Human polyclonal immunoglobulin G from transchromosomic bovines inhibits MERS-CoV in vivo.

Abstract

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 MERS-CoV infection and/or other emerging infectious diseases.

• Authors: Thomas Luke, Hua Wu, Jincun Zhao, Rudragouda Channappanavar, Christopher M Coleman, Jin-An Jiao, Hiroaki Matsushita, Ye Liu, Elena N Postnikova, Britini L Ork, Gregory Glenn, David Flyer, Gabriel Defang, Kanakatte Raviprakash, Tadeusz Kochel, Jonathan Wang, Wensheng Nie, Gale Smith, Lisa E Hensley, Gene G Olinger, Jens H Kuhn, Michael R Holbrook, Reed F Johnson, Stanley Perlman, Eddie Sullivan, Matthew B Frieman
• Journal: Science translational medicine (Sci Transl Med) Vol. 8 Issue 326 Pg. 326ra21 (Feb 17 2016) ISSN: 1946-6242 [Electronic] United States
• PMID: 26888429 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, N.I.H., Intramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2016, American Association for the Advancement of Science.

Chemical References

• Antibodies, Neutralizing
• Immunoglobulin G
• RNA, Messenger
• DPP4 protein, human
• Dipeptidyl Peptidase 4

Topics

• Animals
• Antibodies, Neutralizing (immunology)
• Antibody-Dependent Enhancement
• Cattle
• Chromosomes, Mammalian (genetics)
• Dipeptidyl Peptidase 4 (metabolism)
• Enzyme-Linked Immunosorbent Assay
• Humans
• Immunoglobulin G (immunology)
• Mice, Inbred BALB C
• Middle East Respiratory Syndrome Coronavirus (genetics, immunology, physiology)
• Neutralization Tests
• RNA, Messenger (genetics, metabolism)
• Transduction, Genetic
• Vaccination
• Virus Replication