DOE PAGES title logo U.S. Department of Energy
Office of Scientific and Technical Information

Title: Evaluation of candidate vaccine approaches for MERS-CoV

Abstract

The emergence of Middle East respiratory syndrome coronavirus (MERS-CoV) as a cause of severe respiratory disease highlights the need for effective approaches to CoV vaccine development. Efforts focused solely on the receptor-binding domain (RBD) of the viral Spike (S) glycoprotein may not optimize neutralizing antibody (NAb) responses. Here we show that immunogens based on full-length S DNA and S1 subunit protein elicit robust serum-neutralizing activity against several MERS-CoV strains in mice and non-human primates. Serological analysis and isolation of murine monoclonal antibodies revealed that immunization elicits NAbs to RBD and, non-RBD portions of S1 and S2 subunit. Multiple neutralization mechanisms were demonstrated by solving the atomic structure of a NAb-RBD complex, through sequencing of neutralization escape viruses and by constructing MERS-CoV S variants for serological assays. Immunization of rhesus macaques confers protection against MERS-CoV-induced radiographic pneumonia, as assessed using computerized tomography, supporting this strategy as a promising approach for MERS-CoV vaccine development.

Authors:
; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; more »; ; ; ; ; ; ; ; ; ; « less
Publication Date:
Research Org.:
Argonne National Lab. (ANL), Argonne, IL (United States). Advanced Photon Source (APS)
Sponsoring Org.:
USDOE Office of Science (SC), Basic Energy Sciences (BES)
OSTI Identifier:
1214709
Grant/Contract Number:  
AC02-06CH11357; W-31-109-ENG-38
Resource Type:
Accepted Manuscript
Journal Name:
Nature Communications
Additional Journal Information:
Journal Volume: 6; Journal ID: ISSN 2041-1723
Publisher:
Nature Publishing Group
Country of Publication:
United States
Language:
English
Subject:
59 BASIC BIOLOGICAL SCIENCES; 60 APPLIED LIFE SCIENCES

Citation Formats

Wang, Lingshu, Shi, Wei, Joyce, M. Gordon, Modjarrad, Kayvon, Zhang, Yi, Leung, Kwanyee, Lees, Christopher R., Zhou, Tongqing, Yassine, Hadi M., Kanekiyo, Masaru, Yang, Zhi-yong, Chen, Xuejun, Becker, Michelle M., Freeman, Megan, Vogel, Leatrice, Johnson, Joshua C., Olinger, Gene, Todd, John P., Bagci, Ulas, Solomon, Jeffrey, Mollura, Daniel J., Hensley, Lisa, Jahrling, Peter, Denison, Mark R., Rao, Srinivas S., Subbarao, Kanta, Kwong, Peter D., Mascola, John R., Kong, Wing-Pui, and Graham, Barney S. Evaluation of candidate vaccine approaches for MERS-CoV. United States: N. p., 2015. Web. doi:10.1038/ncomms8712.
Wang, Lingshu, Shi, Wei, Joyce, M. Gordon, Modjarrad, Kayvon, Zhang, Yi, Leung, Kwanyee, Lees, Christopher R., Zhou, Tongqing, Yassine, Hadi M., Kanekiyo, Masaru, Yang, Zhi-yong, Chen, Xuejun, Becker, Michelle M., Freeman, Megan, Vogel, Leatrice, Johnson, Joshua C., Olinger, Gene, Todd, John P., Bagci, Ulas, Solomon, Jeffrey, Mollura, Daniel J., Hensley, Lisa, Jahrling, Peter, Denison, Mark R., Rao, Srinivas S., Subbarao, Kanta, Kwong, Peter D., Mascola, John R., Kong, Wing-Pui, & Graham, Barney S. Evaluation of candidate vaccine approaches for MERS-CoV. United States. https://doi.org/10.1038/ncomms8712
Wang, Lingshu, Shi, Wei, Joyce, M. Gordon, Modjarrad, Kayvon, Zhang, Yi, Leung, Kwanyee, Lees, Christopher R., Zhou, Tongqing, Yassine, Hadi M., Kanekiyo, Masaru, Yang, Zhi-yong, Chen, Xuejun, Becker, Michelle M., Freeman, Megan, Vogel, Leatrice, Johnson, Joshua C., Olinger, Gene, Todd, John P., Bagci, Ulas, Solomon, Jeffrey, Mollura, Daniel J., Hensley, Lisa, Jahrling, Peter, Denison, Mark R., Rao, Srinivas S., Subbarao, Kanta, Kwong, Peter D., Mascola, John R., Kong, Wing-Pui, and Graham, Barney S. Tue . "Evaluation of candidate vaccine approaches for MERS-CoV". United States. https://doi.org/10.1038/ncomms8712. https://www.osti.gov/servlets/purl/1214709.
@article{osti_1214709,
title = {Evaluation of candidate vaccine approaches for MERS-CoV},
author = {Wang, Lingshu and Shi, Wei and Joyce, M. Gordon and Modjarrad, Kayvon and Zhang, Yi and Leung, Kwanyee and Lees, Christopher R. and Zhou, Tongqing and Yassine, Hadi M. and Kanekiyo, Masaru and Yang, Zhi-yong and Chen, Xuejun and Becker, Michelle M. and Freeman, Megan and Vogel, Leatrice and Johnson, Joshua C. and Olinger, Gene and Todd, John P. and Bagci, Ulas and Solomon, Jeffrey and Mollura, Daniel J. and Hensley, Lisa and Jahrling, Peter and Denison, Mark R. and Rao, Srinivas S. and Subbarao, Kanta and Kwong, Peter D. and Mascola, John R. and Kong, Wing-Pui and Graham, Barney S.},
abstractNote = {The emergence of Middle East respiratory syndrome coronavirus (MERS-CoV) as a cause of severe respiratory disease highlights the need for effective approaches to CoV vaccine development. Efforts focused solely on the receptor-binding domain (RBD) of the viral Spike (S) glycoprotein may not optimize neutralizing antibody (NAb) responses. Here we show that immunogens based on full-length S DNA and S1 subunit protein elicit robust serum-neutralizing activity against several MERS-CoV strains in mice and non-human primates. Serological analysis and isolation of murine monoclonal antibodies revealed that immunization elicits NAbs to RBD and, non-RBD portions of S1 and S2 subunit. Multiple neutralization mechanisms were demonstrated by solving the atomic structure of a NAb-RBD complex, through sequencing of neutralization escape viruses and by constructing MERS-CoV S variants for serological assays. Immunization of rhesus macaques confers protection against MERS-CoV-induced radiographic pneumonia, as assessed using computerized tomography, supporting this strategy as a promising approach for MERS-CoV vaccine development.},
doi = {10.1038/ncomms8712},
journal = {Nature Communications},
number = ,
volume = 6,
place = {United States},
year = {2015},
month = {7}
}

Journal Article:
Free Publicly Available Full Text
Publisher's Version of Record

Citation Metrics:
Cited by: 42 works
Citation information provided by
Web of Science

Save / Share:

Works referenced in this record:

Epidemiological, demographic, and clinical characteristics of 47 cases of Middle East respiratory syndrome coronavirus disease from Saudi Arabia: a descriptive study
journal, September 2013

  • Assiri, Abdullah; Al-Tawfiq, Jaffar A.; Al-Rabeeah, Abdullah A.
  • The Lancet Infectious Diseases, Vol. 13, Issue 9
  • DOI: 10.1016/S1473-3099(13)70204-4

Interhuman transmissibility of Middle East respiratory syndrome coronavirus: estimation of pandemic risk
journal, August 2013


Middle East respiratory syndrome coronavirus: quantification of the extent of the epidemic, surveillance biases, and transmissibility
journal, January 2014

  • Cauchemez, Simon; Fraser, Christophe; Van Kerkhove, Maria D.
  • The Lancet Infectious Diseases, Vol. 14, Issue 1
  • DOI: 10.1016/S1473-3099(13)70304-9

Human Infection with MERS Coronavirus after Exposure to Infected Camels, Saudi Arabia, 2013
journal, June 2014

  • Memish, Ziad A.; Cotten, Matthew; Meyer, Benjamin
  • Emerging Infectious Diseases, Vol. 20, Issue 6
  • DOI: 10.3201/eid2006.140402

A decade after SARS: strategies for controlling emerging coronaviruses
journal, November 2013

  • Graham, Rachel L.; Donaldson, Eric F.; Baric, Ralph S.
  • Nature Reviews Microbiology, Vol. 11, Issue 12
  • DOI: 10.1038/nrmicro3143

Coronavirus IBV: Structural Characterization of the Spike Protein
journal, December 1983


Contributions of the structural proteins of severe acute respiratory syndrome coronavirus to protective immunity
journal, June 2004

  • Buchholz, U. J.; Bukreyev, A.; Yang, L.
  • Proceedings of the National Academy of Sciences, Vol. 101, Issue 26
  • DOI: 10.1073/pnas.0403492101

Purified coronavirus spike protein nanoparticles induce coronavirus neutralizing antibodies in mice
journal, May 2014


Inhibition of Middle East Respiratory Syndrome Coronavirus Infection by Anti-CD26 Monoclonal Antibody
journal, September 2013

  • Ohnuma, K.; Haagmans, B. L.; Hatano, R.
  • Journal of Virology, Vol. 87, Issue 24
  • DOI: 10.1128/JVI.02448-13

Exceptionally Potent Neutralization of Middle East Respiratory Syndrome Coronavirus by Human Monoclonal Antibodies
journal, April 2014

  • Ying, Tianlei; Du, Lanying; Ju, Tina W.
  • Journal of Virology, Vol. 88, Issue 14
  • DOI: 10.1128/JVI.00912-14

Potent Neutralization of MERS-CoV by Human Neutralizing Monoclonal Antibodies to the Viral Spike Glycoprotein
journal, April 2014


A SARS DNA vaccine induces neutralizing antibody and cellular immune responses in healthy adults in a Phase I clinical trial
journal, November 2008


A DNA vaccine induces SARS coronavirus neutralization and protective immunity in mice
journal, April 2004

  • Yang, Zhi-yong; Kong, Wing-pui; Huang, Yue
  • Nature, Vol. 428, Issue 6982
  • DOI: 10.1038/nature02463

Efficient transfer, integration, and sustained long-term expression of the transgene in adult rat brains injected with a lentiviral vector.
journal, October 1996

  • Naldini, L.; Blomer, U.; Gage, F. H.
  • Proceedings of the National Academy of Sciences, Vol. 93, Issue 21
  • DOI: 10.1073/pnas.93.21.11382

Evasion of antibody neutralization in emerging severe acute respiratory syndrome coronaviruses
journal, January 2005

  • Yang, Z. -y.; Werner, H. C.; Kong, W. -p.
  • Proceedings of the National Academy of Sciences, Vol. 102, Issue 3
  • DOI: 10.1073/pnas.0409065102

Regulation of antibody isotype secretion by subsets of antigen-specific helper T cells
journal, July 1988

  • Stevens, Tracy L.; Bossie, Alexis; Sanders, Virginia M.
  • Nature, Vol. 334, Issue 6179
  • DOI: 10.1038/334255a0

DNA-Mediated Immunization in Mice Induces a Potent MHC Class I-Restricted Cytotoxic T Lymphocyte Response to the Hepatitis B Envelope Protein
journal, November 1995


Molecular basis of binding between novel human coronavirus MERS-CoV and its receptor CD26
journal, July 2013


Structure of Severe Acute Respiratory Syndrome Coronavirus Receptor-binding Domain Complexed with Neutralizing Antibody
journal, April 2006

  • Prabakaran, Ponraj; Gan, Jianhua; Feng, Yang
  • Journal of Biological Chemistry, Vol. 281, Issue 23
  • DOI: 10.1074/jbc.M600697200

Potent cross-reactive neutralization of SARS coronavirus isolates by human monoclonal antibodies
journal, July 2007

  • Zhu, Z.; Chakraborti, S.; He, Y.
  • Proceedings of the National Academy of Sciences, Vol. 104, Issue 29
  • DOI: 10.1073/pnas.0701000104

A Generic Approach to Pathological Lung Segmentation
journal, December 2014

  • Mansoor, Awais; Bagci, Ulas; Xu, Ziyue
  • IEEE Transactions on Medical Imaging, Vol. 33, Issue 12
  • DOI: 10.1109/TMI.2014.2337057

Rapid generation of a mouse model for Middle East respiratory syndrome
journal, March 2014

  • Zhao, Jincun; Li, Kun; Wohlford-Lenane, Christine
  • Proceedings of the National Academy of Sciences, Vol. 111, Issue 13
  • DOI: 10.1073/pnas.1323279111

The Middle East Respiratory Syndrome Coronavirus (MERS-CoV) Does Not Replicate in Syrian Hamsters
journal, July 2013


Identification of human neutralizing antibodies against MERS-CoV and their role in virus adaptive evolution
journal, April 2014

  • Tang, X. -C.; Agnihothram, S. S.; Jiao, Y.
  • Proceedings of the National Academy of Sciences, Vol. 111, Issue 19
  • DOI: 10.1073/pnas.1402074111

DNA priming and influenza vaccine immunogenicity: two phase 1 open label randomised clinical trials
journal, December 2011


Prime-Boost Interval Matters: A Randomized Phase 1 Study to Identify the Minimum Interval Necessary to Observe the H5 DNA Influenza Vaccine Priming Effect
journal, April 2013

  • Ledgerwood, Julie E.; Zephir, Kathryn; Hu, Zonghui
  • The Journal of Infectious Diseases, Vol. 208, Issue 3
  • DOI: 10.1093/infdis/jit180

Structure-Based Design of a Fusion Glycoprotein Vaccine for Respiratory Syncytial Virus
journal, October 2013


Structure of RSV Fusion Glycoprotein Trimer Bound to a Prefusion-Specific Neutralizing Antibody
journal, April 2013


Phase I clinical evaluation of a six-plasmid multiclade HIV-1 DNA candidate vaccine
journal, May 2007


A Simple Method of Estimating Fifty per cent Endpoints12
journal, May 1938


[20] Processing of X-ray diffraction data collected in oscillation mode
book, January 1997


Phaser crystallographic software
journal, July 2007

  • McCoy, Airlie J.; Grosse-Kunstleve, Ralf W.; Adams, Paul D.
  • Journal of Applied Crystallography, Vol. 40, Issue 4
  • DOI: 10.1107/S0021889807021206

Features and development of Coot
journal, March 2010

  • Emsley, P.; Lohkamp, B.; Scott, W. G.
  • Acta Crystallographica Section D Biological Crystallography, Vol. 66, Issue 4
  • DOI: 10.1107/S0907444910007493

Refinement of severely incomplete structures with maximum likelihood in BUSTER–TNT
journal, November 2004

  • Blanc, E.; Roversi, P.; Vonrhein, C.
  • Acta Crystallographica Section D Biological Crystallography, Vol. 60, Issue 12
  • DOI: 10.1107/S0907444904016427

Three-dimensional structure of an Fv from a human IgM immunoglobulin
journal, November 1992


Structural Insights into Immune Recognition of the Severe Acute Respiratory Syndrome Coronavirus S Protein Receptor Binding Domain
journal, May 2009

  • Pak, John E.; Sharon, Chetna; Satkunarajah, Malathy
  • Journal of Molecular Biology, Vol. 388, Issue 4
  • DOI: 10.1016/j.jmb.2009.03.042

PHENIX: a comprehensive Python-based system for macromolecular structure solution
journal, January 2010

  • Adams, Paul D.; Afonine, Pavel V.; Bunkóczi, Gábor
  • Acta Crystallographica Section D Biological Crystallography, Vol. 66, Issue 2, p. 213-221
  • DOI: 10.1107/S0907444909052925

MolProbity : all-atom structure validation for macromolecular crystallography
journal, December 2009

  • Chen, Vincent B.; Arendall, W. Bryan; Headd, Jeffrey J.
  • Acta Crystallographica Section D Biological Crystallography, Vol. 66, Issue 1
  • DOI: 10.1107/S0907444909042073

Reverse genetics with a full-length infectious cDNA of the Middle East respiratory syndrome coronavirus
journal, September 2013

  • Scobey, T.; Yount, B. L.; Sims, A. C.
  • Proceedings of the National Academy of Sciences, Vol. 110, Issue 40
  • DOI: 10.1073/pnas.1311542110

Exploring the gas access routes in a [NiFeSe] hydrogenase using crystals pressurized with krypton and oxygen
journal, August 2020

  • Zacarias, Sónia; Temporão, Adriana; Carpentier, Philippe
  • JBIC Journal of Biological Inorganic Chemistry, Vol. 25, Issue 6
  • DOI: 10.1007/s00775-020-01814-y

PARP1 exhibits enhanced association and catalytic efficiency with γH2A.X-nucleosome
journal, December 2019


Cavin1 intrinsically disordered domains are essential for fuzzy electrostatic interactions and caveola formation
journal, February 2021


Rapid lateral flow immunoassay for the fluorescence detection of SARS-CoV-2 RNA
journal, December 2020


Inhibitory effects of aprotinin on influenza A and B viruses in vitro and in vivo
journal, May 2021


Rapid generation of a mouse model for Middle East respiratory syndrome
text, January 2014

  • Christine, Wohlford-Lenane,; B., McCray, Paul; Jincun, Zhao,
  • The University of North Carolina at Chapel Hill University Libraries
  • DOI: 10.17615/45jv-j334

Identification of human neutralizing antibodies against MERS-CoV and their role in virus adaptive evolution
text, January 2014

  • A., Marasco, Wayne; Jared, Sheehan,; L., Graham, Rachel
  • The University of North Carolina at Chapel Hill University Libraries
  • DOI: 10.17615/7xm3-1892

Reverse genetics with a full-length infectious cDNA of the Middle East respiratory syndrome coronavirus
text, January 2013

  • Yount, Boyd L.; Menachery, Vineet D.; Graham, Rachel L.
  • The University of North Carolina at Chapel Hill University Libraries
  • DOI: 10.17615/kqa5-9507

A decade after SARS: strategies for controlling emerging coronaviruses
text, January 2013

  • Graham, Rachel L.; Donaldson, Eric F.; Baric, Ralph S.
  • Macmillan Publishers
  • DOI: 10.17615/ss8c-tg10

PHENIX: a comprehensive Python-based system for macromolecular structure solution.
text, January 2010

  • Adams, Paul D.; Afonine, Pavel V.; Bunkóczi, Gábor
  • Apollo - University of Cambridge Repository
  • DOI: 10.17863/cam.45787

Works referencing / citing this record:

Viromimetic STING Agonist‐Loaded Hollow Polymeric Nanoparticles for Safe and Effective Vaccination against Middle East Respiratory Syndrome Coronavirus
journal, April 2019

  • Lin, Leon Chien‐Wei; Huang, Chen‐Yu; Yao, Bing‐Yu
  • Advanced Functional Materials, Vol. 29, Issue 28
  • DOI: 10.1002/adfm.201807616

Production of a Monoclonal Antibody Targeting the M Protein of MERS-CoV for Detection of MERS-CoV Using a Synthetic Peptide Epitope Formulated with a CpG–DNA–Liposome Complex
journal, July 2018

  • Park, Byoung Kwon; Lee, Su In; Bae, Joon-Yong
  • International Journal of Peptide Research and Therapeutics, Vol. 25, Issue 3
  • DOI: 10.1007/s10989-018-9731-8

Cryo-EM structures of MERS-CoV and SARS-CoV spike glycoproteins reveal the dynamic receptor binding domains
journal, April 2017

  • Yuan, Yuan; Cao, Duanfang; Zhang, Yanfang
  • Nature Communications, Vol. 8, Issue 1
  • DOI: 10.1038/ncomms15092

Junctional and allele-specific residues are critical for MERS-CoV neutralization by an exceptionally potent germline-like antibody
journal, September 2015

  • Ying, Tianlei; Prabakaran, Ponraj; Du, Lanying
  • Nature Communications, Vol. 6, Issue 1
  • DOI: 10.1038/ncomms9223

A roadmap for MERS-CoV research and product development: report from a World Health Organization consultation
journal, July 2016

  • Modjarrad, Kayvon; Moorthy, Vasee S.; Ben Embarek, Peter
  • Nature Medicine, Vol. 22, Issue 7
  • DOI: 10.1038/nm.4131

Coronaviruses — drug discovery and therapeutic options
journal, February 2016

  • Zumla, Alimuddin; Chan, Jasper F. W.; Azhar, Esam I.
  • Nature Reviews Drug Discovery, Vol. 15, Issue 5
  • DOI: 10.1038/nrd.2015.37

SARS and MERS: recent insights into emerging coronaviruses
journal, June 2016

  • de Wit, Emmie; van Doremalen, Neeltje; Falzarano, Darryl
  • Nature Reviews Microbiology, Vol. 14, Issue 8
  • DOI: 10.1038/nrmicro.2016.81

Structural definition of a neutralization epitope on the N-terminal domain of MERS-CoV spike glycoprotein
journal, July 2019


Immunogenicity of Candidate MERS-CoV DNA Vaccines Based on the Spike Protein
journal, March 2017

  • Al-amri, Sawsan S.; Abbas, Ayman T.; Siddiq, Loai A.
  • Scientific Reports, Vol. 7, Issue 1
  • DOI: 10.1038/srep44875

Immunogenicity and structures of a rationally designed prefusion MERS-CoV spike antigen
journal, August 2017

  • Pallesen, Jesper; Wang, Nianshuang; Corbett, Kizzmekia S.
  • Proceedings of the National Academy of Sciences, Vol. 114, Issue 35
  • DOI: 10.1073/pnas.1707304114

MERS-CoV spike protein: a key target for antivirals
journal, December 2016


Prospects for a MERS-CoV spike vaccine
journal, August 2018


Development of Middle East Respiratory Syndrome Coronavirus vaccines – advances and challenges
journal, November 2017


Towards a solution to MERS: protective human monoclonal antibodies targeting different domains and functions of the MERS-coronavirus spike glycoprotein
journal, January 2019


An emerging coronavirus causing pneumonia outbreak in Wuhan, China: calling for developing therapeutic and prophylactic strategies
journal, January 2020


Protective Efficacy of Nucleic Acid Vaccines Against Transmission of Zika Virus During Pregnancy in Mice
journal, July 2019

  • Jagger, Brett W.; Dowd, Kimberly A.; Chen, Rita E.
  • The Journal of Infectious Diseases, Vol. 220, Issue 10
  • DOI: 10.1093/infdis/jiz338

Rapid development of a DNA vaccine for Zika virus
journal, September 2016


Comparative Serological Study for the Prevalence of Anti-MERS Coronavirus Antibodies in High- and Low-Risk Groups in Qatar
journal, February 2019

  • Al Kahlout, Reham A.; Nasrallah, Gheyath K.; Farag, Elmoubasher A.
  • Journal of Immunology Research, Vol. 2019
  • DOI: 10.1155/2019/1386740

Narrative review of Middle East respiratory syndrome coronavirus (MERS-CoV) infection: updates and implications for practice
journal, July 2019


Epitope‐based peptide vaccine design and target site depiction against Middle East Respiratory Syndrome Coronavirus: an immune-informatics study
journal, November 2019

  • Tahir ul Qamar, Muhammad; Saleem, Saman; Ashfaq, Usman Ali
  • Journal of Translational Medicine, Vol. 17, Issue 1
  • DOI: 10.1186/s12967-019-2116-8

Adjuvants and the vaccine response to the DS-Cav1-stabilized fusion glycoprotein of respiratory syncytial virus
journal, October 2017


Middle East respiratory syndrome: current status and future prospects for vaccine development
journal, July 2015


Vaccines for the prevention against the threat of MERS-CoV
journal, April 2016


Recent Advances in the Vaccine Development Against Middle East Respiratory Syndrome-Coronavirus
journal, August 2019


Subunit Vaccines Against Emerging Pathogenic Human Coronaviruses
journal, February 2020


From SARS to MERS, Thrusting Coronaviruses into the Spotlight
journal, January 2019

  • Song, Zhiqi; Xu, Yanfeng; Bao, Linlin
  • Viruses, Vol. 11, Issue 1
  • DOI: 10.3390/v11010059

Advances in MERS-CoV Vaccines and Therapeutics Based on the Receptor-Binding Domain
journal, January 2019

  • Zhou, Yusen; Yang, Yang; Huang, Jingwei
  • Viruses, Vol. 11, Issue 1
  • DOI: 10.3390/v11010060

Middle East Respiratory Syndrome Vaccine Candidates: Cautious Optimism
journal, January 2019

  • Schindewolf, Craig; Menachery, Vineet
  • Viruses, Vol. 11, Issue 1
  • DOI: 10.3390/v11010074

Efficacy of an Adjuvanted Middle East Respiratory Syndrome Coronavirus Spike Protein Vaccine in Dromedary Camels and Alpacas
journal, March 2019

  • Adney, Danielle; Wang, Lingshu; van Doremalen, Neeltje
  • Viruses, Vol. 11, Issue 3
  • DOI: 10.3390/v11030212