Human Challenge Trials for vaccines

From an anonymous reader:

As you are of course aware, testing on vaccines for Covid-19 are beginning to be undertaken. The scientific community has seemingly decided that Human Challenge Trials (HCT) where test subjects are directly exposed to the virus following vaccination are unethical, instead using the typical protocol of vaccine/placebo inoculation followed by months of observation in order to observe effectiveness. This seems to me a grave moral error based on the following argument.

1) There exists a large cohort of young, healthy, fully informed, willing participants who would undergo HCT.

2) Given the mortality profile of this disease, these participants would be undertaking an exceptionally small mortality risk (perhaps 5-10 per 100k, based on data from Spain/Italy/NYC, assuming zero vaccine effectiveness).

3) Society deems acceptable other activities with much higher fatality risk (at least 5-10x) in both professional (soldiers, logging workers) and recreational (motorcycling, mountaineering) capacities.

4) HCT would speed up the vaccine testing process by many months, saving tens of thousands of lives and avoiding enormous economic damage.

5) HCT actually poses significantly less risk to participants in terms of allergic reaction or ADE risk compared to a standard testing protocol since the number of participants could be much smaller and they would be medically observed.

I fail to find any ethical justification for the current stance of the medical community, from either a utilitarian or deontological perspective, and believe a highly consequential error is being made. This error may be based on false analogies to past unethical testing practices in history where participants were not informed or willing and danger was significant. The current case bears no ethical resemblance, in my judgement, to these past cases.

The simplest model of such errors is that many members of the biomedical establishment do not wish to have bad feelings about any “sins of commission” and to see their status lowered as a result of “dirty hands,” and the readily criticized logistics of Human Challenge Trials.  Since HCTs do not “feel right” to them, they self-deceive into associating that feeling with a concern for the greater public good.

You should not be surprised to see grave moral errors committed in a crisis, however.  Our “mainstream” protection against grave moral errors, in normal circumstances, simply is that usually we are not given the opportunity to commit them.

I do understand that a Human Challenge Trial does not necessarily suffice to show that a given vaccine is safe.  Nonetheless it should be in the “armor of our discourse,” so to speak, as a morally acceptable alternative.  So if you are a biomedical professional, or a public intellectual, I hope you will speak up.

Here is a Matt Yglesias piece on the urgency of developing a vaccine as quickly as possible.  Eric Weinstein notes that women risk their lives every time they proceed with having children.

Comments

Instead we're basically conducting human challenge trials with grocery workers and delivery people.

People per square meter is indicative of salient gauge, as per basic vector field theory.

They have been given vaccines?

Grocery workers and delivery people are working low risk jobs. Covid19 seems to spread most to people spending time together in confined environments for extended periods of time -- nursing homes, hospitals, factories, offices, perhaps public transportation, within families under lockdown. Casual contact in stores and such is low risk. The rate of coronavirus infections among grocery workers is actually lower than the rate of infection among the general population.

We could combine the president forcing meat packing plants to operate with providing candidate vaccines to the plant workers.

Voluntarily, of course.

Three week old quotes aren't going to get you the ratings. Here is what a real leader was saying yesterday. “Tremendous progress has been made, we think, on a vaccine. You always have to say think and then you have to test it, and that takes a period of time. But uh, a lot of movement and a lot of progress has been made on a vaccine. But I think what happens is it's going to go away. This is going to go away. And whether it comes back in a modified form in the fall, we'll be able to handle it, we'll be able to put out spurts, and we're very prepared to handle it. We've learned a lot, we've learned a lot about it, the invisible enemy."

If you want to outdo Trump, low energy Joe, you need to keep this pace up day after day, week after week, month after month. Just face it, you will never achieve Trump's mastery of the ratings.

We have to make sure all survivors - survivors of people of color, survivors of immigrants, survivors of natives, native native native of Americans survivors, older survivors, survivors with disabilities, the LGB - the LG - the LGB - the LGBT community survivors, they all need support. We have to make sure survivors and services can be connected - I worked very make - to make that hotline as uh, as uh, uh, uh - state of the art telecommunications. Now - is time to push again

Nobody cares, no ratings Joe, not even google. You will never win against someone able to say things like this, day after day.

The reporter then asks Trump to clarify whether he thinks the country can conduct 5 million tests per day and the president doubled down.

‘Oh, we’re going to be there very soon. If you look at the numbers, it could be that we’re getting very close. I mean, I don’t have the exact numbers. We would have had them if you asked me the same question a while ago because people with the statistics were there. We’re going to be there very soon.’

The U.S. ran its most tests in a single day, 314,182, on April 22, according to the Covid Tracking Project.

Come on, man, I heard you liked me! You’re nothing to me. Nothing.

Nobody likes a senile old white male boomer. But given the pick between an embarassing senile white male boomer and our current president, you just might have a chance at being elected the Democrat's first white male senile president.

To the detriment of America, but we already know American political parties have a hard time stopping themselves from nominating senile white male boomers.

Bernie in 2024.

Wow, that took a dark turn. Keep it up Joe!!!

What force has been used? So far seems like an empty gesture.

The U.S. is less than 5% of the world population. Have all other countries come to the same conclusion?

China will probably be first with a vaccine. They had a couple months' head start studying this virus, they made progress in the past on SARS vaccines before they became moot, they won't be tied up in bioethicist red tape, and they strongly desire the propaganda victory.

Valid points, but I'd be more inclined to trust infant formula from China than vaccine testing results from China.

I.e. whatever tests the Chinese run, need to be repeated by Western labs. Maybe Hong Kong could serve as a stepping stone, a first adopter whose results maybe could be trusted.

China has prisons full of "volunteers". Vaccines that China develops can easily be tested on some breed of monkeys to test validity. Plus China would love to make friends around the world, wouldn't help to kill them.

If you have tested a vaccine candidate to determine its safety is low, and as a manufacturing powerhouse, why not produce a million doses and vaccinate a million front line health care workers with varying dose levels and varying adjuvants, why a small trial of a few thousands that get exposed to high levels of virus?

A high level of virus is not natural and might overwhelm the immune system, and even trigger a immune system cascade which results in an autoimmune response.

Health care workers from EMTs to test and trace workers, to urgent care workers, to GPs will be in contact with hundreds of people who are I'll, and in an epidemic or early stage of outbreak will be exposed at 5-10 times the rate of the general public, with only institutional residents and careers have equivalent exposure, like dorm students, assisted living facilities, prisons.

Clearly, the proposal to use HCTs is an effort to not pay workers, based on the free lunch economics of the GOP that holds an economy of profit equal to 100% of GDP will be the best economy ever. But that requires government print money equal to 100% of profit to fund consumerr spending.

An American economist unaware of why ethics plays such a major role in human experimentation. No need to Godwin any discussion, we could just mention highlights like the dirty hands involved in the 4 decade long Tuskegee experiment. 'Nonetheless it should be in the “armor of our discourse,” so to speak, as a morally acceptable alternative.' You first. Sounds like a wonderful opportunity to raise your status, volunteering to put your moral principles above your words.

This is just a stupid argument. “The Tuskegee experiment happened, ergo any human challenge studied are evil.” Did you know Hitler was a vegetarian? I guess this means you have to eat meat to not be a Nazi.

You’re not making an ethical argument; you’re making a conspiratorial analogy.

Hitler was not a vegetarian until the end of his life, which either means you are not making a factual argument or you are making a conspiratorial analogy. He was also a teetotaller, but that does not undercut TC's dedication to banning alcohol either.

Hey it could be worse. Nazis could have been for nature and wind power...OOPs, they were.

Were the Tuskegee subjects volunteering with informed consent? No. Tuskegee was not an example of a Human Challenge Trial. It was, however, an example of free, government-provided healthcare: "the African American men in the study were only told they were receiving free health care from the Federal government of the United States." [https://en.wikipedia.org/wiki/Tuskegee_syphilis_experiment]

Then there was the first flu vaccine, tested on patients at a Michigan mental hospital. They did things differently in the old days.

Your response is a strawman because no one is suggesting that researchers ignore the principle of informed consent.

Instead, the question is of "beneficence." And, here, I think Prof. Cowen has the better of the argument. First, a potential vaccine has possibly significant rewards for research subjects: if the vaccine works and if the research wraps up quickly, they can be some of the first people to go back to normal living. Second, many mainstream authorities predict that a significant percentage of the world's population will eventually become infected with covid-19 in the absence of a vaccine. So the marginal risk research subjects are exposed to may be only a few times higher than the risk they are exposed to just through normal living. Third, the mortality risk is low among young, healthy people -- it is significantly lower than the mortality risk we routinely expose astronauts to. Fourth and finally, there were 180,000 deaths in the past month from covid-19. The risks of research among willing and able research participants are small compared to the risks of proceeding as we are currently.

What is the argument on the other side, other than ad hominem?

We ask young people to join the military with the knowledge that some of them may die in combat or even training. Is it immoral to have a military? What is the difference between the risks while the benefit for society seems much greater with the vaccine. As I mentioned above, you can get a good indication of the potential success with animal testing. And by all indications young healthy people are at minimal risk. Especially given the potential success of Remdesivir.

I'd add that models suggest that the counterfactual (i.e., months longer trial period, therefore months longer before mass vacation) will result in a significant number of deaths.

Just based on body counts, which policy results in fewer dead people? And which set of dead people (trial participants vs. nursing home residents) actually gave informed consent??

No real public choice economist would ever be arguing that America needs to be able to lower its moral standards to that of a totalitarian state in a crisis.

Democracies don't ask citizens to risk their lives for the common good? Do you oppose the military, police, fire, and health care workers fighting a disease that infects them at a very high rate? Where is the moral line between health care workers volunteering to treat patients and volunteers to test a vaccine?

I don’t think there’s much hope here, Tyler. I say as someone who works in one of these fields: the ethics of medical researchers and physicians are a religion, and the professional bioethicists employed by their institutions (whose jobs really are effectively about regulatory compliance and liability minimization) are the priests. The rules they follow are largely received wisdom not subject to rational discourse.

In addition to people in this field being among the least numerate in the sciences, this is something many feel ‘in their bones’ is ‘just wrong,’ and no argument will persuade them otherwise. It will be like arguing with a Christian fundamentalist, and speaking up could be hazardous to one’s career, since it’s not like just being wrong on a scientific matter; you’re basically publicly proclaiming yourself to be ethically challenged in the minds of the mainstream consensus.

Could someone link to this supposed rejection of HCT?

This is MR, where taking things on faith is expected from loyal readers.

You must have abysmal GRE scores.

"this is something many feel ‘in their bones’ is ‘just wrong,’ and no argument will persuade them otherwise."

Persuasion shouldn't be a part of this.

This is the single most promising strategy for getting back to normal this year — by many orders of magnitude.

Killing tens of thousands, maiming hundreds of thousands and costing the world trillions to eliminate minimal risk to hundreds is nothing short of criminal negligence.

Anyone who is standing in the way of this needs to be removed from their jobs, immediately.

Would you have to pay volunteers?

Lots of professions have professional ethics about why paying for something is unethical. For example, the prestige press was aghast when Gennifer Flowers sold her story about her affair with Bill Clinton to the National Enquirer in 1992 and refused to report on it.

No payment needed. Heck, you could probably get people to pay YOU to volunteer, presumably they would later be allowed to brag about how they've saved the world.

There are millions of people who have already volunteered to do it for free, just so they could help society emerge from this faster.

Edit: Sorry, thousands. But more thousands than we probably need.

suspect globally we could find tens of millions of volunteers

Paying research subjects is kosher. In fact, participating in relatively harmless research studies is a well-known strategy among broke students to earn some extra beer money. An hour of your time can go for $15 to $25.

The problems start if you try to offer thousands of dollars. Then, the IRB is going to feel the whole business is a bit shady and will ask you to prove that you aren't attempting to exploit anyone. But compensating people at slightly-above market rates for their time is not a problem.

Do you demand that the cap the salary of health care workers who risk their lives treating Covid patients? Do you cap of prison officials and nursing home workers who become infected working with populations that have high rates of infection?

Can we be sure the vaccine won't kill 0.1% of the people who receive it? You usually determine this with a large and long term trial.

Look at the rates they accepted when testing polio. Plus you have enough cases to get good predictions. Plus animal studies project a much lower rate of infection and therefore much lower expected mortality.

Presumably, you still do phase 0/1. HCT just replaces phase 3 or 2/3

I would like someone to ask Bill Gates that if the vaccine comes in 12-18 months, would it do any good anymore or will the virus have infected everyone already?

Are people willing to lockdown for so long that the vaccine will help at all?

Lots of places are already reopening, so lockdown is not the right perspective. The cruise industry might have a bit of a PR problem though, and they are praying for a vaccine. One could even imagine a free HCT cruise on a fine luxury vessel to help speed things up.

Colleges are praying for a vaccine that will let them open in the fall

There's also a problem around selection. Tyler might have commented about the risks of selection before... well, this is a difficult cohort to recruit without selection bias. Though they might be more amenable to that right now.

Of course, one other commenter is right - other countries might do the HCT on behalf of the world. Brazil looks like a probable place

Maybe if Brazil had a warm, humid, sunny climate, they would not have more cases than China, and 5,000 fatal victims as of today.

Observe the test subjects doing what exactly? 90% of us have no symptoms, and all of the subjects will have anti-bodies. So, we expect the saliva RNA tests to find more dead corona in one than the other? But they are both vaccinated, one with the virus and one without.

There is just a null hypothesis, someone think this trough for me. The exceptions to the rule are the highly allergic, and from the experiment set up I think you will find those in both groups.

The unethical part is paying docs to do the useless.

1.9% asymptomatic per this study:

https://wwwnc.cdc.gov/eid/article/26/8/20-1274_article

uh, no

Of the 97 persons with confirmed COVID-19, only 4 (1.9%) remained asymptomatic within 14 days of quarantine,

also they note the model estimates are closer to 30%... four people in one call center outbreak study doesn't tell us much

anyways antibody studies strongly argue around 90% were never symptomatic enough to seek medical attention

They cite a previous study that had said 30%, but clearly think that 30% is wrong.

The 14-day asymptomatic rate is 4.1%, not 1.9%, though. It's quoted wrong in the abstract, but it's correct in the body. Obviously 4/97 is not 1.9%.

"We defined a confirmed case-patient as a PUI with a positive COVID-19 laboratory test. We confirmed the diagnosis of COVID-19 by using real-time reverse transcription PCR assays. "

Most likely the four asymptomatic cases were just false positives on the test, though, and this result is consistent with "there are no asymptomatic COVID-19 cases, just presymptomatic cases."

except all the antibody studies found actual infections are around 10x confirmed cases... we don't know what symptoms they had, as few of them ever got near a hospital

They've been debunked though, haven't they?

I mean it would be a really helpful result, but they were savaged for methodology and elementary errors.

there are dozens of them, even Cuomo started citing them

Long Island, 16.7%
New York City, 21.2%
Westchester/Rockland, 11.7%
The rest of state 3.6%

At this point, is there really any room for doubt? I mean come on:

There’s also new information about the timeline of the outbreak. It appears New York City may have already had 10,000 infected carriers of the coronavirus prior to its first confirmed case on March 1.

https://newyork.cbslocal.com/2020/04/23/coronavirus-survey-reveals-13-9-percent-in-new-york-have-covid-19-antibodies-cuomo-says/

Similar results from several wastewater and antibody studies around the country/globe... the ratio of confirmed to infected is usually about 10:1 (varying wildly for any number of reasons).

In New Zealand, the asymptomatic number of cases is reportedly zero in over one thousand cases.

The range of asymptomatic infection varies so wildly that one imagines that variation among strains causes great variation in viral loading. Indeed, according to a Chinese scientist last week in the SCMP, that seems to be the case,

low asympto rates among confirmed cases often seems to mean only that testing was mainly done for the symptomatic... let's see what % of antibodies random samples and wastewater find in NZ

but yeah very likely some strains are far less symptomatic than others, supposedly there are 30+... would explain large variances in death rates within regions

That doesn't seem to have been the case in the Korean study cited above. I think they tested substantially everybody in the building. They got 97 positive tests. After two weeks only four of those 97 positives remained asymptomatic.

That's pretty strong evidence that the asymptomatic infection rate is quite low and may be zero. To be clear, that says nothing about the dangers of presymptomatic spread - spread before the infected person starts to feel sick - which may still be a real problem.

I think we need to let the antibody test science gel for a while before we start using it as an argument for policy. The high false positive rate / low case incidence / biased sampling critiques were pretty damning. I hold out hope, but it doesn't seem like an idea ready for prime time.

one building tells us nothing, they also admit their methodology has some gaps

It seems like we can count of human challenge trials happening - if not in the good old US of A then in China which would certainly rather be remembered as the country that delivered a vaccine to the world in record time.

"Given the mortality profile of this disease, these participants would be undertaking an exceptionally small mortality risk (perhaps 5-10 per 100k, based on data from"

My only doubt about this is all those weird reports of organ and neurological damage from Covid, most of which may be unconnected to the disease, but if something like that does turn out to be true, the trials could end up like Thalidomide.

Yea, given the multiple recent reports of faulty Chinese medical supplies, multiple bio leaks from their labs over the years (which suggests some process and QA issues), their lack of credibility and transparency on reporting on the virus, the intense economic and political pressure for a vaccine - I’d be cautious about being an early adopter of a Chinese developed vaccine.

Would not a vaccine with a genetically marked difference to the natural virus, at lest to people likely to face exposure, work just as well without HCT's

The researchers could send a strong signal by volunteering their own children/grandchildren.

The military should do it. They have many young healthy people and are not under the same restrictions. It'd just take an order from the President and that's it.

There is no shortage of volunteers: 8000 at this point https://1daysooner.org/ . I've signed up.

it was a grave moral error not to seal the borders in December (that error killed tens of thousands of Americans), but of course hindsight isn't insight

would volunteer for the Moderna mRNA vaccine once it passes Stage One trials, based on my understanding it poses close to zero risk since it only codes for a protein fragment

they might have millions by now... this article is a month old

https://www.wbur.org/bostonomix/2020/04/01/moderna-covid-19-coronavirus-vaccine-production

Other candidates:
1) the decision to close colleges/universities, thereby dispersing those students: (i) throughout the country; and (ii) into to their elderly parents' homes
2) the decision to *not* to quarantine NYC in the traditional sense.

It's the trolley problem!

"(perhaps 5-10 per 100k, based on data from Spain/Italy/NYC, assuming zero vaccine effectiveness)."

This is really wrong, isn't it?

The worst case isn't "the vaccine has no effect," it's "the vaccine has a negative effect, making your COVID-19 case much worse."

Someone with more knowledge will have to comment, but I thought "the trial vaccine makes the disease much worse" was a reasonably common outcome in the early stages of vaccine research.

To be clear, I'd still be in favor of it as large risks seem warranted under the circumstances, but people volunteering thinking the risk is low seem misinformed.

I don't really know much about modern vaccine research, but I did think the chance of a bad result was still pretty significant.

One practical problem with limiting volunteers to younger adults is that it may not tell us about the efficacy or risks in older adults. It is not unusual for vaccine efficacy to be considerably less in older adults and risk profiles can also be vastly different. Perhaps a challenge trial with young adult volunteers might be useful in ruling out bad vaccine candidates more quickly but it I cannot imagine giving a vaccine tested only on young adults to older adults and children without a full trial. The possibility of doing more harm than good is too high.

It gives you greater control over the trial. Current flu vaccines don't work that well in the elderly but they still get the shots. It may not give complete immunity but it can make the disease less severe. Plus the vaccine can give herd immunity to the population. If the vaccine works, the fact that some smaller segment of the population might not be helped, well we should have such problems.

The first thing this reminded me of was interviews with Michael Osterholm (on Peter Attia's podcast) in which he states that the worst case with a vaccine is actually over-activating a patient's immune system, compromising their system and making them more prone to a serious reaction. So, a worst case wouldn't be the fatality rate of the virus itself but possibly much higher. That's why they test vaccines for so long.

The other thought was that there are likely to be multiple vaccines and treatments out there, probably from multiple countries. What does the West do if China gets one first? Their credibility is shot at this point, so I doubt I'd trust a Chinese vaccine without months of third party data proving its safety.

China would likely give you data on millions within a couple of months. They have been doing animal studies that so far look very good. Is it without risks? No. But we ask the military, police, fire, and health care workers to take risks on a daily basis. I asked above what is the moral line between asking health care workers to treat Covid patients vs working with volunteers to test a vaccine?

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