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Table 3 Summary of studies using mice models of COVID-19

From: Evidence of a wide gap between COVID-19 in humans and animal models: a systematic review

Species (ref)

Number age (gender)

Virus strain dose* (inoculation route)†

Clinical signs & observation duration (DPI) §

Viral replication‡ (DPI)

Pathology & sacrificing date (DPI)

Immune response

Seroconversion

(DPI)

Outcome Measures

Mice

WT-BALB/c, n = 3

2 × 105 TCID50 of P 4†† or 2 × 106 of P 6†† (IN)

NA

Lung (3)

Mild lung pathology (2)

Mild inflammatory response

NA

Interferon response to SARS-CoV-2 infection

BALB/c:

SCID, n = 3

 

(14)

No difference in viral load WT vs. SCID

No difference in lung pathology WT vs. SCID

(2, 4, 7, 14)

WT¶

 

SCID||

6–8 weeks (F)

C57BL/6:

C57BL/6 n = 5

2 × 105 TCID50 of P 4 or 2 × 106 of P 6 (IN)

NA

(14)

Lung (3)

Greater intra-alveolar hemorrhage and peribronchiolar inflammation in IFNar1−/− mice than WT and IL28r−/− mice (3)

Higher inflammatory response in IFNar1−/− vs. WT and IL28r−/− mice

NA

WT

IFNar1−/−¶¶ n = 14

Ifnar1−/−

 

Higher viral replication in IFNar1−/− mice vs. WT and IL28r−/− mice

(2, 4, 7, 14)

Il28r−/−

6–8 weeks (F)

Boudewijns et al. (2020) [56]

C57BL/6, n = 5

2 × 105 TCID50 of P 4 or 2 × 106 of P 6 (IN)

NA

(14)

Lung (3)

Mild lung pathology (3)

Mild inflammatory response

NA

IL28r−/−, n = 5

No difference in viral load between WT and IL28r−/−

(2, 4, 7, 14)

6–8 weeks (F)

Mice

hACE2 mice

SARS-CoV-2 (BetaCoV/Wuhan/IVDC-HB-01/2020|EPI_ISL_402119)

Slight

Highest viral load

Moderate interstitial pneumonia

MAC2, CD3+ T and CD19+ B cells in alveolar septum

IgG antibody response against SARS-CoV-2 (21)

Pathogenesis of COVID-19

hACE2 transgenic mice

(ACE2-HB-01)

Bristles

In lung (3)

Thickened alveolar septa

Weight loss

Intestine (1)

n = 19

105 TCID50 (IN)

Arched back

(14)

Alveolar macrophage, and alveolar epithelia (3)

Lymphocytes, macrophages, and monocytes infiltrates in the interstitial and alveolar space

6–11 months (M/F)

Bronchioles degeneration (3)

No pathology in intestine, spleen, heart, liver, kidney, brain, and testis

(1, 3, 5, 7)

Bao et al. (2020) [50]

WT-HB-01 (n = 15)

SARS-CoV-2 (BetaCoV/Wuhan/IVDC-HB-01/2020|EPI_ISL_402119)

105 TCID50 (IN)

No

(14)

No viral RNA detectable in lung or intestine (1)

No

(1, 3, 5, 7)

No

No

6–11 months (M/F)

Mock-treated hACE2 mice (n = 15)

PBS 50 μl

(IN)

No

(14)

No viral RNA detectable in lung or intestine

No

(1, 3, 5, 7)

No

No

6–11 months (M/F)

Mice

n = 5

6–8 weeks (M)

SARS-CoV-2 (BetaCoV/Hong Kong/VM20001061/2020 [KH1])

NA

NA

NA

NA

IgG antibody response against SARS-CoV and SARS-CoV-2 spike protein and RBD

Cross-reactivity of antibodies against SARS-CoV and SARS-CoV-2

Infection

SARS-CoV (HK39849, SCoV)

105 PFU (IN)

BALB/c:

n = 5

Immunization with heat-inactivated plasma from SARS-CoV and SARS-CoV-2 (IP)

NA

NA

NA

NA

Cross-reactive antibody binding responses SARS-CoV-2 and SARS-CoV

No cross-neutralization SARS-CoV-2 and SARS-CoV

WT

6–8 weeks (M)

Lv et al. (2020) [53]

Immunization

 

n = 6

Vehicle (IN)

NA

NA

NA

NA

 

6–8 weeks (M)

control

Transgenic mice

n = 7

SARS1/SARS2-RdRp §§

Improvement of pulmonary function

reduced lung viral load 102 PFU/lobe (5)

Decreased lung hemorrhage (5)

(5)

NA

NA

Antiviral therapy testing

C57BL/6***:

17 weeks (F)

103 PFU (IN)

(5)

Ces1c−/−

Remdesivir given at 1dpi

Pruijssers et al. (2020) [55]

Remdesivir

n = 7

SARS1/SARS2-RdRp

Reduced pulmonary function by WPH†††

(5)

Lung viral load

Lung hemorrhage (5)

(5)

NA

NA

17 weeks (F)

103 PFU (IN)

105 PFU/lobe (5)

Control

Vehicle

 

n = 3

Mouse-adapted SARS-CoV-2 (BetaCoV/Wuhan/AMMS01/2020)

Weight loss old mice (5)

(7)

Trachea, lung, heart, liver, and intestine, pneumocytes Type II

Thickened alveolar septa

Increased TNF-α, IL-1β, IL-6, and IL-5, MCP-1, G-CSF, and GM-CSF (3)

NA

Establishment of mouse-adapted SARSCoV-2 model of COVID19

Young, 6 weeks (F)

Alveolar damage and focal exudation

Hemorrhage,

n = 3

7.2 × 105 PFU (IN)

 

Viral replication similar in old vs. young cells (3)

Inflammatory cell infiltration

Higher and sustained cytokines levels in aged mice vs. young

Denaturation of endothelial tissues (3)

Mice

Old, 9 months (F)

 

Lung pathology similar in old vs. young mice

(3, 5, 7)

BALB/c:

WT

Control mice

NA

No weight loss

No viral protein

NO

NO

 

Evaluation of candidates vaccine

Gu et al. (2020) [54]

NA

n = 10

Immunization day 1, 14

NA

No viral replication detectable in lungs (5)

No

NA

Higher IgG antibody response against SARS-CoV-2 (14)

6–8 weeks

Challenged with mouse adapted SARS-CoV-2

Immunized with SARS-CoV-2 RBD-Fc protein

(IN), 4 weeks after second immunization

PBS control with aluminum adjuvant

  

High viral load in the trachea and lungs (5)

Focal perivascular and peribronchiolar inflammation

Thickened alveolar septa

NA

NA

Mice

n = 5

SARS-CoV-2

No

(2)

No viral replication detectable in lung (2)

NA

NA

IgG1 ab1 protects hACE2 transgenic mice from SARS-CoV-2 infection.

(2)

Evaluation of prophylaxis with monoclonal antibody

6–9 weeks (F)

105 PFU (IN)

C3B6: hACE2 mice

 

Immunization

Human monoclonal IgG1 antibody (12 h)

C3B6:

 

Prior the virus challenges (IP)

hACE2 transgenic mice

n = 6

SARS-CoV-2

No

(2)

Viral replication 103 PFU per lung (2)

NA

NA

No

6–9 weeks (F)

105 PFU (IN)

C3B6: hACE2 mice

 

BALB/c mice

Control

IgG1 m336 (no activity in vitro)

Li et al. (2020) [51]

Balb/c, n = 5

Mouse ACE2 adapted SARS-CoV-2‡‡

No

(2)

No viral replication detectable in lung lobe at different dosages (2)

NA

NA

IgG1 ab1 protected mice SARS-CoV-2 challenge

(2)

10–12 months (F)

105 PFU (IN)

Human monoclonal IgG1 ab1 antibody (12 h)

Prior the virus challenges (IP)

Mice

hACE2 mice

SARS-CoV-2

Weight loss

Lung (2), brain (5)

NA

(2, 5)

NA

NA

Evaluation of vaccine and therapy in mouse-adapted SARS-CoV-2 model

BALB/c:

And

hACE2

NA

105 PFU (IN)

Mortality 40% (5)

(5)

Transgenic mice

BALB/c mice

SARS-CoV-2MA§

Pulmonary obstruction (WBP)†††

Upper airway

 

NA

NA

Dinnon et al. (2020) [52]

n = 33

105 PFU (IN)

 

Lung (2,4)

Greater lung inflammation and hemorrhage in old vs. young mice (2,4)

Young 12 weeks

BALB/c mice

 

Greater

Higher replication in old vs. young mice

n = 34

 

Weight and pulmonary

12 months

 

Function loss in old vs. young mice

Vaccination

SARS-CoV-2 spike (S) or nucleocapsid (N)

NA

Vaccine with spike S reduced lung and nasal turbinate titer (2)

NA

NA

NA

n = 8–10

10 weeks

Challenged 4 weeks post-inoculation with SARS-CoV-2 MA

BALB/c

105 PFU (IN)

Prophylaxis

Subcutaneous administration interferon (IFN) lambda-1a 2 μg

 

Reduced SARS-CoV-2 MA replication in the lung (2)

NA

NA

NA

Therapy

18 h prior or 12 h after

BALB/c

SARS-CoV-2 MA

12 weeks

105 PFU (IN)

n = NA

 
  1. *TCID50 Median Tissue Culture Infectious Dose at which 50% of the cells are infected, PFU plaque-forming unit, † IN intranasal, IP intraperitoneal. ‡ Viral replication: RNA copies (PCR), viral antigen (immunostaining), viral particles (electron microscopy). § dpi day post-inoculation. ¶ WT wild type, || SCID severe combined immunodeficiency (lacking functional T and B cells). ** SARS-CoV-2MA A recombinant mouse ACE2 adapted SARS-CoV-2 variant remodeled by introduction of two amino acid changes at the ACE2 binding pocket in the receptor-binding domain to facilitate efficient binding to mouse ACE2. †† P4 and P6: Number of serial passaging of patient SARS-CoV-2 on HuH7 and Vero-E6 cells. ‡‡ Remodeling of the SARS-CoV-2 spike protein in the receptor-binding domain to facilitate efficient binding to mouse ACE2. §§ Chimeric mouse-adapted SARS-CoV1 MA15 variant encoding the SARS-CoV2 RNA-dependent RNA polymerase (“SARS1/SARS2-RdRp”). ¶¶ Genetic ablation of type I (Ifnar1−/−), III interferon (IFN) receptors (Il28r−/−), and Signal transducer and activator of transcription 2 (STAT2−/−). hACE2 chimera expressing human ACE2 receptor. *** C57BL/6 Mice Ces1c−/−: lack a serum esterase, an enzyme that is not present in humans, that reduces markedly the Remdesivir half-life. ††† WPH whole-body plethysmography