A mouse-adapted SARS-CoV-2 model for the evaluation of COVID-19 medical countermeasures

Authors: Dinnon et al

Link to paper: https://www.biorxiv.org/content/10.1101/2020.05.06.081497v1.full

Journal/ Pre-Print: BioRxiv

Tags: Immunology/Immunity, Therapeutics, Drug discovery/ Drug repurposing

Research Highlights 

1. Generation of a small animal (murine) SARS-CoV2 model using a modified SARS-CoV-2 virus that utilises mACE2 as an entry receptor which has some features that are more clinically relevant than those seen in the hACE2 murine model

2. Mice vaccinated with viral particles expressing SARS-2-S protein were protected from infection with the mouse adapted virus

3. Use of the model shows both therapeutic and prophylactic IFN lambda administration reduces viral load in the lung

Summary 

Dinnon et al established a murine model of SARS-CoV-2 by remodelling the SARS-CoV-2 spike receptor binding domain, generating a virus that efficiently binds murine ACE2. The mouse-adapted virus replicates in the lungs of infected animals with more severe disease seen in older compared to younger mice. The disease phenotype had features that the authors believed were more clinically relevant than those seen in transgenic mice expressing human ACE2. This model could be used to study vaccine and therapeutic efficacy in vivo. It revealed that both therapeutic and prophylactic IFN lambda administration reduces viral load in the lung and that vaccination with wild type spike protein protects against infection with the modified virus.

Impact for SARS-CoV2/COVID19 research efforts 

Develop a vaccine for SARS-CoV2/COVID19 - Novel murine model can be used to develop and test vaccines preclinically

[Development of small animal model to study SARS-CoV2 and test treatments preclinically]

Study Type

· In vivo study (e.g. mouse, NHP)

Strengths and limitations of the paper

Novelty: Development of a new murine model of SARS-CoV-2 that has features that are more relevant to clinical disease than the transgenic hACE2 model, such as greater disease severity in aged mice

Standing in the field: It adds to the growing number of murine models of SARS-CoV2 that are available for preclinical studies.

Appropriate statistics: appropriate statistics were used

Viral model used: Mouse adapted SARS-CoV-2 virus (SARS-CoV-2 MA)

Translatability: They established a mouse model which bears similarities to human disease, but as with all mouse models, the question remains whether the findings in mice can be fully translated to human disease.

Main limitations:

· No characterisation of the immune response, particularly the systemic immune response in the model

· Short duration of the disease in the animals - virus is cleared by day 4

· Translatability from the model into human is unknown as significant differences exist between the mouse and human immune systems

· Engineering of the virus as opposed to host receptor may mean that some drug therapies or vaccines work differently in this model to humans infected with SARS-CoV-2