Disclaimer: I'm neither a genetics professional nor an anti-vax fanatic, I just tried to compare COVID-19 vaccine types currently available on the market and got some questions that I'd like to answer rationally.

Some of the vaccines that are being actively used now are based on adenoviral vectors, such as ChAdOx1, Ad26, or Ad5. These vectors are replication-defective, usually due to removed E1/E3 regions.

I looked for existing information about adenoviral vectors and found some facts that may relate to safety, but I can't conclude if they are rational or not for vaccine applications, since most studies are made for gene therapy or animal models.

Proteins activity

Wild-type adenoviruses are considered to be able to lead to tumors in rodents (Wiki: DNA oncoviruses), mostly due to E1 region activity, but E4 also adds to its oncogenic effect (Cell transformation by the adenovirus oncogenes E1 and E4), and may affect DSB repair (Expression of the adenovirus E4 34k oncoprotein inhibits repair of double-strand breaks). That may be related to the “hit-and-run” mutagenesis theory.

For Ad9, E4 alone can show that effect, E1 is dispensable (Adenovirus type 9 E4 open reading frame 1 encodes a transforming protein required for the production of mammary tumors in rats)

Genome integration

It's thought that adenoviruses do not integrate into the host genome, since they don't have a tool for that, but occasionally it happens with low probability (10^-3 .. 10^-7 per cell), particularly in cells where the virus can't replicate and lysis doesn't happen, which is always the case for replication-defective vectors (Chromosomal Integration of Adenoviral Vector DNA In Vivo, Frequency and Stability of Chromosomal Integration of Adenovirus Vectors, Insertion vectors for gene therapy, Illegitimate DNA integration in mammalian cells, Viral Vectors: The Road to Reducing Genotoxicity, Viral Epigenetics).

That raises questions about the possibility of insertional mutagenesis. As I see, such questions are often discussed in the context of DNA vaccines, but extremely rarely for adenoviral vectors which also deliver DNA into cells.

Finally, the question itself:

Should risks of insertional mutagenesis due to viral genome integration and E4 region's proteins activity be considered and discussed or they are not important / do not exists at all for adenoviral vector vaccines? Have I missed any studies about these topics?

Can these risks be estimated in numbers and compared with similar natural events?


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