I didn't have time to comment on your interesting post at the time. A few thoughts:
1. The ethics are murky. I'm really old, and my prior is in favor of your suggestion. As a kid I learned the Walter Reed experiments on yellow fever from the perspective that he was a hero, and I still believe it, despite the very dubious informed consent. Some of this is generational. Nuremberg had an impact, and so have subsequent scandals. Part of the problem is that ethics wants to be absolute and universal, but IMHO there's a big difference between medical experiments dealing with some rare and minimally dangerous problem vs dealing with an <expletive-deleted> RAGING PANDEMIC of CATACLYSMIC DIMENSIONS, and the operative ethics differ importantly.
2. As one with perhaps more intimate contact with the criminal justice system than most of your readers, I think it's a mistake to exclude prisoners from medical experiments.
3. Challenge trials aren't as useful as you imply. What really matters for efficacy of a vaccine is its real-world effects, not how good it is at preventing some experimental infection. It's really hard to experimentally emulate community contagion, and basically impossible if it's a new disease.
Reading about variants this morning and it makes the argument even more powerful - if you wait until the virus is widespread enough that phase III works with people just walking around, you end up with with mutations rendering the vaccine you're testing useless.
The absolutely wretched failure I had convincing anybody, including various scientists and science communicators, to budge on being 100% anti-HCT made me very sad about humanity and also my persuasion skills. Is there.... some kind of communication strategy that could possibly work to move the needle here?
How novel, a message board that actually has very interesting comments where people aren't screaming at each other! I think this article raises a fascinating question about what we, as a society, would have done if NPIs were more effective and it took many months or even years to gather sufficient data through traditional phase 3 testing. Would we just stay in semi-lockdown for all that time? I miss my family. Surely there must be ways to speed up the data gathering? I understand in this case manufacturing and logistics are holding things up anyway, but what if they weren't are there were billions of dose ready to go? Also I would argue that the current Phase 3 testing has it's own ethical issues. I sit working at home in my nice house with 0% risk of catching COVID, while others are forced out to work and live, and catch COVID-19 to prove the efficacy of a vaccine I will eventually receive. Knowing what we know about COVID, my health and the overall safety of mRNA vaccines I would sign up for a challenge trial in a heartbeat....EBOLA not so much.
There is a very ugly history of medical testing on disadvantaged subsets of the population - this is a major reason that this sort of thing is not done for ethical reasons. I'm really not interested in anything that remotely resembles the "Tuskegee Syphilis Experiment", or the Nazi malarial "experiments".
Obviously this won’t be completely analogous, but I have participated in a challenge trial for food allergies. In fact, to my understanding, such challenge trials are a common way to figure out how much of an allergen a person can consume before going reacting. In other words the goal is to trigger a reaction just like how in Matt’s above proposal the goal is to get some patients infected with covid. If someone didn’t tell me I could possibly have a reaction or get sick that would piss me off, but they told me and so it was fine. Lots of doctors are already ok with this! Just like with an allergen, you could probably limit the ‘viral load’ someone is exposed to in order to minimize the severity of their illness. Food for thought.
I can't figure out why Trump didn't do Challenge Trials. Reading the comments here, the argument against Challenge Trials seems to relate to medical ethics concerns. Whether or not you agree with those, it's hard to believe that Trump would care about them. If Trump had done Challenge Trials in July, he could've had a vaccine ready to go before the election. Why didn't he?
Was the issue even brought to his attention? Was this even under consideration in the US? Were Pfizer, Moderna et al willing to use this protocol? I think there are a number of questions that have to be asked. Also, politics: I'd imagine some of Trump's advisers might have balked at the political risk, and would have warned him greenlighting challenge trials would've been risky in an election year.
I think one of the threads I see in anti-challenge trial proponents is much more of an acceptance of lockdowns. I view months long lockdowns as such a severe cost to humanity that I gladly signed up for The Challenge Trial That Wasn't. Part of the problem in these conversations is I genuinely don't think people have even remotely similar cost-benefit analyses. "Why would I do this if I could just advocate keeping the whole world socially distant for over a year" seems to be something a lot of people find reasonable. I think you did a good job explaining why that is still problematic, but it has genuinely been shocking to me how many people seem to treat various states of lockdown for a year as not that big of a deal, or a trivial thing to ask of people as long as they are "socially conscious."
I'm really glad you are writing things like this. I am a little worried that people just want everything to be over so badly that we won't seriously think about how we could have done better. I really enjoyed reading this.
Great article! A few thoughts: (1) Phase I studies look at immediate adverse effects in healthy volunteers; if those were done first that eliminates the acute risk of getting the vaccine itself. (2) The main risk of getting the vaccine and then being infected was thought to be ‘antibody-dependent enhancement’ as is seen with Dengue fever or CMV, so I don’t think a placebo control is necessary—you just want to know that vaccinated people don’t get sick and don’t get more sick than has been seen in the real world. Also we know that unvaccinated people themselves get infected, so the placebo group isn’t really necessary to establish that. (3) Another safety/efficacy proxy that one could measure before a human challenge would be to determine if sera from vaccinated volunteers neutralizes the virus. Overall, I’d propose: (1) do the animal study to show it’s safe and prevents infection (this is done anyway); (2) do the phase I study to determine safety of the vaccine itself (this is done anyway); (3) determine neutralizing effect of sera from vaccinated people to show likely efficacy in humans (this is almost certainly done anyway); THEN (4) do the human challenge trial with no placebo group to see if the vaccine protects. An animal placebo group could be used to verify that the dose of the virus given is indeed infectious.
This is a trolly problem, isn’t it. And just like more people would switch the tracks than push the old man, it gets harder for us as humans to underwrite a morally “equivalent” act the more of our fingerprints it requires. I agree with the article. But I’m still ambivalent about challenge trials. 🤷♂️
Side Question: Does anyone know our current vaccine manufacturing rate?
I've been able to find data on patient dosing (ourworldindata.org/grapher/daily-covid-19-vaccination-doses) which is going up. However, we are going to figure out the logistics at some point and I expect injection rates will slow as they catch up with the rate that doses are leaving the factory. Does anyone know what that rate looks like?
I'm just here to say that this is clearly a thorny issue that I don't know enough about to really have an informed opinion. And so I'm grateful to Matt and to the many thoughtful and respectful commenters for teaching me so much and for giving me so much to chew on, as I continue to think about this.
Society has gotten to the point where some professions can distance without much pain and a few introverts actually like distancing. Many scientists are not very sociable. Predictably, these folks often worry more about stale protocols than ending the pandemic.
There is no sense of urgency about vaccination. No serious scientist thinks the AstraZeneca vaccine is, on balance, harmful. It ought to be approved and mass produced.
- Why were masks initially were contra-recommended? [Yes, it probably something to do with what is a “mask” not recommending surgical grade masks, but still, why the confusion?]
- Why initial, exclusive emphasis on diagnostic level PCR tests and not screening tests
-. And why no massive screaming of asymptomatic people so those who test positive can self-isolate with compensation for lost income
- Why was all the messaging about social distancing/mask wearing about protecting oneself and not protecting others?
- Why do we not have systemation investigation on now to reduce infections -- ventilation capacity limits, traffic flow --at lower cost than total closure of certain venues?
- Why are recommendations not made on the basis of explicit evolving models? [No spike in cases arose after Thanksgiving. Was he prediction of a spike a failure of the model or failure of the data input or was the prediction based on a model at all?]
- Are we really keeping second vaccine doses in reserve? If so why?
- Why are we throwing vaccines away; not vaccinating nights + weekends + holidays
Why does the entire response seem as if no one had every considered the possibility of a pandemic and so everything except vaccine development was improvised?
And it is is not improvised and there are good answers to these questions, why have we not heard them from public health professionals
There have been times where I wish I just got covid and was done with it (young-ish). I would sign up for the challenge trial if the promise was my self sacrifice would get society moving again. And yet I have center left views. Crazy!
Apparently, The UK has given a green light on Challenge trials.
I didn't have time to comment on your interesting post at the time. A few thoughts:
1. The ethics are murky. I'm really old, and my prior is in favor of your suggestion. As a kid I learned the Walter Reed experiments on yellow fever from the perspective that he was a hero, and I still believe it, despite the very dubious informed consent. Some of this is generational. Nuremberg had an impact, and so have subsequent scandals. Part of the problem is that ethics wants to be absolute and universal, but IMHO there's a big difference between medical experiments dealing with some rare and minimally dangerous problem vs dealing with an <expletive-deleted> RAGING PANDEMIC of CATACLYSMIC DIMENSIONS, and the operative ethics differ importantly.
2. As one with perhaps more intimate contact with the criminal justice system than most of your readers, I think it's a mistake to exclude prisoners from medical experiments.
3. Challenge trials aren't as useful as you imply. What really matters for efficacy of a vaccine is its real-world effects, not how good it is at preventing some experimental infection. It's really hard to experimentally emulate community contagion, and basically impossible if it's a new disease.
Reading about variants this morning and it makes the argument even more powerful - if you wait until the virus is widespread enough that phase III works with people just walking around, you end up with with mutations rendering the vaccine you're testing useless.
The absolutely wretched failure I had convincing anybody, including various scientists and science communicators, to budge on being 100% anti-HCT made me very sad about humanity and also my persuasion skills. Is there.... some kind of communication strategy that could possibly work to move the needle here?
How novel, a message board that actually has very interesting comments where people aren't screaming at each other! I think this article raises a fascinating question about what we, as a society, would have done if NPIs were more effective and it took many months or even years to gather sufficient data through traditional phase 3 testing. Would we just stay in semi-lockdown for all that time? I miss my family. Surely there must be ways to speed up the data gathering? I understand in this case manufacturing and logistics are holding things up anyway, but what if they weren't are there were billions of dose ready to go? Also I would argue that the current Phase 3 testing has it's own ethical issues. I sit working at home in my nice house with 0% risk of catching COVID, while others are forced out to work and live, and catch COVID-19 to prove the efficacy of a vaccine I will eventually receive. Knowing what we know about COVID, my health and the overall safety of mRNA vaccines I would sign up for a challenge trial in a heartbeat....EBOLA not so much.
There is a very ugly history of medical testing on disadvantaged subsets of the population - this is a major reason that this sort of thing is not done for ethical reasons. I'm really not interested in anything that remotely resembles the "Tuskegee Syphilis Experiment", or the Nazi malarial "experiments".
Obviously this won’t be completely analogous, but I have participated in a challenge trial for food allergies. In fact, to my understanding, such challenge trials are a common way to figure out how much of an allergen a person can consume before going reacting. In other words the goal is to trigger a reaction just like how in Matt’s above proposal the goal is to get some patients infected with covid. If someone didn’t tell me I could possibly have a reaction or get sick that would piss me off, but they told me and so it was fine. Lots of doctors are already ok with this! Just like with an allergen, you could probably limit the ‘viral load’ someone is exposed to in order to minimize the severity of their illness. Food for thought.
I can't figure out why Trump didn't do Challenge Trials. Reading the comments here, the argument against Challenge Trials seems to relate to medical ethics concerns. Whether or not you agree with those, it's hard to believe that Trump would care about them. If Trump had done Challenge Trials in July, he could've had a vaccine ready to go before the election. Why didn't he?
Was the issue even brought to his attention? Was this even under consideration in the US? Were Pfizer, Moderna et al willing to use this protocol? I think there are a number of questions that have to be asked. Also, politics: I'd imagine some of Trump's advisers might have balked at the political risk, and would have warned him greenlighting challenge trials would've been risky in an election year.
I think one of the threads I see in anti-challenge trial proponents is much more of an acceptance of lockdowns. I view months long lockdowns as such a severe cost to humanity that I gladly signed up for The Challenge Trial That Wasn't. Part of the problem in these conversations is I genuinely don't think people have even remotely similar cost-benefit analyses. "Why would I do this if I could just advocate keeping the whole world socially distant for over a year" seems to be something a lot of people find reasonable. I think you did a good job explaining why that is still problematic, but it has genuinely been shocking to me how many people seem to treat various states of lockdown for a year as not that big of a deal, or a trivial thing to ask of people as long as they are "socially conscious."
I'm really glad you are writing things like this. I am a little worried that people just want everything to be over so badly that we won't seriously think about how we could have done better. I really enjoyed reading this.
Great article! A few thoughts: (1) Phase I studies look at immediate adverse effects in healthy volunteers; if those were done first that eliminates the acute risk of getting the vaccine itself. (2) The main risk of getting the vaccine and then being infected was thought to be ‘antibody-dependent enhancement’ as is seen with Dengue fever or CMV, so I don’t think a placebo control is necessary—you just want to know that vaccinated people don’t get sick and don’t get more sick than has been seen in the real world. Also we know that unvaccinated people themselves get infected, so the placebo group isn’t really necessary to establish that. (3) Another safety/efficacy proxy that one could measure before a human challenge would be to determine if sera from vaccinated volunteers neutralizes the virus. Overall, I’d propose: (1) do the animal study to show it’s safe and prevents infection (this is done anyway); (2) do the phase I study to determine safety of the vaccine itself (this is done anyway); (3) determine neutralizing effect of sera from vaccinated people to show likely efficacy in humans (this is almost certainly done anyway); THEN (4) do the human challenge trial with no placebo group to see if the vaccine protects. An animal placebo group could be used to verify that the dose of the virus given is indeed infectious.
This is a trolly problem, isn’t it. And just like more people would switch the tracks than push the old man, it gets harder for us as humans to underwrite a morally “equivalent” act the more of our fingerprints it requires. I agree with the article. But I’m still ambivalent about challenge trials. 🤷♂️
Side Question: Does anyone know our current vaccine manufacturing rate?
I've been able to find data on patient dosing (ourworldindata.org/grapher/daily-covid-19-vaccination-doses) which is going up. However, we are going to figure out the logistics at some point and I expect injection rates will slow as they catch up with the rate that doses are leaving the factory. Does anyone know what that rate looks like?
I'm just here to say that this is clearly a thorny issue that I don't know enough about to really have an informed opinion. And so I'm grateful to Matt and to the many thoughtful and respectful commenters for teaching me so much and for giving me so much to chew on, as I continue to think about this.
Society has gotten to the point where some professions can distance without much pain and a few introverts actually like distancing. Many scientists are not very sociable. Predictably, these folks often worry more about stale protocols than ending the pandemic.
There is no sense of urgency about vaccination. No serious scientist thinks the AstraZeneca vaccine is, on balance, harmful. It ought to be approved and mass produced.
Matt’s is not the only question
- Why were masks initially were contra-recommended? [Yes, it probably something to do with what is a “mask” not recommending surgical grade masks, but still, why the confusion?]
- Why initial, exclusive emphasis on diagnostic level PCR tests and not screening tests
-. And why no massive screaming of asymptomatic people so those who test positive can self-isolate with compensation for lost income
- Why was all the messaging about social distancing/mask wearing about protecting oneself and not protecting others?
- Why do we not have systemation investigation on now to reduce infections -- ventilation capacity limits, traffic flow --at lower cost than total closure of certain venues?
- Why are recommendations not made on the basis of explicit evolving models? [No spike in cases arose after Thanksgiving. Was he prediction of a spike a failure of the model or failure of the data input or was the prediction based on a model at all?]
- Are we really keeping second vaccine doses in reserve? If so why?
- Why are we throwing vaccines away; not vaccinating nights + weekends + holidays
Why does the entire response seem as if no one had every considered the possibility of a pandemic and so everything except vaccine development was improvised?
And it is is not improvised and there are good answers to these questions, why have we not heard them from public health professionals
There have been times where I wish I just got covid and was done with it (young-ish). I would sign up for the challenge trial if the promise was my self sacrifice would get society moving again. And yet I have center left views. Crazy!