Guidance on the Regulation of Select Agent and Toxin Nucleic Acids: Introduction
The Federal Select Agent Program (FSAP) is providing guidance to entities that create or use nucleic acids that are capable of producing infectious forms of select agent viruses or encode for the toxic form(s) of any select toxins if the nucleic acids (i) can be expressed in vivo or in vitro, or (ii) are in a vector or recombinant host genome and can be expressed in vivo or in vitro; including complete genomes as well as recombinant and/or synthetic nucleic acids. The following genetic elements, recombinant and/or synthetic nucleic acids, and recombinant and/or synthetic organisms are regulated as select agents (See sections 3(c) 4(c) of 42 CFR Part 73external icon, 9 CFR Part 121external icon, and section 3(c) of 7 CFR Part 331external icon):
- Nucleic acids that can produce infectious forms of any of the select agent viruses.
- Recombinant and/or synthetic nucleic acids that encode for the toxic form(s) of select toxins if the nucleic acids:
- Can be expressed in vivo or in vitro, or
- Are in a vector or recombinant host genome and can be expressed in vivo or in vitro.
- Select agents and toxins that have been genetically modified.
The purpose of this guidance is to address advances in molecular biology that may influence the production of infectious forms of select agent viruses, or the toxic forms of select toxins from recombinant and/or synthetic nucleic acids. For example, positive strand RNA viruses and certain double strand DNA viruses that utilize host polymerases contain nucleic acids that can produce infectious forms of the viruses. Such nucleic acids are subject to the select agent regulations.
Tier 1 nucleic acids
To ensure that select agents and toxins are secured according to the appropriate level of risk, a subset (Tier 1) of the select agent list has been identified that presents the greatest risk of deliberate misuse with most significant potential for mass casualties or devastating effects to the economy, critical infrastructure, or public confidence. Currently, only nucleic acids that encode for the toxic forms of Botulinum neurotoxins, or infectious forms of Foot-and-Mouth Disease virus, are regulated as Tier 1 agents and therefore all Tier 1 regulatory requirements apply to these nucleic acids.
Genetic elements are sequences of nucleic acids. Genetic elements from select agents are regulated if:
- They encode for a toxic form of a select toxin and can be expressed in vivo or in vitro or they are in a vector or recombinant host genome and can be expressed in vivo or in vitro, or
- The nucleic acids are inherently infectious, as discussed above.
Organisms containing regulated recombinant and/or synthetic nucleic acids
Any organisms that contain regulated recombinant or synthetic nucleic acids are subject to the regulations unless the organisms or nucleic acids are excluded as:
- A non-viable select agent or nontoxic toxin
- An excluded attenuated strain
- An excluded select toxin modified to be less potent or toxic
- Regulated nucleic acids that can produce infectious forms of any select agent virus that has been subjected to a validated inactivation procedure that is confirmed through a viability testing protocol. Surrogate strains that are known to possess equivalent properties with respect to inactivation can be used to validate an inactivation procedure; however, if there are known strain-to-strain variations in the resistance of a select agent to an inactivation procedure, then an inactivation procedure validated on a lesser resistant strain must also be validated on the more resistant strains.
- Regulated nucleic acids that can produce infectious forms of any select agent virus not subjected to a validated inactivation procedure if the material is determined by the HHS Secretary to be effectively inactivated. To apply for a determination an individual or entity must submit a written request and supporting scientific information to CDC. A written decision granting or denying the request will be issued.
Please see the Exclusions Guidance Document for more information.
If currently regulated select agent recombinant and/or synthetic nucleic acids (see above) are introduced into either a select agent organism or an organism used for molecular cloning (e.g., E. coli), the resulting recombinant and/or synthetic organism would be subject to the select agent regulations, including Tier 1 requirements for Tier 1 agents and toxins.
Synthetic nucleic acids and genomes
The Department of Health and Human Services’ Screening Framework Guidance for Providers of Synthetic Double-Stranded DNA “sets forth recommended baseline standards for the gene and genome synthesis industry and other providers of synthetic double-stranded DNA products regarding the screening of orders so that they are filled in compliance with current U.S. regulations…”  The guidance also encourages “best practices in addressing biosecurity concerns associated with the potential misuse of their products to bypass existing regulatory controls.”  Even when the double-stranded DNA sequence being processed does not fall under the current select agent regulations, providers are advised to refer to this policy for additional guidance on screening such orders.