Phenotypic characterization of a SARS-CoV-2 clinical strain bio-bank and risk assessment of evolving virus variants

BackgroundIn late 2019 a novel coronavirus (CoV), now termed SARS-CoV-2 and the causative agent of the disease COVID-19, emerged in China. SARS-CoV-2 has caused a pandemic and an unprecedented international health crisis of unknown outcome. Although coronaviruses are known to frequently cross species barriers with SARS-CoV-2 as the 7th human pathogenic coronavirus, we still lack profound knowledge on the genomic alteration for host adaptation. As this virus entered into the human population recently with an estimated spill-over event from an yet unknown animal host in late 2019, it is expected that SARS-CoV-2 will undergo genetic mutations and further adaptation to the human host during the course of the pandemic. Of note, adaptations can go either way and enhance but also mitigate, e.g. virulence or disease severity. In this outbreak, metagenomic data are readily available to track the epidemic in real-time, but in silico analysis based on sequence data alone cannot sufficiently predict viral phenotypes. Potential changes in the replicative capacity, in receptor affinity, interferon susceptibility or escape from adaptive immune response of evolving strain will have significant impact on public health, treatment or vaccine strategies. However such changes can only be assessed by functional experimental studies using relevant clinical virus strains. Still, isolation of new viruses is often limited to a few initial strains at the beginning of an epidemic but abandoned in the long run, leading to a lack of low-passage virus isolates representative of the diversity of relevant circulating and evolving strains.Project & aims.In the proposed project, we aim to set up a SARS-CoV-2 strain biobank of virus isolates from well-defined clinical samples over the course of the epidemic and assess key phenotypic traits of low-passage strains. In the project, we will 1.) isolate at least 30 clinical strains during the first 2 years of the epidemic from patients at the University Hospital of Geneva and across Switzerland 2.) characterize them for replicative capacity on cell lines and primary airway cultures as well as interferon susceptibility 3.) analyse neutralizing capacity of early-epidemic convalescent sera against evolving SARS-CoV-2 variants and VSV-based-pseudotyped viruses harbouring SARS-CoV-2 spike-protein variants as surrogates for work under BSL-2 conditions. Metagenomic and related clinical data are available through a prospective clinical cohort study on COVID-19. Our functional data on key traits of evolving virus variants in addition to viral metagenomic data can help to guide and adapt immediate response strategies to this pandemic.Impact & rationale Our functional data on key traits of evolving virus variants complement viral metagenomic data and can help to guide and adapt immediate response strategies to this pandemic. Results will be aligned in real-time to collaborating groups from epidemiology, immunology and clinical research to adapt their analysis in the light of evolving variants. All SARS-CoV-2 isolates and surrogate viruses will be made available to the research community. Due to the unique position of our Centre with access to clinically well-defined specimens and an adjacent virology laboratory with BSL-3 facilities, our proposal is central and highly synergistic to the emerging research landscape on SARS-CoV-2 currently forming in Switzerland. With the proposed project, we will be able to centralize and maximize the collaborative output of our Centre necessary to rapidly address this complex and challenging situation.