Table 7.
Summary of therapeutics for COVID-19 disease tested in nonhuman primates.
| Therapeutic‡(Reference) | Number and NHP species§, virus strain, challenge route† | Experimental groups, route†, dpi* | Clinical signs, virus load dpi* | Imaging gross and histologic lung pathology# | Conclusion |
|---|---|---|---|---|---|
| Baricitinib (48) | 8 RM 2019-nCoV/USA-WA1/2020 Combined IT, IN | Group 1: 4 RM received 4 mg Baricitinib daily for 8-9 d starting 2 dpi | All developed:↓ Activity, appetite and weight, altered respiratory rate and SpO2, hunched posture, shivering, paleness, agitation vRNA levels similar in all | CXR: 2/4 Controls GGOs and pulmonary infiltration, 2/4 normal 8/8 Euthanized 10-11 dpi Treated group: ↓ alveolar damage and interstitial pneumonia | Baricitinib was safe and well tolerated, reduced pathology and inflammation, but did not impact SARS-CoV-2 replication kinetics. |
| Group 2: 4 RM infection controls | |||||
| Dalbavancin (122) | 6 RM SARS-CoV-2 strain was a clinical isolate Combined IT, IN | Group 1: 3 RM treated with loading dose of Dalbavancin 60 mg/kg IV at time of infection, Dalbavancin 30 mg/kg IV repeated at 4 dpi Group 2 3 RM Infection controls | None noted | CXR: Less severe pneumonia in treated compared with controls 6/6 Euthanized 7 dpi: Treated group had minimal to moderate interstitial pneumonia Controls had severe interstitial pneumonia significantly ↓vRNA in lungs of treated compared with controls | Dalbavancin significantly inhibited viral replication and histopathologic injuries. |
| HCQ, AZH (71) | 31 CM BetaCoV/France/IDF/0372/2020 Combined IT, IN | Group 1: 5 CM - ↑dose HCQ starting 1 dpi | Mild clinical signs in controls, that is, coughing, sneezing, early lymphopenia | CT scans: GGOs in treatment and controls vRNA load kinetics similar in all groups Neither HCQ nor HCQ/AZTH had a significant effect on viral load in tissues. All had increased inflammatory cytokines. | HCQ had no antiviral activity nor clinical efficacy regardless of timing of treatment initiation. Treatment with HCQ is unlikely to have antiviral activity in respiratory compartments. |
| Group 2: 4 CM- ↓ dose HCQ starting 1 dpi | |||||
| Group 3: 5 CM – ↑dose HCQ + AZTH starting 1 dpi | |||||
| Group 4: 4 CM – ↓ dose HCQ starting 5 dpi | |||||
| Group 5: 5 CM – ↑ dose 7 d before infection | |||||
| Group 6: 8 CM – Infection controls | |||||
| HCQ (94) | 20 RM nCoV-WA1-2020 Combined IT, IN, PO, CJ | 5 RM HCQ 6.5 mg/kg PO before infection 5 RM HCQ 6.5 mg/kg PO at 12 h postinfection 10 vehicle controls | No difference in clinical signs between control and treatment groups All RM had ruffled fur, pale appearance, irregular or ↑ abdominal respiration | No significant difference between treated and controls | HCQ used at the standard dosing regimen for malaria prophylaxis and treatment had no beneficial effect on SARS-CoV-2 replication, shedding, disease progression or outcome. |
| Remdesivir (131) | 12 RMnCoV-WA1-2020 Combined IT, IN, PO, CJ | 6 RM treated with loading dose of 10 mg/kg Remdesivir, then daily maintenance dose of 5 mg/kg 6 RM were vehicle controls | 1/6 in Remdesivir group developed dyspnea, all controls had dyspnea | Treated RM: CXR had ↓pulmonary infiltrates, ↓ vRNA in BALF by 12 h after first treatment. By 3 dpi no infectious virus in BALF but detected in 4/6 controls Euthanized 7 dpi: ↓ vRNA and lung damage in treated compared with controls | Treatment of RM with Remdesivir during early infection has a clear clinical benefit. Data support use of Remdesivir in COVID-19 patients to prevent progression to severe pneumonia. |
| Remdesivir (29) | Analyzed data from Williamson paper using a mathematical model to predict Remdesivir effect. | Model predicted Remdesivir will lengthen SARS-CoV-2 infection. | Predicted Remdesivir will slow viral decay, slowing infected cell death and lengthening SARS-CoV-2 infection period, questioning potential clinical benefit. | ||
| Ly-CoV555 nAb (54) | 7 RMSARS-CoV-2 (USA-WA1/2020) Combined IT, IN | 4 RM treated with different doses of LY-CoV555 nAb (1, 2.5, 15, or 50 mg/kg) IV one day before infection 3 RM controls, received IgG1 before infection | Minimal to none Treated RM had dose-related↓ gRNA and sgRNA in respiratory tract, maximal protection at doses ≥ 2.5 mg/kg | Euthanized 6 dpi: Mild lobar congestion and hyperemia across control and treated groups | Ly-CoV555 nAb can prevent and treat SARS-CoV-2 infection,↓ viral replication in upper airway, may ↓transmission efficiency. Currently in human clinical trial. |
| Beta-galactosidase prodrug SSK1 (66) | 9 RM (1 juvenile, 1 adult and 1 aged in each Group) SARS-CoV-2 from CDC, Guangdong Province China Combined IT, IN, CJ | Group 1: 3 RM vehicle treated infection controls Group 2: 3 RM low dose (0.5 mg/kg) SSK1 Group 3: 3 RM high dose (2 mg/kg) SSK1 Treatment started 22 dpi for 7 d | SSK1 prevented weight loss Adult and aged vehicle controls lost 17% body weight | Euthanized 5 d after treatment stopped 2/3 controls: red lung lesions, variable degree of thickened alveolar septum, edema and hemorrhage SSK1 treated: Slight lung lesions in 1/6 | SSK1 effectively treated COVID-19 pneumonia by decreasing inflammation, clinical signs and pneumonia. SSK1 is a potential treatment for SARS-CoV-2 hyperinflammation. |
| Catalase [n(CAT)](88) | 7 RMSARSCov-2/KM 1/2010 (Likely a misprint, should be 2020)IN | Group 1: 2 RM, infection controlsGroup 2: 3 RM, 5 mg n(CAT) nebulized 2, 4, 6 dpiGroup 3: 2 RM, 5 mg/kg n(CAT) IV2, 4, 6 dpi | Treated groups lost less weight than controls. | All euthanized 7 dpi, except for 1 RM in Group 2 euthanized at 21 dpi.n(CAT) repressed viral replication, protected alveolar cells from oxidative injury | Catalase was not toxic in RM and may provide an effective therapeutic for COVID-19 and treatment of hyperinflammation in general. |
| Convalescent Serum (21) | 10 AGM SARS-CoV-2/ INMI1-Isolate/ 2020/Italy Combined IT, IN | Group 1: 2 AGM, untreated controls Group 2: 4 AGM ↑ dose (HD) pooled convalescent sera from infected AGM Group 3: 4 AGM, ↓ dose (LD) pooled sera from infected AGM | HD: 1/ 4 ↓appetite LD: 2/4 ↓ appetite, 1/ 4 tachypnea Infection Controls: None Convalescent sera ↓ viral replication and shedding | Euthanized 5 dpi: All had multifocal pulmonary consolidation, hyperemia, hemorrhage, less severe in HD and LD groups compared with controls HD Group: normalized coagulation times, fibrinogen, platelet count and cytokines | Data mirror results of human studies supporting convalescent plasma as an effective treatment strategy and indicate need to use donors with high potency nAb against SARS-CoV-2 for maximal benefit early in disease stage. |
| CT-P59 nAb (56) | 8 RM NMC-nCoV02, clinical isolate from a Korean patient Combined IT, IN, PO, CJ | Group 1: 2 RM, 45 mg/kg CT-P59 IV one day after viral challenge Group 2: 3 RM, 90 mg/kg CT-P59, one day after viral challenge Group 3: 3 RM, vehicle controls | No clinical signs in any RM on study CT-P59 rapidly reduced virus loads and eliminated infectious virus in both treatment groups compared with controls. | Euthanized 6 dpi: No infectious virus detected in lungs of either vehicle controls or CT-P59 treated RM | CT-P59 significantly reduced viral titer in SARS-CoV-2 infected NHP suggesting that human mAb CT-P59 is a candidate for treatment of COVID-19. |
| CB6 (LALA) nAb (104) | 9 RM Viral strain not provided IT | Treatment Group 1: 3 RM, treated with 50 mg/kg CB6(LALA) IV 1 and 3 dpi Prophylactic Group 2: 3 RM, treated with 50 mg/kg CB6(LALA) IV one dose 1 d prior to viral challenge Control Group 3: 3 RM | Did not report any clinical signs CB6 (LALA) given prior to infection prevented infection When give after infection, ↓ viral load immediately, by 4 dpi viral titer ↓ βψ 3 λoγσ χoμπαρεδ ωιτη χoντρoλ γρoυπ | Euthanized 1 RM from each group 5 dpi Control – interstitial pneumonia, thrombus in pulmonary capillary Treatment/ Prophylactic – limited lung damage | CB6, a nAb isolated from a patient recovering from COVID-19, could be a potential therapeutic for COVID-19. |
| MW05/LALA nAb (124) | 9 RM SARS-CoV-2 (WIV04) IT | Group 1: 3 RM, 1 dose 40 mg/kg IV MW05/LALA 1 dpc Group 2: 3 RM, 1 dose 20 mg/kg IV MW05/LALA IV 1 d before challenge Group 3: 3 RM, treated with hIgG1 | No clinical signs MW05/LALA prevented infection and as a therapeutic, immediately reduced virus load, clearing virus by 3 dpi | Euthanized 1 RM from each group at 5, 6, 7 dpi Controls – GGOs on thoracic radiographs, interstitial pneumonia, lungs had multifocal hemorrhagic lesions Milder lung pathology in treatment and prophylactic groups | Data show prophylactic and therapeutic efficacy of MW05/LALA in RM and demonstrates the effectiveness of nAb for prophylactic and therapeutic treatment of COVID-19. |
| COV2-2196 and COV2-2381 nAb (146) | 12 RM | Group 1: 4 RM, IV COV2-2196, 3 d before challenge Group 2: 4 RM, IV COV2-2381 3 d before challenge | Clinical signs not described ↑ sgRNA in bronchoalveolar lavage fluid and nasal swabs of isotype mAb controls | Not euthanized | COV2-2196 and 2381 nAbs protected RM from infection and may provide COVID-19 immunotherapy in humans. |
| 2019-nCoV/USA-WA1/2020 Combined IT, IN | Group 3: 4 RM Infection control, treated IV with control mAb 3 d before challenge | No sgRNA detected in the nAb treatment groups | Therapeutic nAb cocktails more likely to prevent viral escape mutations than single nAb. | ||
| REGN-COV2 (REGN10987 + REGN10933) (5) | 36 RM USA-WA1/2020 Combined IT, IN | Group 1 – Prophylaxis: 6 RM 50 mg/kg REGN-COV2, 6 RM placebo, treated 3 d before viral challenge Group 2 – 4 RM high dose and 4 RM low REGN-COV2, 4 RM placebo, treated 3 d before challenge with high dose virus Group 3 – 4 RM high dose and 4 RM low REGN-COV2, given 1 dpi with high dose viral challenge, 4 RM placebo | Clinical signs not described REGN-COV2 accelerated viral clearance in nasal and oropharyngeal swabs when used prophylactically or as a treatment | Euthanized 5 dpi As a treatment, REGN-COV2 reduced the incidence and severity of interstitial pneumonia compared with placebo | REGN-COV2 used prophylactically can completely block establishment of viral infection and reduces viral load in the upper and lower respiratory tract. REGN-COV2 is currently in clinical trials. |
‡ HCQ Hydroxychloroquine, AZH azithromycin, siRNA small interfering ribonucleic acid, nAb neutralizing antibody. § RM rhesus macaque, CM cynomolgus macaque, AGM African green monkey. † IT intratracheal, IN intranasal, PO per oral, CJ conjunctival, IM intramuscular, IV intravascular. * dpi days post infection. # GGOs ground glass opacities, CXR chest radiograph, vRNA viral ribonucleic acid, BALF bronchoalveolar lavage fluid, sgRNA subgenomic ribonucleic acid.