COVID-19 Vaccines Are NOT Gene Therapy

Key concepts for gene therapy. Gene therapy aims to (a) replace the function of a defective gene with a functional one, (b) suppress a pathologic genetic variant, or (c) repair a defective gene directly through genome editing.

Anguela, X. M. & High, K. A. Entering the modern era of gene therapy. Annu. Rev. Med. 70, 273–288 (2019). Figure 2

Recently I’ve seen a surge in concerns that the COVID-19 vaccines are gene therapy. I am not sure what the source is, and furthermore whether or not COVID-19 vaccines are gene therapy is irrelevant for questions about their safety or effectiveness. But, regardless, COVID-19 vaccines are NOT gene therapy.

COVID-19 vaccines cannot affect your DNA, as I detailed before here in the context of mRNA vaccines; for information about the adenovirus vectors, I refer you to CHOP’s summary here (they too cannot affect the human genome because they lack the machinery to do so even though they are DNA viruses whose genetic material does enter the nucleus). However, this does not a gene therapy make. For example, as Figure 2 from Anguela and High shows, gene suppression of a pathologic variant via a miRNA (microRNA) or shRNA (short hairpin RNA) (as well as the related RNA interference and antisense oligonucleotides) is also a form of gene therapy- yet this does not affect the DNA. A review of RNA therapeutics generally can be found here. These all act post-transcriptionally (after the RNA product is made from the DNA template) as control mechanisms that target the immediate gene product- an RNA sequence. In doing so it also suppresses production of a protein that the pathologic gene may produce (though there are likely some cases where the RNA itself is the pathologic product) without affecting the patient’s genome.

Some have argued that essentially by virtue of the fact that these vaccines contain genetic material, they should be considered gene therapy. The technology is certainly similar, if not the same. Adenoviruses in particular have been used for gene therapy for instance. Moderna had been trying initially to create gene therapies by maintaining a constant supply of a healthy RNA sequence to the diseased host before it shifted its focus to vaccines. But, would you regard the vaccines for measles-mumps-rubella, smallpox, yellow fever, varicella (chickenpox), rotavirus, and oral polio vaccines to be gene therapy then? All of these are live attenuated vaccines which include replication-competent virus that enters our cells, releases its genome, and reproduces, triggering responses from our immune system which protect us in the process. If not, you have some inconsistencies to address with your ideas of what a gene therapy is. The reality is that the targets and products of the genetic information being delivered are a relevant consideration in whether or not something is “gene therapy.”

Perhaps the simplest and most direct evidence comes from the fact that the FDA has a list of approved gene therapies (and as the Pfizer/BioNTech vaccine has just been granted full licensure or Biologics Licensure Application -which indeed was approved- it should appear there), yet no COVID-19 vaccines appear there. In fact, no vaccines of any kind appear there.

It’s probably prudent to start with a definition for gene therapy first and go from there. A recent review writes:

Gene therapy is the transfer of genetic material to a patient to treat a disease.

That’s a very straightforward, concise definition and I like it for that. It makes it unambiguous that COVID-19 vaccines cannot be a gene therapy because they are not intending to TREAT a disease but rather they are prevent it from occurring. But this source is perhaps not sufficiently authoritative for some. FDA writes:

Human gene therapy seeks to modify or manipulate the expression of a gene or to alter the biological properties of living cells for therapeutic use.

FDA offers additional details in the following:

Human gene therapy product: FDA generally considers human gene therapy products to include all products that mediate their effects by transcription or translation of transferred genetic material or by specifically altering host (human) genetic sequences. Some examples of gene therapy products include nucleic acids (e.g., plasmids, in vitro transcribed ribonucleic acid (RNA)), genetically modified microorganisms (e.g., viruses, bacteria, fungi), engineered site- specific nucleases used for human genome editing, 10 and ex vivo genetically modified human cells. Gene therapy products meet the definition of “biological product” in section 351(i) of the Public Health Service (PHS) Act (42 U.S.C. 262(i)) when such products are applicable to the prevention, treatment, or cure of a disease or condition of human beings. 11

Human gene therapy is sort of vaguely defined. The definition given for human gene therapy product is more informative and it’s tempting to read it and think that because mRNA vaccines are in vitro transcribed RNA and adenovirus vectors are viruses they qualify, but this overlooks some key pieces to the definition- namely that they be therapeutics. None of the COVID-19 vaccines are therapeutics- they are prophylactic. They are given to healthy people to prevent them from developing COVID-19, especially severe COVID-19, the syndrome that occurs from infection by SARS-CoV-2. This distinction is well known in vaccinology because there are therapeutic vaccines, most prominently used in the context of cancer. It is correct that vaccines are biologics, defined by the FDA as:

virus, therapeutic serum, toxin, antitoxin, vaccine, blood, blood component or derivative, allergenic product, or analogous product, … applicable to the prevention, treatment, or cure of a disease or condition of human beings.

That makes sense as the FDA relies on the Vaccines and Related Biological Products Advisory Committee (VRBPAC) to recommend whether or not to authorize and license vaccines. However note that while a human gene therapy product may be a biologic, the definition does not allow the equivalency that a biologic is a gene therapy product. Which hopefully makes sense as it would be strange to regard most of the things listed in that definition as gene therapy.

The EMA definition is actually even less ambiguous:

Gene therapy medicinal product means a biological medicinal product which has the following characteristics:

(a) it contains an active substance which contains or consists of a recombinant nucleic acid used in or administered to human beings with a view to regulating, repairing, replacing, adding or deleting a genetic sequence;

(b) its therapeutic, prophylactic or diagnostic effect relates directly to the recombinant nucleic acid sequence it contains, or to the product of genetic expression of this sequence.

Gene therapy medicinal products shall not include vaccines against infectious diseases.

It should be noted that in order to be considered a gene therapy medicinal product, both the characteristics (a) and (b) have to be fulfilled.

So under the EMA definition, no vaccine against an infectious disease can qualify as gene therapy. That makes sense, as, once more, vaccines are not therapeutics.

Hope that helps to clarify any confusion.

References

1.Gene and cell therapy: Therapeutic mechanisms and strategies, fourth edition. (CRC Press, 2015). doi:10.1201/b18002.

2.Anguela, X. M. & High, K. A. Entering the modern era of gene therapy. Annu. Rev. Med. 70, 273–288 (2019).

3.The Children’s Hospital of Philadelphia. News & views: Getting familiar with COVID-19 Adenovirus-replication-deficient vaccines. Chop.edu https://www.chop.edu/news/news-views-getting-familiar-covid-19-adenovirus-replication-deficient-vaccines.

4.The science and fundamentals of mRNA technology. Modernatx.com https://www.modernatx.com/mrna-technology/science-and-fundamentals-mrna-technology.

5.Center for Biologics Evaluation & Research. Approved cellular and gene therapy products. Fda.gov https://www.fda.gov/vaccines-blood-biologics/cellular-gene-therapy-products/approved-cellular-and-gene-therapy-products (2021).

6.Crooke, S. T., Witztum, J. L., Bennett, C. F. & Baker, B. F. RNA-targeted therapeutics. Cell Metab. 27, 714–739 (2018).

7.Rossor, A. M., Reilly, M. M. & Sleigh, J. N. Antisense oligonucleotides and other genetic therapies made simple. Pract. Neurol. 18, 126–131 (2018).

8.Saxena, M., van der Burg, S. H., Melief, C. J. M. & Bhardwaj, N. Therapeutic cancer vaccines. Nat. Rev. Cancer 21, 360–378 (2021).

9.Saliminejad, K., Khorram Khorshid, H. R., Soleymani Fard, S. & Ghaffari, S. H. An overview of microRNAs: Biology, functions, therapeutics, and analysis methods: SALIMINEJAD et al. J. Cell. Physiol. 234, 5451–5465 (2019).

10.Funke, D. & Today, U. Fact check: FDA has fully approved Pfizer’s coronavirus vaccine. USA today (2021).

11.Wold, W. & Toth, K. Adenovirus vectors for gene therapy, vaccination and cancer gene therapy. Curr. Gene Ther. 13, 421–433 (2014).

12.Cellular & Gene Therapy Products. Fda.gov https://www.fda.gov/vaccines-blood-biologics/cellular-gene-therapy-products.

13.Long Term Follow-Up After Administration of Human Gene Therapy Products Guidance for Industry. Fda.gov https://www.fda.gov/media/113768/download.

14.Reflection paper on classification of advanced therapy medicinal products. Europa.eu https://www.ema.europa.eu/en/documents/scientific-guideline/reflection-paper-classification-advanced-therapy-medicinal-products_en-0.pdf.