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Neutralizing antibody-dependent and -independent immune responses against SARS-CoV-2 in cynomolgus macaques

Hirohito Ishigaki, Misako Nakayama, Yoshinori Kitagawa, Cong Thanh Nguyen, Kaori Hayashi, Masanori Shiohara, Bin Gotoh, View ORCID ProfileYasushi Itoh
doi: https://doi.org/10.1101/2020.08.18.256446
Hirohito Ishigaki
1Division of Pathogenesis and Disease Regulation, Department of Pathology, Shiga University of Medical Science, Otsu, Japan
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Misako Nakayama
1Division of Pathogenesis and Disease Regulation, Department of Pathology, Shiga University of Medical Science, Otsu, Japan
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Yoshinori Kitagawa
2Division of Microbiology and Infectious Diseases, Department of Pathology, Shiga University of Medical Science, Otsu, Japan
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Cong Thanh Nguyen
1Division of Pathogenesis and Disease Regulation, Department of Pathology, Shiga University of Medical Science, Otsu, Japan
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Kaori Hayashi
1Division of Pathogenesis and Disease Regulation, Department of Pathology, Shiga University of Medical Science, Otsu, Japan
3Department of Obstetrics and Gynecology, Shiga University of Medical Science, Otsu, Japan
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Masanori Shiohara
1Division of Pathogenesis and Disease Regulation, Department of Pathology, Shiga University of Medical Science, Otsu, Japan
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Bin Gotoh
2Division of Microbiology and Infectious Diseases, Department of Pathology, Shiga University of Medical Science, Otsu, Japan
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Yasushi Itoh
1Division of Pathogenesis and Disease Regulation, Department of Pathology, Shiga University of Medical Science, Otsu, Japan
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  • ORCID record for Yasushi Itoh
  • For correspondence: yasushii@belle.shiga-med.ac.jp
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Abstract

Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infectious disease (COVID-19) has been threatening the world because of severe symptoms and relatively high mortality. To develop vaccines and antiviral drugs for COVID-19, an animal model of SARS-CoV-2 infection is required to evaluate the efficacy of prophylactics and therapeutics in vivo. Therefore, we examined the pathogenicity of SARS-CoV-2 in cynomolgus macaques until 28 days after virus inoculation in the present study. Cynomolgus macaques showed body temperature rises after infection and X-ray radiographic viral pneumonia was observed in one of three macaques. However, none of the macaques showed life-threatening clinical signs of disease corresponding that approximately 80% of human patients did not show a critical disease in COVID-19. A neutralizing antibody against SARS-CoV-2 and T-lymphocytes that produced interferon (IFN)-γ and interleukin (IL)-2 specifically for SARS-CoV-2 N protein were detected on day 14 in the macaque that showed viral pneumonia. On the other hand, in the other macaques, in which a neutralizing antibody was not detected, T-lymphocytes that produced IFN-γ specifically for SARS-CoV-2 N protein increased on day 7 to day 14 prior to an increase in the number of T-lymphocytes that produced IL-2. These results suggest that not only a neutralizing antibody but also cellular immunity augmented by IFN-γ has a role in the elimination of SARS-CoV-2. Thus, because of the mild clinical signs of disease and low/no antibody responses against SARS-CoV-2 in two thirds of the macaques, cynomolgus macaques are appropriate to extrapolate human responses in vaccine and drug development.

Author Summary Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infectious disease (COVID-19) has been threatening the world. To develop vaccines and antiviral drugs for COVID-19, an animal model of SARS-CoV-2 infection is required to evaluate their efficacy in vivo. Therefore, we examined the pathogenicity of SARS-CoV-2 in a non-human primate model until 28 days after virus inoculation. Cynomolgus macaques showed a fever after infection and X-ray radiographic viral pneumonia was observed in one of three macaques. However, none of the macaques showed life-threatening symptoms. A neutralizing antibody against SARS-CoV-2 and T-lymphocytes that produced interferon (IFN)-γ and interleukin (IL)-2 specifically for SARS-CoV-2 protein were detected on day 14 in the macaque that showed viral pneumonia. In the other macaques, in which a neutralizing antibody was not detected, T-lymphocytes that produced IFN-γ specifically for SARS-CoV-2 N protein increased on day 7 to day 14. These results suggest that not only a neutralizing antibody but also cellular immunity augmented by IFN-γ has a role in the elimination of SARS-CoV-2. Thus, because of the mild symptoms and low/no antibody responses against SARS-CoV-2 in two thirds of the macaques, cynomolgus macaques are appropriate to extrapolate human responses in vaccine and drug development.

Competing Interest Statement

The authors have declared no competing interest.

Copyright 
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Posted August 19, 2020.
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Neutralizing antibody-dependent and -independent immune responses against SARS-CoV-2 in cynomolgus macaques
Hirohito Ishigaki, Misako Nakayama, Yoshinori Kitagawa, Cong Thanh Nguyen, Kaori Hayashi, Masanori Shiohara, Bin Gotoh, Yasushi Itoh
bioRxiv 2020.08.18.256446; doi: https://doi.org/10.1101/2020.08.18.256446
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Neutralizing antibody-dependent and -independent immune responses against SARS-CoV-2 in cynomolgus macaques
Hirohito Ishigaki, Misako Nakayama, Yoshinori Kitagawa, Cong Thanh Nguyen, Kaori Hayashi, Masanori Shiohara, Bin Gotoh, Yasushi Itoh
bioRxiv 2020.08.18.256446; doi: https://doi.org/10.1101/2020.08.18.256446

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