Guidance on the Regulation of Select Agent and Toxin Nucleic Acids: Regulated Materials
FSAP regulates select agent and toxin nucleic acids that are:
- Inherently infectious and are immediate precursors to virus production (i.e., the nucleic acids are capable of generating infectious forms of a regulated virus by utilizing host polymerases but without the need for any additional exogenous factors [proteins, nucleic acids, etc.])
- Encode for the toxic form(s) of any of the 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, or
- That have been genetically modified.
For regulated genetic elements and recombinant and/or synthetic nucleic acids, the select agent regulations (security, biosafety requirements, etc.) are the same as those applied to the respective select agents and toxins.
Examples of Nucleic Acid Materials of Select Agents and Toxins That May Be Regulated
Inherently infectious materials that are immediate precursors to virus production
Positive strand RNA virus genomes are regulated. For the viruses listed below, regulation is limited to positive strand RNA forms of the viral genome which can be translated into protein precursors for virus production. A cDNA copy of the viral genomes listed below would not be regulated because they would first need to be transcribed into RNA then translated into protein and therefore would not be an immediate precursor to virus. Positive strand RNA forms subjected to regulation include:
- Classical swine fever virus
- Eastern equine encephalitis virus (North American genotypes)
- Foot-and-mouth disease virus (FMDV)
- Kyasanur Forest disease virus
- Omsk hemorrhagic fever virus
- SARS-associated coronavirus (SARS-CoV)
- Swine vesicular disease virus
- Tick-borne encephalitis complex (flavi) viruses:
- Far Eastern subtype
- Siberian subtype
- Venezuelan equine encephalitis virus subtypes IAB and IC
Recombinant and/or synthetic nucleic acids that encode for the toxic form(s) of the regulated toxins
Recombinant and/or synthetic nucleic acids that encode for the toxic form(s) of the regulated toxins are regulated 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.
Genetically modified select agents and toxins
Depending upon the extent of the modification, genetically modified select agents or toxins may be regulated. Genetic modifications include but are not limited to deletion mutants, insertion mutants, point mutants, and chimeric select agents. If the genetic modification renders the select agent or toxin attenuated or less potent or toxic then the select agent or toxin may be excluded.
Chimeric viruses whose genomes contain the backbone and replication machinery of a select agent virus or contain genes from different select agent viruses are regulated. Regulated chimeric viruses have to be evaluated on a case-by-case basis to determine if the viruses exhibit sufficient attenuation to be excluded. The select agent regulations do not apply to nucleic acids encoding for genetically modified select agents unless they can produce infectious forms of any of the select agent viruses which is currently limited to positive strand RNA virus genomes (see above) or encode for the toxic form(s) of any of the 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. For example, the nucleic acids encoding for a chimeric Mpox virus would not be regulated while nucleic acids encoding for a chimeric EEE virus would be regulated.
Chimeras that are comprised of select agent and non-select agent genes
Chimeras that are comprised of select agent and non-select agent genes from the same virus family require careful review to determine select agent status. It is the entity’s responsibility to determine if the resultant chimera is a select agent; however, FSAP encourages entities to submit these types of chimeras for review.
FSAP also regulates select agent bacteria that are genetically modified. Regulated genetically modified bacteria have to be evaluated on a case-by-case basis to determine if the bacteria exhibit sufficient attenuation to be excluded. The select agent regulations do not apply to nucleic acids that encode for genetically modified bacteria as these nucleic acids are not considered infectious.