Generation of a Broadly Useful Model for COVID-19 Pathogenesis, Vaccination, and Treatment.

COVID-19, caused by SARS-CoV-2, is a virulent pneumonia, with >4,000,000 confirmed cases worldwide and >290,000 deaths as of May 15, 2020. It is critical that vaccines and therapeutics be developed very rapidly. Mice, the ideal animal for assessing such interventions, are resistant to SARS-CoV-2. Here, we overcome this difficulty by exogenous delivery of human ACE2 with a replication-deficient adenovirus (Ad5-hACE2). Ad5-hACE2-sensitized mice developed pneumonia characterized by weight loss, severe pulmonary pathology, and high-titer virus replication in lungs. Type I interferon, T cells, and, most importantly, signal transducer and activator of transcription 1 (STAT1) are critical for virus clearance and disease resolution in these mice. Ad5-hACE2-transduced mice enabled rapid assessments of a vaccine candidate, of human convalescent plasma, and of two antiviral therapies (poly I:C and remdesivir). In summary, we describe a murine model of broad and immediate utility to investigate COVID-19 pathogenesis and to evaluate new therapies and vaccines.

Sun J ，Zhuang Z ，Zheng J ，Li K ，Wong RL ，Liu D ，Huang J ，He J ，Zhu A ，Zhao J ，Li X ，Xi Y ，Chen R ，Alshukairi AN ，Chen Z ，Zhang Z ，Chen C ，Huang X ，Li F ，Lai X ，Chen D ，Wen L ，Zhuo J ，Zhang Y ，Wang Y ，Huang S ，Dai J ，Shi Y ，Zheng K ，Leidinger MR ，Chen J ，Li Y ，Zhong N ，Meyerholz DK ，McCray PB Jr ，Perlman S ，Zhao J ... -  《-》

Comparison of transgenic and adenovirus hACE2 mouse models for SARS-CoV-2 infection.

Rathnasinghe R ，Strohmeier S ，Amanat F ，Gillespie VL ，Krammer F ，García-Sastre A ，Coughlan L ，Schotsaert M ，Uccellini MB ... -  《Emerging Microbes & Infections》

A SARS-CoV-2 Infection Model in Mice Demonstrates Protection by Neutralizing Antibodies.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused a pandemic with millions of human infections. One limitation to the evaluation of potential therapies and vaccines to inhibit SARS-CoV-2 infection and ameliorate disease is the lack of susceptible small animals in large numbers. Commercially available laboratory strains of mice are not readily infected by SARS-CoV-2 because of species-specific differences in their angiotensin-converting enzyme 2 (ACE2) receptors. Here, we transduced replication-defective adenoviruses encoding human ACE2 via intranasal administration into BALB/c mice and established receptor expression in lung tissues. hACE2-transduced mice were productively infected with SARS-CoV-2, and this resulted in high viral titers in the lung, lung pathology, and weight loss. Passive transfer of a neutralizing monoclonal antibody reduced viral burden in the lung and mitigated inflammation and weight loss. The development of an accessible mouse model of SARS-CoV-2 infection and pathogenesis will expedite the testing and deployment of therapeutics and vaccines.

Hassan AO ，Case JB ，Winkler ES ，Thackray LB ，Kafai NM ，Bailey AL ，McCune BT ，Fox JM ，Chen RE ，Alsoussi WB ，Turner JS ，Schmitz AJ ，Lei T ，Shrihari S ，Keeler SP ，Fremont DH ，Greco S ，McCray PB Jr ，Perlman S ，Holtzman MJ ，Ellebedy AH ，Diamond MS ... -  《-》

Replication-Competent Vesicular Stomatitis Virus Vaccine Vector Protects against SARS-CoV-2-Mediated Pathogenesis in Mice.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused millions of human infections, and an effective vaccine is critical to mitigate coronavirus-induced disease 2019 (COVID-19). Previously, we developed a replication-competent vesicular stomatitis virus (VSV) expressing a modified form of the SARS-CoV-2 spike gene in place of the native glycoprotein gene (VSV-eGFP-SARS-CoV-2). Here, we show that vaccination with VSV-eGFP-SARS-CoV-2 generates neutralizing immune responses and protects mice from SARS-CoV-2. Immunization of mice with VSV-eGFP-SARS-CoV-2 elicits high antibody titers that neutralize SARS-CoV-2 and target the receptor binding domain that engages human angiotensin-converting enzyme-2 (ACE2). Upon challenge with a human isolate of SARS-CoV-2, mice that expressed human ACE2 and were immunized with VSV-eGFP-SARS-CoV-2 show profoundly reduced viral infection and inflammation in the lung, indicating protection against pneumonia. Passive transfer of sera from VSV-eGFP-SARS-CoV-2-immunized animals also protects naive mice from SARS-CoV-2 challenge. These data support development of VSV-SARS-CoV-2 as an attenuated, replication-competent vaccine against SARS-CoV-2.

Case JB ，Rothlauf PW ，Chen RE ，Kafai NM ，Fox JM ，Smith BK ，Shrihari S ，McCune BT ，Harvey IB ，Keeler SP ，Bloyet LM ，Zhao H ，Ma M ，Adams LJ ，Winkler ES ，Holtzman MJ ，Fremont DH ，Whelan SPJ ，Diamond MS ... -  《-》

The pathogenicity of SARS-CoV-2 in hACE2 transgenic mice.

Bao L ，Deng W ，Huang B ，Gao H ，Liu J ，Ren L ，Wei Q ，Yu P ，Xu Y ，Qi F ，Qu Y ，Li F ，Lv Q ，Wang W ，Xue J ，Gong S ，Liu M ，Wang G ，Wang S ，Song Z ，Zhao L ，Liu P ，Zhao L ，Ye F ，Wang H ，Zhou W ，Zhu N ，Zhen W ，Yu H ，Zhang X ，Guo L ，Chen L ，Wang C ，Wang Y ，Wang X ，Xiao Y ，Sun Q ，Liu H ，Zhu F ，Ma C ，Yan L ，Yang M ，Han J ，Xu W ，Tan W ，Peng X ，Jin Q ，Wu G ，Qin C ... -  《-》