OmniVira

Adaptation of SARS-CoV-2 in BALB/c mice for testing vaccine efficacy.

Hongjing Gu1 Qi Chen1 Guan Yang2 Lei He1 Hang Fan1 Yong-Qiang Deng1 Yanxiao Wang2 Yue Teng1 Zhongpeng Zhao1 Yujun Cui1 Yuchang Li1 Xiao-Feng Li1 Jiangfan Li1 Na-Na Zhang1 Xiaolan Yang1 Shaolong Chen1 Yan Guo1 Guangyu Zhao1 Xiliang Wang1 De-Yan Luo1 Hui Wang1 Xiao Yang2 Yan Li3 Gencheng Han3 Yuxian He4 Xiaojun Zhou5 Shusheng Geng6 Xiaoli Sheng6 Shibo Jiang7 Shihui Sun8 Cheng-Feng Qin8 Yusen Zhou1
Affiliations 8 institutions
  1. State Key Laboratory of Pathogen and Biosecurity, Beijing Institute of Microbiology and Epidemiology, Academy of Military Medical Sciences, Beijing 100071, China.
  2. State Key Laboratory of Proteomics, Beijing Proteome Research Center, National Center for Protein Sciences (Beijing), Beijing Institute of Lifeomics, Beijing 102206, China.
  3. Institute of Military Cognition and Brain Sciences, Beijing 100850, China.
  4. Institute of Pathogen Biology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China.
  5. Laboratory Animal Center, Academy of Military Medical Sciences, Beijing 100071, China.
  6. Beijing JOINN Biologics Co., Beijing 100176, China.
  7. Key Laboratory of Medical Molecular Virology (MOE/NHC/CAMS), School of Basic Medical Sciences, Fudan University, Shanghai 200032, China. [email protected] [email protected] [email protected].
  8. State Key Laboratory of Pathogen and Biosecurity, Beijing Institute of Microbiology and Epidemiology, Academy of Military Medical Sciences, Beijing 100071, China. [email protected] [email protected] [email protected].
PMID32732280 DOI10.1126/science.abc4730 Year2020 Journal Science (New York, N.Y.) Science Languageeng Statusppublish

Abstract

The ongoing coronavirus disease 2019 (COVID-19) pandemic has prioritized the development of small-animal models for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). We adapted a clinical isolate of SARS-CoV-2 by serial passaging in the respiratory tract of aged BALB/c mice. The resulting mouse-adapted strain at passage 6 (called MASCp6) showed increased infectivity in mouse lung and led to interstitial pneumonia and inflammatory responses in both young and aged mice after intranasal inoculation. Deep sequencing revealed a panel of adaptive mutations potentially associated with the increased virulence. In particular, the N501Y mutation is located at the receptor binding domain (RBD) of the spike protein. The protective efficacy of a recombinant RBD vaccine candidate was validated by using this model. Thus, this mouse-adapted strain and associated challenge model should be of value in evaluating vaccines and antivirals against SARS-CoV-2.

Supporting text Virus Host Location
Disease Models, Animal 77 Mice 253 Administration, Intranasal 2 Angiotensin-Converting Enzyme 2 177 Animals 1948 Betacoronavirus 78 Coronavirus Infections 171 COVID-19 425 COVID-19 Vaccines 11 Female 289 High-Throughput Nucleotide Sequencing 39 Humans 1440 Immunogenicity, Vaccine 1 Lung 65 Lung Diseases, Interstitial 2 Mice, Inbred BALB C 73 Mice, Transgenic 13 Mutation 209 Pandemics 108 Peptidyl-Dipeptidase A 57 Pneumonia, Viral 42 SARS-CoV-2 453 Spike Glycoprotein, Coronavirus 274 Vaccines, Synthetic 2

Evidence records

3 total
Experimental Infection
2 records · 2 evidence types
Evidence type Pathogenicity Experiment
1 records
OVE3999 Pathogenicity Experiment
Key finding

Mouse-adapted SARS-CoV-2 strain MASCp6 caused interstitial pneumonia and inflammatory responses in young and aged mice after intranasal inoculation.

Virus
Severe acute respiratory syndrome coronavirus 2
Host
house mouse Mus musculus Experimental system
Location
Not specified
Supporting text

The resulting mouse-adapted strain at passage 6 (called MASCp6) showed increased infectivity in mouse lung and led to interstitial pneumonia and inflammatory responses in both young and aged mice after intranasal inoculation.

Method
serial passaging in the respiratory tract of aged BALB/c mice | intranasal inoculation
Experimental system
intranasal inoculation of young and aged mice with a mouse-adapted SARS-CoV-2 strain
Evidence type Host Range Experiment
1 records
OVE4001 Host Range Experiment
Key finding

Serial passaging of a clinical SARS-CoV-2 isolate in BALB/c mice produced a mouse-adapted strain (MASCp6) that replicated efficiently in mouse lung, demonstrating experimental infection and host-range adaptation.

Virus
Severe acute respiratory syndrome coronavirus 2
Host
house mouse Mus musculus Experimental system human Homo sapiens Natural host
Location
Not specified
Supporting text

We adapted a clinical isolate of SARS-CoV-2 by serial passaging in the respiratory tract of aged BALB/c mice. The resulting mouse-adapted strain at passage 6 (called MASCp6) showed increased infectivity in mouse lung.

Method
serial passaging | intranasal inoculation | infection assay | lung infectivity assessment
Sample type
lung tissue
Experimental system
in vivo mouse challenge model using serial passaging and intranasal infection
Functional Mechanism
1 records · 1 evidence types
Evidence type Molecular Adaptation
1 records
OVE4000 Molecular Adaptation
Key finding

The N501Y mutation in the spike receptor binding domain of SARS-CoV-2 strain MASCp6 was identified as an adaptive mutation potentially associated with increased virulence in mice.

Virus
Severe acute respiratory syndrome coronavirus 2
Host
Not specified
Location
Not specified
Supporting text

The resulting mouse-adapted strain at passage 6 (called MASCp6) showed increased infectivity in mouse lung and led to interstitial pneumonia and inflammatory responses in both young and aged mice after intranasal inoculation. Deep sequencing revealed a panel of adaptive mutations potentially associated with the increased virulence. In particular, the N501Y mutation is located at the receptor binding domain (RBD) of the spike protein.

Genes or proteins
spike protein | receptor binding domain (RBD)
Mutations
N501Y
Mechanism types
receptor binding | virulence adaptation | host-range expansion