FAQ: Regulation of SARS‑CoV/SARS‑CoV-2 Chimeric Viruses

HHS/CDC amended its regulations to add 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 to the list of HHS select agents and toxins. HHS/CDC needed to regulate this agent and require prior approval from CDC to conduct deliberate manipulation of SARS-CoV-2 to incorporate nucleic acids coding for SARS-CoV virulence factors because these chimeric viruses have the potential to pose a severe threat to public health and safety.

No, currently SARS-CoV-2 is not a select agent. However, SARS-CoV/SARS-CoV-2 chimeric viruses and products resulting from deliberate manipulation of SARS-CoV-2 to incorporate nucleic acids coding for SARS-CoV virulence factors or vice versa are regulated.

Virulence factors are genes or gene modifications that are associated with virulence. Virulence factors determine a pathogen’s ability to replicate, modify host defenses, spread within the host and to other individuals (transmissibility), and produce products that are toxic to the host. These factors may impact infectivity, transmissibility, immunity, vaccine sensitivity, drug resistance, pathogenicity, and disease severity.

Please refer to the SARS-CoV/SARS-CoV-2 Chimeric Virus Guidance Document for more information about SARS-CoV/SARS-CoV-2 chimeric viruses and how they are regulated.

Please refer to the SARS-CoV/SARS-CoV-2 Chimeric Virus Guidance Document for more information about the regulation of SARS-CoV/SARS-CoV-2 chimeric virus genomic material.

Experiments to create these chimeric viruses must be submitted to the FSAP for prior approval. When requesting to conduct a restricted experiment, the entity should submit the following relevant information via the General Discussion tab on the landing page in the eFSAP information system:

• Synopsis of the proposed experiment(s) and the intended objective(s).
• Description (including relevant sequence alignments) of the modified nucleic acid sequences (if applicable) and the predicted biological characteristics of the synthetic/recombinant product.
• Method for creating the chimeric virus(es).
• Identification and characteristics of the host organism used for molecular cloning (if applicable).
• Description of biosafety level including facility containment, equipment, and special practices to be utilized for the proposed experiment(s).
• Synopsis of any planned animal experiments (if applicable) or other relevant animal work.
• Expected timeframe of the proposed experiment(s).
• Description of long-term and short-term storage plans for samples.
• Scientific references or supporting documentation, particularly with respect to the biosafety aspects of the proposed experimental product.

The restricted experiment request should not be submitted as part of a registration amendment request. If the restricted experiment is approved, the entity should then request to amend their registration by submitting the appropriate Animal and Plant Health Inspection Service (APHIS)/CDC Form 1 sections related to the experiment. The Responsible Official (RO) will be notified in writing if an application to amend a certificate of registration is approved or denied. Note that approval may be contingent upon inspection or submission of additional information.

Possession of a product resulting from a restricted experiment requires pre-approval from the FSAP before a transfer request is approved. The potential receiver must submit the following documentation to the FSAP for review prior to transfer:

• Synopsis of the proposed experiments (if applicable) and the intended objectives.
• Description of biosafety level including facility containment, equipment, and special practices to be utilized for the proposed experiments.
• Synopsis of any planned animal experiments (if applicable) or other relevant animal work.
• Description of the transferor (e.g., entity, name of person initiating transfer, point of contact information).
• Description of occupational health and medical surveillance procedures [applicable to non-Tier 1 select agents as recommended in Biosafety in Microbiological and Biomedical Laboratories (BMBL) (e.g., SARS–CoV)].
• Scientific references or supporting documentation, particularly with respect to the biosafety aspects of the proposed experimental product. The supporting documentation should reflect the safety measures in place that would support the request to acquire the product of a restricted experiment from another entity.

If the request to possess the product from a restricted experiment is approved, the entity should then request to amend their registration by submitting the appropriate APHIS/CDC Form 1 section updates.

In addition, the APHIS/CDC Form 2, Request to Transfer Select Agents and Toxins, must be completed and submitted through the eFSAP information system prior to transferring any select agent(s). Please refer to the APHIS/CDC Form 2 instructions and guidance documents for more information.

To apply for the exclusion of an attenuated strain of a select agent, an applicant must submit the request to the FSAP. Requests from a registered entity for the exclusion of a select agent should be sent by the RO to the FSAP through the eFSAP electronic information system. If the applicant is a non-registered entity, please submit the exclusion request to CDC at lrsat@cdc.gov.

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 of 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.

The 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)].

If the change affects a virulence factor and makes the virus genetically more similar to SARS-CoV, the virus could be regulated even if it is only one nucleic acid that is modified. For additional information, refer to the “Examples of SARS-CoV/SARS-CoV-2 Chimeric Virus Restricted Experiments” section on the SARS-CoV/SARS-CoV-2 Chimeric Virus Guidance document.

Yes, that is a restricted experiment under 42 CFR 73.13(a)(3).

Please refer to the SARS-CoV/SARS-CoV-2 Chimeric Virus Guidance document.