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Table 2 Summary of studies using nonhuman primate 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
Rhesus macaques n = 8 SARS-CoV-2 nCoV-WA1–2020 Fever Nose, oropharynx, lung Anemia At 1 dpi only, significant increases in IL1ra, IL6, IL10, IL15, MCP-1, MIP-1b IgG antibody anti-spike protein (10) Pathogenesis of COVID-19
Adults Weight loss Rectum (1) Mild to moderate, interstitial pneumonia,
Munster et al. (2020) [37] (M/F) 4 ×  105 TCID50 (IT, IN, PO) Dyspnea Tachypnea Edema
Piloerection Hyaline membranes formation At 3 dpi decrease in TGFα
Reduced appetite Hyperplasia type II pneumocytes
Hunched posture Swollen mediastinal lymph nodes (3, 4, 21)
Pale appearance
Dehydration (21)
Rhesus macaques n = 3 BetaCoV/Wuhan/IVDC-HB-01/2020 Weight loss Nose, oropharynx, lung Interstitial pneumonia Decreased CD4+ T and CD8+ T cells in young and old. IgG antibody anti- SARS-CoV-2 (14) Pathogenesis of COVID-19 in aging animals
3–5 years   Asthenia Rectum, alveolar epithelia Inflammation
Yu et al. (2020) [38] n = 2 1 ×  106 TCID50 (IT) More severe in old than young (14) Macrophages (3) Edema
15 years (NA)    Higher replication in old than young More severe in old than young (7)
Rhesus macaques n = 4 per group (6 vaccinated groups) DNA vaccine** NA (14) Lowest BAL levels of viral RNA with full-length S protein encoding vaccine NA Upregulation IFN-γ antipeptide spike proteins. IgG antibody anti- SARS-CoV-2 (day14 post-vaccination) Evaluation of candidate DNA vaccine
IM at week 0 and week 3
Yu et al. (2020) [39] 6–12 years (M/F) 1.1 × 104 PFU (IN and IT) (day 21 post-vaccine)     S1 and RBD lower response than other variant Spike proteins**
n = 10 sham control 1.1 × 104 PFU (IN and IT)   High BAL levels of viral RNA NA Anamnestic humoral and cellular immune responses including IFN-γ ELISPOT responses NA
6–12 years (M/F)
Rhesus macaques n = 6 vaccine 2.5 × 1010 ChAdOx1 nCoV-19 (IM) Tachypnea (3/6), dyspnea (2/6), Nose, BAL (2/6) NO Upregulation of IFN-γ (1) IgG antibody anti-SARS-CoV-2 spike protein (day 14 post-vaccination) Evaluation of DNA vaccine
M/F SARS-CoV-2 nCoV-WA1-2020 Ruffled fur (1/6) (7) Lung (very low), oropharynx, mediastinal, duodenum (3)   
2.6 × 106 TCID50 (IT, IN, PO, CJ) (day 28 post-vaccine)   No BAL subgenomic viral RNA   No difference in TNF-α, IL-2, IL-4, IL-6, and IL-10 vaccine vs. control
Van Doremalen et al. (2020) [40] n = 3 control` Vaccinated with 2.5 × 1010 ChAdOx1 GFP (IM) Tachypnea (3/3) Ruffled fur (2/3) Diarrhea (1/3) Pale appearance (1/3) BAL, nasal swabs, lung, cervical, mediastinal lymph nodes, duodenum, urinary bladder Interstitial pneumonia (2 of 3) TNF-α, IL-2, IL-4, IL-6, and IL-10 NA
Thickening of alveolar septae
M/F`   Red nose (1/3)   Edema
  SARS-CoV-2 nCoV-WA1-2020   BAL subgenomic viral RNA (3, 5) Hyperplasia type I & II pneumocytes syncytial cells
2.6 × 106 TCID50 (IT, IN, PO, CJ) (day 28 post-vaccine) No extra pulmonary injury
Rhesus macaques n = 4 per vaccine group PiCoVacc 6 μg/dose (high) or 3 μg/dose (low) at 0, 7, and 14 days (IM) NA Pharyngeal, anal, and pulmonary (3) Mild and focal histopathological changes both lower lobes No differences CD3+, CD4+, CD8+, TNF-α, IFN-γ, IL-2, IL-4, IL-5, IL-6 vaccine vs. control IgG antibody anti-SARS-CoV-2 (day 14 post-vaccination) Evaluation of an inactivated vaccine
3–4 years (M/F) SARS-CoV-2-2/human/CHN/CN1/2020
1 × 106 TCID50 (IT) (day 22 post-vaccine)
Gao et al. (2020) [41] n = 4 control Vaccinated with Al(OH)3 adjuvant (sham) or physiological saline (control) at 0, 7, and 14 days NA (7) Oropharynx, crissum, lung, rectum (3) Severe interstitial pneumonia CD3+, CD4+, CD8+, TNF-α, IFN-γ, IL-2, IL-4, IL-5, IL-6  
3–4 years (M/F) IM
SARS-CoV-2-2/human/CHN/CN1/2020
1 × 106 TCID50 (IT)
(22 days post-vaccine)
Rhesus macaques n = 6 SARS-CoV-2 nCoV-WA1-2020 Dyspnea (1/6) (7) Nose, oropharynx, lung (1) Minimal interstitial pneumonia subpleural spaces (3/6) (7) (7) NA NA Testing of antiviral therapy
Remdesivir Low BAL titers (1)
(M/F) 2.6 × 106 TCID50 (IT, IN, OC, PO)   No virus in BAL (3) No extra pulmonary injury
Williamson, B.N. et al. (2020) [42] n = 6 control Vehicle solution Tachypnea, dyspnea Nose, oropharynx, lung, and BAL (1) Multifocal, mild to moderate, interstitial pneumonia (7) NA NA
(M/F) SARS-CoV-2 CoV-WA1–2020    No extra pulmonary injury
2.6 × 106 TCID50 (IT, IN, OC, PO)
Rhesus macaques n = 9 SARS-CoV-2 USA-WA1/2020 Reduced appetite
(35)
Nose, pharynx, trachea, lung, gastrointestinal tract, liver, kidney, pneumocytes I & II, ciliated bronchial epithelial cells (1) Acute interstitial pneumonia Neutropenia IgG anti- SARS-CoV-2 Spike protein (35) Immune protection after a second exposure
Consolidation Lymphopenia (mild and transitory in high dose group)
6–12 years initial inoculation    Edema IFN-γ upregulation
1.1 × 106, n = 3 Multiple Inflammatory foci
(M/F) 1.1 × 105, n = 3 Hyaline membranes
1.1 × 104 PFU, n = 3 Damage to type I and type II pneumocytes
(IN, IT) Necrotic bronchiolar epithelium
Bronchiolar epithelial syncytial cells
No extra pulmonary injury
Chandrashekar et al. (2020) [43]c n = 9 SARS-CoV-2 USA-WA1/2020 No (14) 5 log10 reduction BAL & nasal viral loads (1) NA Increased virus-specific Nab titers  
  Second inoculation  
day 35 post-initial infection
6–12 years 1.1 × 106
1.1 × 105
(M/F) 1.1 × 104 PFU (IN, IT)
Rhesus macaques n = 7 SARS-CoV-2 Fever Nose, oropharynx, lung, gut, spinal cord, bladder, rectum (3) Thickened alveolar septa Increase CD4+ T cells IgG antibody anti-SARS-CoV-2 (14) Immune protection after a second exposure
WH-09/hum/2020 Weight loss Macrophages accumulation in alveoli Degeneration alveolar epithelia
3–5 years   Posture change   Inflammatory infiltrates (5, 7)
  Initial inoculation Rapid breathing
(NA) 1 × 106 TCID50 (IT) Reduced appetite (28)
Bao et al. (2020) [44] (n = 4) SARS-CoV-2 Transient temperature increase
(14)
Negative No pathology (5) CD4+ T higher at 7 day post-exposure vs. post-initial exposure Higher IgG antibody anti-SARS-CoV-2 (14) vs. initial exposure
WH-09/hum/2020
3–5 years  
(NA) second inoculation day 28 post-initial infection
1 × 106 TCID50 (IT)
Rhesus macaques (n = 5) SARS-CoV-2 WH-09/hum/2020 weight loss (IT route) (21) Nasal, oropharynx, rectum (IG route) Interstitial pneumonia (IT route) NA IgG anti-SARS-CoV-2 on 21 dpi (CJ route) Viral infection routes
Conjunctival (CJ route) Mild interstitial pneumonia (CJ route)
Deng, W. et al. (2020) [45] 3–5 years (M) 1 × 106 TCID50 (IT, CJ, IG) Lung, ileum, caecum (IT) (1) No pneumonia (IG route) (7)
Rhesus macaques n = 4 young SARS-CoV-2 CDC, Guangdong, China Fever Nose, oropharynx, trachea Inflammatory cell infiltrates Peak CD4+ T cells, CD8+ T cells, and monocytes (2) IgG antibody anti-SARS-CoV-2 (4) Pathogenesis of COVID-19 in different species of nonhuman primates
n = 6 adult Weight loss (21) Bronchus, lung, rectum Diffuse hemorrhage and necrosis
n = 4 old Blood, spleen (2) Swollen lymph nodes (hilar, mediastinal, mesenteric)
  4.75 × 106 PFU (IT, IN, CJ)    Pericardial effusion Young stronger B cell responses vs. adults vs. old IgG levels lower in young vs. adult vs. old
(NA) (50% given to young)    Mild hepatic steatosis Increased G-CSF, IL-1A, IL-8, IL-15, IL-18, MCP-1, MIP-1B, sCD40-L  
splenic hemorrhage (4, 7, 12, 13, 15)
Common Marmoset n = 6 SARS-CoV-2 None Nose, oropharynx, rectum Broken pulmonary septum NA No
CDC, Guangdong   Blood (2) Inflammatory infiltrates
Age = NA (M/F) 1 × 106 PFU (IN)    Splenic hemorrhage
Swollen hepatocytes
Renal inflammatory infiltrate
Cynomolgus macaques n = 6 SARS-CoV-2 CDC, Guangdong Fever Nose, oropharynx, trachea Inflammatory cell infiltrates CD4+ T cells, CD8+ T cells, and monocytes (2) IgG antibody anti-SARS-CoV-2 (4)
Weight loss Bronchus, lung, rectum Diffuse hemorrhage and necrosis
Adult 4.75 × 106 PFU (IT, IN, PO)   Blood, spleen (2) Swollen lymph nodes (hilar, mediastinal) Young stronger B cell responses vs. adults vs. old
Hepatic steatosis
Lu et al. (2020) [46] (M/F)     Splenic hemorrhage Increased G-CSF, IL-1A, IL-8, IL-15, IL-18, MCP-1, MIP-1B, sCD40-L
Cynomolgus macaques n = 4 SARS-Cov-2 BetaCoV/Munich/BavPat1/2020 serous nasal discharge (1/4 old monkey) (21) Nose, oropharynx, lung Foci pulmonary consolidation NA IgG antibody anti-SARS-CoV-2 (14) Comparisons of pathogenesis between COVID-19, SARS-CoV and MERS-CoV
Pneumocytes I & II Diffuse alveolar damage
4–5 y (F)    Ciliated nasal, bronchial & bronchiolar epithelial cells Hyaline membrane
15–20 years (F) 2 × 105 TCID50 (IT, IN)    Multinucleated giant cells
  Type I & II pneumocytes hyperplasia
Earlier detection in young (2) vs. old (4). Alveolar edema
  Leukocyte infiltration
Higher nasal replication in old vs. young (4)
Rockx et al. (2020) [48] n = 10 MERS-CoV No Nose, oropharynx, lung Foci pulmonary consolidation   IgG antibody anti-MERS-CoV (21)
EMC strain, accession no. NC_019843   Pneumocytes II Alveolar edema
3–5 years 106 TCID50   & rectal swabs (2) Leukocyte infiltration
Type II pneumocytes hyperplasia
F (IT, IN)    
NA NA No Nose, oropharynx, lung Type I & II pneumocytes hyperplasia NA NA
Pneumocytes I & II Alveolar edema (aged only)
Leukocyte infiltration
Hyaline membrane (aged only)
Cynomolgus macaques n = 6 2019-nCoV/USA-WA1-A12/2020 None (30) Nose, eye, oropharynx, rectum (2) CT scan: Ground glass appearance Increased CXCL8, IL6, IL13, IL15, IL1RN, and TNF (6) in one macaque. IgG antibody anti-SARS-CoV-2 spike S1 subunit (10) Evaluation of medical interventions
Reticulonodular opacities
Finch et al. (2020) [47] 4–4.5 years (M/F) 3.65 × 106 PFU (IT, IN)    Peri-bronchial thickening
Subpleural nodules
Alveolar dense consolidation (n = 1)
PET scan: FDG uptake lung and regional lymph nodes (2), mediastinal lymph nodes and spleen (6)
African green monkey n = 6 SARS-CoV-2-2/INMI1-/2020/Italy Reduced appetite Nasal, oropharynx, lung, rectum, pneumocytes I & II, alveolar macrophages (2) Interstitial pneumonia Increased CRP ¶ (n = 2) IgG antibody against SARS-CoV-2 b (5) Pathogenesis of COVID-19
Bronchiolitis
Fever (31)
Woolsey et al. (2020) [49] NA 5 × 105 PFU (IT, IN)    Edema IL-8, IP-10, IL-12, IL-6, IFN-beta, IL10, and MCP-1 (2)
Hemorrhage
Hyaline membrane
Hyperplasia type II pneumocytes
Distention and flaccidity small intestines segments
(5)
  1. *TCID50 Median Tissue Culture Infectious Dose at which 50% of the cells are infected, PFU plaque-forming unit, †IT intratracheal, IN intranasal, CJ intraconjunctival, OC ocular, IG intragastric, PO per oral. ‡ Viral replication: RNA copies (PCR), viral antigen (immunostaining), viral particles (electron microscopy). § dpi day post-inoculation, ¶ CRP C-reactive protein, || NA Not available. **Vaccine encoding spike protein variants: Full-length SARS-CoV-2 S protein, S.dCT Deletion of the cytoplasmic tail of SARS-CoV-2 S protein, S.dTM deletion of the transmembrane domain and cytoplasmic tail reflecting the soluble ectodomain, S1 S1 domain with a fold on trimerization tag, RBD Receptor-binding domain with a fold on trimerization tag, S.dTM.PP a prefusion stabilized soluble ectodomain with deletion of the furin cleavage site, two proline mutations, and a fold on trimerization tag, IM Intramuscular