December 1, 2020

The Niche

Knoepfler lab stem cell blog

Why I’m planning to get a COVID-19 RNA vaccine: low, mostly theoretical risks

I’m not a virologist, but I’m still getting asked these days about what the risks might be from the new generation of RNA vaccines for COVID-19.

Approaching this question instead as a biologist and genetics/genomics researcher, I can see a handful of at least hypothetical risks. Below I discuss these possible risks and why I’m generally not so concerned.

Barring some new worrisome data, I’m planning to get a COVID-19 vaccine when the time comes that it’s available to me. The early data suggests excellent efficacy at least in the short term so this post is more focused on thinking about safety.

moderna covid 19 rna vaccine study 1 1
Moderna COVID-19 RNA vaccine study composition. Screenshot of image from Moderna on their “COVE” study.

A little about RNA vaccines

RNA vaccines like the ones from Moderna and Pfizer that have given us all real hope recently based on company press releases work in a different way than traditional vaccines.

These new vaccines inject RNA into people and then rely upon our cells’ machinery to crank out viral protein coded by the injected RNA. These proteins then trigger an immune response. In contrast, more traditional vaccines, many of which are also in development for COVID-19, inject the actual viral proteins or weakened viruses.

I asked Laurie Garrett, who is more of an authority on these issues, on Twitter what her feeling was about possible risks of these vaccines and she was upbeat so far (see below).

Note that while any vaccine could pose some risk and one or more of the many COVID-19 vaccines could have unexpected outcomes like antibody-dependent enhancement, these possible issues are not specific to RNA vaccines. For background, antibody-dependent enhancement is where a vaccine-generated antibody actually can make a disease worse.

So what are the theoretical risks specifically of RNA vaccines?

Risk of genome alteration by RNA vaccines is extremely low, maybe zero

Since RNA vaccines use what could loosely be called “genetic material” (although I’m not a fan of applying that term to RNA) could those getting immunized end up with some cells in their arms or their blood with altered DNA? If you search the web for this kind of question you quickly fall down a rabbit hole and find yourself in a swamp of misinformation.

The reality is that the risk of an RNA vaccine changing your DNA is nearly zero and probably zero. Here’s why.

  • Location. First, it is thought that RNA injected into tissues and taken up by cells almost entirely stays in the cytoplasm of the cell. Since the genome is in the nucleus, RNA in the cytoplasm can’t readily interact with the DNA.
  • Human reverse transcriptase activity seems low to absent. Second, although RNA could hypothetically alter a genome if that RNA was first changed into DNA and then that DNA went into the nucleus, that seems extremely unlikely. Research suggests that there is very little if any permissive reverse transcriptase (RT) activity in human cells. While some enzymes like telomerase have very well-defined RT activity, they don’t just go around changing any old RNA into DNA.

mRNAs are very unstable

Not only is RNA unable to infect other cells (a possible risk of live, attenuated vaccines), but also the body chews up RNA quickly. In my view that makes RNA vaccines likely to be inherently safer than many others. That RNA instability, in addition to lowering the near-zero risk of DNA alterations in vaccine recipients, also just makes the vaccine safer more generally. For instance, protein or attenuated virus-based vaccines may be relatively more likely to hang around in the body longer than mRNA vaccine material.

Part of the reason RNAs are so fleeting is that there are enzymes called RNases whose whole purpose is to eat RNAs. While the COVID-19 RNAs are intended to be stabilized by being encased in nanoparticles, once those “bubbles” pop so to speak, the RNAs are going to be degraded.

Unknown risks since only short-term data on side effects?

A possible wildcard with RNA vaccines their newness. Since we don’t know them that well, there is a remote possibility that something strange like auto-immunity to RNA could occur sometimes. I’ve been around in biomedical science long enough to know that you cannot anticipate how every experiment is going to turn out, whether it’s basic or clinical science. The more data you have, the better you can predict what’s going to happen in future studies. Even in terms of animal studies, these vaccines have only been around a few years and to my knowledge they’ve never been used in people before.

There are things about RNA vaccines that we just don’t know yet and cannot easily anticipate until they are widely used. This makes me wish that within the COVID-19 arena there was time for longer studies involving more people to have a clearer picture of possible risks.

For example, the Pfizer and Moderna vaccines or others could end up being widely used quickly. It seems likely that they will be injected into hundreds of millions of people with only some months of safety data. The good news is that the Pfizer and Moderna data, as reported by the firm, suggests a solid safety profile in the short-term for its vaccine, mRNA-1273.

Like I said up top, I’m planning to get vaccinated against COVID-19 unless something radically changes in terms of the data, but it’s good and even reassuring to think these things through and ask questions. The hope is that via vaccination against COVID-19 the world may be getting more back to normal by the middle of next year.

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