We should rethink the ethics of vaccine challenge tests to be more like those of a battle


As vaccine approval nears, you've no doubt heard proposals to speed up vaccine testing with what is known as a "challenge" trial, where you deliberately infect volunteers with the virus. This approach is controversial, but has been around for some time. There are already organizations collecting volunteers, and tens of thousands have signed up.

It is suspected this may have been done in China and Russia to speed deployment of their vaccines, which came out much sooner. What's also clear, in hindsight, is that challenge testing would have been a huge success on the Moderna and Pfizer vaccines -- had they been given to 1,000 volunteers, about 50 would have gotten mild cases from which they would have recovered quickly, and in just a few weeks we would have had solid data on their high efficacy. It's less clear this would have happened with some of the other candidates. The vaccines would have been deployed months sooner, and due to the recent winter surge (which many felt was coming) many tens of thousands of lives would have been saved.

We didn't do it, because naturally, this sort of practice is normally anathema in ethical medical research. It cuts to the core of "First, do no harm." I evokes many unethical practices of the past. Deliberately putting people at risk to do research just isn't done.

In spite of this, the movement grows because of an interesting variation in philosophical mindset. This isn't just medical research, it's a war against a foreign enemy. In war, an army of volunteers (or even conscripts) are put at risk to protect the nation and its people. Far from being unethical, in a battle this is considered one of the highest callings -- a distinct honour.

In theory, with just a small cadre of volunteers, you will learn a great deal about the efficacy of a vaccine candidate within as little as a week. (You need more than a week for the full data, but you'll know in just a few days if it's either ineffective or highly effective, and over time you'll quickly learn more details, and from there can expand to other populations, particularly the elderly, if the results were good.

In hindsight, with such amazing efficacy, it would have been great. But it can be argued this is true even when some of the vaccines tested might be low efficacy.

One issue, as this article arguing against challenge testing points out, is you may only learn how effective the vaccine is on healthy young adults, because that's who the volunteers will be. Evidence suggests they catch the disease the same as others, but are much less harmed by it, with a death rate in the range of 0.1% and lower rates of many complications.

These vaccines have already had trials for safety. If you find out they work in a week, and (as is happening for promising vaccines already) you have started pre-manufacturing supply, you can be deploying that vaccine fast. The article above argues that it's not that much faster, but that's because it uses the normally laudable cautious approach of medical research, not a battle.

If you get the vaccine out 1-2 months sooner, you are going to save a lot of people from getting the virus. Especially if you do so when a big surge might be anticipated. On top of that, you're going to bring the economy back much quicker. Vaccines would be prioritized not just to health care workers but also to the so-called essential workers and people who are out of work because of lockdowns. Travelers and fight attendants -- the people needed to bring the global economy back. All months sooner.

First volunteers would, as noted, all be young. And they would be provided with the very best treatment should they get infected, better than they likely would have gotten if they were naturally infected out in the world. But their risk will still be real. There could be a few deaths, and there would perhaps be some of the other long term survivor injuries still being studied. Most vaccines are not close to 100% effective, some some volunteers would definitely get it.

They would probably also be compensated, perhaps quite well. This is also a controversial step, because it can lead, essentially, to using the poor for medical experiments. Of course, this happens a lot already, but we're not fond of it.

One thought is to choose volunteers who have high risk jobs. For example, being a logger has a 1 in 1000 chance per year of death, which is higher than the risk from Covid for a young, healthy person. It is one of the worst in the USA, but there are other occupations around the world that are worse, such as mining in China. Many who die at dangerous jobs are somewhat at fault for the error which led to their demise, so it's better to look at jobs which don't have that pattern.

It's also clear that society seems willing to tolerate people accepting a risk similar to the risk of Covid infection simply to make a living, for no great benefit to society. Should it be unable to accept that when the social benefit is so great? Should we be more afraid of it because the benefit is so great?

Put simply, if you paid people enough money to give up a job like logging for a year to become a vaccine tester, you would actually be reducing their risk of death that year. (To be fair, somebody else would move to take their job so the net is not as good.)

There are other (also controversial) compensations which can be offered, such as reduction in prison sentences, purging of criminal records and more. Drug trials with prisoners are common and have existed for some time, but are definitely a source of debate.

Of course, volunteers could literally come from the armed forces. It would not even be contrary to war ethics to order them to do this -- and this virus has already killed more people than many wars.

All of these issues are real, but it's also real that getting confirmation of an effective vaccine for this virus is the highest value medical result we may have ever seen in modern times. From a purely utilitarian (greatest good for greatest number) standpoint -- risk taken vs. positive results -- it's a very solid win. But members of the public, and the research community, are very rarely utilitarian. The dark side of utilitarianism is known by the more pejorative term "the ends justify the means."

The public's moral philosophy

To answer this question, you need to understand the public's concept of moral philosophy. Generally, broad opinion is an inconsistent mix of results based morals (known as consequentialist morals, including utilitarism) and rules based morals (known as deontological morals.) Indeed, individuals are often a mix of these two opposing theories. Philosophers study this, and the famous "trolley problem" which is so hated by myself and everybody else in self-driving cars actually has an original purpose in this area which is of value.

One of the classic dichotomies is that while the majority of people asked in that problem say yes to switching the trolley to run over one person tied to the tracks to save five, almost none say yes in the version where there are 5 patients in need of organs, and you can grab an innocent man off the street to harvest them, even though the result is the same.

This issue isn't as simple as either pole. In spite of the talk above about paying the subjects, there are already more than enough volunteers, willing to do it for the good of society, and perhaps to get first crack at being immune. Tons of people are protesting and want to go back to normal life, not caring about the virus risk. For them, this is a way to do that (after a month or so of isolation) with a lower risk, not a higher one.

There's another bit of math. Consider a challenge test of 200 volunteers exposed to the virus on day 1. Compare with a standard study with 20,000, half of whom are in the control group with no vaccine, running for 4 months. It's entirely plausible that more than 200 people in the study will be exposed (half with no vaccine) in that period of time. In fact, the study requires it, that's why it has to last for several months. So even in the study group more people will be infected, and with half of them unprotected, more of them will suffer negative consequences or death. To get a result that's not as conclusive.

Because things work fast, you can start with a small challenge volunteer group and get a very quick rough number, and get information quickly on what to do next. You would not do a challenge trial on at-risk people but you can better inform what vaccines and doses you test on them in other ways. With a small group you can also do daily PCR testing so you can measure how many people got asymptomatic but spreadable infections -- which was not done with the existing vaccines.

Even now, it is not too late to rethink these ethics and realize we're in something as big as a war.


For this vaccine I don't think enough is gained from giving people a placebo. They could get hundreds of thousands of volunteers for a 50% (or 60%, or 80%, or whatever) chance of getting the vaccine. The other 20-50% would still be studied, but they would know they didn't get a vaccine. We'd know in a couple weeks if it's likely that the vaccine was highly effective if you give it to hundreds of thousands of people. Sure, you might not know the exact percentage as closely as with a double-blind study, but so what?

I see why they do the placebo thing. It does provide more information. But 1) people who know they got the vaccine are likely to take more risks, so you get a minimum effectiveness, and 2) most of the people who got one of the mRNA vaccines were well aware of it anyway, as they experienced a significant immune response.

Tens of thousands of people are dying because of stupid FDA regulations.

As far as vaccine challenge tests, as long as people so it voluntarily after knowing the risks, I don't see an ethical problem with it. But it doesn't seem necessary or even very helpful. In fact, and perhaps most importantly, it probably provides much less real world information than a short, massive, non-placebo-controlled study. Knowing whether or not the vaccine protects against a mild case of COVID is not very helpful. The Moderna vaccine is highly effective in protecting from severe COVID. You'd learn that from a non-placebo-controlled, study, but not from a challenge test.

I do agree, that this is a situation where double-blind was not needed for the efficacy study, though you still may need to do it for the safety and side-effects studies. In some of these trials they give the control group a vaccine for another virus so they will experience sore arms etc.

The ethical problem stems from the medial doctrine of not deliberately harming, ever. Even to volunteers. What I write above is, perhaps we should consider something like covid more like a battle with an enemy invader than like medical research.

As you point out, there are lots of risks that people take all the time. I don't see why you have to falsely compare this to a war to show why there's no ethical problem with asking people to voluntarily take some risks.

I don't know all the details of how the doctrine to do no harm applies to medical research, so I can't really comment on that.

The links in the article made some of the case for that. They vary, but the strongest ones relate as well to the temptation it offers. You don't want to skate even close to the edge of mad science, Nazi medicine. It is too easy to find volunteers for things (especially drugs, because the victims of disease are desperate) and so there is a fear it goes beyond, and you get volunteers who are not fully informed, and you kill a bunch of them.

https://www.pnas.org/content/117/46/28538 is a good explanation for why human challenge studies for SARS-CoV-2 vaccine development are unethical. The article raises some of the same points I raise above.

It's not because human challenge studies are always unethical. It's because human challenge studies aren't likely to be very useful for COVID vaccine development. Okay, after the study, which might take months, we know that the vaccine is highly effective in preventing minor illness in healthy people. We still don't know if it is effective in preventing severe illness in older or unhealthy individuals, which is exactly who we're trying to get these vaccines out to first.

It cuts to the core of "First, do no harm."

So, I looked it up. "First, do no harm" is a not an ethical principle common to medical researchers. https://www.health.harvard.edu/blog/first-do-no-harm-201510138421 https://www.bmj.com/content/366/bmj.l4734/rr-2

Deliberately putting people at risk to do research just isn't done.

It's done all the time. All vaccine trials pose a risk. pretty much all medical research poses risks. You need informed consent.

"The Nuremberg Code made voluntary consent and freedom from coercion necessary conditions of clinical research studies." As long as you receive informed consent you should be fine.

Vaccines would be prioritized not just to health care workers but also to the so-called essential workers and people who are out of work because of lockdowns.

Giving this vaccine to anyone without a pre-existing condition before everyone over 74 who wants a vaccine has gotten a vaccine, is a huge mistake.

Tens of thousands of people in the USA are going to die because health care workers are top priority.

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