key: cord-0951137-c4fs5hyu authors: Lin, Qisheng; Lu, Chunni; Hong, Yuqi; Li, Runfeng; Chen, Jinding; Chen, Weisan; Chen, Jianxin title: Animal models for studying coronavirus infections and developing antiviral agents and vaccines date: 2022-05-21 journal: Antiviral Res DOI: 10.1016/j.antiviral.2022.105345 sha: 209e25f3bbf7b85364bb50c154793e4a182bee7f doc_id: 951137 cord_uid: c4fs5hyu In addition to severe acute respiratory syndrome coronavirus (SARS-CoV) and Middle East respiratory syndrome coronavirus (MERS-CoV), SARS-CoV-2 has become the third deadly coronavirus that infects humans and causes the new coronavirus disease (COVID-19). COVID-19 has already caused more than six million deaths worldwide and it is likely the biggest pandemic of this century faced by mankind. Although many studies on SARS-CoV-2 have been conducted, a detailed understanding of SARS-CoV-2 and COVID-19 is still lacking. Animal models are indispensable for studying its pathogenesis and developing vaccines and antivirals. In this review, we analyze animal models of coronavirus infections and explore their applications on antivirals and vaccines. Animal models used in SARS-specific therapy and vaccine evaluation 2 ND: Not Determined; *Targeting SARS-CoV S protein. Animal models used in MERS-specific therapy and vaccine evaluation 2 ND: Not Determined; *Targeting MERS-CoV S protein. easily cross cell membranes due to its negatively charge . Notably, oral administration 23 of remdesivir parent GS-441524 was demonstrated to inhibit SARS-CoV-2 replication and its spread 24 in ferrets (Cox et al., 2021a). Furthermore, GS-441524 effectively inhibited SARS-CoV-2 25 replication and reduced lung inflammation and injury in AAV-hACE2 mice when administrated 26 intraperitoneally (Li et al., 2022b) . 27 Viruses are intracellular obligate parasites, and their replication relied on a variety of host proteins. 28 variation occurs at the target site. Another important strategy for developing drugs against SARS-1 CoV-2 infection is to target host factors that, often possess broad-spectrum antiviral activity, which 2 breaks free from the variability of SARS-CoV-2 (Kausar et al., 2021). SARS-CoV-2 requires host-3 derived Transmembrane protease serine 2 (TMPRSS2) for membrane fusion with host cells. Hence, 4 drugs that inhibit TMPRSS2, such as camostat mesylate, can effectively block the entry of SARS- In addition, clofazimine and remdesivir showed synergistic antiviral effects in hamster (Yuan et al., 25 2021b) . As a result, remdesivir dosage was reduced 10-fold and clofazimine dosage was reduced 26 1.6-fold. Furthermore, the drug combinations effectively inhibited viral shedding in the nasal wash, 27 which could not be achieved with remdesivir or clofazimine alone (Yuan et al., 2021b) . Combining 28 anti-inflammatory methylprednisolone with remdesivir was more effective in inhibiting viral replication, reducing inflammation and tissue damage in SARS-CoV-2-infected hamsters compared 1 with single administration (Ye et al., 2021) . Combining drugs targeting different viral proteases, 2 such as molnupiravir and PF-07321332, was shown to be synergistic in inhibiting SARS-CoV- 2 3 Omicron variant infection in Calu-3 cells (Li et al., 2022a; White et al., 2021) ; however, the 4 effectiveness of this combination needs to be further investigated in animal models and clinical trials. demonstrated that it could effectively prevent BALB/c mice infected with mouse-adapted SARS-8 CoV-2 strain (MP7) body weight loss and reduce viral titer in the lung and nasal turbinate (Li et al., 9 2021a ). Such evidence supports the use of monoclonal antibody against COVID-19. In Ad5-10 hACE2-transduced mouse model, pre-treatment with an anti-SARS-CoV-2 mAb 1B07, which 11 recognizes SARS-CoV-2 S protein RBD, was shown to effectively block SARS-CoV-2 infection, 12 prevent body weight loss, and inhibit the production of several pro-inflammatory cytokines and on Evusheld/AZD7442 in animal models are still to be conducted. Moreover, an in vitro study demonstrated that COVA1-18 in a cocktail with COVA1-16 could effectively neutralize SARS-1 CoV-2 variant D614G, Alpha and Beta . Taken together, monoclonal, 2 especially cocktail monoclonal antibodies hold great promise for future COVID-19 treatment, 3 especially for those who have preclinical conditions including compromised immunity and old age, 4 as these could be ever ready and mixed with great flexibility to take into account of variant 5 specificities. and ferrets vaccinated with a replication-defective human adenovirus type 5-based COVID- 19 19 vaccine candidate (Ad5-nCoV) encoding the full-length SARS-CoV-2 S protein . An ideal animal model should mimic human SARS, MERS and COVID-19 in aspects such as 3 viral receptor expression and distribution, infection route, correlation between virus titer and disease 4 severity, pathogenesis as well as morbidity and mortality (Gretebeck and Subbarao, 2015) . Here, 5 we review the ability of six animal models to recapitulate the COVID-19 characteristics in figure 3. 6 However, it is difficult, if not impossible, to develop an animal model that could perfectly 7 recapitulate all the characteristics of human SARS, MERS and COVID-19. Therefore, it is important 8 to understand both the advantages and limitations of the above reviewed animal models (Table 5) . show asymptomatic, which is not conducive to severe SARS-CoV-2 pathogenesis. In this regard, 10 marmosets seem to be the best model for studying SARS-CoV and MERS-CoV because they We have been witnessing the enormous impact of COVID-19 pandemic on global public health 2 since the end of 2019. Currently, the newly emerging SARS-CoV-2 variants, such as the Delta and 3 Omicron, coupled with the relatively slow vaccination pose a continuous threat worldwide. It is 4 therefore extremely important to effectively sped up the vaccination process globally and to urgently 5 and rigorously evaluate current vaccines since their safety and efficacy are still debated. volunteers. Since the outbreak of COVID-19, many animal models have been successfully 21 developed as summarized in this review. We firmly believe that many ground-breaking studies will 22 follow using these precious models. We anticipate a much better understanding of the coronaviruses, 23 especially SARS-CoV2 and COVID-19 in the near future, which ultimately will help us to bring the 24 current pandemics under control. 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