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Equine hyperimmune globulin raised against the SARS-CoV-2 spike glycoprotein has extremely high neutralizing titers

Luis Eduardo R. Cunha, Adilson A. Stolet, View ORCID ProfileMarcelo A. Strauch, View ORCID ProfileVictor A. R. Pereira, Carlos H. Dumard, Patrícia N. C. Souza, Juliana G. Fonseca, Francisco E. Pontes, Leonardo G. R. Meirelles, José W. M. Albuquerque, Carolina Q. Sacramento, Natalia Fintelman-Rodrigues, Tulio M. Lima, Renata G. F. Alvim, View ORCID ProfileRussolina B. Zingali, Guilherme A. P. Oliveira, View ORCID ProfileThiago M. L. Souza, Amilcar Tanuri, View ORCID ProfileAndre M. O. Gomes, View ORCID ProfileAndréa C. Oliveira, View ORCID ProfileHerbert L. M. Guedes, View ORCID ProfileLeda R. Castilho, View ORCID ProfileJerson L. Silva
doi: https://doi.org/10.1101/2020.08.17.254375
Luis Eduardo R. Cunha
1Vital Brazil Institute, Niterói, RJ, 24230-410, Brazil
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Adilson A. Stolet
1Vital Brazil Institute, Niterói, RJ, 24230-410, Brazil
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  • For correspondence: jerson@bioqmed.ufrj.br leda@peq.coppe.ufrj.br adilsonstolet.ivb@gmail.com
Marcelo A. Strauch
1Vital Brazil Institute, Niterói, RJ, 24230-410, Brazil
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Victor A. R. Pereira
2Institute of Medical Biochemistry Leopoldo de Meis, National Center of Nuclear Magnetic Resonance Jiri Jonas, Federal University of Rio de Janeiro (UFRJ), Rio de Janeiro, RJ, 21941-901, Brazil
3National Institute of Science and Technology for Structural Biology and Bioimaging, Federal University of Rio de Janeiro (UFRJ), Rio de Janeiro, RJ, 21941-901, Brazil
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Carlos H. Dumard
2Institute of Medical Biochemistry Leopoldo de Meis, National Center of Nuclear Magnetic Resonance Jiri Jonas, Federal University of Rio de Janeiro (UFRJ), Rio de Janeiro, RJ, 21941-901, Brazil
3National Institute of Science and Technology for Structural Biology and Bioimaging, Federal University of Rio de Janeiro (UFRJ), Rio de Janeiro, RJ, 21941-901, Brazil
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Patrícia N. C. Souza
1Vital Brazil Institute, Niterói, RJ, 24230-410, Brazil
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Juliana G. Fonseca
1Vital Brazil Institute, Niterói, RJ, 24230-410, Brazil
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Francisco E. Pontes
1Vital Brazil Institute, Niterói, RJ, 24230-410, Brazil
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Leonardo G. R. Meirelles
1Vital Brazil Institute, Niterói, RJ, 24230-410, Brazil
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José W. M. Albuquerque
1Vital Brazil Institute, Niterói, RJ, 24230-410, Brazil
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Carolina Q. Sacramento
4Immunopharmacology Laboratory, Oswaldo Cruz Institute, Oswaldo Cruz Foundation (Fiocruz), Rio de Janeiro, RJ, 21040-900, Brazil
5National Institute for Science and Technology on Innovation in Diseases of Neglected Populations (INCT/IDPN), Center for Technological Development in Health (CDTS), Fiocruz, Rio de Janeiro, RJ, 21040-900, Brazil
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Natalia Fintelman-Rodrigues
4Immunopharmacology Laboratory, Oswaldo Cruz Institute, Oswaldo Cruz Foundation (Fiocruz), Rio de Janeiro, RJ, 21040-900, Brazil
5National Institute for Science and Technology on Innovation in Diseases of Neglected Populations (INCT/IDPN), Center for Technological Development in Health (CDTS), Fiocruz, Rio de Janeiro, RJ, 21040-900, Brazil
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Tulio M. Lima
6Cell Culture Engineering Lab., COPPE, Federal University of Rio de Janeiro (UFRJ), Rio de Janeiro, RJ, 21941-598, Brazil
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Renata G. F. Alvim
6Cell Culture Engineering Lab., COPPE, Federal University of Rio de Janeiro (UFRJ), Rio de Janeiro, RJ, 21941-598, Brazil
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Russolina B. Zingali
2Institute of Medical Biochemistry Leopoldo de Meis, National Center of Nuclear Magnetic Resonance Jiri Jonas, Federal University of Rio de Janeiro (UFRJ), Rio de Janeiro, RJ, 21941-901, Brazil
3National Institute of Science and Technology for Structural Biology and Bioimaging, Federal University of Rio de Janeiro (UFRJ), Rio de Janeiro, RJ, 21941-901, Brazil
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Guilherme A. P. Oliveira
2Institute of Medical Biochemistry Leopoldo de Meis, National Center of Nuclear Magnetic Resonance Jiri Jonas, Federal University of Rio de Janeiro (UFRJ), Rio de Janeiro, RJ, 21941-901, Brazil
3National Institute of Science and Technology for Structural Biology and Bioimaging, Federal University of Rio de Janeiro (UFRJ), Rio de Janeiro, RJ, 21941-901, Brazil
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Thiago M. L. Souza
4Immunopharmacology Laboratory, Oswaldo Cruz Institute, Oswaldo Cruz Foundation (Fiocruz), Rio de Janeiro, RJ, 21040-900, Brazil
5National Institute for Science and Technology on Innovation in Diseases of Neglected Populations (INCT/IDPN), Center for Technological Development in Health (CDTS), Fiocruz, Rio de Janeiro, RJ, 21040-900, Brazil
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Amilcar Tanuri
3National Institute of Science and Technology for Structural Biology and Bioimaging, Federal University of Rio de Janeiro (UFRJ), Rio de Janeiro, RJ, 21941-901, Brazil
7Institute of Biology, Federal University of Rio de Janeiro (UFRJ), Rio de Janeiro, RJ, 21941-901, Brazil
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Andre M. O. Gomes
2Institute of Medical Biochemistry Leopoldo de Meis, National Center of Nuclear Magnetic Resonance Jiri Jonas, Federal University of Rio de Janeiro (UFRJ), Rio de Janeiro, RJ, 21941-901, Brazil
3National Institute of Science and Technology for Structural Biology and Bioimaging, Federal University of Rio de Janeiro (UFRJ), Rio de Janeiro, RJ, 21941-901, Brazil
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Andréa C. Oliveira
2Institute of Medical Biochemistry Leopoldo de Meis, National Center of Nuclear Magnetic Resonance Jiri Jonas, Federal University of Rio de Janeiro (UFRJ), Rio de Janeiro, RJ, 21941-901, Brazil
3National Institute of Science and Technology for Structural Biology and Bioimaging, Federal University of Rio de Janeiro (UFRJ), Rio de Janeiro, RJ, 21941-901, Brazil
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Herbert L. M. Guedes
8Immunopharmacology Lab, Carlos Chagas Filho Institute of Biophysics, Federal University of Rio de Janeiro (UFRJ), Rio de Janeiro, RJ, 21941-902, Brazil
9Duque de Caxias Campus, Federal University of Rio de Janeiro (UFRJ), Duque de Caxias, RJ, 25245-390, Brazil
10Institute of Microbiology Paulo de Goes, Federal University of Rio de Janeiro (UFRJ), Rio de Janeiro, RJ, 21941-902, Brazil
11Interdisciplinary Medical Research Laboratory, Oswaldo Cruz Institute, Oswaldo Cruz Foundation (Fiocruz), 21040-900, Rio de Janeiro, RJ, Brazil
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Leda R. Castilho
6Cell Culture Engineering Lab., COPPE, Federal University of Rio de Janeiro (UFRJ), Rio de Janeiro, RJ, 21941-598, Brazil
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  • For correspondence: jerson@bioqmed.ufrj.br leda@peq.coppe.ufrj.br adilsonstolet.ivb@gmail.com
Jerson L. Silva
2Institute of Medical Biochemistry Leopoldo de Meis, National Center of Nuclear Magnetic Resonance Jiri Jonas, Federal University of Rio de Janeiro (UFRJ), Rio de Janeiro, RJ, 21941-901, Brazil
3National Institute of Science and Technology for Structural Biology and Bioimaging, Federal University of Rio de Janeiro (UFRJ), Rio de Janeiro, RJ, 21941-901, Brazil
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  • For correspondence: jerson@bioqmed.ufrj.br leda@peq.coppe.ufrj.br adilsonstolet.ivb@gmail.com
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Abstract

COVID-19 pandemic caused approximately 750,000 deaths and over 20 million confirmed cases of infection by SARS-CoV-2 within 8 months since the emergence of the virus. While there are no vaccines approved and considering the difficulty in meeting the large vaccination demand worldwide, the potential use of passive immunization should be considered based on existing successful therapies against many diseases. Here we demonstrate that hyperimmune globulin preparations raised in horses against the recombinant trimeric spike (S) glycoprotein of SARS-CoV-2 in the prefusion conformation provide very high ELISA titers as well as highly potent neutralizing activity against SARS-CoV-2. Five horses were subcutaneously inoculated for 6 weeks with the recombinant S protein (ectodomain, residues 1-1208). Four out of the 5 horses presented a strong immune response. Considering the average of all 5 horses, ELISA titers above 1:1,000,000 and neutralizing titers (PRNT90) reaching 1:14,604 were observed. When compared with the plasma of three convalescent COVID-19 patients, sera of immunized horses displayed approximately 140-fold higher neutralizing titers measured as PRNT90. To prevent eventual side effects caused by horse antiserum, IgG was digested with pepsin and purified by fractional salt precipitation to eliminate Fc fragments, a process that is industrially used for the production of passive immunization F(ab’)2 concentrates against rabies, tetanus and snake venoms. The high neutralizing titers against SARS-CoV-2 obtained for the unprocessed sera were confirmed for the F(ab’)2 fragments and were 150-fold higher than the PRNT90 neutralizing titers of plasma of three COVID-19 convalescent patients. The great advantage of using the recombinant trimeric S glycoprotein is that it is safe and provides quick adaptive immunity in horses. Our data show the perspective of using hyperimmune anti-SARS-CoV-2 F(ab’)2 preparations as a passive immunization therapy in humans, similar to therapies that have been safely used for decades against rabies, tetanus and snake venoms.

Competing Interest Statement

The authors have declared no competing interest.

Footnotes

  • We have revised the spelling in the methodology (mL); Supplemental Figure 1 included.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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Posted August 21, 2020.
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Equine hyperimmune globulin raised against the SARS-CoV-2 spike glycoprotein has extremely high neutralizing titers
Luis Eduardo R. Cunha, Adilson A. Stolet, Marcelo A. Strauch, Victor A. R. Pereira, Carlos H. Dumard, Patrícia N. C. Souza, Juliana G. Fonseca, Francisco E. Pontes, Leonardo G. R. Meirelles, José W. M. Albuquerque, Carolina Q. Sacramento, Natalia Fintelman-Rodrigues, Tulio M. Lima, Renata G. F. Alvim, Russolina B. Zingali, Guilherme A. P. Oliveira, Thiago M. L. Souza, Amilcar Tanuri, Andre M. O. Gomes, Andréa C. Oliveira, Herbert L. M. Guedes, Leda R. Castilho, Jerson L. Silva
bioRxiv 2020.08.17.254375; doi: https://doi.org/10.1101/2020.08.17.254375
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Equine hyperimmune globulin raised against the SARS-CoV-2 spike glycoprotein has extremely high neutralizing titers
Luis Eduardo R. Cunha, Adilson A. Stolet, Marcelo A. Strauch, Victor A. R. Pereira, Carlos H. Dumard, Patrícia N. C. Souza, Juliana G. Fonseca, Francisco E. Pontes, Leonardo G. R. Meirelles, José W. M. Albuquerque, Carolina Q. Sacramento, Natalia Fintelman-Rodrigues, Tulio M. Lima, Renata G. F. Alvim, Russolina B. Zingali, Guilherme A. P. Oliveira, Thiago M. L. Souza, Amilcar Tanuri, Andre M. O. Gomes, Andréa C. Oliveira, Herbert L. M. Guedes, Leda R. Castilho, Jerson L. Silva
bioRxiv 2020.08.17.254375; doi: https://doi.org/10.1101/2020.08.17.254375

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