Advice on tightening conditions for generic downscaling of containment requirements for the use of transgenes in alphavirus replicons

In 2022 COGEM advised that laboratory work with viral replicons derived from alphaviruses and flaviviruses can be performed on a lower containment level when certain conditions are met. In viral replicons, certain structural genes are removed so that virus particles can no longer be formed and, in theory, cannot spread. New genes can be inserted at the positions of the deleted genes. One of the conditions for generic downscaling is that the new genes introduced into the replicon do not restore the removed functions. As the insertion of specific genes from other viruses in alphavirus replicons can lead to the formation of transmissible virus-like vesicles (VLVs), the use of structural genes from three virus families was ruled out.

In view of the growing number of scientific publications that describe the formation of VLVs when structural genes from viruses in families other than those previously excluded are used, COGEM advises to further tighten up the conditions for the use of such inserts. Instead of excluding structural genes from specific virus families, the Commission advises that alphavirus replicons containing genes or combinations of genes that give the replicon the capacity to spread, should be excluded from generic downscaling to a lower containment level. COGEM is of the opinion that by including this condition in its previous generic advice on assigning containment levels for work with alphavirus replicons, human and environmental safety will be safeguarded.