Much of the concern about mRNA vaccines has had to do with their novelty, but the reality is that this is a fairly extreme mischaracterization. The first instance of naked mRNA inducing an immune response was demonstrated in 1990 with mice and research into the concept has been ongoing since. Under ordinary circumstances it can take decades for a vaccine to make it from bench to bedside so it isn't especially surprising that we do not have them in routine use yet. The major problem with nucleic acid vaccines in general has not been their safety, but their efficacy. It's quite challenging to get any nucleic acid vaccine reliably in a cell and doing the things you want it to do, especially RNA. However, some studies have demonstrated very promising results. There has for instance been an mRNA vaccine tried that
encoded rabies envelope glycoprotein which demonstrated protection against rabies in pigs upon challenge with the virus supplied directly to the brain and excellent antibody responses as well.
Another concern raised has been the idea that mRNA can somehow alter the host's genome. That would actually be super cool and be huge for gene therapy (and I could finally give myself the giant bat wings I've always wanted) but this is not so. This is ordinarily impossible except if there is also a reverse transcriptase enzyme present that produces DNA from the RNA template, which is how retroviruses work. There is no such risk with any mRNA vaccine candidate. mRNA vaccines act entirely within the cytosol of the cell- they do not go near the nucleus where all the DNA is. That's actually a major advantage of RNA-based vaccines over DNA ones.
Another concern I've heard raised is the possibility of long-term consequences that do not present until years after vaccination. This is the ever-present specter that the anti-vaccine movement likes to toss out with every vaccine and is honestly a mythical entity. While vaccines can vanishingly rarely produce conditions that become chronic (e.g. Guillain-Barre syndrome), these manifest soon after vaccination. As I've discussed before,
Shoenfeld's syndrome has no good evidence to support it. mRNA inside the cell is extremely short-lived. A great deal of work has been done to come up with new ways in mRNA pharmacology to make it last longer without having to give another dose and much progress has been made in that regard but nonetheless, mRNA is an incredibly unstable molecule. In fact it can degrade itself if exposed to even a little bit of heat or base and for that reason has to be stored at- 80 Ā°C (which is why no mRNA vaccine candidate is likely going to be the fix for COVID-19 in lower and middle income nations).
Some individuals have also zeroed in on the importance of interferon responses in the action of mRNA vaccines and raised questions about autoimmunity. The fact of the matter is that interferons represent an extremely effective and ubiquitous mechanism to deal with viral infection and while
aberrant interferon signaling does play a role in some autoimmune diseases one has to hold this in context: virtually every viral infection you encounter is going to elicit the production of interferons. This is how we evolved to deal with viruses. If somehow you find yourself in the position that you are on the brink of autoimmune disease and all that's needed is some interferon to kick that into gear (and we have no way of knowing who such individuals are) then the reality is avoiding an mRNA vaccine is going to do essentially nothing to modify your risk of developing that autoimmune disease. You are bound to develop an infection at some point which will produce those interferons.
With COVID-19 specifically, there has been concern raised based on previous vaccines against coronaviruses for
Th2(/Th17)-mediated immunopathology due to a vaccine. This is definitely a valid safety concern. The absolute worst thing that could happen from a vaccine is that it not only fails to prevent the disease but actually causes more severe disease upon encounter with the pathogen. But here there is excellent news:
mRNA vaccines produce a highly-Th1 polarized immune response with minimal Th2 or Th17 activation. Thus given what we know about COVID-19 and vaccines against its related predecessors, it is quite rational to pursue an mRNA vaccine-based platform.
edwardnirenberg.medium.com
