Syrian hamsters as a small animal model for SARS-CoV-2 infection and countermeasure development

Imai, Masaki; Iwatsuki‐Horimoto, Kiyoko; Hatta, Masato; Loeber, Samantha; Halfmann, Peter; Nakajima, N.; Watanabe, Tokiko; Ujie, Michiko; Takahashi, Keiichi; Ito, Mutsumi; Yamada, S.; Fan, Shufang; Chiba, Shiho; Kuroda, Makoto; Guan, Lizheng; Takada, Kenjiro; Armbrust, Tammy; Balogh, Aaron; Furusawa, Yuri; Okuda, Moe; Ueki, Hiroshi; Yasuhara, Atsuhiro; Sakai‐Tagawa, Yuko; Lopes, Tiago J. S.; Kiso, Maki; Yamayoshi, Seiya; Iwamoto, Noriko; Ohmagari, Norio; Hattori, Shin-ichiro; Takeda, Makoto; Mitsuya, Hiroaki; Krammer, Florian; Suzuki, Tadaki; Kawaoka, Yoshihiro

doi:10.1073/pnas.2009799117

Cited by 1,029 publications

(1,424 citation statements)

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“…To date, the Syrian golden hamster is the only animal species in which experimental SARS-CoV-2 infection results in moderate to severe pneumonia, with clinical signs, as well as shedding of virus 12,13,15 . Therefore, the prophylactic potential of the 47D11 MAb and convalescent human plasma was evaluated in this hamster model.…”

Section: Neutralizing Antibodies Protect Against Body Weight Loss Fromentioning

confidence: 99%

“…Results from a randomized clinical trial did not show a benefit 6,7 , while results from the small cohorts suggested clinical benefit but lacked controls for proper interpretation [8][9][10][11] . Although preclinical research indicated a limited protective effect of hamster serum when given to hamsters infected with SARS-CoV-2 early in the disease course 12,13 , effects of human plasma have not been analyzed in this animal model. Importantly, data on the level of neutralizing antibodies that are required to provide a clinically meaningful protective effect are not available.…”

Section: Introductionmentioning

confidence: 99%

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SARS-CoV-2 neutralizing human antibodies protect against lower respiratory tract disease in a hamster model

Haagmans

Noack

Okba

et al. 2020

Preprint

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Effective clinical intervention strategies for COVID-19 are urgently needed. Although several clinical trials have evaluated the use of convalescent plasma containing virus-neutralizing antibodies, the effectiveness has not been proven. We show that hamsters treated with a high dose of human convalescent plasma or a monoclonal antibody were protected against weight loss showing reduced pneumonia and pulmonary virus replication compared to control animals. However, a ten-fold lower dose of convalescent plasma showed no protective effect. Thus, variable and relatively low levels of virus neutralizing antibodies in convalescent plasma may limit their use for effective antiviral therapy, favouring concentrated, purified (monoclonal) antibodies.

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Section: Neutralizing Antibodies Protect Against Body Weight Loss Fromentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

SARS-CoV-2 neutralizing human antibodies protect against lower respiratory tract disease in a hamster model

Haagmans

Noack

Okba

et al. 2020

Preprint

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“…The interaction analysis of mutated and wild type RBDs with ACE2 receptor indicated that bats and pangolins could be suitable natural reservoirs for Indian isolates of this virus and this finding falls parallel with other earlier reports 29,30 . As hamster has been reported as a suitable animal model to study SARS-CoV-2 pathogenesis, the interaction of RBD of the Indian isolates included in the current study makes the earlier report more relevant 10 . Though the susceptibility of infection and death rate could be affected by several factors, mutation in the virus genome and its ability to adapt to new environment could be crucial.…”

Section: Discussionmentioning

confidence: 89%

“…From the phylogenetic tree analysis, four RMRC RBD sequences were selected from four random clusters for further investigation of their interactions with ACE2 receptor of probable natural hosts of SARS-CoV-2. Hamsters were reported to be the best suitable animal model to carry out SARS-CoV-2 related experiments; therefore it was essential to understand the interaction of its ACE2 receptor with isolated Indian SARS-CoV-2 RBDs 10 Chinese and Indian bat, which has prompted us to predict their three dimensional (3D) structure through homology modelling using Modeller v 9.19 tool followed by structure validation. Suitable templates were identified for 3D model building of ACE2 using BLASTp 11 search against PDB (Protein Data Bank) database.…”

Section: Sequence and 3d Structure Analysis Of Ace2 Receptormentioning

confidence: 99%

Sequence analysis of Indian SARS-CoV-2 isolates shows a stronger interaction of mutated receptor binding domain with ACE2 receptor

Dash

Turuk

Behera

et al. 2020

Preprint

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SARS-CoV-2 is a RNA Coronavirus responsible for the pandemic of the Severe Acute Respiratory Syndrome (COVID-19). It has affected the whole world including Odisha, a state in eastern India. Many people migrated in the state from different countries as well as states during this SARS-CoV-2 pandemic. As per the protocol laid by ICMR and Health & Family welfare of India, all the suspected cases were tested for SARS-CoV-2 infection. The aim of this study was to analyze the RNA binding domain (RBD) sequence of spike protein from the isolates collected from the throat swab samples of COVID-19 positive cases and further to assess the RBD affinity with ACE2 of different species including human.Whole genome sequencing for 35 clinical SARS-CoV-2 isolates from COVID-19 positive patients was performed using ARTIC amplicon based sequencing. Sequence analysis and phylogenetic analysis was carried out for the Spike and RBD region of all isolates. The interaction between the RBD and ACE2 receptor of five different species was also analysed.Except three isolates, spike region of 32 isolates showed one/multiple alterations in nucleotide bases in comparison to the Wuhan reference strain. One of the identified mutation at 1204 (Ref A, RMRC 22 C) in the RBD of spike protein was identified which depicted a stronger binding affinity with human ACE2 receptor compared to the wild type RBD. Furthermore, RBDs of all the Indian isolates are capable of binding to ACE2 of human, bat, hamster and pangolin.As mutated RBD showed stronger interaction with human ACE2, it could potentially result in higher infectivity. The study shows that RBDs of all the studied isolates have binding affinity for all the five species, which suggests that the virus can infect a wide variety of animals which could also act as natural reservoir for SARS-CoV-2.

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“…Several steps in viral replication could be affected including entry/fusion, lipid metabolism related to budding, formation of replication complexes, secretory pathway function and affects on SARS-CoV-2 protein processing, etc. Also, in vivo studies with animal models such as transgenic mice (27), hamsters (28), ferrets (29) or nonhuman primates (30) should be conducted, and oleandrin should be tested for antiviral activity against SARS-CoV and MERS-CoV.…”

Section: Discussionmentioning

confidence: 99%

Prophylactic and Therapeutic Inhibition of In Vitro SARS-CoV-2 Replication by Oleandrin

Plante

Fernández

et al. 2020

Preprint

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With continued expansion of the COVID-19 pandemic, antiviral drugs are desperately needed to treat patients at high risk of life-threatening disease and even to limit spread if administered early during infection. Typically, the fastest route to identifying and licensing a safe and effective antiviral drug is to test those already shown safe in early clinical trials for other infections or diseases. Here, we tested in vitro oleandrin, derived from the Nerium oleander plant and shown previously to have inhibitory activity against several viruses. Using Vero cells, we found that prophylactic oleandrin administration at concentrations down to 0.05 μg/ml exhibited potent antiviral activity against SARS-CoV-2, with an 800-fold reduction in virus production, and a 0.1 μg/ml dose resulted in a greater than 3,000-fold reduction in infectious virus production. The EC50 values were 11.98ng/ml when virus output was measured at 24 hours post-infection, and 7.07ng/ml measured at 48 hours post-infection. Therapeutic (post-infection) treatment up to 24 hours after infection of Vero cells also reduced viral titers, with the 0.1 μg/ml dose causing greater than 100-fold reductions as measured at 48 hours, and the 0.05 μg/ml dose resulting in a 78-fold reduction. The potent prophylactic and therapeutic antiviral activities demonstrated here strongly support the further development of oleandrin to reduce the severity of COVID-19 and potentially also to reduce spread by persons diagnosed early after infection.IMPORTANCECOVID-19, a pandemic disease caused by infection with SARS-CoV-2, has swept around the world to cause millions of infections and hundreds-of-thousands of deaths due to the lack of vaccines and effective therapeutics. We tested oleandrin, derived from the Nerium oleander plant and shown previously to reduce the replication of several viruses, against SARS-CoV-2 infection of Vero cells. When administered both before and after virus infection, nanogram doses of oleandrin significantly inhibited replication by up to 3,000-fold, indicating the potential to prevent disease and virus spread in persons recently exposed to SARS-CoV-2, as well as to prevent severe disease in persons at high risk. These results indicate that oleandrin should be tested in animal models and in humans exposed to infection to determine its medical usefulness in controlling the pandemic.

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Syrian hamsters as a small animal model for SARS-CoV-2 infection and countermeasure development

Cited by 1,029 publications

References 31 publications

SARS-CoV-2 neutralizing human antibodies protect against lower respiratory tract disease in a hamster model

SARS-CoV-2 neutralizing human antibodies protect against lower respiratory tract disease in a hamster model

Sequence analysis of Indian SARS-CoV-2 isolates shows a stronger interaction of mutated receptor binding domain with ACE2 receptor

Prophylactic and Therapeutic Inhibition of In Vitro SARS-CoV-2 Replication by Oleandrin

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