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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