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

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The Department of Health and Human Services (HHS) select agent regulations, 42 CFR Part 73, were also modified as part of this rulemaking to designate SARS-CoV/SARS-CoV-2 chimeric virus restricted experiments as those that involve the creation of SARS-CoV/SARS-CoV-2 chimeric viruses resulting from any deliberate manipulation of SARS-CoV-2 to incorporate nucleic acids coding for SARS-CoV virulence factors or vice versa. “Vice versa” means that the deliberate manipulation of SARS-CoV to incorporate nucleic acids coding for SARS-CoV-2 virulence factors would also be a restricted experiment and require prior approval from FSAP before generating the chimeric virus. The phrase “nucleic acids” includes entire genes, groups of genes, parts of a gene, or any modifications that may lead to phenotypic changes.

The restricted experiment provision applies to the deliberate manipulation of SARS-CoV-2 to incorporate nucleic acids coding for SARS-CoV virulence factors,or vice versa. If virulence is diminished instead of enhanced in the SARS-CoV/SARS-CoV-2 chimeric virus, the entity can submit an exclusion request for the resulting chimeric virus. If non-deliberate modifications occur that are consistent with the description above, entities should contact FSAP for further guidance.

Resources to Assist Entities Assessing Whether Their Work is Regulated or Considered a Restricted Experiment

There are several factors to consider when assessing whether proposed work may be regulated or a restricted experiment. Review of genetic sequence information and the incorporation of nucleic acids coding for virulence factors are key elements to consider in this assessment.

Entities should refer to public sequence repositories to determine whether the experiment they are considering may involve the creation of SARS-CoV/SARS-CoV-2 chimeric viruses. SARS-CoV/SARS-CoV-2 chimeric viruses result from any deliberate manipulation of SARS-CoV-2 to incorporate nucleic acids coding for SARS-CoV virulence factors or vice versa.

Public sequence repositories such as the National Center for Biotechnology Information (NCBI)/National Library of Medicine (NLM) (https://www.ncbi.nlm.nih.gov/sars-cov-2) and Global Initiative on Sharing Avian Influenza Data (GISAID) (https://www.gisaid.org) contain references for the SARS-CoV-2 genome, including variant information. For SARS-CoV, reference sequences from common laboratory strains to include Tor2 and Urbani can be found here: https://www.ncbi.nlm.nih.gov/nuccore/AY274119 and https://www.ncbi.nlm.nih.gov/nuccore/AY278741 for comparison to SARS-CoV-2.

Virulence factors are those genes or gene modifications that are associated with virulence, including those that lead to changes in structures, molecules, immunological regulatory systems, etc. Virulence factors determine a pathogen’s ability to replicate, modify infectivity and host defenses, spread within the host and to other individuals (transmissibility), and produce products that are toxic to the host. These factors may impact vaccine sensitivity, resistance to medical countermeasures, pathogenicity, transmissibility, and disease severity.

Experiments with these virulence factor genes alone are not regulated. However, experiments to create SARS-CoV/SARS-CoV-2 chimeric viruses from the deliberate transfer of virulence factors from SARS-CoV to SARS-CoV-2 or vice versa are regulated. The following list of virulence factors is not all-inclusive but is provided to assist entities in determining if the work they are performing is subject to the select agent regulations.

Examples of Virulence Factors:

  • Open Reading Frame 3a structural protein (ORF3a)
  • Open Reading Frame 8b structural protein (ORF8b)
  • Envelope protein (E), spike glycoprotein (S), transmembrane glycoprotein (M), and double membrane vesicle protein (DMV)
  • Non-structural proteins (NSP) 1,3,4,6,15,16
  • Suppressors of cytokine signaling (SOCS)

See Appendix for additional examples of SARS-CoV and SARS-CoV-2 virulence factors.

It is the entity’s responsibility to submit proposed work to create SARS-CoV/SARS-CoV-2 chimeric viruses from the deliberate transfer of virulence factors from SARS-CoV to SARS-CoV-2 or vice versa to FSAP for review and approval prior to initiating work.