Guidance on the Regulation of SARS‑CoV/SARS‑CoV-2 Chimeric Viruses: Examples of SARS-CoV/SARS-CoV-2 Chimeric Virus Restricted Experiments

The purpose of this section is to give examples of experiments that meet the definition of a restricted experiment and would therefore require prior approval before creating the chimeric virus. The experiments described here are not exclusive. If you are uncertain whether a potential chimeric virus is regulated or an experiment is restricted and requires prior approval, please contact FSAP for further guidance.

Example 1

A researcher wants to understand the gene functions in SARS-CoV-2 to identify potential targets for therapeutic drug development. The researcher wishes to replace SARS-CoV-2 genes thought to be associated with cell death or inflammation, such as ORF3a and NSP4, with SARS-CoV genes. The result would be a set of SARS-CoV-2/SARS-CoV chimeric viruses. Since this experiment involves the creation of SARS-CoV-2 chimeric viruses where nucleotides in regions associated with virulence would be exchanged for the SARS-CoV nucleotide sequence, it would be considered a restricted experiment.

Example 2

A researcher wants to create chimeric viruses by replacing nucleic acids within the receptor-binding domain of SARS-CoV-2 spike protein with the corresponding nucleic acids from the SARS-CoV spike protein to understand the importance of different amino acid sequences on viral binding. The binding properties of spike protein play an important role in transmissibility and virus pathogenicity. It is possible that making changes to this region could result in a more transmissible virus than the parent. Since this experiment involves the creation of SARS-CoV-2 chimeric viruses where nucleotides in regions associated with virulence would be exchanged for the SARS-CoV nucleotide sequence, it would be considered a restricted experiment

Example 3

A pharmaceutical company is interested in developing an mRNA vaccine that results in production of neutralizing antibodies against the N-terminal domain of the spike protein of SARS-CoV and SARS-CoV-2. To identify the best sequence to use in the mRNA vaccine, the company would like to create a series of SARS-CoV-2 viruses with different nucleotide sequences in the N-terminal domain, including the sequence from SARS-CoV. The viruses would be used to infect an animal model and analyze the neutralizing antibodies created. The result would be a set of SARS-CoV-2/SARS-CoV chimeric viruses. Since this experiment involves the creation of SARS-CoV-2 chimeric viruses where nucleotides in regions associated with virulence would be exchanged for the SARS-CoV nucleotide sequence, it would be considered a restricted experiment.

Example 4

A biotech company is studying the role of coronavirus proteins in viral infection. They plan to create a series of chimeric SARS-CoV viruses where SARS-CoV-2 Open Reading Frames (ORFs) for regulatory or accessory proteins thought to be associated with virulence will be incorporated. The effect on virus-host interactions and pathogenicity for many of these ORFs is not known. The result would be a set of SARS-CoV-2/SARS-CoV chimeric viruses. Since this experiment involves the creation of SARS-CoV chimeric viruses in which nucleotides that are expected to be associated with virulence would be exchanged for SARS-CoV-2 nucleotide sequences, it would be considered a restricted experiment.