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Hydroxychloroquine Proves Ineffective in Hamsters and Macaques Infected with SARS-CoV-2.

ABSTRACT: We remain largely without effective prophylactic/therapeutic interventions for COVID-19. Although many human clinical trials are ongoing, there remains a deficiency of supportive preclinical drug efficacy studies. Here we assessed the prophylactic/therapeutic efficacy of hydroxychloroquine (HCQ), a drug of interest for COVID-19 management, in two animal models. When used for prophylaxis or treatment neither the standard human malaria dose (6.5 mg/kg) nor a high dose (50 mg/kg) of HCQ had any beneficial effect on clinical disease or SARS-CoV-2 kinetics (replication/shedding) in the Syrian hamster disease model. Similarly, HCQ prophylaxis/treatment (6.5 mg/kg) did not significantly benefit clinical outcome nor reduce SARS-CoV-2 replication/shedding in the upper and lower respiratory tract in the rhesus macaque disease model. In conclusion, our preclinical animal studies do not support the use of HCQ in prophylaxis/treatment of COVID-19.

SUBMITTER: Rosenke K

PROVIDER: S-EPMC7301902 | biostudies-literature | 2020 Jun

REPOSITORIES: biostudies-literature

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Hydroxychloroquine Proves Ineffective in Hamsters and Macaques Infected with SARS-CoV-2.

Rosenke Kyle K Jarvis Michael A MA Feldmann Friederike F Schwarz Benjamin B Okumura Atsushi A Lovaglio Jamie J Saturday Greg G Hanley Patrick W PW Meade-White Kimberly K Williamson Brandi N BN Hansen Frederick F Perez-Perez Lizette L Leventhal Shanna S Tang-Huau Tsing-Lee TL Nason Martha M Callison Julie J Haddock Elaine E Scott Dana D Sewell Graham G Bosio Catharine M CM Hawman David D de Wit Emmie E Feldmann Heinz H

bioRxiv : the preprint server for biology 20200611

We remain largely without effective prophylactic/therapeutic interventions for COVID-19. Although many human clinical trials are ongoing, there remains a deficiency of supportive preclinical drug efficacy studies. Here we assessed the prophylactic/therapeutic efficacy of hydroxychloroquine (HCQ), a drug of interest for COVID-19 management, in two animal models. When used for prophylaxis or treatment neither the standard human malaria dose (6.5 mg/kg) nor a high dose (50 mg/kg) of HCQ had any ben ...[more]

PMID: 32577633

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Project description:Animal models recapitulating human COVID-19 disease, especially severe disease, are urgently needed to understand pathogenesis and to evaluate candidate vaccines and therapeutics. Here, we develop novel severe-disease animal models for COVID-19 involving disruption of adaptive immunity in Syrian hamsters. Cyclophosphamide (CyP) immunosuppressed or RAG2 knockout (KO) hamsters were exposed to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) by the respiratory route. Both the CyP-treated and RAG2 KO hamsters developed clinical signs of disease that were more severe than those in immunocompetent hamsters, notably weight loss, viral loads, and fatality (RAG2 KO only). Disease was prolonged in transiently immunosuppressed hamsters and was uniformly lethal in RAG2 KO hamsters. We evaluated the protective efficacy of a neutralizing monoclonal antibody and found that pretreatment, even in immunosuppressed animals, limited infection. Our results suggest that functional B and/or T cells are not only important for the clearance of SARS-CoV-2 but also play an early role in protection from acute disease.IMPORTANCE Syrian hamsters are in use as a model of disease caused by SARS-CoV-2. Pathology is pronounced in the upper and lower respiratory tract, and disease signs and endpoints include weight loss and viral RNA and/or infectious virus in swabs and organs (e.g., lungs). However, a high dose of virus is needed to produce disease, and the disease resolves rapidly. Here, we demonstrate that immunosuppressed hamsters are susceptible to low doses of virus and develop more severe and prolonged disease. We demonstrate the efficacy of a novel neutralizing monoclonal antibody using the cyclophosphamide transient suppression model. Furthermore, we demonstrate that RAG2 knockout hamsters develop severe/fatal disease when exposed to SARS-CoV-2. These immunosuppressed hamster models provide researchers with new tools for evaluating therapies and vaccines and understanding COVID-19 pathogenesis.

Dataset Information

Hydroxychloroquine Proves Ineffective in Hamsters and Macaques Infected with SARS-CoV-2.

Publications

Hydroxychloroquine Proves Ineffective in Hamsters and Macaques Infected with SARS-CoV-2.

Similar Datasets

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