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. More broadly, keep in mind that vaccines work.
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 including the Pfizer Biontech vaccine inject RNA for the COVID virus spike protein 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).
So far, none. Watch this space, but so far, they look very safe.
— Laurie Garrett (@Laurie_Garrett) November 17, 2020
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 lipid 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.
Paul,
1. Pfizer’s Covid vaccine was not tested on anyone above the age of 65, people with compromised immune systems, transplant patients on immunosuppressants, people with a multitude of allergies, and people with autoimmune diseases. How will these vaccines affect these people?
2. I have multiple autoimmune diseases, 6 at last count. Which is the better vaccine for use in people like myself with one or more autoimmune diseases?
3. Last time I received a flu vaccine I became allergic to all the constituents in the vaccine. I know vaccines produced in chicken eggs (flu) probably have different constituents than the Covid vaccines. How do the constituents differ between the different types of vaccines?
Just to comment on point 1, the Pfizer vaccine phase 3 trial did involve volunteers >65 yo. There were round 4000 seniors in the treatment arm and another 4000 in the placebo arm. Based on the published data the performance seems consistent in the seniors. You can refer to Table S4 in the supplementary material of their new nejm article. Analyses against age groups and comorbidities were shown.
I’m quite a senior and a total amateur in science.
This has been a most informative article I read so far, yet I end up with several simple questions.
1. Why- both being the RNA based vaccines-, do they require far apart frozen temperatures for the storage and transportation?
2. What’s the logic behind one requiring the second shot after 3 weeks and the other 4 weeks?
3. When do they expect their final results to come in?
4. The top image – Why are they juxtaposing the actual numbers and % without giving the total?
For example: If 53% were male, does 14,000 female translate to 47%? No figure is given for Asians.
In the final report, I’d like to see the % of those who turned positive or got serious side effects by age and chronically ill groups, particularly those in their 70s, 80s and above instead of simply an average for all.
Hi Mitzi,
These are great questions. I’ll do my best to answer them where I can.
1. Although these are both RNA vaccines, apparently their formulations are quite different in that they have different coatings around the RNAs to stabilize them. Apparently one works a lot better temperature-wise.
2. I’m not sure exactly why the timing is a bit different between the 1st and 2nd shots, but presumably it has something to do with the amount of immune response the 2 companies have seen in clinical trial participants so far.
3. In a sense their semi-final results are in, but practically speaking because of the short timelines on the trials the real final data will come from the experiences of millions of us who get the vaccines. There’s nearly 100% chance out of millions of people, at least a few will have significant side effects, but I’m hoping and predicting that that side effect number is way way way below the number of people who would have gotten sick or died from the COVID cases that were prevented.
4. I guess they’re just trying to give the big pictures numbers/%’s at one given time of some notable categories?
The FDA gets to see the full real data. I wish the firms would be more transparent with the data so we can all consider the #’s ourselves.
Thank you very much for your detailed reply.
Yesterday I read the interim results for Astra Zeneca/Oxford.
This one uses the conventional virus vector, and as such can be stored at 2-8C, which is a great news for the 3rd world who can’t afford -70C transportation and storage.
Their initial announcement said 70% effective, and I didn’t realize that was an average from 62% and nearly 90% respectively.
What really puzzled me was that 62% was achieved by the designed amount given for the 2 shots. The second, 90% happened by chance. A trial group in England, by mistake, gave half the amount for the 1st shot. This group showed much less side effects than the others, so they went ahead and gave the other half for the 2nd shot, and it turned out this group showed 90% effectiveness.
More is obviously not better in vaccines, it seems.
It must be a very delicate trial and error process to reach the optimum amount.
I would like to ask if anyone get to the information what kind of viral sequences those mRNA constucts have? Pfizer said this construct can replicate so I can rise the question for how long is it in the cell? It is injected into muscle which is not dividing. As someone who is using transfection vectors for eucariotic cells, most likely it will be lost after cell replication. Did they chcecked which cells are transfected after injection? Is immune system of the host killing the transfected cells? Seeing adverse effects probably yes. I would prefer protein based vaccination which is not using my own cells for creating immunity. One more question, maybe someone knows how it is produced? Clonning, viral prodution or sythetic? This probably wil also impact the safty.
Hey. Good questions. I thought Pfizer contains mRNA which is not self-replicating. Where have you found the data?
I’m not in the hard sciences, and I don’t pretend to be. I’m an MSW (and I’ve also volunteered in politics for a *long* time.) But I do know that the results of these vaccine trials happened in a very small fraction of the 20 years it normally takes for vaccines to be approved, and that they are telling everyone exactly, precisely what they want to hear. But in a a systematic review of the world literature from 1953-2013, nearly 10% of all new drugs were withdrawn from the market because of unexpected and serious side effects. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4740994/ In the time period from 2001-2010, that proportion rose to *one-third* of all new drugs released. https://www.health.harvard.edu/blog/the-trouble-with-new-drugs-2019050216562 And these were medications that were not frantically rushed and under political pressure every step of the way. When all of these factors are in place *and* everyone is being told 100% what they wanted to hear in basically every detail, then a lot of human biases towards wanting to think that everything will work out perfectly are very much in play. That’s all that I want people to realize and remember here. I feel like Cassandra the Voice of Doom trying to ruin everyone’s party, but we need to put the factors together and accept that everything may not work out so flawlessly in the long run after all.
@Catie,
I think it is fine to raise concerns and uncertainties. There’s a strong possibility that at least some side effects will emerge in at least a few people once millions of people are vaccinated. I’m predicting that the benefit will outweigh the downsides.
The Pfizer vaccine requires 2 doses several weeks apart. The Moderna vaccine press release does not indicate if it is 2 doses or not. From both companies I don’t see information about neutralizing antibody levels. I only read covid cases developed during the study. As of yet we have no indication how often patients would require boosters. Some published data suggest antibodies to primary infection last only a few months. Most vaccines are developed to be given in year periods not months. Are there indications or theoretical concerns that a vaccination schedule for covid on the order of 3-6 months with mRNA based vaccine could result in either a higher rate and/or severity of complications? Any information would be much appreciated.
With those of us who have diminished immunity (eg:age/autoimmune disease), might prefer to avoid RNA vaccine risk and try to get a competing vaccine from Oxford Vaccine Group (backed by NHS in the UK) – coronavirus vaccine called ChAdOx1 nCoV-19. It works by genetically re-programming the adenovirus — a DNA virus that causes a mild cold in humans and elicits a strong immune response.
Your thoughts re. comparison of safety?
I think that one of the great things here is that there are so many traditional and novel vaccines being developed for this. There will be pros and cons to each, but the benefit is that hopefully there will be a solution for nearly all scenarios.
The Oxford Vaccine is showing a 70% response…Moderna and Pfizers 90-95%..but again the question I have is for those already with Autoimmunity which would be safest? I have Autoimmune disease and Autoinflammatory disease…When I get my annual Flu Vaccine I get quite sick about 2 weeks after being inoculated..which persists for a few weeks…as I understand it the body at 2 weeks has its antibody production ramped up ..Love to know peoples speculative thoughts as to which would be the best Covid Vaccine option for the worlds multi-millions with existing Autoimmune Disease.