Guidance on the Regulation of SARS‑CoV/SARS‑CoV-2 Chimeric Viruses: Seeking Exclusions for Attenuated SARS-CoV/SARS-CoV-2 Chimeric Viruses

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Section 3 of the select agent regulations provide criteria for the exclusion of select agents that have been modified to be attenuated such that they no longer have the potential to pose a severe threat to public health and safety. Some of the criteria used to determine if an attenuated SARS-CoV/SARS-CoV-2 chimeric virus should be excluded are given below.

The applicant’s request should contain the following:

  • Documented history of not causing disease in humans or relevant animal models.
  • Defined genetic mutations or alterations known to attenuate virulence in humans or relevant animal models.
  • Data showing the mutations have a low frequency of reversion to wild-type virulence.
  • Level of difficulty in engineering the attenuated strain to restore wild-type virulence. For each pathogen, the sample size and type of animal models used to test virulence is important.
  • Quantitative measures demonstrating a change in virulence in an appropriate animal model with appropriate controls.
  • Information regarding results from tests that were conducted to differentiate animals exposed to the attenuated strain from those infected with the wild-type organism.
  • Related published scientific papers supporting the methods and data provided for the exclusion.

FSAP will grant or deny the request and will state, in writing, the reasons for the decision. Exclusions are effective upon notification to the applicant.

If an excluded attenuated strain is subjected to any manipulation that restores or enhances its virulence, the resulting select agent will be subject to the select agent regulations [42 CFR 73.3(e)(2)].

For regulated nucleic acids from positive-stranded RNA viruses to be excluded from the regulations, they must be rendered incapable of forming an infectious virus using an in-house validated inactivation procedure that includes viability testing. For additional information about inactivation requirements, see Guidance on the Inactivation or Removal of Select Agents and Toxins for Future Use.