TY - JOUR
T1 - Human polyclonal immunoglobulin G from transchromosomic bovines inhibits MERS-CoV in vivo
AU - Luke, Thomas
AU - Wu, Hua
AU - Zhao, Jincun
AU - Channappanavar, Rudragouda
AU - Coleman, Christopher M.
AU - Jiao, Jin An
AU - Matsushita, Hiroaki
AU - Liu, Ye
AU - Postnikova, Elena N.
AU - Ork, Britini L.
AU - Glenn, Gregory
AU - Flyer, David
AU - Defang, Gabriel
AU - Raviprakash, Kanakatte
AU - Kochel, Tadeusz
AU - Wang, Jonathan
AU - Nie, Wensheng
AU - Smith, Gale
AU - Hensley, Lisa E.
AU - Olinger, Gene G.
AU - Kuhn, Jens H.
AU - Holbrook, Michael R.
AU - Johnson, Reed F.
AU - Perlman, Stanley
AU - Sullivan, Eddie
AU - Frieman, Matthew B.
N1 - Funding Information:
The views expressed in this article are those of the authors and do not necessarily reflect the official policy or position of the Department of the Navy, Department of Defense, Department of Health and Human Services, or of the institutions and companies affiliated with the authors. Some of the authors are employees of the U.S. Government, and this work was prepared as part of their official duties. Title 17 United States Code (U.S.C.) s105 provides that "Copyright protection under this title is not available for any work of the United States Government." Title 17 U.S.C. s101 defines a U.S. Government work as a work prepared by a military service member or employee of the U.S. Government as part of that person''s official duties. The Jordan-N3/2012 strain (GenBank KC776174.1) of MERS-CoV was isolated and provided by G. Defang (Naval Medical Research Unit-3, Ca7iro, Egypt) (39). The clinical sample from which the MERS-CoV Jordan-N3/2012 strain was isolated was provided by T. Al-Sanouri and A. Haddadin (Jordan Ministry of Health). The EMC/2012 strain (passage 8) of MERS-CoV was provided by B. Haagmans and R. Fouchier (Erasmus Medical Center). This research used methods and materials from U.S. patents (7074983, 7803981, 7491867, and 7928285) and applications (14/056517, 14/416870, and 13/510327). We thank L. Bollinger and J. Wada from the Integrated Research Facility for critically editing this manuscript and figure preparation, respectively. We thank C. Olsen for statistical assistance. Funding: This work was supported in part by the Global Emerging Infections Surveillance Response System (GEIS) funds work unit #847705.82000.25GB.E0018. This project has been funded in part by a supplement to NIH RO1 AI095569 (M.B.F.), PO1 AI060699, and RO1 AI091322 (S.P.). The work was supported in part by the Division of Intramural Research of the National Institute of Allergy and Infectious Diseases (NIAID), the Integrated Research Facility (NIAID, Division of Clinical Research), and Battelle Memorial Institute''s prime contract with NIAID (contract HHSN272200700016I). B.L.O. andM.R.H. performed this work as employees of Battelle Memorial Institute. Subcontractors to Battelle Memorial Institute who performed this work are as follows: J.H.K. and E.N.P., as employees of Tunnell Government Services Inc., and G.G.O., as an employee of MRIGlobal. This project was supported in part by the Viral and Rickettsial Diseases Department of the Naval Medical Research Center and The Henry Jackson Foundation for the Advancement of Military Medicine contract with the U.S. Navy (contract Omnibus III DO-0005). Author contributions: T.L., S.P., E.S., M.B.F., and L.E.H.: study conception and design. T.L., H.W., J.-A.J., H.M., J.Z., R.C., C.M.C., B.L.O., Y.L., E.N.P., L.E.H., G.G.O., J.H.K., G.G., D.F., G.D., K.R., T.K., J.W., W.N., G.S., M.R.H., R.F.J., S.P., E.S., and M.B.F.: acquisition of data, analytical plan, and drafting the manuscript. T.L., L.E.H., G.G.O., S.P., E.S., and M.B.F.: critical revision of the manuscript for important intellectual content. H.W., J.-A.J., H.M., and E.S.: Tc bovine vaccination, plasma collection, TC hIgG production, and ELISA conception and development. J.Z., R.C., and S.P.: Ad5-DPP4 model conception and development. C.M.C., B.L.O., and M.B.F.: PRNT and ADE conception and development. J.W., G.G., D.F., W.N., G.S., C.M.C., M.B.F., and Y.L.: SPNV conception and development. E.N.P., L.E.H., G.G.O., J.H.K., M.R.H., and R.F.J.: FRNA conception and development. T.L., G.D., K.R., T.K., L.E.H., and R.F.J.: Jordan strain acquisition and characterization. T.K., K.R., and T.L.:WKVV conception and development. Competing interests: H.M. is a patent holder on the Tc bovine, and E.S., H.W., J.-A.J., and H.M. have an equity interest in SAB Biotherapeutics. Data and materials availability: Jordan-N3/2012 MERS-CoV strain (GenBank KC776174.1) is available on request.
Publisher Copyright:
Copyright 2016 by the American Association for the Advancement of Science; all rights reserved.
PY - 2016/2/17
Y1 - 2016/2/17
N2 - As of 13 November 2015, 1618 laboratory-confirmed human cases of Middle East respiratory syndrome coronavirus (MERS-CoV) infection, including 579 deaths, had been reported to the World Health Organization. No specific preventive or therapeutic agent of proven value against MERS-CoV is currently available. Public Health England and the International Severe Acute Respiratory and Emerging Infection Consortium identified passive immunotherapy with neutralizing antibodies as a treatment approach that warrants priority study. Two experimental MERS-CoV vaccines were used to vaccinate two groups of transchromosomic (Tc) bovines that were genetically modified to produce large quantities of fully human polyclonal immunoglobulin G (IgG) antibodies. Vaccination with a clade A γ-irradiated whole killed virion vaccine (Jordan strain) or a clade B spike protein nanoparticle vaccine (Al-Hasa strain) resulted in Tc bovine sera with high enzyme-linked immunosorbent assay (ELISA) and neutralizing antibody titers in vitro. Two purified Tc bovine human IgG immunoglobulins (Tc hIgG), SAB-300 (produced after Jordan strain vaccination) and SAB-301 (produced after Al-Hasa strain vaccination), also had high ELISA and neutralizing antibody titers without antibody- dependent enhancement in vitro. SAB-301 was selected for in vivo and preclinical studies. Administration of single doses of SAB-301 12 hours before or 24 and 48 hours after MERS-CoV infection (Erasmus Medical Center 2012 strain) of Ad5-hDPP4 receptor-transduced mice rapidly resulted in viral lung titers near or below the limit of detection. Tc bovines, combined with the ability to quickly produce Tc hIgG and develop in vitro assays and animal model(s), potentially offer a platform to rapidly produce a therapeutic to prevent and/or treat MERSCoV infection and/or other emerging infectious diseases.
AB - As of 13 November 2015, 1618 laboratory-confirmed human cases of Middle East respiratory syndrome coronavirus (MERS-CoV) infection, including 579 deaths, had been reported to the World Health Organization. No specific preventive or therapeutic agent of proven value against MERS-CoV is currently available. Public Health England and the International Severe Acute Respiratory and Emerging Infection Consortium identified passive immunotherapy with neutralizing antibodies as a treatment approach that warrants priority study. Two experimental MERS-CoV vaccines were used to vaccinate two groups of transchromosomic (Tc) bovines that were genetically modified to produce large quantities of fully human polyclonal immunoglobulin G (IgG) antibodies. Vaccination with a clade A γ-irradiated whole killed virion vaccine (Jordan strain) or a clade B spike protein nanoparticle vaccine (Al-Hasa strain) resulted in Tc bovine sera with high enzyme-linked immunosorbent assay (ELISA) and neutralizing antibody titers in vitro. Two purified Tc bovine human IgG immunoglobulins (Tc hIgG), SAB-300 (produced after Jordan strain vaccination) and SAB-301 (produced after Al-Hasa strain vaccination), also had high ELISA and neutralizing antibody titers without antibody- dependent enhancement in vitro. SAB-301 was selected for in vivo and preclinical studies. Administration of single doses of SAB-301 12 hours before or 24 and 48 hours after MERS-CoV infection (Erasmus Medical Center 2012 strain) of Ad5-hDPP4 receptor-transduced mice rapidly resulted in viral lung titers near or below the limit of detection. Tc bovines, combined with the ability to quickly produce Tc hIgG and develop in vitro assays and animal model(s), potentially offer a platform to rapidly produce a therapeutic to prevent and/or treat MERSCoV infection and/or other emerging infectious diseases.
UR - http://www.scopus.com/inward/record.url?scp=84973153410&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84973153410&partnerID=8YFLogxK
U2 - 10.1126/scitranslmed.aaf1061
DO - 10.1126/scitranslmed.aaf1061
M3 - Article
C2 - 26888429
AN - SCOPUS:84973153410
SN - 1946-6234
VL - 8
JO - Science translational medicine
JF - Science translational medicine
IS - 326
M1 - 326ra21
ER -