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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