My guess is every engineering student since the mid 1940’s has had to watch the video of the Tacoma Narrows Bridge collapse. Other professions have similar cautionary tales of hubris, short cuts, innocent mistakes, misunderstanding of nature, and things that went terribly wrong. They are often clear in hindsight, but lost in the immediate noise and pressure of crisis decision making. Often progress requires risk – but the two require a rational balance. Now that a number of potential vaccines are approaching approval and distribution, everyone from government officials to individuals are soon facing difficult decisions: who gets what vaccine, when or if to take it, and what level of persuasion (or even coercion) should be used to get people to take them. Yes, these are difficult decisions, and to be blunt anyone who says it’s a “no brainer,” simple, or obvious is either fostering an agenda, being disingenuous, or doesn’t know what they are talking about. These questions are even more difficult because several of the potential vaccines on the verge of distribution are using technologies that have never seen wide spread distribution and use. Compounding that are issues of politics, National pride, and commercialism. The details are complex, and most of the simplified explanations I’ve seen (and more than a few technical ones as well) are biased either towards “trust us; don’t worry” or “it could be a beaker full of death.”
As with most issues, the truth lies well within the extremes, but the the decisions are ultimately fairly straightforward. We have to weigh the consequences of COVID19 (to society and the economy as well as physical health) against the effectiveness and risks (known and unknown) of the various vaccines. Given the complexity, both advocates and detractors (some quite vocal) among the general public really don’t fully understand how any of the vaccines work or their implications. For the vaccines under development, there are four broad classes (link goes to Nature article with good graphics). The major vaccines that have been approved or are closest to certification are in three classes: killed virus (the Chinese Sinovac), viral vector, such as those based on the Human adenovirus (like the Gamaleya vaccine) or Chimpanzee adenovirus (AstraZeneca/Oxford); and those based on nucleic acid – the mRNA vaccines (Pfizer, Moderna). The killed virus approach is how most current vaccines work. The viral vector vaccines are fairly recent, but there are a few that have been approved and in use for over a decade. The mRNA vaccines are substantively different. And it is here we have a bit of a problem.
mRNA vaccines and related technology have only seen small scale experimental use, usually in the context of cancer or other deadly diseases, and have never before been certified. In theory they should be safe, perhaps even safer than traditional approaches, but there are some potential risks and more than a few unknowns. At least some viral vector based technology has been around for 17 years and Gameleya, for instance, has a number of vaccines (including an Ebola vaccine) that have been approved and in use for years. For those vaccines there have also been long term studies as to adverse reactions. So while the actual vaccine for SARS-COV-2 is new (since, obviously, the virus is new), the vaccine methodology itself isn’t – in fact, one was in development after the SARS-COV-1 scare back in 2008. For the mRNA vaccines there have been no long term trials or monitoring, and no previous vaccines approved for human use based on these technologies. Another factor is that the various studies are not using consistent criteria and methodologies. This is a distinction lost on many in the media, such as the NY Times article last Sunday discussing the commencement of distribution in China (Sinovac), Russia (Gamaleya’s SputnikV), versus Great Britain (the Pfizer vax). The FDA briefing materials for the Thursday Pfizer approval meeting also glosses over this issue, but is clear there are a lot of unknowns.
With all of the vaccines, there are unknowns, and always some side effects. How effective is it in the real world? And by “effective”, be very careful how that is defined – some of the criteria in the current Phase III studies seem like pretty low bars compared to past studies. Do they minimize transmission, protect the person inoculated from getting sick, minimize (but not prevent) symptoms? How long does immunity last – and how do the inevitable mutations impact effectiveness? But the ultimate question is do the advantages in reducing the consequences of COVID outweigh the potential side effects of the vaccine – especially given the need for mass inoculations of 80%+ of the population? There is little doubt that the benefit/cost radio of vaccination will be in favor of vaccination if – and it’s still a big IF – they work as the early results indicate, and adverse reaction rates are similar to other vaccines. But can we assume that? Most advocates are. With the mRNA vaccines there are additional unknowns as to the long term impact of the underlying delivery methodology. Again, in theory it should be as safe, and perhaps even safer than more traditional approaches using a live, killed approaches. But we just don’t know. While the short-term impacts seem low based on the early trials, they are just that: short term, relatively small scale studies (weeks to months, thousands of people). No one knows what, if any, the long term consequences of this kind of vaccine as a whole might be when applied to the general population over time. It’s never been done before. There is no reason at the moment to suspect there is some hidden gotcha – but the designer of the Tacoma Narrows Bridge didn’t think it would rip itself apart either.
Opinion and Conclusion: As I have said before, COVID-19 falls in a gray area. If it were causing wide scale deaths across a wide range of groups, and mRNA vaccines were the only viable option, then maybe we would need to “roll the bones” with a new technology. And yet, COVID is bad. But for all the disruption and pain COVID has caused, it’s not smallpox or the black death, much less the FGC-347601 virus Dr. McCoy had to deal with (and recall in that tale, the disease itself was actually an unforeseen side effect of a noble original objective).
Make no mistake: mRNA therapies have the potential to be a major innovation in the treatment of all kinds of diseases from cancer to COVID. But while pressure often leads to rapid advances, we’ve also seen far too often in the history of technical advances that the temporal or economic pressure to do something now leads to catastrophe. Tacoma Narrows. Challenger. Mars Climate Orbiter. The pharmaceutical industry isn’t immune either: Thalidomide, or more recently Vioxx. Darvocet. That said, don’t fall into the anti-vaxxer trap of seeing every adverse reaction as evidence of a conspiracy. It’s painful to say it but a certain adverse reaction rate is acceptable in light of the impacts of the pandemic. And, yes, Big Pharma sees this as a huge money making opportunity, and that requires monitoring and regulation. But Pharma have done a lot of good work, and in the present system, being profitable is how things get done.
When you weigh all the factors, in my opinion it is simply too soon for the wide scale application of some of these vaccines in relation to the risk from COVID (again, not to minimize that risk). Much of the harm of this virus has been self inflicted – a coherent global response would have cut the economic impact five fold, and the death toll by a third in my estimation. If everyone would just behave responsibly, between mitigation and other measures we would have some time to sort this out. Let’s take a deep breath, proceed cautiously, roll out the various vaccines in a reasonable way and not get hung up on national pride (noting some vendors in China have an unfortunate reputation), or commercialism, while moving expeditiously to apply new technologies in parallel as they are validated. The rollout of the new, untested vaccines can and should be spaced over several years. Supply chain issues may force that in practice anyway, but that should have been the plan from the start. And foreign developed vaccines – properly vetted for safety, without nationalistic biases – should be allowed in as part of the mix. The Gamaleya vaccine is likely a prime example. But even the vaccines based on established methodologies need more testing.
I think it is reckless to push the wide spread distribution of novel vaccines on tens of millions of people until there is a longer safety and performance baseline. As noted above we have absolutely no idea what the medium term (2-3 years), much less long term (5-10 years) implications are with respect to adverse outcomes for some of these approaches. It is especially reckless where there are several candidate vaccines with more well understood risks. Maybe the mRNA based vaccines are fantastic, but not only do we not know, we don’t even have the data to know and won’t for several years. To coerce hundreds of millions of people to take these vaccines in an experiment of this magnitude is simply unethical. Should ever increasing numbers try it? Of course – with an appreciation of the risks, under careful supervision and long term monitoring. Those at highest risk? Absolutely – although I’d be careful with otherwise healthy members of the health care community upon which we depend. Tens or hundreds of Millions? It’s just too soon.
Don’t mistake this post as “anti-vax“. It isn’t. I got a flu shot back in September. I get other vaccinations and boosters as needed for travel, etc. For what it’s worth, I’ll try to get one of the vaccines based on established methodologies when available, or, as a number of biomedical researchers have said – usually privately but in this link one does publicly – wait a couple of years until there is a longer term baseline regarding both effectiveness and adverse reactions. The bottom line is that in every medical decision, you have to weigh the pros and cons. Primum non nocere – first, do no harm. Are we doing that by rushing out the novel COVID vaccines for mass vaccination? Needless to say, I’m concerned.
Addendum: I’m not a physician, but I do understand a lot of the issues surrounding this at a fairly detailed level More importantly, I am pretty knowledgeable (some would say expert) in emergency management decision making and how things go wrong in complex scientific and technical processes. To be absolutely clear, I’m not advising anyone not to get one of the new vaccines. I think a lot of people probably should get them. At the moment there is no reason to suspect there is anything wrong with them. In fact many if not most of the fears of the mRNA vaccines are way overblown. But that doesn’t mean it isn’t rational to have some concerns, and saying “we don’t have any reason to suspect there is anything wrong” is VERY VERY DIFFERENT from saying “here is a 5 year followup study that shows nothing is wrong”. Read the actual FDA briefing materials to see how often the word unknown is used. There are lots of competing blog posts and opinionating on all of this, and much of it lacks nuance. Don’t be stampeded into one position or another out of fear. Fear is the mind killer …