37196593 DOI: 10.1016/j.ajem.2023.04.037] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2023] [Revised: 04/07/2023] [Accepted: 04/24/2023] [Indexed: 05/19/2023] Open
Abstract
INTRODUCTION Ebolavirus, the causative agent of Ebola virus disease (EVD) has been responsible for sporadic outbreaks mainly in sub-Saharan Africa since 1976. EVD is associated with high risk of transmission, especially to healthcare workers during patient care. OBJECTIVE The purpose of this review is to provide a concise review of EVD presentation, diagnosis, and management for emergency clinicians. DISCUSSION EVD is spread through direct contact, including blood, bodily fluids or contact with a contaminated object. Patients may present with non-specific symptoms such as fevers, myalgias, vomiting, or diarrhea that overlap with other viral illnesses, but rash, bruising, and bleeding may also occur. Laboratory analysis may reveal transaminitis, coagulopathy, and disseminated intravascular coagulation. The average clinical course is approximately 8-10 days with an average case fatality rate of 50%. The mainstay of treatment is supportive care, with two U.S. Food and Drug Administration-approved monoclonal antibody treatments (Ebanga and Inmazeb). Survivors of the disease may have a complicated recovery, marked by long-term symptoms. CONCLUSION EVD is a potentially deadly condition that can present with a wide range of signs and symptoms. Emergency clinicians must be aware of the presentation, evaluation, and management to optimize the care of these patients.
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Affiliation(s)
- Summer Chavez
- Department of Health Systems and Population Health Sciences, Tilman J. Fertitta Family College of Medicine, United States of America.
| | - Alex Koyfman
- The University of Texas Southwestern Medical Center, Department of Emergency Medicine, 5323 Harry Hines Boulevard, Dallas 75390, TX, United States of America
| | - Michael Gottlieb
- Department of Emergency Medicine, Rush University Medical Center, Chicago, IL, United States of America
| | - William J Brady
- Department of Emergency Medicine, University of Virginia School of Medicine, Charlottesville, VA, United States of America.
| | | | - Stephen Y Liang
- Divisions of Emergency Medicine and Infectious Diseases, Washington University School of Medicine, 660 S. Euclid Ave, St. Louis 63110, MO, United States of America.
| | - Brit Long
- SAUSHEC, Emergency Medicine, Brooke Army Medical Center, United States of America
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24
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Jain S, Khaiboullina S, Martynova E, Morzunov S, Baranwal M. Epidemiology of Ebolaviruses from an Etiological Perspective. Pathogens 2023; 12:248. [PMID: 36839520 PMCID: PMC9963726 DOI: 10.3390/pathogens12020248] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2022] [Revised: 01/21/2023] [Accepted: 01/29/2023] [Indexed: 02/05/2023] Open
Abstract
Since the inception of the ebolavirus in 1976, 32 outbreaks have resulted in nearly 15,350 deaths in more than ten countries of the African continent. In the last decade, the largest (2013-2016) and second largest (2018-2020) ebolavirus outbreaks have occurred in West Africa (mainly Guinea, Liberia, and Sierra Leone) and the Democratic Republic of the Congo, respectively. The 2013-2016 outbreak indicated an alarming geographical spread of the virus and was the first to qualify as an epidemic. Hence, it is imperative to halt ebolavirus progression and develop effective countermeasures. Despite several research efforts, ebolaviruses' natural hosts and secondary reservoirs still elude the scientific world. The primary source responsible for infecting the index case is also unknown for most outbreaks. In this review, we summarize the history of ebolavirus outbreaks with a focus on etiology, natural hosts, zoonotic reservoirs, and transmission mechanisms. We also discuss the reasons why the African continent is the most affected region and identify steps to contain this virus.
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Affiliation(s)
- Sahil Jain
- Department of Biotechnology, Thapar Institute of Engineering and Technology, Patiala 147004, Punjab, India
- Department of Biochemistry and Molecular Biology, Faculty of Life Sciences, Tel-Aviv University, Tel-Aviv 6997801, Israel
| | - Svetlana Khaiboullina
- Institute of Fundamental Medicine and Biology, Kazan Federal University, 420008 Kazan, Tatarstan, Russia
| | - Ekaterina Martynova
- Institute of Fundamental Medicine and Biology, Kazan Federal University, 420008 Kazan, Tatarstan, Russia
| | - Sergey Morzunov
- Department of Pathology, School of Medicine, University of Nevada, Reno, NV 89557, USA
| | - Manoj Baranwal
- Department of Biotechnology, Thapar Institute of Engineering and Technology, Patiala 147004, Punjab, India
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25
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Bettini A, Lapa D, Garbuglia AR. Diagnostics of Ebola virus. Front Public Health 2023; 11:1123024. [PMID: 36908455 PMCID: PMC9995846 DOI: 10.3389/fpubh.2023.1123024] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2022] [Accepted: 01/31/2023] [Indexed: 02/25/2023] Open
Abstract
Ebola is a highly pathogenic virus, which in humans reaches a mortality rate above 50%. Due to a lack of laboratories in territories where Ebola viruses are endemic and the limited number of surveillance programmes, tests for the confirmation of suspected cases of Ebola are often performed in Reference Laboratories. While this provides guarantees regarding the accuracy of results, the shipment of samples to a centralized facility where the diagnostic test can be performed and the time required to achieve the results takes several days, which increases costs and entails delays in the isolation of positive subjects and therapeutic intervention with negative consequences both for patients and the community. Molecular tests have been the most frequently used tool in Ebola diagnosis in recent outbreaks. One of the most commonly used molecular tests is the Real-Star Altona, which targets a conserved area of the L gene. This assay showed different sensitivities depending on the Ebola virus: 471 copies/mL (EBOV) and 2871 copies/ml (SUDAN virus). The Cepheid system also showed good sensitivity (232 copies/mL). The LAMP platform is very promising because, being an isothermal reaction, it does not require high-precision instrumentation and can be considered a Point of Care (PoC) tool. Its analytical sensitivity is 1 copy/reaction. However, since data from real life studies are not yet available, it is premature to give any indications on its feasibility. Moreover, in November 2014, the WHO recommended the development of rapid diagnostic tests (RDT) according to ASSURED criteria. Several RDT assays have since been produced, most of which are rapid tests based on the search for antibody anti-Ebola viral proteins with immunochromatographic methods. Several viral antigens are used for this purpose: VP40, NP and GP. These assays show different sensitivities according to the protein used: VP40 57.4-93.1%, GP 53-88.9% and 85% for NP compared to reference molecular assays. From these results, it can be deduced that no RDT reaches the 99% sensitivity recommended by the WHO and therefore any RDT negative results in suspected cases should be confirmed with a molecular test.
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Affiliation(s)
- Aurora Bettini
- Laboratory of Virology, National Institute for Infectious Diseases Lazzaro Spallanzani (IRCCS), Rome, Italy
| | - Daniele Lapa
- Laboratory of Virology, National Institute for Infectious Diseases Lazzaro Spallanzani (IRCCS), Rome, Italy
| | - Anna Rosa Garbuglia
- Laboratory of Virology, National Institute for Infectious Diseases Lazzaro Spallanzani (IRCCS), Rome, Italy
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26
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Kayiwa J, Homsy J, Nelson LJ, Ocom F, Kasule JN, Wetaka MM, Kyazze S, Mwanje W, Kisakye A, Nabunya D, Nyirabakunzi M, Aliddeki DM, Ojwang J, Boore A, Kasozi S, Borchert J, Shoemaker T, Nabatanzi S, Dahlke M, Brown V, Downing R, Makumbi I. Establishing a Public Health Emergency Operations Center in an Outbreak-Prone Country: Lessons Learned in Uganda, January 2014 to December 2021. Health Secur 2022; 20:394-407. [PMID: 35984936 PMCID: PMC10985018 DOI: 10.1089/hs.2022.0048] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
Abstract
Uganda is highly vulnerable to public health emergencies (PHEs) due to its geographic location next to the Congo Basin epidemic hot spot, placement within multiple epidemic belts, high population growth rates, and refugee influx. In view of this, Uganda's Ministry of Health established the Public Health Emergency Operations Center (PHEOC) in September 2013, as a central coordination unit for all PHEs in the country. Uganda followed the World Health Organization's framework to establish the PHEOC, including establishing a steering committee, acquiring legal authority, developing emergency response plans, and developing a concept of operations. The same framework governs the PHEOC's daily activities. Between January 2014 and December 2021, Uganda's PHEOC coordinated response to 271 PHEs, hosted 207 emergency coordination meetings, trained all core staff in public health emergency management principles, participated in 21 simulation exercises, coordinated Uganda's Global Health Security Agenda activities, established 6 subnational PHEOCs, and strengthened the capacity of 7 countries in public health emergency management. In this article, we discuss the following lessons learned: PHEOCs are key in PHE coordination and thus mitigate the associated adverse impacts; although the functions of a PHEOC may be legalized by the existence of a National Institute of Public Health, their establishment may precede formally securing the legal framework; staff may learn public health emergency management principles on the job; involvement of leaders and health partners is crucial to the success of a public health emergency management program; subnational PHEOCs are resourceful in mounting regional responses to PHEs; and service on the PHE Strategic Committee may be voluntary.
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Affiliation(s)
- Joshua Kayiwa
- Joshua Kayiwa, MSc, is a Plans Chief and Information Analyst, Public Health Emergency Operations Center, Ministry of Health, Kampala, Uganda
| | - Jaco Homsy
- Jaco Homsy, MD, MPH, is an Associate Clinical Professor, Epidemiology and Biostatistics, Institute for Global Health Sciences, University of California San Francisco School of Medicine, San Francisco, CA
| | - Lisa J Nelson
- Lisa J. Nelson, MD, MPH, MSc, is a Medical Officer and Uganda Country Director, US Centers for Disease Control and Prevention (CDC) Country Office, Kampala, Uganda
| | - Felix Ocom
- Felix Ocom, MD, is Deputy Director, Public Health Emergency Operations Center, Ministry of Health, Kampala, Uganda
| | - Juliet N Kasule
- Juliet N. Kasule, MSc, is an Early Warning Specialist, US Centers for Disease Control and Prevention (CDC) Country Office, Kampala, Uganda
| | - Milton M Wetaka
- Milton M. Wetaka is a Logistics Chief and Laboratory Specialist, Public Health Emergency Operations Center, Ministry of Health, Kampala, Uganda
| | - Simon Kyazze
- Simon Kyazze, MSc, is an Operations Chief, Public Health Emergency Operations Center, Ministry of Health, Kampala, Uganda
| | - Wilbrod Mwanje
- Wilbrod Mwanje, MPH, is an Epidemiologist, Public Health Emergency Operations Center, Ministry of Health, Kampala, Uganda
| | - Anita Kisakye
- Anita Kisakye, MSc, is a Monitoring and Evaluation Specialist, Public Health Emergency Operations Center, Ministry of Health, Kampala, Uganda
| | - Dorothy Nabunya
- Dorothy Nabunya is an Administrative Specialist, Public Health Emergency Operations Center, Ministry of Health, Kampala, Uganda
| | - Margaret Nyirabakunzi
- Margaret Nyirabakunzi is an Administrative Assistant, Public Health Emergency Operations Center, Ministry of Health, Kampala, Uganda
| | - Dativa Maria Aliddeki
- Dativa Maria Aliddeki, MSc, is an Epidemiologist, Public Health Emergency Operations Center, Ministry of Health, Kampala, Uganda
| | - Joseph Ojwang
- Joseph Ojwang, MPH, is an Epidemiologist, US Centers for Disease Control and Prevention (CDC) Country Office, Kampala, Uganda
| | - Amy Boore
- Amy Boore, PhD, is Director, Division of Global Health Protection, US Centers for Disease Control and Prevention (CDC) Country Office, Kampala, Uganda
| | - Sam Kasozi
- Sam Kasozi is a Systems Developer, Health Information Systems Program Uganda, Kampala, Uganda
| | - Jeff Borchert
- Jeff Borchert, MSc, is a Public Health Advisor, Division of Vector-Borne Diseases, National Center for Emerging and Zoonotic Infectious Diseases (NCEZID), US CDC, Fort Collins, CO
| | - Trevor Shoemaker
- Trevor Shoemaker, PhD, is an Epidemiologist, Division of High-Consequence Pathogens and Pathology, NCEZIDUS CDC, Atlanta, GA
| | - Sandra Nabatanzi
- Sandra Nabatanzi, MSc, is an Epidemiologist, Monitoring and Evaluation Technical Support Program, Makerere University School of Public Health, Kampala, Uganda
| | - Melissa Dahlke
- Melissa Dahlke, MSc, is an Epidemiologist, Global Immunization Division, Center for Global Health, US CDC, Atlanta, GA
| | - Vance Brown
- Vance Brown, MA, is a Public Health Advisor, Division of Global Health Protection, NCEZID, US CDC, Atlanta, GA
| | - Robert Downing
- Robert Downing, PhD, is a Laboratory Specialist, Uganda Virus Research Institute, Ministry of Health, Entebbe, Uganda
| | - Issa Makumbi
- Issa Makumbi, MSc, is Director, Public Health Emergency Operations Center, Ministry of Health, Kampala, Uganda
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27
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Schoeder CT, Gilchuk P, Sangha AK, Ledwitch KV, Malherbe DC, Zhang X, Binshtein E, Williamson LE, Martina CE, Dong J, Armstrong E, Sutton R, Nargi R, Rodriguez J, Kuzmina N, Fiala B, King NP, Bukreyev A, Crowe JE, Meiler J. Epitope-focused immunogen design based on the ebolavirus glycoprotein HR2-MPER region. PLoS Pathog 2022; 18:e1010518. [PMID: 35584193 PMCID: PMC9170092 DOI: 10.1371/journal.ppat.1010518] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2021] [Revised: 06/06/2022] [Accepted: 04/12/2022] [Indexed: 01/09/2023] Open
Abstract
The three human pathogenic ebolaviruses: Zaire (EBOV), Bundibugyo (BDBV), and Sudan (SUDV) virus, cause severe disease with high fatality rates. Epitopes of ebolavirus glycoprotein (GP) recognized by antibodies with binding breadth for all three ebolaviruses are of major interest for rational vaccine design. In particular, the heptad repeat 2 -membrane-proximal external region (HR2-MPER) epitope is relatively conserved between EBOV, BDBV, and SUDV GP and targeted by human broadly-neutralizing antibodies. To study whether this epitope can serve as an immunogen for the elicitation of broadly-reactive antibody responses, protein design in Rosetta was employed to transplant the HR2-MPER epitope identified from a co-crystal structure with the known broadly-reactive monoclonal antibody (mAb) BDBV223 onto smaller scaffold proteins. From computational analysis, selected immunogen designs were produced as recombinant proteins and functionally validated, leading to the identification of a sterile alpha motif (SAM) domain displaying the BDBV-HR2-MPER epitope near its C terminus as a promising candidate. The immunogen was fused to one component of a self-assembling, two-component nanoparticle and tested for immunogenicity in rabbits. Robust titers of cross-reactive serum antibodies to BDBV and EBOV GPs and moderate titers to SUDV GP were induced following immunization. To confirm the structural composition of the immunogens, solution NMR studies were conducted and revealed structural flexibility in the C-terminal residues of the epitope. Overall, our study represents the first report on an epitope-focused immunogen design based on the structurally challenging BDBV-HR2-MPER epitope.
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Affiliation(s)
- Clara T. Schoeder
- Department of Chemistry, Vanderbilt University, Nashville, Tennessee, United States of America
- Center for Structural Biology, Vanderbilt University, Nashville, Tennessee, United States of America
- Institute for Drug Discovery, University Leipzig Medical School, Leipzig, Germany
| | - Pavlo Gilchuk
- Vanderbilt Vaccine Center, Vanderbilt University Medical Center, Tennessee, United States of America
| | - Amandeep K. Sangha
- Department of Chemistry, Vanderbilt University, Nashville, Tennessee, United States of America
- Center for Structural Biology, Vanderbilt University, Nashville, Tennessee, United States of America
| | - Kaitlyn V. Ledwitch
- Department of Chemistry, Vanderbilt University, Nashville, Tennessee, United States of America
- Center for Structural Biology, Vanderbilt University, Nashville, Tennessee, United States of America
| | - Delphine C. Malherbe
- Department of Pathology, University of Texas Medical Branch, Galveston, Texas, United States of America
- Galveston National Laboratory, Galveston, Texas, United States of America
| | - Xuan Zhang
- Department of Chemistry, Vanderbilt University, Nashville, Tennessee, United States of America
- Center for Structural Biology, Vanderbilt University, Nashville, Tennessee, United States of America
| | - Elad Binshtein
- Vanderbilt Vaccine Center, Vanderbilt University Medical Center, Tennessee, United States of America
| | - Lauren E. Williamson
- Vanderbilt Vaccine Center, Vanderbilt University Medical Center, Tennessee, United States of America
- Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, Tennessee, United States of America
| | - Cristina E. Martina
- Department of Chemistry, Vanderbilt University, Nashville, Tennessee, United States of America
- Center for Structural Biology, Vanderbilt University, Nashville, Tennessee, United States of America
| | - Jinhui Dong
- Vanderbilt Vaccine Center, Vanderbilt University Medical Center, Tennessee, United States of America
| | - Erica Armstrong
- Vanderbilt Vaccine Center, Vanderbilt University Medical Center, Tennessee, United States of America
| | - Rachel Sutton
- Vanderbilt Vaccine Center, Vanderbilt University Medical Center, Tennessee, United States of America
| | - Rachel Nargi
- Vanderbilt Vaccine Center, Vanderbilt University Medical Center, Tennessee, United States of America
| | - Jessica Rodriguez
- Vanderbilt Vaccine Center, Vanderbilt University Medical Center, Tennessee, United States of America
| | - Natalia Kuzmina
- Department of Pathology, University of Texas Medical Branch, Galveston, Texas, United States of America
- Galveston National Laboratory, Galveston, Texas, United States of America
| | - Brooke Fiala
- Department of Biochemistry, University of Washington, Seattle, Washington, United States of America
- Institute for Protein Design, University of Washington, Seattle, Washington, United States of America
| | - Neil P. King
- Department of Biochemistry, University of Washington, Seattle, Washington, United States of America
- Institute for Protein Design, University of Washington, Seattle, Washington, United States of America
| | - Alexander Bukreyev
- Department of Pathology, University of Texas Medical Branch, Galveston, Texas, United States of America
- Galveston National Laboratory, Galveston, Texas, United States of America
- Department of Microbiology & Immunology, University of Texas Medical Branch, Galveston, Texas, Unites States, United States of America
| | - James E. Crowe
- Vanderbilt Vaccine Center, Vanderbilt University Medical Center, Tennessee, United States of America
- Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, Tennessee, United States of America
- Departments of Pediatrics, Vanderbilt University Medical Center, Nashville, Tennessee, United States of America
| | - Jens Meiler
- Department of Chemistry, Vanderbilt University, Nashville, Tennessee, United States of America
- Center for Structural Biology, Vanderbilt University, Nashville, Tennessee, United States of America
- Institute for Drug Discovery, University Leipzig Medical School, Leipzig, Germany
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Balinandi S, Hayer J, Cholleti H, Wille M, Lutwama JJ, Malmberg M, Mugisha L. Identification and molecular characterization of highly divergent RNA viruses in cattle, Uganda. Virus Res 2022; 313:198739. [PMID: 35271887 DOI: 10.1016/j.virusres.2022.198739] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2022] [Revised: 03/04/2022] [Accepted: 03/06/2022] [Indexed: 10/18/2022]
Abstract
The risk for the emergence of novel viral zoonotic diseases in animals and humans in Uganda is high given its geographical location with high biodiversity. We aimed to identify and characterize viruses in 175 blood samples from cattle selected in Uganda using molecular approaches. We identified 8 viral species belonging to 4 families (Flaviviridae, Peribunyaviridae, Reoviridae and Rhabdoviridae) and 6 genera (Hepacivirus, Pestivirus, Orthobunyavirus, Coltivirus, Dinovernavirus and Ephemerovirus). Four viruses were highly divergent and tetantively named Zikole virus (Family: Flaviviridae), Zeboroti virus (Family: Reoviridae), Zebtine virus (Family: Rhabdoviridae) and Kokolu virus (Family: Rhabdoviridae). In addition, Bovine hepacivirus, Obodhiang virus, Aedes pseudoscutellaris reovirus and Schmallenberg virus were identified for the first time in Ugandan cattle. We report 8 viral species belonging to 4 viral families including divergent ones in the blood of cattle in Uganda. Hence, cattle may be reservoir hosts for likely emergence of novel viruses with pathogenic potential to cause zoonotic diseases in different species with serious public health implications.
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Affiliation(s)
- Stephen Balinandi
- Uganda Virus Research Institute; Entebbe, Uganda; College of Veterinary Medicine, Animal Resources and Biosecurity, Makerere University, Kampala, Uganda
| | - Juliette Hayer
- Department of Animal Breeding and Genetics, Swedish University of Agricultural Sciences, Uppsala, Sweden
| | - Harindranath Cholleti
- Department of Biomedical Sciences and Veterinary Public Health, Swedish University of Agricultural Sciences, Uppsala, Sweden
| | - Michelle Wille
- Sydney Institute for Infectious Diseases, School of Life and Environmental Sciences and School of Medical Sciences, The University of Sydney, Sydney, NSW 2006, Australia; Department of Microbiology and Immunology, at the Peter Doherty Institute for Infection and Immunity, The University of Melbourne, Melbourne, Victoria, Australia
| | | | - Maja Malmberg
- Department of Animal Breeding and Genetics, Swedish University of Agricultural Sciences, Uppsala, Sweden; Department of Biomedical Sciences and Veterinary Public Health, Swedish University of Agricultural Sciences, Uppsala, Sweden
| | - Lawrence Mugisha
- College of Veterinary Medicine, Animal Resources and Biosecurity, Makerere University, Kampala, Uganda; Ecohealth Research Group, Conservation & Ecosystem Health Alliance (CEHA), Kampala, Uganda.
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29
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Shaffer KCL, Hui S, Bratcher A, King LB, Mutombe R, Kavira N, Kompany JP, Tambu M, Musene K, Mukadi P, Mbala P, Gadoth A, West BR, Ilunga BK, Kaba D, Muyembe-Tanfum JJ, Hoff NA, Rimoin AW, Saphire EO. Pan-ebolavirus serology study of healthcare workers in the Mbandaka Health Region, Democratic Republic of the Congo. PLoS Negl Trop Dis 2022; 16:e0010167. [PMID: 35255093 PMCID: PMC8929691 DOI: 10.1371/journal.pntd.0010167] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2021] [Revised: 03/17/2022] [Accepted: 01/13/2022] [Indexed: 01/03/2023] Open
Abstract
Although multiple antigenically distinct ebolavirus species can cause human disease, previous serosurveys focused on only Zaire ebolavirus (EBOV). Thus, the extent of reactivity or exposure to other ebolaviruses, and which sociodemographic factors are linked to this seroreactivity, are unclear. We conducted a serosurvey of 539 healthcare workers (HCW) in Mbandaka, Democratic Republic of the Congo, using ELISA-based analysis of serum IgG against EBOV, Sudan ebolavirus (SUDV) and Bundibugyo ebolavirus (BDBV) glycoproteins (GP). We compared seroreactivity to risk factors for viral exposure using univariate and multivariable logistic regression. Seroreactivity against different GPs ranged from 2.2-4.6%. Samples from six individuals reacted to all three species of ebolavirus and 27 samples showed a species-specific IgG response. We find that community health volunteers are more likely to be seroreactive against each antigen than nurses, and in general, that HCWs with indirect patient contact have higher anti-EBOV GP IgG levels than those with direct contact. Seroreactivity against ebolavirus GP may be associated with positions that offer less occupational training and access to PPE. Those individuals with broadly reactive responses may have had multiple ebolavirus exposures or developed cross-reactive antibodies. In contrast, those individuals with species-specific BDBV or SUDV GP seroreactivity may have been exposed to an ebolavirus not previously known to circulate in the region.
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Affiliation(s)
- Kelly C. L. Shaffer
- Center for Infectious Disease and Vaccine Research, La Jolla Institute for Immunology, La Jolla, California, United States of America
| | - Sean Hui
- Center for Infectious Disease and Vaccine Research, La Jolla Institute for Immunology, La Jolla, California, United States of America
| | - Anna Bratcher
- Department of Epidemiology, UCLA Fielding School of Public Health, University of California, Los Angeles, Los Angeles, California, United States of America
| | - Liam B. King
- Center for Infectious Disease and Vaccine Research, La Jolla Institute for Immunology, La Jolla, California, United States of America
- Department of Medicine, University of California, San Diego, La Jolla, California, United States of America
- Department of Immunology and Microbiology, The Scripps Research Institute, La Jolla, California, United States of America
| | - Rachel Mutombe
- Institut National de Recherche Biomedicale, Kinshasa, Democratic Republic of the Congo
| | - Nathalie Kavira
- Institut National de Recherche Biomedicale, Kinshasa, Democratic Republic of the Congo
| | - Jean Paul Kompany
- Institut National de Recherche Biomedicale, Kinshasa, Democratic Republic of the Congo
| | - Merly Tambu
- Institut National de Recherche Biomedicale, Kinshasa, Democratic Republic of the Congo
| | - Kamy Musene
- Institut National de Recherche Biomedicale, Kinshasa, Democratic Republic of the Congo
| | - Patrick Mukadi
- Institut National de Recherche Biomedicale, Kinshasa, Democratic Republic of the Congo
| | - Placide Mbala
- Institut National de Recherche Biomedicale, Kinshasa, Democratic Republic of the Congo
| | - Adva Gadoth
- Department of Epidemiology, UCLA Fielding School of Public Health, University of California, Los Angeles, Los Angeles, California, United States of America
| | - Brandyn R. West
- Department of Immunology and Microbiology, The Scripps Research Institute, La Jolla, California, United States of America
| | - Benoit Kebela Ilunga
- Directorate of Disease Control, Ministry of Public Health, Kinshasa, Democratic Republic of the Congo
| | - Didine Kaba
- Kinshasa School of Public Health, Kinshasa, Democratic Republic of the Congo
| | | | - Nicole A. Hoff
- Department of Epidemiology, UCLA Fielding School of Public Health, University of California, Los Angeles, Los Angeles, California, United States of America
| | - Anne W. Rimoin
- Department of Epidemiology, UCLA Fielding School of Public Health, University of California, Los Angeles, Los Angeles, California, United States of America
| | - Erica Ollmann Saphire
- Center for Infectious Disease and Vaccine Research, La Jolla Institute for Immunology, La Jolla, California, United States of America
- Department of Medicine, University of California, San Diego, La Jolla, California, United States of America
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30
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Nyakarahuka L, Mulei S, Whitmer S, Jackson K, Tumusiime A, Schuh A, Baluku J, Joyce A, Ocom F, Tusiime JB, Montgomery JM, Balinandi S, Lutwama JJ, Klena JD, Shoemaker TR. First laboratory confirmation and sequencing of Zaire ebolavirus in Uganda following two independent introductions of cases from the 10th Ebola Outbreak in the Democratic Republic of the Congo, June 2019. PLoS Negl Trop Dis 2022; 16:e0010205. [PMID: 35192613 PMCID: PMC8896669 DOI: 10.1371/journal.pntd.0010205] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2021] [Revised: 03/04/2022] [Accepted: 01/26/2022] [Indexed: 11/18/2022] Open
Abstract
Uganda established a domestic Viral Hemorrhagic Fever (VHF) testing capacity in 2010 in response to the increasing occurrence of filovirus outbreaks. In July 2018, the neighboring Democratic Republic of Congo (DRC) experienced its 10th Ebola Virus Disease (EVD) outbreak and for the duration of the outbreak, the Ugandan Ministry of Health (MOH) initiated a national EVD preparedness stance. Almost one year later, on 10th June 2019, three family members who had contracted EVD in the DRC crossed into Uganda to seek medical treatment.
Samples were collected from all the suspected cases using internationally established biosafety protocols and submitted for VHF diagnostic testing at Uganda Virus Research Institute. All samples were initially tested by RT-PCR for ebolaviruses, marburgviruses, Rift Valley fever (RVF) virus and Crimean-Congo hemorrhagic fever (CCHF) virus. Four people were identified as being positive for Zaire ebolavirus, marking the first report of Zaire ebolavirus in Uganda. In-country Next Generation Sequencing (NGS) and phylogenetic analysis was performed for the first time in Uganda, confirming the outbreak as imported from DRC at two different time point from different clades. This rapid response by the MoH, UVRI and partners led to the control of the outbreak and prevention of secondary virus transmission.
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Affiliation(s)
- Luke Nyakarahuka
- Department of Arbovirology, Emerging and Re-emerging Infectious Diseases, Uganda Virus Research Institute, Entebbe, Uganda
- Department of Biosecurity, Ecosystems and Veterinary Public Health, Makerere University, Kampala, Uganda
- * E-mail:
| | - Sophia Mulei
- Department of Arbovirology, Emerging and Re-emerging Infectious Diseases, Uganda Virus Research Institute, Entebbe, Uganda
| | - Shannon Whitmer
- Viral Special Pathogens Branch, Division of High-Consequence Pathogens and Pathology, United States Centers for Disease Control and Prevention, Atlanta, Georgia, United States of America
| | - Kyondo Jackson
- Department of Arbovirology, Emerging and Re-emerging Infectious Diseases, Uganda Virus Research Institute, Entebbe, Uganda
| | - Alex Tumusiime
- Department of Arbovirology, Emerging and Re-emerging Infectious Diseases, Uganda Virus Research Institute, Entebbe, Uganda
| | - Amy Schuh
- Viral Special Pathogens Branch, Division of High-Consequence Pathogens and Pathology, United States Centers for Disease Control and Prevention, Atlanta, Georgia, United States of America
| | - Jimmy Baluku
- Department of Arbovirology, Emerging and Re-emerging Infectious Diseases, Uganda Virus Research Institute, Entebbe, Uganda
| | - Allison Joyce
- Viral Special Pathogens Branch, Division of High-Consequence Pathogens and Pathology, United States Centers for Disease Control and Prevention, Atlanta, Georgia, United States of America
| | - Felix Ocom
- Uganda Public Health Emergency Operations Center, Kampala, Uganda
| | | | - Joel M. Montgomery
- Viral Special Pathogens Branch, Division of High-Consequence Pathogens and Pathology, United States Centers for Disease Control and Prevention, Atlanta, Georgia, United States of America
| | - Stephen Balinandi
- Department of Arbovirology, Emerging and Re-emerging Infectious Diseases, Uganda Virus Research Institute, Entebbe, Uganda
| | - Julius J. Lutwama
- Department of Arbovirology, Emerging and Re-emerging Infectious Diseases, Uganda Virus Research Institute, Entebbe, Uganda
| | - John D. Klena
- Viral Special Pathogens Branch, Division of High-Consequence Pathogens and Pathology, United States Centers for Disease Control and Prevention, Atlanta, Georgia, United States of America
| | - Trevor R. Shoemaker
- Viral Special Pathogens Branch, Division of High-Consequence Pathogens and Pathology, United States Centers for Disease Control and Prevention, Atlanta, Georgia, United States of America
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31
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Sherwood LJ, Hayhurst A. Generating Uniformly Cross-Reactive Ebolavirus spp. Anti-nucleoprotein Nanobodies to Facilitate Forward Capable Detection Strategies. ACS Infect Dis 2022; 8:343-359. [PMID: 34994194 DOI: 10.1021/acsinfecdis.1c00478] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
Abstract
It is often challenging for a single monoclonal antibody to cross-react equally with all species of a particular viral genus that are separated by time and geographies to ensure broad long-term global immunodiagnostic use. Here, we set out to isolate nanobodies or single-domain antibodies (sdAbs) with uniform cross-reactivity to the genus Ebolavirus by immunizing a llama with recombinant nucleoprotein (NP) representing the 5 cultivated species to assemble a phage display repertoire for mining. Screening sdAbs for reactivity against the C-terminal domain of NP guided the isolation of clones that could perform as both captor and tracer for polyvalent antigen in sandwich assays. Two promising sdAbs had equivalent reactivities across all 5 species and greatly enhanced the equilibrium concentration at 50% (EC50) for recombinant NP when compared with a differentially cross-reactive nonimmune sdAb isolated previously. Uniform reactivity and enhanced sensitivity were relayed to live virus titrations, resulting in lower limits of detection of 2-5 pfu for the best sdAbs, representing 10-, 20-, and 100-fold improvements for Zaire, Sudan/Reston, and Taï Forest viruses, respectively. Fusions of the sdAbs with ascorbate peroxidase (APEX2) and mNeonGreen generated one-step immunoreagents useful for colorimetric and fluorescent visualization of cellular NP. Both sdAbs were also able to recognize recombinant NPs from the recently discovered Bombali virus, a putative sixth Ebolavirus species unknown at the start of these experiments, validating the forward capabilities of the sdAbs. The simplicity and modularity of these sdAbs should enable advances in antigen-based diagnostic technologies to be retuned toward filoviral detection relatively easily, thereby proactively safeguarding human health.
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Affiliation(s)
- Laura Jo Sherwood
- Disease Intervention and Prevention, Texas Biomedical Research Institute, San Antonio, Texas 78227, United States
| | - Andrew Hayhurst
- Disease Intervention and Prevention, Texas Biomedical Research Institute, San Antonio, Texas 78227, United States
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32
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Estimating Risk of Introduction of Ebola Virus Disease from the Democratic Republic of Congo to Tanzania: A Qualitative Assessment. EPIDEMIOLGIA (BASEL, SWITZERLAND) 2022; 3:68-80. [PMID: 36417268 PMCID: PMC9620938 DOI: 10.3390/epidemiologia3010007] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 10/14/2021] [Revised: 12/11/2021] [Accepted: 12/17/2021] [Indexed: 12/14/2022]
Abstract
Between April 2018 and November 2020, the Democratic Republic of Congo (DRC) experienced its 11th Ebola virus disease (EVD) outbreak. Tanzania's cross-border interactions with DRC through regular visitors, traders, and refugees are of concern, given the potential for further spread to neighboring countries. This study aimed to estimate the risk of introducing EVD to Tanzania from DRC. National data for flights, boats, and car transport schedules from DRC to Tanzania covering the period of May 2018 to June 2019 were analyzed to describe population movement via land, port, and air travel and coupled with available surveillance data to model the risk of EVD entry. The land border crossing was considered the most frequently used means of travel and the most likely pathway of introducing EVD from DRC to Tanzania. High probabilities of introducing EVD from DRC to Tanzania through the assessed pathways were associated with the viability of the pathogen and low detection capacity at the ports of entry. This study provides important information regarding the elements contributing to the risk associated with the introduction of EBV in Tanzania. It also indicates that infected humans arriving via land are the most likely pathway of EBV entry, and therefore, mitigation strategies including land border surveillance should be strengthened.
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33
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Diakou KI, Mitsis T, Pierouli K, Papakonstantinou E, Bongcam-Rudloff E, Wayengera M, Vlachakis D. Ebola Virus Disease and Current Therapeutic Strategies: A Review. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2022; 1339:131-137. [PMID: 35023100 DOI: 10.1007/978-3-030-78787-5_18] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Indexed: 10/19/2022]
Abstract
The Ebola virus disease is a severe hemorrhagic fever that affects humans and other primates. Ebola virus, the causative agent of the disease, is transmitted to humans from wild animals and is highly contagious and aggressive with an estimated fatality rate to be around 50%. Since 1976, 11 outbreaks of Ebola virus disease have been reported in total, affecting mostly sub-Saharan Africa, while the most recent ongoing outbreak in the Democratic Republic of the Congo has more than 3000 reported cases and 72 deaths. Although an effective vaccine against Ebola virus disease has become available, no targeted treatment with proven efficacy upon infection is developed. Herein, we review the epidemiology of Ebola virus and the current situation in terms of prevention, diagnosis, and treatment of the disease.
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Affiliation(s)
- Kalliopi Io Diakou
- Laboratory of Genetics, Department of Biotechnology, School of Applied Biology and Biotechnology, Agricultural University of Athens, Athens, Greece
| | - Thanasis Mitsis
- Laboratory of Genetics, Department of Biotechnology, School of Applied Biology and Biotechnology, Agricultural University of Athens, Athens, Greece
| | - Katerina Pierouli
- Laboratory of Genetics, Department of Biotechnology, School of Applied Biology and Biotechnology, Agricultural University of Athens, Athens, Greece
| | - Eleni Papakonstantinou
- Laboratory of Genetics, Department of Biotechnology, School of Applied Biology and Biotechnology, Agricultural University of Athens, Athens, Greece
| | - Erik Bongcam-Rudloff
- SLU-Global Bioinformatics Centre, Department of Animal Breeding and Genetics Science, University of Agricultural Sciences, Uppsala, Sweden
| | - Misaki Wayengera
- Department of Pathology, Unit of Genetics & Genomics, School of Biomedical Sciences, Makerere University College of Health Sciences, Kampala, Uganda
| | - Dimitrios Vlachakis
- DarkDNA Group, Laboratory of Genetics, Department of Biotechnology, School of Applied Biology and Biotechnology, Agricultural University of Athens, Athens, Greece. .,Lab of Molecular Endocrinology, Center of Clinical, Experimental Surgery and Translational Research, Biomedical Research Foundation of the Academy of Athens, Athens, Greece. .,Department of Informatics, Faculty of Natural and Mathematical Sciences, King's College London, Strand, London, UK.
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34
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Zhang L, Chen F, Zeng Z, Xu M, Sun F, Yang L, Bi X, Lin Y, Gao Y, Hao H, Yi W, Li M, Xie Y. Advances in Metagenomics and Its Application in Environmental Microorganisms. Front Microbiol 2022; 12:766364. [PMID: 34975791 PMCID: PMC8719654 DOI: 10.3389/fmicb.2021.766364] [Citation(s) in RCA: 78] [Impact Index Per Article: 26.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2021] [Accepted: 11/18/2021] [Indexed: 01/04/2023] Open
Abstract
Metagenomics is a new approach to study microorganisms obtained from a specific environment by functional gene screening or sequencing analysis. Metagenomics studies focus on microbial diversity, community constitute, genetic and evolutionary relationships, functional activities, and interactions and relationships with the environment. Sequencing technologies have evolved from shotgun sequencing to high-throughput, next-generation sequencing (NGS), and third-generation sequencing (TGS). NGS and TGS have shown the advantage of rapid detection of pathogenic microorganisms. With the help of new algorithms, we can better perform the taxonomic profiling and gene prediction of microbial species. Functional metagenomics is helpful to screen new bioactive substances and new functional genes from microorganisms and microbial metabolites. In this article, basic steps, classification, and applications of metagenomics are reviewed.
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Affiliation(s)
- Lu Zhang
- Department of Hepatology Division 2, Beijing Ditan Hospital, Capital Medical University, Beijing, China
| | - FengXin Chen
- Department of Hepatology Division 2, Beijing Ditan Hospital, Capital Medical University, Beijing, China
| | - Zhan Zeng
- Department of Hepatology Division 2, Peking University Ditan Teaching Hospital, Beijing, China
| | - Mengjiao Xu
- Department of Hepatology Division 2, Beijing Ditan Hospital, Capital Medical University, Beijing, China
| | - Fangfang Sun
- Department of Hepatology Division 2, Beijing Ditan Hospital, Capital Medical University, Beijing, China
| | - Liu Yang
- Department of Hepatology Division 2, Beijing Ditan Hospital, Capital Medical University, Beijing, China
| | - Xiaoyue Bi
- Department of Hepatology Division 2, Beijing Ditan Hospital, Capital Medical University, Beijing, China
| | - Yanjie Lin
- Department of Hepatology Division 2, Peking University Ditan Teaching Hospital, Beijing, China
| | - YuanJiao Gao
- Department of Hepatology Division 2, Beijing Ditan Hospital, Capital Medical University, Beijing, China
| | - HongXiao Hao
- Department of Hepatology Division 2, Beijing Ditan Hospital, Capital Medical University, Beijing, China
| | - Wei Yi
- Department of Gynecology and Obstetrics, Beijing Ditan Hospital, Capital Medical University, Beijing, China
| | - Minghui Li
- Department of Hepatology Division 2, Beijing Ditan Hospital, Capital Medical University, Beijing, China.,Department of Hepatology Division 2, Peking University Ditan Teaching Hospital, Beijing, China
| | - Yao Xie
- Department of Hepatology Division 2, Beijing Ditan Hospital, Capital Medical University, Beijing, China.,Department of Hepatology Division 2, Peking University Ditan Teaching Hospital, Beijing, China
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35
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Schuh AJ, Kyondo J, Graziano J, Balinandi S, Kainulainen MH, Tumusiime A, Nyakarahuka L, Mulei S, Baluku J, Lonergan W, Mayer O, Masereka R, Masereka F, Businge E, Gatare A, Kabyanga L, Muhindo S, Mugabe R, Makumbi I, Kayiwa J, Wetaka MM, Brown V, Ojwang J, Nelson L, Millard M, Nichol ST, Montgomery JM, Taboy CH, Lutwama JJ, Klena JD. Rapid establishment of a frontline field laboratory in response to an imported outbreak of Ebola virus disease in western Uganda, June 2019. PLoS Negl Trop Dis 2021; 15:e0009967. [PMID: 34860831 PMCID: PMC8673597 DOI: 10.1371/journal.pntd.0009967] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2021] [Revised: 12/15/2021] [Accepted: 11/03/2021] [Indexed: 12/12/2022] Open
Abstract
The Democratic Republic of the Congo (DRC) declared an Ebola virus disease (EVD) outbreak in North Kivu in August 2018. By June 2019, the outbreak had spread to 26 health zones in northeastern DRC, causing >2,000 reported cases and >1,000 deaths. On June 10, 2019, three members of a Congolese family with EVD-like symptoms traveled to western Uganda’s Kasese District to seek medical care. Shortly thereafter, the Viral Hemorrhagic Fever Surveillance and Laboratory Program (VHF program) at the Uganda Virus Research Institute (UVRI) confirmed that all three patients had EVD. The Ugandan Ministry of Health declared an outbreak of EVD in Uganda’s Kasese District, notified the World Health Organization, and initiated a rapid response to contain the outbreak. As part of this response, UVRI and the United States Centers for Disease Control and Prevention, with the support of Uganda’s Public Health Emergency Operations Center, the Kasese District Health Team, the Superintendent of Bwera General Hospital, the United States Department of Defense’s Makerere University Walter Reed Project, and the United States Mission to Kampala’s Global Health Security Technical Working Group, jointly established an Ebola Field Laboratory in Kasese District at Bwera General Hospital, proximal to an Ebola Treatment Unit (ETU). The laboratory consisted of a rapid containment kit for viral inactivation of patient specimens and a GeneXpert Instrument for performing Xpert Ebola assays. Laboratory staff tested 76 specimens from alert and suspect cases of EVD; the majority were admitted to the ETU (89.3%) and reported recent travel to the DRC (58.9%). Although no EVD cases were detected by the field laboratory, it played an important role in patient management and epidemiological surveillance by providing diagnostic results in <3 hours. The integration of the field laboratory into Uganda’s National VHF Program also enabled patient specimens to be referred to Entebbe for confirmatory EBOV testing and testing for other hemorrhagic fever viruses that circulate in Uganda. Following an imported outbreak of Ebola virus disease in Uganda’s western Kasese District, the Uganda Virus Research Institute and the United States Centers for Disease Control and Prevention jointly established a frontline field laboratory to test specimens collected from alert and suspect cases for Ebola virus disease. Using a single room equipped with a rapid containment kit to safely inactivate patient specimens and a GeneXpert to perform the Xpert Ebola Assay, the field laboratory rapidly ruled-out Ebola virus disease as the cause of illness in 76 patients during its 46 operational days. All specimens were also referred to Uganda Virus Research Institute (Entebbe) for confirmatory Ebola virus testing and testing against a panel of viruses known to cause hemorrhagic fever in Uganda, in line with the National Viral Hemorrhagic Fever Program’s testing protocol and mandate. The Ebola field laboratory served as a valuable asset in the outbreak response by supporting patient management and epidemiological surveillance.
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Affiliation(s)
- Amy J. Schuh
- Viral Special Pathogens Branch, Division of High-Consequence Pathogens and Pathology, United States Centers for Disease Control and Prevention, Atlanta, Georgia, United States of America
- United States Public Health Service Commissioned Corps, Rockville, Maryland, United States of America
- * E-mail: (AJS); (JDK)
| | - Jackson Kyondo
- Department of Arbovirology, Emerging and Reemerging Infectious Diseases, Uganda Virus Research Institute, Entebbe, Uganda
| | - James Graziano
- Viral Special Pathogens Branch, Division of High-Consequence Pathogens and Pathology, United States Centers for Disease Control and Prevention, Atlanta, Georgia, United States of America
| | - Stephen Balinandi
- Department of Arbovirology, Emerging and Reemerging Infectious Diseases, Uganda Virus Research Institute, Entebbe, Uganda
| | - Markus H. Kainulainen
- Viral Special Pathogens Branch, Division of High-Consequence Pathogens and Pathology, United States Centers for Disease Control and Prevention, Atlanta, Georgia, United States of America
| | - Alex Tumusiime
- Department of Arbovirology, Emerging and Reemerging Infectious Diseases, Uganda Virus Research Institute, Entebbe, Uganda
| | - Luke Nyakarahuka
- Department of Arbovirology, Emerging and Reemerging Infectious Diseases, Uganda Virus Research Institute, Entebbe, Uganda
| | - Sophia Mulei
- Department of Arbovirology, Emerging and Reemerging Infectious Diseases, Uganda Virus Research Institute, Entebbe, Uganda
| | - Jimmy Baluku
- Department of Arbovirology, Emerging and Reemerging Infectious Diseases, Uganda Virus Research Institute, Entebbe, Uganda
| | - William Lonergan
- Viral Special Pathogens Branch, Division of High-Consequence Pathogens and Pathology, United States Centers for Disease Control and Prevention, Atlanta, Georgia, United States of America
| | - Oren Mayer
- Viral Special Pathogens Branch, Division of High-Consequence Pathogens and Pathology, United States Centers for Disease Control and Prevention, Atlanta, Georgia, United States of America
- United States Public Health Service Commissioned Corps, Rockville, Maryland, United States of America
| | | | | | | | | | | | | | - Raymond Mugabe
- Uganda Central Public Health Laboratories, Kampala, Uganda
| | - Issa Makumbi
- Uganda Public Health Emergency Operations Center, Kampala, Uganda
| | - Joshua Kayiwa
- Uganda Public Health Emergency Operations Center, Kampala, Uganda
| | | | - Vance Brown
- United States Centers for Disease Control and Prevention, Kampala, Uganda
| | - Joseph Ojwang
- United States Centers for Disease Control and Prevention, Kampala, Uganda
| | - Lisa Nelson
- United States Centers for Disease Control and Prevention, Kampala, Uganda
| | | | - Stuart T. Nichol
- Viral Special Pathogens Branch, Division of High-Consequence Pathogens and Pathology, United States Centers for Disease Control and Prevention, Atlanta, Georgia, United States of America
| | - Joel M. Montgomery
- Viral Special Pathogens Branch, Division of High-Consequence Pathogens and Pathology, United States Centers for Disease Control and Prevention, Atlanta, Georgia, United States of America
- United States Public Health Service Commissioned Corps, Rockville, Maryland, United States of America
| | - Celine H. Taboy
- Viral Special Pathogens Branch, Division of High-Consequence Pathogens and Pathology, United States Centers for Disease Control and Prevention, Atlanta, Georgia, United States of America
| | - Julius J. Lutwama
- Department of Arbovirology, Emerging and Reemerging Infectious Diseases, Uganda Virus Research Institute, Entebbe, Uganda
| | - John D. Klena
- Viral Special Pathogens Branch, Division of High-Consequence Pathogens and Pathology, United States Centers for Disease Control and Prevention, Atlanta, Georgia, United States of America
- * E-mail: (AJS); (JDK)
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Yamaoka S, Ebihara H. Pathogenicity and Virulence of Ebolaviruses with Species- and Variant-specificity. Virulence 2021; 12:885-901. [PMID: 33734027 PMCID: PMC7993122 DOI: 10.1080/21505594.2021.1898169] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2020] [Revised: 02/10/2021] [Accepted: 02/19/2021] [Indexed: 01/05/2023] Open
Abstract
Ebola virus (EBOV), belonging to the species Zaire ebolavirus in the genus Ebolavirus, causes a severe febrile illness in humans with case fatality rates (CFRs) up to 90%. While there have been six virus species classified, which each have a single type virus in the genus Ebolavirus, CFRs of ebolavirus infections vary among viruses belonging to each distinct species. In this review, we aim to define the ebolavirus species-specific virulence on the basis of currently available laboratory and experimental findings. In addition, this review will also cover the variant-specific virulence of EBOV by referring to the unique biological and pathogenic characteristics of EBOV variant Makona, a new EBOV variant isolated from the 2013-2016 EBOV disease outbreak in West Africa. A better definition of species-specific and variant-specific virulence of ebolaviruses will facilitate our comprehensive knowledge on genus Ebolavirus biology, leading to the development of therapeutics against well-focused pathogenic mechanisms of each Ebola disease.
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Affiliation(s)
- Satoko Yamaoka
- Department of Molecular Medicine, Mayo Clinic, Rochester, USA
| | - Hideki Ebihara
- Department of Molecular Medicine, Mayo Clinic, Rochester, USA
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Gilchuk P, Murin CD, Cross RW, Ilinykh PA, Huang K, Kuzmina N, Borisevich V, Agans KN, Geisbert JB, Zost SJ, Nargi RS, Sutton RE, Suryadevara N, Bombardi RG, Carnahan RH, Bukreyev A, Geisbert TW, Ward AB, Crowe JE. Pan-ebolavirus protective therapy by two multifunctional human antibodies. Cell 2021; 184:5593-5607.e18. [PMID: 34715022 PMCID: PMC8716180 DOI: 10.1016/j.cell.2021.09.035] [Citation(s) in RCA: 27] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2021] [Revised: 07/27/2021] [Accepted: 09/27/2021] [Indexed: 01/14/2023]
Abstract
Ebolaviruses cause a severe and often fatal illness with the potential for global spread. Monoclonal antibody-based treatments that have become available recently have a narrow therapeutic spectrum and are ineffective against ebolaviruses other than Ebola virus (EBOV), including medically important Bundibugyo (BDBV) and Sudan (SUDV) viruses. Here, we report the development of a therapeutic cocktail comprising two broadly neutralizing human antibodies, rEBOV-515 and rEBOV-442, that recognize non-overlapping sites on the ebolavirus glycoprotein (GP). Antibodies in the cocktail exhibited synergistic neutralizing activity, resisted viral escape, and possessed differing requirements for their Fc-regions for optimal in vivo activities. The cocktail protected non-human primates from ebolavirus disease caused by EBOV, BDBV, or SUDV with high therapeutic effectiveness. High-resolution structures of the cocktail antibodies in complex with GP revealed the molecular determinants for neutralization breadth and potency. This study provides advanced preclinical data to support clinical development of this cocktail for pan-ebolavirus therapy.
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Affiliation(s)
- Pavlo Gilchuk
- Vanderbilt Vaccine Center, Vanderbilt University Medical Center, Nashville, TN 37232, USA
| | - Charles D Murin
- Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, CA 92037, USA
| | - Robert W Cross
- Galveston National Laboratory, Galveston, TX 77550, USA; Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, TX 77555, USA
| | - Philipp A Ilinykh
- Galveston National Laboratory, Galveston, TX 77550, USA; Department of Pathology, University of Texas Medical Branch, Galveston, TX 77555, USA
| | - Kai Huang
- Galveston National Laboratory, Galveston, TX 77550, USA; Department of Pathology, University of Texas Medical Branch, Galveston, TX 77555, USA
| | - Natalia Kuzmina
- Galveston National Laboratory, Galveston, TX 77550, USA; Department of Pathology, University of Texas Medical Branch, Galveston, TX 77555, USA
| | - Viktoriya Borisevich
- Galveston National Laboratory, Galveston, TX 77550, USA; Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, TX 77555, USA
| | - Krystle N Agans
- Galveston National Laboratory, Galveston, TX 77550, USA; Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, TX 77555, USA
| | - Joan B Geisbert
- Galveston National Laboratory, Galveston, TX 77550, USA; Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, TX 77555, USA
| | - Seth J Zost
- Vanderbilt Vaccine Center, Vanderbilt University Medical Center, Nashville, TN 37232, USA
| | - Rachel S Nargi
- Vanderbilt Vaccine Center, Vanderbilt University Medical Center, Nashville, TN 37232, USA
| | - Rachel E Sutton
- Vanderbilt Vaccine Center, Vanderbilt University Medical Center, Nashville, TN 37232, USA
| | | | - Robin G Bombardi
- Vanderbilt Vaccine Center, Vanderbilt University Medical Center, Nashville, TN 37232, USA
| | - Robert H Carnahan
- Vanderbilt Vaccine Center, Vanderbilt University Medical Center, Nashville, TN 37232, USA; Department of Pediatrics, Vanderbilt University Medical Center, Nashville, TN 37232, USA
| | - Alexander Bukreyev
- Galveston National Laboratory, Galveston, TX 77550, USA; Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, TX 77555, USA; Department of Pathology, University of Texas Medical Branch, Galveston, TX 77555, USA
| | - Thomas W Geisbert
- Galveston National Laboratory, Galveston, TX 77550, USA; Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, TX 77555, USA
| | - Andrew B Ward
- Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, CA 92037, USA
| | - James E Crowe
- Vanderbilt Vaccine Center, Vanderbilt University Medical Center, Nashville, TN 37232, USA; Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN 37232, USA; Department of Pediatrics, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
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Levine CB, Mire CE, Geisbert TW. Comparison of Zaire and Bundibugyo Ebolavirus Polymerase Complexes and Susceptibility to Antivirals through a Newly Developed Bundibugyo Minigenome System. J Virol 2021; 95:e0064321. [PMID: 34379503 PMCID: PMC8475504 DOI: 10.1128/jvi.00643-21] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2021] [Accepted: 07/28/2021] [Indexed: 11/20/2022] Open
Abstract
Members of the genus Ebolavirus cause lethal disease in humans, with Zaire ebolavirus (EBOV) being the most pathogenic (up to 90% morality) and Bundibugyo ebolavirus (BDBV) the least pathogenic (∼37% mortality). Historically, there has been a lack of research on BDBV, and there is no means to study BDBV outside of a high-containment laboratory. Here, we describe a minigenome replication system to study BDBV transcription and compare the efficacy of small-molecule inhibitors between EBOV and BDBV. Using this system, we examined the ability of the polymerase complex proteins from EBOV and BDBV to interact and form a functional unit as well as the impact of the genomic untranslated ends, known to contain important signals for transcription (3'-untranslated region) and replication (5'-untranslated region). Various levels of compatibility were observed between proteins of the polymerase complex from each ebolavirus, resulting in differences in genome transcription efficiency. Most pronounced was the effect of the nucleoprotein and the 3'-untranslated region. These data suggest that there are intrinsic specificities in the polymerase complex and untranslated signaling regions that could offer insight regarding observed pathogenic differences. Further adding to the differences in the polymerase complexes, posttransfection/infection treatment with the compound remdesivir (GS-5734) showed a greater inhibitory effect against BDBV than EBOV. The delayed growth kinetics of BDBV and the greater susceptibility to polymerase inhibitors indicate that disruption of the polymerase complex is a viable target for therapeutics. IMPORTANCE Ebolavirus disease is a viral infection and is fatal in 25 to 90% of cases, depending on the viral species and the amount of supportive care available. Two species have caused outbreaks in the Democratic Republic of the Congo, Zaire ebolavirus (EBOV) and Bundibugyo ebolavirus (BDBV). Pathogenesis and clinical outcome differ between these two species, but there is still limited information regarding the viral mechanism for these differences. Previous studies suggested that BDBV replicates slower than EBOV, but it is unknown if this is due to differences in the polymerase complex and its role in transcription and replication. This study details the construction of a minigenome replication system that can be used in a biosafety level 2 laboratory. This system will be important for studying the polymerase complex of BDBV and comparing it with other filoviruses and can be used as a tool for screening inhibitors of viral growth.
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Affiliation(s)
- Corri B. Levine
- Galveston National Laboratory, University of Texas Medical Branch, Galveston, Texas, USA
- Institute for Translational Sciences, University of Texas Medical Branch, Galveston, Texas, USA
| | - Chad E. Mire
- Galveston National Laboratory, University of Texas Medical Branch, Galveston, Texas, USA
- Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, Texas, USA
| | - Thomas W. Geisbert
- Galveston National Laboratory, University of Texas Medical Branch, Galveston, Texas, USA
- Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, Texas, USA
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Hulseberg CE, Kumar R, Di Paola N, Larson P, Nagle ER, Richardson J, Hanson J, Wauquier N, Fair JN, Makuwa M, Mulembakani P, Muyembe-Tamfum JJ, Schoepp RJ, Sanchez-Lockhart M, Palacios GF, Kuhn JH, Kugelman JR. Molecular analysis of the 2012 Bundibugyo virus disease outbreak. Cell Rep Med 2021; 2:100351. [PMID: 34467242 PMCID: PMC8385243 DOI: 10.1016/j.xcrm.2021.100351] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2020] [Revised: 04/25/2021] [Accepted: 06/24/2021] [Indexed: 01/24/2023]
Abstract
Bundibugyo virus (BDBV) is one of four ebolaviruses known to cause disease in humans. Bundibugyo virus disease (BVD) outbreaks occurred in 2007-2008 in Bundibugyo District, Uganda, and in 2012 in Isiro, Province Orientale, Democratic Republic of the Congo. The 2012 BVD outbreak resulted in 38 laboratory-confirmed cases of human infection, 13 of whom died. However, only 4 BDBV specimens from the 2012 outbreak have been sequenced. Here, we provide BDBV sequences from seven additional patients. Analysis of the molecular epidemiology and evolutionary dynamics of the 2012 outbreak with these additional isolates challenges the current hypothesis that the outbreak was the result of a single spillover event. In addition, one patient record indicates that BDBV's initial emergence in Isiro occurred 50 days earlier than previously accepted. Collectively, this work demonstrates how retrospective sequencing can be used to elucidate outbreak origins and provide epidemiological contexts to a medically relevant pathogen.
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Affiliation(s)
- Christine E. Hulseberg
- Center for Genome Sciences, United States Army Medical Research Institute of Infectious Diseases, Frederick, MD 21702, USA
| | - Raina Kumar
- Center for Genome Sciences, United States Army Medical Research Institute of Infectious Diseases, Frederick, MD 21702, USA
| | - Nicholas Di Paola
- Center for Genome Sciences, United States Army Medical Research Institute of Infectious Diseases, Frederick, MD 21702, USA
| | - Peter Larson
- Center for Genome Sciences, United States Army Medical Research Institute of Infectious Diseases, Frederick, MD 21702, USA
| | - Elyse R. Nagle
- National Biodefense Analysis and Countermeasures Center, Frederick, MD 21702, USA
| | - Joshua Richardson
- Center for Genome Sciences, United States Army Medical Research Institute of Infectious Diseases, Frederick, MD 21702, USA
| | - Jarod Hanson
- Center for Genome Sciences, United States Army Medical Research Institute of Infectious Diseases, Frederick, MD 21702, USA
| | - Nadia Wauquier
- Metabiota, Inc., Kinshasa, Democratic Republic of the Congo
| | - Joseph N. Fair
- Metabiota, Inc., Kinshasa, Democratic Republic of the Congo
| | - Maria Makuwa
- Metabiota, Inc., Kinshasa, Democratic Republic of the Congo
| | | | | | - Randal J. Schoepp
- Diagnostic Systems Division, United States Army Medical Research Institute of Infectious Diseases, Frederick, MD 21702, USA
| | - Mariano Sanchez-Lockhart
- Center for Genome Sciences, United States Army Medical Research Institute of Infectious Diseases, Frederick, MD 21702, USA
| | - Gustavo F. Palacios
- Center for Genome Sciences, United States Army Medical Research Institute of Infectious Diseases, Frederick, MD 21702, USA
| | - Jens H. Kuhn
- Integrated Research Facility at Fort Detrick, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Frederick, MD 21702, USA
| | - Jeffrey R. Kugelman
- Center for Genome Sciences, United States Army Medical Research Institute of Infectious Diseases, Frederick, MD 21702, USA
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Bundibugyo ebolavirus Survival Is Associated with Early Activation of Adaptive Immunity and Reduced Myeloid-Derived Suppressor Cell Signaling. mBio 2021; 12:e0151721. [PMID: 34372693 PMCID: PMC8406165 DOI: 10.1128/mbio.01517-21] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
Ebolaviruses Bundibugyo virus (BDBV) and Ebola virus (EBOV) cause fatal hemorrhagic disease in humans and nonhuman primates. While the host response to EBOV is well characterized, less is known about BDBV infection. Moreover, immune signatures that mediate natural protection against all ebolaviruses remain poorly defined. To explore these knowledge gaps, we transcriptionally profiled BDBV-infected rhesus macaques, a disease model that results in incomplete lethality. This approach enabled us to identify prognostic indicators. As expected, survival (∼60%) correlated with reduced clinical pathology and circulating infectious virus, although peak viral RNA loads were not significantly different between surviving and nonsurviving macaques. Survivors had higher anti-BDBV antibody titers and transcriptionally derived cytotoxic T cell-, memory B cell-, and plasma cell-type quantities, demonstrating activation of adaptive immunity. Conversely, a poor prognosis was associated with lack of an appropriate adaptive response, sustained innate immune signaling, and higher expression of myeloid-derived suppressor cell (MDSC)-related transcripts (S100A8, S100A9, CEBPB, PTGS2, CXCR1, and LILRA3). MDSCs are potent immunosuppressors of cellular and humoral immunity, and therefore, they represent a potential therapeutic target. Circulating plasminogen activator inhibitor 1 (PAI-1) and tissue plasminogen activator (tPA) levels were also elevated in nonsurvivors and in survivors exhibiting severe illness, emphasizing the importance of maintaining coagulation homeostasis to control disease progression.
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41
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Huang Y, Xiao S, Yuan Z. Comparison and Evaluation of Real-Time Taqman PCR for Detection and Quantification of Ebolavirus. Viruses 2021; 13:1575. [PMID: 34452440 PMCID: PMC8402893 DOI: 10.3390/v13081575] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2021] [Revised: 08/05/2021] [Accepted: 08/05/2021] [Indexed: 01/12/2023] Open
Abstract
Given that ebolavirus causes severe and frequently lethal disease, its rapid and accurate detection using available and validated methods is essential for controlling infection. Real-time reverse-transcription PCR (RT-PCR) has proven to be an invaluable tool for ebolaviruses diagnostics. Many assays with different targets have been developed, but they have not been externally compared or validated, and limits of detection are not uniformly reported. Here we compared and evaluated the sensitivity, reproducibility and specificity of 23 in-house assays under the same conditions. Our results showed that these assays were highly gene- and species- specific when evaluated using in vitro RNA transcripts and viral RNA, and the potential limits of detection were uniformly reported ranging from 102 to 106 in vitro synthesized RNA transcripts copies perμL and 1-100 TCID50/mL. The comparison of these assays indicated that those targeting the more conservative NP gene could be the better option for EVD case definition and quantitative measurement because of its higher sensitivity for the same species. Our analysis could contribute to the standardization of ebolavirus detection and quantification assays, which can offer a better understanding of the meaning of results across laboratories and time points, as well as make them easy to implement, especially under outbreak conditions.
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Affiliation(s)
- Yi Huang
- National Biosafety Laboratory, Chinese Academy of Sciences, Wuhan 430020, China
| | - Shuqi Xiao
- Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan 430020, China;
| | - Zhiming Yuan
- National Biosafety Laboratory, Chinese Academy of Sciences, Wuhan 430020, China
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42
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Dasari CM, Bhukya R. Explainable deep neural networks for novel viral genome prediction. APPL INTELL 2021; 52:3002-3017. [PMID: 34764607 PMCID: PMC8232563 DOI: 10.1007/s10489-021-02572-3] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 05/26/2021] [Indexed: 11/27/2022]
Abstract
Viral infection causes a wide variety of human diseases including cancer and COVID-19. Viruses invade host cells and associate with host molecules, potentially disrupting the normal function of hosts that leads to fatal diseases. Novel viral genome prediction is crucial for understanding the complex viral diseases like AIDS and Ebola. While most existing computational techniques classify viral genomes, the efficiency of the classification depends solely on the structural features extracted. The state-of-the-art DNN models achieved excellent performance by automatic extraction of classification features, but the degree of model explainability is relatively poor. During model training for viral prediction, proposed CNN, CNN-LSTM based methods (EdeepVPP, EdeepVPP-hybrid) automatically extracts features. EdeepVPP also performs model interpretability in order to extract the most important patterns that cause viral genomes through learned filters. It is an interpretable CNN model that extracts vital biologically relevant patterns (features) from feature maps of viral sequences. The EdeepVPP-hybrid predictor outperforms all the existing methods by achieving 0.992 mean AUC-ROC and 0.990 AUC-PR on 19 human metagenomic contig experiment datasets using 10-fold cross-validation. We evaluate the ability of CNN filters to detect patterns across high average activation values. To further asses the robustness of EdeepVPP model, we perform leave-one-experiment-out cross-validation. It can work as a recommendation system to further analyze the raw sequences labeled as ‘unknown’ by alignment-based methods. We show that our interpretable model can extract patterns that are considered to be the most important features for predicting virus sequences through learned filters.
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Affiliation(s)
| | - Raju Bhukya
- National Institute of Technology, Warangal, Telangana 506004 India
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Paquin-Proulx D, Gunn BM, Alrubayyi A, Clark DV, Creegan M, Kim D, Kibuuka H, Millard M, Wakabi S, Eller LA, Michael NL, Schoepp RJ, Hepburn MJ, Hensley LE, Robb ML, Alter G, Eller MA. Associations Between Antibody Fc-Mediated Effector Functions and Long-Term Sequelae in Ebola Virus Survivors. Front Immunol 2021; 12:682120. [PMID: 34093585 PMCID: PMC8173169 DOI: 10.3389/fimmu.2021.682120] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2021] [Accepted: 05/05/2021] [Indexed: 11/13/2022] Open
Abstract
Antibodies that mediate non-neutralizing functions play an important role in the immune response to Ebola virus (EBOV) and are thought to impact disease outcome. EBOV has also been associated with long term sequelae in survivors, however, the extent to which antibodies that mediate non-neutralizing functions are associated with the development of these sequelae is unknown. Here, the presence of antibodies mediating different effector functions and how they relate to long-term sequelae two years after the 2007 Bundibugyo Ebola virus (BDBV) outbreak was investigated. The majority of survivors demonstrated robust antibody effector functional activity and demonstrated persistent polyfunctional antibody profiles to the EBOV glycoprotein (GP) two years after infection. These functions were strongly associated with the levels of GP-specific IgG1. The odds of developing hearing loss, one of the more common sequelae to BDBV was reduced when antibodies mediating antibody dependent cellular phagocytosis (ADCP), antibody dependent complement deposition (ADCD), or activating NK cells (ADNKA) were observed. In addition, hearing loss was associated with increased levels of several pro-inflammatory cytokines and levels of these pro-inflammatory cytokines were associated with lower ADCP. These results are indicating that a skewed antibody profile and persistent inflammation may contribute to long term outcome in survivors of BDBV infection.
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Affiliation(s)
- Dominic Paquin-Proulx
- U.S. Military HIV Research Program, Walter Reed Army Institute of Research, Silver Spring, MD, United States.,Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc., Bethesda, MD, United States
| | - Bronwyn M Gunn
- Ragon Institute of MGH, MIT, and Harvard, Cambridge, MA, United States
| | - Aljawharah Alrubayyi
- U.S. Military HIV Research Program, Walter Reed Army Institute of Research, Silver Spring, MD, United States.,Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc., Bethesda, MD, United States
| | - Danielle V Clark
- Austere environments Consortium for Enhanced Sepsis Outcomes (ACESO), Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc., Bethesda, MD, United States
| | - Matthew Creegan
- U.S. Military HIV Research Program, Walter Reed Army Institute of Research, Silver Spring, MD, United States.,Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc., Bethesda, MD, United States
| | - Dohoon Kim
- U.S. Military HIV Research Program, Walter Reed Army Institute of Research, Silver Spring, MD, United States.,Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc., Bethesda, MD, United States
| | - Hannah Kibuuka
- Makerere University Walter Reed Project, Kampala, Uganda
| | - Monica Millard
- Makerere University Walter Reed Project, Kampala, Uganda
| | - Salim Wakabi
- Makerere University Walter Reed Project, Kampala, Uganda
| | - Leigh Anne Eller
- U.S. Military HIV Research Program, Walter Reed Army Institute of Research, Silver Spring, MD, United States.,Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc., Bethesda, MD, United States
| | - Nelson L Michael
- Center for Infectious Disease Research, Walter Reed Army Institute of Research, Silver Spring, MD, United States
| | - Randal J Schoepp
- Diagnostic Systems Division, US Army Medical Research Institute of Infectious Diseases, Fort Detrick, MD, United States
| | - Matthew J Hepburn
- Medical Division, US Army Medical Research Institute of Infectious Diseases, Fort Detrick, MD, United States
| | - Lisa E Hensley
- Integrated Research Facility at Fort Detrick, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Frederick, MD, United States
| | - Merlin L Robb
- U.S. Military HIV Research Program, Walter Reed Army Institute of Research, Silver Spring, MD, United States.,Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc., Bethesda, MD, United States
| | - Galit Alter
- Ragon Institute of MGH, MIT, and Harvard, Cambridge, MA, United States
| | - Michael A Eller
- Vaccine Research Program, Division of AIDS, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, United States
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Chen X, Cheng K, Sun X, Zhang Y, Cao Z, Li J, Bai J, Lu H, Gu S, Zhang L, Xu J, Jiang P, Liang S. Comparison of traditional methods and high-throughput genetic sequencing in the detection of pathogens in pulmonary infectious diseases. ANNALS OF TRANSLATIONAL MEDICINE 2021; 9:702. [PMID: 33987400 PMCID: PMC8106068 DOI: 10.21037/atm-21-1322] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 11/14/2022]
Abstract
Background The major causes of pulmonary infections are various microorganisms. This study aimed to compare the positive rates of pathogenic microorganism DNA/RNA high-throughput genetic sequencing (PMseq), which is an emerging technique, with traditional methods for pulmonary disease detection, and to investigate the differences in different sample types. Methods Bronchoalveolar lavage fluid (BALF) and venous blood samples from 104 patients were collected for detection. Results The positive rates of PMseq in BALF and venous blood were both significantly higher than those of traditional methods in the same sample (P<0.001). For BALF, the detection sensitivities were 96.9% for non-febrile patients and 100% for febrile patients. For venous blood, the detection sensitivities were 50.0% for non-febrile patients and 81.3% for febrile patients. There was no statistical difference in the sensitivity of venous blood samples with or without fever (P=0.075). For patients without fever, the sensitivity of BALF was much higher than venous blood samples (P<0.001). In patients with fever, there were no significant differences between different samples. Conclusions This study showed that PMseq has a higher positive rate for the detection of pulmonary diseases. For patients without fever, it is recommended to use BALF instead of venous blood samples because of the higher sensitivity. However, for patients with fever, venous blood samples can be used when bronchoalveolar lavage is inconvenient.
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Affiliation(s)
- Xianqiu Chen
- Department of Respiratory and Critical Care Medicine, Shanghai Pulmonary Hospital, Tongji University, School of Medicine, Shanghai, China
| | - Kebin Cheng
- Department of Respiratory and Critical Care Medicine, Shanghai Pulmonary Hospital, Tongji University, School of Medicine, Shanghai, China
| | - Xiaoli Sun
- Department of Respiratory and Critical Care Medicine, Shanghai Pulmonary Hospital, Tongji University, School of Medicine, Shanghai, China
| | - Yuan Zhang
- Department of Respiratory and Critical Care Medicine, Shanghai Pulmonary Hospital, Tongji University, School of Medicine, Shanghai, China
| | - Zu Cao
- Department of Respiratory and Critical Care Medicine, Shanghai Pulmonary Hospital, Tongji University, School of Medicine, Shanghai, China
| | - Jianxiong Li
- Department of Respiratory and Critical Care Medicine, Shanghai Pulmonary Hospital, Tongji University, School of Medicine, Shanghai, China
| | - Jiuwu Bai
- Department of Respiratory and Critical Care Medicine, Shanghai Pulmonary Hospital, Tongji University, School of Medicine, Shanghai, China
| | - Haiwen Lu
- Department of Respiratory and Critical Care Medicine, Shanghai Pulmonary Hospital, Tongji University, School of Medicine, Shanghai, China
| | - Shuyi Gu
- Department of Respiratory and Critical Care Medicine, Shanghai Pulmonary Hospital, Tongji University, School of Medicine, Shanghai, China
| | - Li Zhang
- Department of Respiratory and Critical Care Medicine, Shanghai Pulmonary Hospital, Tongji University, School of Medicine, Shanghai, China
| | - Jinfu Xu
- Department of Respiratory and Critical Care Medicine, Shanghai Pulmonary Hospital, Tongji University, School of Medicine, Shanghai, China
| | - Ping Jiang
- Department of Respiratory and Critical Care Medicine, Shanghai Pulmonary Hospital, Tongji University, School of Medicine, Shanghai, China
| | - Shuo Liang
- Department of Respiratory and Critical Care Medicine, Shanghai Pulmonary Hospital, Tongji University, School of Medicine, Shanghai, China
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Villa TG, Abril AG, Sánchez S, de Miguel T, Sánchez-Pérez A. Animal and human RNA viruses: genetic variability and ability to overcome vaccines. Arch Microbiol 2021; 203:443-464. [PMID: 32989475 PMCID: PMC7521576 DOI: 10.1007/s00203-020-02040-5] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2020] [Revised: 06/29/2020] [Accepted: 09/12/2020] [Indexed: 02/06/2023]
Abstract
RNA viruses, in general, exhibit high mutation rates; this is mainly due to the low fidelity displayed by the RNA-dependent polymerases required for their replication that lack the proofreading machinery to correct misincorporated nucleotides and produce high mutation rates. This lack of replication fidelity, together with the fact that RNA viruses can undergo spontaneous mutations, results in genetic variants displaying different viral morphogenesis, as well as variation on their surface glycoproteins that affect viral antigenicity. This diverse viral population, routinely containing a variety of mutants, is known as a viral 'quasispecies'. The mutability of their virions allows for fast evolution of RNA viruses that develop antiviral resistance and overcome vaccines much more rapidly than DNA viruses. This also translates into the fact that pathogenic RNA viruses, that cause many diseases and deaths in humans, represent the major viral group involved in zoonotic disease transmission, and are responsible for worldwide pandemics.
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Affiliation(s)
- T G Villa
- Department of Microbiology, Faculty of Pharmacy, University of Santiago de Compostela, 5706, Santiago de Compostela, Spain.
| | - Ana G Abril
- Department of Microbiology, Faculty of Pharmacy, University of Santiago de Compostela, 5706, Santiago de Compostela, Spain
| | - S Sánchez
- Department of Microbiology, Faculty of Pharmacy, University of Santiago de Compostela, 5706, Santiago de Compostela, Spain
| | - T de Miguel
- Department of Microbiology, Faculty of Pharmacy, University of Santiago de Compostela, 5706, Santiago de Compostela, Spain
| | - A Sánchez-Pérez
- Sydney School of Veterinary Science, Faculty of Science, University of Sydney, Sydney, NSW, 2006, Australia
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Minakshi P, Ghosh M, Kumar R, Brar B, Lambe UP, Banerjee S, Ranjan K, Kumar B, Goel P, Malik YS, Prasad G. An Insight into Nanomedicinal Approaches to Combat Viral Zoonoses. Curr Top Med Chem 2021; 20:915-962. [PMID: 32209041 DOI: 10.2174/1568026620666200325114400] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2019] [Revised: 12/31/2019] [Accepted: 12/31/2019] [Indexed: 12/12/2022]
Abstract
BACKGROUND Emerging viral zoonotic diseases are one of the major obstacles to secure the "One Health" concept under the current scenario. Current prophylactic, diagnostic and therapeutic approaches often associated with certain limitations and thus proved to be insufficient for customizing rapid and efficient combating strategy against the highly transmissible pathogenic infectious agents leading to the disastrous socio-economic outcome. Moreover, most of the viral zoonoses originate from the wildlife and poor knowledge about the global virome database renders it difficult to predict future outbreaks. Thus, alternative management strategy in terms of improved prophylactic vaccines and their delivery systems; rapid and efficient diagnostics and effective targeted therapeutics are the need of the hour. METHODS Structured literature search has been performed with specific keywords in bibliographic databases for the accumulation of information regarding current nanomedicine interventions along with standard books for basic virology inputs. RESULTS Multi-arrayed applications of nanomedicine have proved to be an effective alternative in all the aspects regarding the prevention, diagnosis, and control of zoonotic viral diseases. The current review is focused to outline the applications of nanomaterials as anti-viral vaccines or vaccine/drug delivery systems, diagnostics and directly acting therapeutic agents in combating the important zoonotic viral diseases in the recent scenario along with their potential benefits, challenges and prospects to design successful control strategies. CONCLUSION This review provides significant introspection towards the multi-arrayed applications of nanomedicine to combat several important zoonotic viral diseases.
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Affiliation(s)
- Prasad Minakshi
- Department of Animal Biotechnology, LLR University of Veterinary and Animal Sciences, Hisar-125001, Haryana, 125004, India
| | - Mayukh Ghosh
- Department of Veterinary Physiology and Biochemistry, RGSC, Banaras Hindu University, Mirzapur (UP) - 231001, India
| | - Rajesh Kumar
- Department of Veterinary Physiology and Biochemistry, Lala Lajpat Rai University of Veterinary and Animal Sciences, Hisar-125001, Haryana, 125004, India
| | - Basanti Brar
- Department of Animal Biotechnology, LLR University of Veterinary and Animal Sciences, Hisar-125001, Haryana, 125004, India
| | - Upendra P Lambe
- Department of Animal Biotechnology, LLR University of Veterinary and Animal Sciences, Hisar-125001, Haryana, 125004, India
| | - Somesh Banerjee
- Department of Veterinary Microbiology, Immunology Section, LUVAS, Hisar-125004, India
| | - Koushlesh Ranjan
- Department of Veterinary Physiology and Biochemistry, Sardar Vallabhbhai Patel University of Agriculture and Technology, Meerut, 250110, India
| | | | - Parveen Goel
- Department of Veterinary Medicine, LLR University of Veterinary and Animal Sciences, Hisar, Haryana, 125004, India
| | - Yashpal S Malik
- Division of Standardisation, Indian Veterinary Research Institute Izatnagar - Bareilly (UP) - 243122, India
| | - Gaya Prasad
- Sardar Vallabhbhai Patel University of Agriculture and Technology, Meerut, UP, 250110, India
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Schiffman Z, Yan F, He S, Tierney K, Zhu W, Emeterio K, Zhang H, Banadyga L, Qiu X. Taï Forest Virus Does Not Cause Lethal Disease in Ferrets. Microorganisms 2021; 9:microorganisms9020213. [PMID: 33494199 PMCID: PMC7909818 DOI: 10.3390/microorganisms9020213] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2020] [Revised: 01/14/2021] [Accepted: 01/15/2021] [Indexed: 11/25/2022] Open
Abstract
Filoviruses are zoonotic, negative-sense RNA viruses, most of which are capable of causing severe disease in humans and nonhuman primates, often with high case fatality rates. Among these viruses, those belonging to the Ebolavirus genus—particularly Ebola virus, Sudan virus, and Bundibugyo virus—represent some of the most pathogenic to humans. Taï Forest virus (TAFV) is thought to be among the least pathogenic ebolaviruses; however, only a single non-fatal case has been documented in humans, in 1994. With the recent success of the ferret as a lethal model for a number of ebolaviruses, we set out to evaluate its suitability as a model for TAFV. Our results demonstrate that, unlike other ebolaviruses, TAFV infection in ferrets does not result in lethal disease. None of the intramuscularly inoculated animals demonstrated any overt signs of disease, whereas the intranasally inoculated animals exhibited mild to moderate weight loss during the early stage of infection but recovered quickly. Low levels of viral RNA were detected in the blood and tissues of several animals, particularly the intranasally inoculated animals, and all animals mounted a humoral immune response, with high titers of GP-specific IgG detectable as early as 14 days post-infection. These data provide additional insight into the pathogenesis of TAFV.
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Affiliation(s)
- Zachary Schiffman
- Department of Medical Microbiology and Infectious Diseases, University of Manitoba, Winnipeg, MB R3E 0J9, Canada; (Z.S.); (K.E.); (H.Z.)
- Special Pathogens Program, National Microbiology Laboratory, Public Health Agency of Canada, Winnipeg, MB R3E 3R2, Canada; (S.H.); (K.T.); (W.Z.); (X.Q.)
| | - Feihu Yan
- Key Laboratory of Jilin Province for Zoonosis Prevention and Control, Changchun Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Changchun 130122, China;
| | - Shihua He
- Special Pathogens Program, National Microbiology Laboratory, Public Health Agency of Canada, Winnipeg, MB R3E 3R2, Canada; (S.H.); (K.T.); (W.Z.); (X.Q.)
| | - Kevin Tierney
- Special Pathogens Program, National Microbiology Laboratory, Public Health Agency of Canada, Winnipeg, MB R3E 3R2, Canada; (S.H.); (K.T.); (W.Z.); (X.Q.)
| | - Wenjun Zhu
- Special Pathogens Program, National Microbiology Laboratory, Public Health Agency of Canada, Winnipeg, MB R3E 3R2, Canada; (S.H.); (K.T.); (W.Z.); (X.Q.)
| | - Karla Emeterio
- Department of Medical Microbiology and Infectious Diseases, University of Manitoba, Winnipeg, MB R3E 0J9, Canada; (Z.S.); (K.E.); (H.Z.)
- Special Pathogens Program, National Microbiology Laboratory, Public Health Agency of Canada, Winnipeg, MB R3E 3R2, Canada; (S.H.); (K.T.); (W.Z.); (X.Q.)
| | - Huajun Zhang
- Department of Medical Microbiology and Infectious Diseases, University of Manitoba, Winnipeg, MB R3E 0J9, Canada; (Z.S.); (K.E.); (H.Z.)
| | - Logan Banadyga
- Special Pathogens Program, National Microbiology Laboratory, Public Health Agency of Canada, Winnipeg, MB R3E 3R2, Canada; (S.H.); (K.T.); (W.Z.); (X.Q.)
- Correspondence:
| | - Xiangguo Qiu
- Special Pathogens Program, National Microbiology Laboratory, Public Health Agency of Canada, Winnipeg, MB R3E 3R2, Canada; (S.H.); (K.T.); (W.Z.); (X.Q.)
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Detection of Ebola Virus Antibodies in Fecal Samples of Great Apes in Gabon. Viruses 2020; 12:v12121347. [PMID: 33255243 PMCID: PMC7761173 DOI: 10.3390/v12121347] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2020] [Revised: 11/18/2020] [Accepted: 11/19/2020] [Indexed: 01/12/2023] Open
Abstract
Based on a large study conducted on wild great ape fecal samples collected in regions of Gabon where previous human outbreaks of Ebola virus disease have occurred between 1994 and 2002, we provide evidence for prevalence of Zaire ebolavirus (EBOV)-specific antibodies of 3.9% (immunoglobulin G (IgG)) and 3.5% (immunoglobulin M (IgM)) in chimpanzees and 8.8% (IgG) and 2.4% (IgM) in gorillas. Importantly, we observed a high local prevalence (31.2%) of anti-EBOV IgG antibodies in gorilla samples. This high local rate of positivity among wild great apes raises the question of a spatially and temporally localized increase in EBOV exposure risk and the role that can be played by these animals as sentinels of the virus’s spread or reemergence in a given area.
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Lo MK, Albariño CG, Perry JK, Chang S, Tchesnokov EP, Guerrero L, Chakrabarti A, Shrivastava-Ranjan P, Chatterjee P, McMullan LK, Martin R, Jordan R, Götte M, Montgomery JM, Nichol ST, Flint M, Porter D, Spiropoulou CF. Remdesivir targets a structurally analogous region of the Ebola virus and SARS-CoV-2 polymerases. Proc Natl Acad Sci U S A 2020; 117:26946-26954. [PMID: 33028676 PMCID: PMC7604432 DOI: 10.1073/pnas.2012294117] [Citation(s) in RCA: 41] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open
Abstract
Remdesivir is a broad-spectrum antiviral nucleotide prodrug that has been clinically evaluated in Ebola virus patients and recently received emergency use authorization (EUA) for treatment of COVID-19. With approvals from the Federal Select Agent Program and the Centers for Disease Control and Prevention's Institutional Biosecurity Board, we characterized the resistance profile of remdesivir by serially passaging Ebola virus under remdesivir selection; we generated lineages with low-level reduced susceptibility to remdesivir after 35 passages. We found that a single amino acid substitution, F548S, in the Ebola virus polymerase conferred low-level reduced susceptibility to remdesivir. The F548 residue is highly conserved in filoviruses but should be subject to specific surveillance among novel filoviruses, in newly emerging variants in ongoing outbreaks, and also in Ebola virus patients undergoing remdesivir therapy. Homology modeling suggests that the Ebola virus polymerase F548 residue lies in the F-motif of the polymerase active site, a region that was previously identified as susceptible to resistance mutations in coronaviruses. Our data suggest that molecular surveillance of this region of the polymerase in remdesivir-treated COVID-19 patients is also warranted.
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Affiliation(s)
- Michael K Lo
- Viral Special Pathogens Branch, US Centers for Disease Control and Prevention, Atlanta, GA 30329;
| | - César G Albariño
- Viral Special Pathogens Branch, US Centers for Disease Control and Prevention, Atlanta, GA 30329
| | | | | | - Egor P Tchesnokov
- Department of Medical Microbiology and Immunology, University of Alberta, Edmonton, AB T6G 2E1, Canada
- Li Ka Shing Institute of Virology, University of Alberta, Edmonton, AB T6G 2E1, Canada
| | - Lisa Guerrero
- Viral Special Pathogens Branch, US Centers for Disease Control and Prevention, Atlanta, GA 30329
| | - Ayan Chakrabarti
- Viral Special Pathogens Branch, US Centers for Disease Control and Prevention, Atlanta, GA 30329
| | - Punya Shrivastava-Ranjan
- Viral Special Pathogens Branch, US Centers for Disease Control and Prevention, Atlanta, GA 30329
| | - Payel Chatterjee
- Viral Special Pathogens Branch, US Centers for Disease Control and Prevention, Atlanta, GA 30329
| | - Laura K McMullan
- Viral Special Pathogens Branch, US Centers for Disease Control and Prevention, Atlanta, GA 30329
| | | | | | - Matthias Götte
- Department of Medical Microbiology and Immunology, University of Alberta, Edmonton, AB T6G 2E1, Canada
- Li Ka Shing Institute of Virology, University of Alberta, Edmonton, AB T6G 2E1, Canada
| | - Joel M Montgomery
- Viral Special Pathogens Branch, US Centers for Disease Control and Prevention, Atlanta, GA 30329
| | - Stuart T Nichol
- Viral Special Pathogens Branch, US Centers for Disease Control and Prevention, Atlanta, GA 30329
| | - Mike Flint
- Viral Special Pathogens Branch, US Centers for Disease Control and Prevention, Atlanta, GA 30329
| | | | - Christina F Spiropoulou
- Viral Special Pathogens Branch, US Centers for Disease Control and Prevention, Atlanta, GA 30329;
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To B or Not to B: Mechanisms of Protection Conferred by rVSV-EBOV-GP and the Roles of Innate and Adaptive Immunity. Microorganisms 2020; 8:microorganisms8101473. [PMID: 32992829 PMCID: PMC7600878 DOI: 10.3390/microorganisms8101473] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2020] [Revised: 09/22/2020] [Accepted: 09/23/2020] [Indexed: 12/28/2022] Open
Abstract
Zaire Ebola virus (EBOV) is a member of the Filoviridae family of negative sense, single-stranded RNA viruses. EBOV infection causes Ebola virus disease (EVD), characterized by coagulopathy, lymphopenia, and multi-organ failure, which can culminate in death. In 2019, the FDA approved the first vaccine against EBOV, a recombinant live-attenuated viral vector wherein the G protein of vesicular stomatitis virus is replaced with the glycoprotein (GP) of EBOV (rVSV-EBOV-GP, Ervebo® by Merck). This vaccine demonstrates high efficacy in nonhuman primates by providing prophylactic, rapid, and post-exposure protection. In humans, rVSV-EBOV-GP demonstrated 100% protection in several phase III clinical trials in over 10,000 individuals during the 2013–2016 West Africa epidemic. As of 2020, over 218,000 doses of rVSV-EBOV-GP have been administered to individuals with high risk of EBOV exposure. Despite licensure and robust preclinical studies, the mechanisms of rVSV-EBOV-GP-mediated protection are not fully understood. Such knowledge is crucial for understanding vaccine-mediated correlates of protection from EVD and to aid the further design and development of therapeutics against filoviruses. Here, we summarize the current literature regarding the host response to vaccination and EBOV exposure, and evidence regarding innate and adaptive immune mechanisms involved in rVSV-EBOV-GP-mediated protection, with a focus on the host transcriptional response. Current data strongly suggest a protective synergy between rapid innate and humoral immunity.
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