Risk Analysis of the Moderna and Pfizer Vaccines, part 4

Health risks of the Moderna and Pfizer vaccines

At this point, I know of three sets of concrete data that can help us determine risk factors here.  First, we have the results of the human trials from both Moderna and Pfizer, which the FDA has made available:  Moderna's Data,  Pfizer's Data.  Together, these trials give us data on about 33,500 people who were given the vaccine (both shots) and the same number who were given a placebo.

I have read through both documents rather thoroughly and believe there is enough similarity between the results of the two trials to combine those results and treat them as if they were the same vaccine for the purposes of risk analysis.  The mRNA technology they both use is close to identical; Moderna's side-effects seem slightly steeper than Pfizer's, but they also chose to go with a larger dosing, so that makes sense.

Second, I'm aware of an initial report on anaphylactic shock from the initial wave of vaccines, hosted by the CDC here: https://www.cdc.gov/vaccines/acip/meetings/downloads/slides-2020-12/slides-12-19/05-COVID-CLARK.pdf.  This report covers a dataset of 272,001 additional doses beyond the vaccine trial doses.

Third, we also at this point have very broad short-term data from the fact that we have now been vaccinating people as quickly as we can and so have given the *first* shots to more than 1.9 million people at this point: https://www.nytimes.com/interactive/2020/us/covid-19-vaccine-doses.html.  That number will become out of date very quickly, but it is a minimum that we can use for now.

Types of health risk

Both of the data sheets from Moderna and Pfizer split possible side-effects from the vaccine into two categories: side effects related to immune response reaction and side effect unrelated to immune response reaction.  There is a very good reason for this: the way a vaccine works, fundamentally, is to provoke an immune response from your body in such a way that it learns to produce antibodies against the desired antigen.  You trick your body into thinking it is infected with a certain disease, so that it fights against it.  Having an "allergic reaction" to a vaccine is therefore not really a side effect--it is the whole point of a vaccine that this should happen.

So these studies recorded every adverse medical event that happened to both the vaccine group and the placebo group, and categorized them into immune response related or not, and then compared how much each type of adverse event happened in the vaccine group compared to the placebo group.  If something was happening more often in the vaccine group, this was counted as a "significant adverse effect".

Actual significant adverse effects they found

What the studies found were essentially no significant adverse effects outside of the expected immune system responses to the vaccine: fever, chills, achiness, etc.  Both studies noted some adverse effects that happened a little more than you might expect in the vaccine group and some adverse effects that happened a little more than you might expect in the placebo group.  This is actually expected: in true random samples, if you look at all data you're going to find things that don't break down evenly just by chance.  Since even the slight amount of difference from even that was seen in some adverse effects was balanced between things that happened more often for the vaccine group vs. things that happened for the placebo group (that is, neither group saw this with more dangerous effects or more often than the other group), we can just ignore these from a risk analysis perspective.  Aside from the immune response reactions, it's a wash in safety between taking the vaccine and not taking it.

The only possible exception to this is a small number of extra cases of Bell's Palsy that occurred in the vaccine groups in both studies at a more elevated rate than the other adverse effects.  This still happened at a low enough rate where it could just be a coincidence, and also this is not a very serious condition that clears up on its own over time.  So I'm not going to bother including it in the risk analysis.

Immune response risks

So what are the actual immune response risks?  Mostly, just the standard "feels sick" symptoms of your immune system working which we've already discussed.  Typically these were mild, frequently they were bad enough to cause a couple days off of work, and rarely (11 cases) they were severe enough to last for a week or more and merit an emergency room visit.  No deaths or lasting effects were discovered from these side effects. 

During the trial, no instances of acute immune response side effect (also known as an allergic response to the vaccine, or anaphylactic shock) were observed.  After the trials, once the vaccine was beginning to be administered in bulk, we did begin to observe some instances of anaphylactic shock: about six in 272,000 doses, which makes sense if the likelihood of acute allergic reaction were just beyond the threshold of being likely to occur in the 33,500 trial cases.

This rate is quite a lot higher than the typical rate for other vaccines: other vaccines in the standard roster have about a 1 in 1 million rate of anaphylactic shock, so this is 22 times more common than seen with vaccines we ordinarily administer.  This has led some people to speculate that one of the materials used to stabilize the microscopic packets of vaccine (polyethylene glycol, or "PEG") is causing an allergic reaction in some people (a theory covered in this article.)

This is one theory, but there are other possible reasons for the high rate of anaphylaxis.  First, most people with severe allergies are told to avoid vaccines, precisely because of the innate tendency of all vaccines to cause allergic reactions.  However, due to the high profile of Covid, many people even with severe allergies are getting this vaccine anyway--in several of the cases of anaphylaxis we have seen, the person had a history of severe allergic reaction to vaccines.  This might be artificially inflating the rates (we do, after all, have only 6 total cases of anaphylactic shock to go off of here--it's entirely possible that 6 severely allergic people decided to be heroes in order to be early testers of the vaccine).

Another possibility is that Covid itself has a higher tendency to provoke an uncontrolled allergic reaction.  The vaccine causes human cell muscles to replicate *part* of the virus--just the spike protein part, not the rest of it.  Although the majority of cases of Covid follow a certain pattern, we have seen a persistent subset of the fatal cases in which the patient seems fine and then goes suddenly and almost inexplicably downhill and dies.  This has led to the theory that cytokine storm (being essentially an allergic reaction) is a key mechanism by which Covid can kill people.  It is therefore also plausible that the spike protein itself has a tendency to provoke an out-of-control immune response in some people.  

Regardless of the cause, it is important to note the allergic reaction as a possible risk.  It is also important to note that this risk can be mitigated.  When the FDA advisory committee was reviewing Pfizer's data, the question of allergic reaction was discussed rather vigorously (8 hour video here if you have the stomach for it).  In the end, it was pointed out that all vaccines have a risk of allergic reaction, and that it is already the case that vaccines are administered in locations with ready access to epinephrine injections and other means of emergency treatment for just such scenarios.  

This risk mitigation factor should also be kept in mind in case it is the spike protein itself that tends to cause an allergic reaction.  If this is the case, then either Covid or the vaccine could produce an allergic reaction, *but* the virus would tend to cause that reaction at your home (which is where you are told to sit and wait out the milder forms of the disease), whereas the vaccine would cause the reaction in a location where they can do something about an acute problem.  Earlier, we estimated that none of the milder, unreported forms of the disease were causing deaths.  However, if a small percentage of these sorts of infection are causing people to drop dead from anaphylactic shock, it may well be that these deaths are not being counted as official Covid-caused deaths, there not being any good reason to test these people for Covid after death.

Quantifying the immune response risks

When the first person to get one of the vaccines had an anaphylactic reaction, this was instantly a news story.  I'm therefore confident that no one so far (at least as of a few days ago) has died from administration of the vaccine.  This means we can confidently put the risk of death at about 1 in 2 million per dose at the worst.  Since you need 2 doses to get the full vaccine, we'll call this 1 in 1 million.  This number is likely to improve with time as we vaccinate more and more people.

The risk of an acute attack and therefore a stay at the hospital of a few days should be put at 6 in 272,000, keeping in mind that this could be an overestimation and that I'm ignoring the possibility that some of this risk could be offset by the counter-balancing risk of allergic reactions to Covid itself.

Unknown risks

This now suffices for all the *known* risks of the vaccine.  There are now two categories of risks from the vaccine we can still talk about: short term risks that are too rare to have shown up in the data so far, and risks for adverse effects that don't show up until the long term, beyond the experience we have so far.

Rare short term, serious but non-fatal risks

Here we are limited by the vaccine trial data.  Since they were looking at all adverse health effects, we know that anything that is more common than about 1 in 33,500 would have been caught. I am inclined to put any risk here into an even lesser frequency on the basis that there isn't a lot new about these new vaccines.  The real novelty of this approach is the delivery of a much smaller genetic load than the typical vaccine.  It is thought that this approach is inherently safer than using a full viral gene sequence that has been neutered somehow, and which can very rarely therefore cause an actual infection (for example, as in the small pox vaccine, which has about a 1 in 1 million chance of doing that.)  Aside from the smaller genetic load, it is packaged in known safe materials that are used in a lot of other common drugs and consumer goods.  The PEG issue was discussed already and is dealt with under the immune response risk.

I will therefore assign a risk of 1 in 50,000 to the possibility that there will be some rare short-term complication caused by the vaccine that hasn't been recognized yet.  This would be, by the way, worse than almost any modern vaccine, including some vaccines that have been recalled by the FDA for safety records that were better than that (see this article).

Unknown long term risks

Some people are concerned about the possible long term effects of the vaccine, due to the rapid way in which it was developed.  There are a few reasons to discount this fear.

First, the vaccine was really in development for a significant portion of its early stage before Covid.  This is not the first coronavirus to emerge and endanger the world, so people were already working on isolating the specific genetic code for the spike protein for a while: see this interview with one of the vaccine inventers for more details.

Second, there are some reasons that vaccine development takes longer typically that don't apply to the Covid mRNA vaccines.  Many vaccine trials take some time before they can recruit enough people, whereas due to the urgent need for a Covid vaccine, both trials easily recruited about 10 times the typical size of a normal vaccine trial in record speed.  Further, a significant portion of the time taken to complete a vaccine trial is to wait for enough people to get sick so that you have statistically significant data with which you can compare effectiveness between vaccine and placebo groups.  The rapid and widespread multiplication of Covid in various places which began this Fall is sad otherwise, but had the beneficial side-effect of causing the correct statistical milestones for these trials to be crossed quickly.  Finally, there is a lot of just administrative cruft in a typical vaccine approval process that was burned through quickly this time because of the perceived urgency.

The third reason to discount the risk of unknown long term effects is how rare long term side effects of vaccines are, if they do not also cause a short-term problem.  As was pointed out in the FDA deliberations, long term effects from a vaccine after 2 months of no short term effects are currently essentially unknown.  If that were to happen with these new vaccines, it would be essentially the very first time.

How I will score this risk, then, is to rely on this article which summarizes the health risks of problematic modern vaccines that did make it through an initial approval.  Of its various examples, the worst case it contains was the yellow fever vaccine which ended up having about a 1.5 out of 1,000,000 rate of unexpected serious side effects.  This is not an example of a long term side effect, but is about the worst plausible "surprise factor" I could find from that article so I will use it here.