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) |