Are the Covid-19 Vaccines Safe?
It has been a long year. We have weathered arguably the biggest global disruption since the Second World War, and many parts of the world are still facing the prospect of a very long winter as cases, hospitalizations, and deaths from Covid-19 continue to increase steadily.
And yet, in this dire nightmare, there is a ray of hope. Three vaccines have now completed phase 3 clinical trials, and while there is some nuance in their approval, we are now looking at a vaccine rollout that is only weeks away rather than the months or years we initially posited.
We know that approvals for drugs and vaccines usually take years, if not decades, while the Covid-19 vaccines have been pushed through in seemingly no time at all. Because of that, everyone in the world is asking the same two questions:
- Are we rushing the vaccines?
- Will the vaccines be safe?
The answers to these questions are fairly complex and take a bit of time to explain but basically boil down to no, we are not rushing the science, and yes, the vaccines will be safe.
Let me explain.
Before I delve into the evidence I’m talking about here, I think it’s important to point out something very big: We are currently operating based on press releases from pharmaceutical companies, which is not ideal. The huge caveat to all this information is that we do still need to see all the data published because otherwise, it is impossible to be certain that everything in the press releases is accurate.
Okay, so we can’t be certain of everything yet. What do we know?
Well, we know quite a bit about what the vaccine trials look like and the early evidence. This is because the manufacturers have, this year, been impressively open with their protocols and methodology. If you follow that link, you’ll find the protocols for half a dozen vaccine trials, which is no small thing — these protocols take enormous amounts of planning and effort to put together and are something of a commercial secret for the companies that do them.
What this means is that we can know almost everything about what the researchers were planning to do and what they said that they have done in their press releases. We know the sample sizes they were aiming for, the safety profile they were looking at, and all of the minutiae to do with the efficacy of the vaccines that is required to get these things approved by regulatory agencies.
And here is the bit where I will fanboy for just a moment. These studies are nothing short of incredible. If you had asked me whether we could go from identifying a new pathogen to a working, more-than-90% efficacious vaccine in under a year before 2020, I would’ve giggled nervously because the idea was just so ridiculous. And yet, the science behind these phase 3 trials is some of the most amazing, well-done work that I have ever had the good fortune to read. The people conducting these trials really did know what they were doing and did it very well.
Take the Moderna trial, for example. In the space of two months, they planned, revised, and implemented a trial protocol to recruit 30,000 people, and then they did just that. I’ve run clinical trials myself — I’m currently working on two of them — and it took us far longer to get everything into place to do so.
Which makes the question of whether we are rushing these things very reasonable. Are we?
To know if we are rushing things, the first important point is the context. Most people are aware that vaccine trials take years to conduct, but they don’t understand why that is. The reality of research is that while you may spend the better part of a decade getting all the studies that you need done, most of that time is spent doing, well, not much at all.
In the “before” times, it took years to get a vaccine funded, months to recruit enough people for phase 1 and 2 trials, years to secure lasting funding for the more expensive phase 3 research, and more years still to actually recruit people into phase 3 trials and have enough events (cases of disease) to know if the vaccine worked.
Those last two points are key — even once you have a vaccine candidate you want to test, it can take a very long time to recruit people into your trial and even longer for them to actually be exposed to the disease enough for you to run a meaningful comparison. Here’s an HIV vaccine trial that took 18 months to meet the target recruitment of 5,000 people and another 18 months to have enough HIV infections to run a statistical analysis. Another example of HPV vaccination only took 13 months to recruit 5,000 people but had to wait three years until enough infections had occurred that they could analyze the results. Because the studies are designed statistically around a certain number of cases, you have to wait until enough people have been infected in both groups before you can actually declare the study complete.
Compare this to Covid-19 vaccines, which have recruited tens of thousands of people in a matter of months and have reached their infection targets only weeks later. Going back to the Moderna trial, for example, they have seen about 200 infections in their sample of 30,000 people, which means that since they started recruiting people in July, nearly 1% of their entire sample has had a Covid-19 infection.
In a very real sense, you can thank (blame?) the massive Covid-19 spread in the United States for the quick turnaround of the vaccine. If fewer people were getting sick, we would not have these results yet.
So it’s actually not correct to say we have rushed these vaccine trials. What’s really happened, by and large, is that we’ve removed the usual hurdles such trials face. Funding has been no object, recruitment has been quicker than ever before, and even minor things like finding trained staff has been much easier this year than in previous ones.
The vaccine science hasn’t really been rushed. But what about safety?
As a scientist, epidemiologist, and general nerd, I know quite a bit about vaccines and their development, so trust me when I say your safety concerns are perfectly reasonable. From the perspective of an expert, it may seem a bit weird that so many people are worried about whether the vaccines are safe, but I think it’s entirely understandable that anyone who didn’t have the time to comb through several 100-page trial protocols might be worried about the vaccines and their safety profile.
When we’re talking about safety, what we usually mean is what’s known as Serious Adverse Events, or SAEs. These are issues that arise due to the vaccine that usually cause hospitalization, the risk of death, or a major issue for a person’s quality of life.
We don’t really care, for example, if a vaccine causes a headache that lasts for a day in 10% of people. Don’t get me wrong: This is vital information for public health authorities, regulators, and doctors, but it’s not the sort of thing that causes great concern for those of us who are getting the vaccination. What we’re really worried about is the potential for a rare side effect to occur that could leave us in the hospital or worse.
At this point, it’s worth reflecting on just how enormous these Covid-19 studies are. Most phase 3 trials recruit fewer than 10,000 people. Very few recruit more than 15,000. The two vaccines now being licensed managed to recruit 30,000 and 44,000 people into just two studies, which really makes them quite large. And while the vaccine trials haven’t been completed — the monitoring for overall safety takes a full 24 months — virtually all SAEs caused by vaccines occur in the first month after the vaccine is given. By the time people actually start getting their shots, we will have at least six months of vaccine data, which while not perfect is still quite robust.
What this means is that once we see the data, of course, we can be quite sure the vaccine is safe for even rare events. If there were an SAE that happened more than once per 1,000 vaccinations, we would be almost certain to pick it up, and more than once per 10,000, we’d probably notice a signal. There may be SAEs that happen even less regularly than that — it’s plausible that something that only occurs to one in a million people will be totally missed — but these will still be some of the safest vaccines ever licensed if the press releases turn out to be true.
The problem with the really rare side effects is that they are basically impossible to pick up in a randomized trial — something that happens to one in a million people requires a sample size in the tens of millions to discern, and that’s just not realistic. However, we do have a mechanism to detect these, called a phase 4 trial. This is the monitoring that looks at the safety of vaccines in a population once they have already been licensed and exists to make sure we haven’t missed anything concerning.
So when we get the vaccines, whether that’s late this year or sometime in the next, there will be a small chance there is a very rare side effect that has not been recognized in the trials. But when it comes to these really rare side effects, it’s worth thinking about the cost-benefit angle. In our study on Covid-19 infection fatality rates by age, my colleagues and I demonstrated that even for younger children, the risk of death from Covid-19 infection is about one in 100,000, and the risk of a serious event requiring hospitalization or long-term care is even higher than that. For anyone over the age of 20, the risk of death from Covid-19 infection is higher than one in 20,000, which means that even without knowing everything, we can be pretty sure at this point that the vaccines will be safer than the disease itself.*
So, will the vaccines be safe?
All of this hinges, as I said right at the start, on full transparency by the manufacturers. As an expert, I trust regulators to do their job, and I’m sure they’ve very carefully combed through the data before approving any vaccines. That being said, there’s nothing like seeing the results for yourself and interpreting the information without the opaque filter of bureaucracy in the way. I would add that vaccine manufacturers have been amazingly open throughout this entire year — I sincerely hope they will continue that trend and release this data as soon as possible.
However, with this caveat, important as it is, I think we can pretty reasonably say that the vaccines are safe and, yes, effective. The amount of effort that has gone into getting them to this point is truly remarkable and may be one of the most impressive scientific achievements of the last 100 years. As long as the press releases hold true, Covid-19 vaccines will be safe to get when they are released.
And on a personal note, as an epidemiologist and just someone who doesn’t like getting deadly infections, I will be first in line once a vaccine is approved.
*Note: While it’s true that this risk also varies depending on your risk of getting Covid-19 in the first place, the probability of being infected at least once approaches 100% as time — and the epidemic — moves forward.