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I am curious if there has ever been a (modern) clinical study where a healthy volunteer was purposefully infected with a pathogen in order to test the effectiveness of a therapeutic or preventative measure (like a vaccine)?

If not, would the FDA allow for ethical exceptions in cases where there is an extreme case of urgency (like in a pandemic)?

Obviously these would be willing volunteers who signed waivers, etc. So Nazi experimentation, the Tuskegee trial, and other studies without total consent from the participants wouldn't qualify here.

Edit: Self-experimentation wouldn't qualify here either because the bioethics of self-experimentation are different than testing on others.

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    $\begingroup$ What counts as "modern"? There is a long history of self-experimentation by medical researchers many of which would seem to fit your criteria ... $\endgroup$ – tyersome Apr 4 at 19:36
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    $\begingroup$ Why is this question being downvoted? Is this stackexchange not appropriate for questions on medical and biological history? $\endgroup$ – Nova Apr 5 at 0:33
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    $\begingroup$ @BryanKrause I was going to contribute that very example as answer, but then I realized it doesn't strictly answer the question. The victims of the Tuskegee Experiment were not deliberately infected with syphillis, rather their existing cases of syphillis were deliberately left untreated, and the diagnosis was concealed from them, "to study the course of the disease". Appallingly unethical, but not quite relevant to this specific question. $\endgroup$ – Charles E. Grant Apr 5 at 1:01
  • $\begingroup$ @Charles Ah good point, I got that detail wrong. I think I'm confusing it with a separate unethical experiment. $\endgroup$ – Bryan Krause Apr 5 at 2:53
  • $\begingroup$ Is 1900 considered modern? Yellow fever, in Cuba, and not just one volunteer, but a whole group. $\endgroup$ – Peter Mortensen Apr 6 at 4:52
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This is a great biological question! It asks a lot about how empirical science is done in the field of modern biology. I'm glad we encourage such questions from curious people who want to learn more.


One can't easily separate ethics from how biology is done, as much as some people have tried. (Though I suppose some have made bioethics into a separate and successful media career, so it can be done in that way.)

In addition to the comment-answer about the Tuskegee Study, Nazi doctors in Germany performed experiments without consent, which included infecting concentration camp prisoners with the bacteria that cause tuberculosis.

Your question is about volunteerism, however, and the victims of the United States and Nazi Germany did not give full — or any — consent to experimentation.

In this week's issue of Nature, there is a news article which interviews bioethicist Nir Eyal about a recent preprint, of which he is a primary author.

In this interview and in the preprint, your very question about coronavirus vaccine research, specifically, is discussed, as it concerns the matters of consent, ethics, and safety of doing accelerated biological research about this virus in a time of emergency.

In answer to your first question about modern clinical studies, Dr. Eyal notes:

Are there any precedents for infecting healthy people with a pathogen?

We do human-challenge studies for less deadly diseases quite frequently. For example, for influenza, typhoid, cholera and malaria. There are some historical precedents for exposure to very deadly viruses. The thing that demarcates the design that we propose from some of these historical instances is that we feel there is a way to make these trials surprisingly safe.

As an example, there was a challenge trial for malaria performed in 2012. Healthy individuals were bitten by mosquitoes carrying the malaria parasite and then treated with antimalarial therapies.

Clinical trials are done under the aegis of government agencies with review and approval processes, some of which are described on the FDA web site. IRBs or Institutional Review Boards provide oversight:

Under FDA regulations, an IRB is an appropriately constituted group that has been formally designated to review and monitor biomedical research involving human subjects. In accordance with FDA regulations, an IRB has the authority to approve, require modifications in (to secure approval), or disapprove research. This group review serves an important role in the protection of the rights and welfare of human research subjects.

History does guide us to worry about the ethical issues surrounding medical trials, especially under exploitative regimes that leave people to fend for themselves during a time of global crisis:

Do you worry that countries with authoritarian governments could conduct such studies on vulnerable groups, such as prisoners or members of persecuted minorities?

We would only recommend conducting the studies in an ethical fashion, with fully informed consent. Vaccine makers want to sell their product to other countries. They want to publish their scientific articles in prestigious journals and there would be many obstacles if their trial doesn’t adhere to widely accepted standards.

But in the modern age, in non-corrupt regimes, science does aim, for the most part, to do the right thing, and there are methods and regulatory mechanisms in place to try to enforce societal standards that move us past the days of Tuskegee and Nazi concentration camps.

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Yes, Dr Barry Marshall self administered Helicobacter pylori to investigate whether it causes stomach ulcers. He won a Nobel Prize for it.

https://en.wikipedia.org/wiki/Barry_Marshall

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All the time!

For example Flucamp does research on influenza, rhinovirus and (non-SARS) coronaviruses, that involves deliberate infection of paid volunteers.

When the trial starts, we only inoculate them with a weak cold or flu virus so the body can fight this off without a high level of risk, before monitoring the disease cycle as they go from healthy to sick to healthy again in our bespoke medical research facility.

Science Magazine notes that such trials are on the rise as we learn ways to weaken a pathogen before introducing it to a human subject.

Today, people are being deliberately infected with malaria, influenza, shigella, dengue, norovirus, tuberculosis, rhinovirus, Escherichia coli, typhoid, giardia, and campylobacter.

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Julius Wagner-Jauregg, an Austrian psychiatrist, while investigating fever to cure forms of insanity (pyrotherapy), infected his patients with malaria. This triggered an immune response that cured neurosyphilis. He was given the Nobel Prize in Medicine in 1927.

Sources:

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  • $\begingroup$ Welcome to Biology.SE! This looks like a reasonable answer and it's great that you provide supporting references. However, please include the complete reference information since links can break. One easy way to get that information is to search for the paper on Google Scholar and click on the ‟ symbol to get reference information. This is a good example of how to format references. Thank you! 😊 $\endgroup$ – tyersome Apr 5 at 18:30
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It used to be fairly common to do this with prison inmates. The inmates would be asked to volunteer, motivated by some reward such as earlier release. An example of this type of study is a 1954 experiment by Rendtorf in which prisoners were given Giardia spores in order to determine the minimum amount that could cause disease. For a description, see Rose 1991. This particular experiment was helpful to society because it clarified how minimal the danger of giardiasis is in many cases where people had previously been concerned. It also posed little serious danger to the inmates, since giardiasis is usually asymptomatic, doesn't kill you, and clears up by itself. Ethics review boards will no longer approve this type of prison study because they consider the setup to be inherently coercive. However, if I were in prison, I would have certainly been very happy to volunteer for Rendtorf's study in order to get out earlier, and I would have been angry at an ethics board that denied me that choice.

Rose 1991 - Rose, Haas, and Regli, "Risk assessment and control of waterborne Giardiasis," Am J Public Health 81 (1991) 709, http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1405147/pdf/amjph00206-0039.pdf

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  • $\begingroup$ "I would have certainly been very happy to volunteer for Rendtorf's study in order to get out earlier" -- and you'd have been a fool to do it. There is no more oversight or accountability for prisoner welfare than there was for the (pre-civil rights) blacks involved in the Tuskeegee fiasco. If it's so safe and harmless, why conduct such experiments on a demographic fundamentally incapable of seeking independent medical opinion (informed consent, ha!) and who lack the means to sue for damages in the event complications do arise? $\endgroup$ – Ivan Apr 7 at 20:11
  • $\begingroup$ @Ivan — Please be mindful of the code of conduct for users of this site and review the relevant help center material. Given the context I'm not flagging your comment as abusive, but it could easily be viewed as such. Thanks! 😊 $\endgroup$ – tyersome Apr 9 at 1:52
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Operation Whitecoat, a research program run by the US Army, used enlisted men who had registered as conscientious objectors and volunteered for the program. The research investigated defenses against possible biological weapons, testing vaccines and antibiotics on these volunteers.

https://en.wikipedia.org/wiki/Operation_Whitecoat

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From the Wikipedia page about the British Common Cold Research Unit, which operated from 1946 to 1989:

Thirty volunteers were required every fortnight during trial periods. The unit advertised in newspapers and magazines for volunteers, who were paid a small amount. A stay at the unit was presented in these advertisements as an unusual holiday opportunity. The volunteers were infected with preparations of cold viruses and typically stayed for ten days.

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