I don’t think challenge trials are warranted. There’s real harm arising from doing challenge trials. They made sense for Covid because hundreds of millions of people caught it, thousands were dying every day, and getting an effective vaccine or treatment just one day sooner could save thousands of lives. So accepting a level of harm during testing is warranted. For a disease where R seems to be not much above 1, but CFR might be as high as 10%, I would say, even if we had a competent and well-funded pandemic prevention authority, they might pass on the challenge trials this time around.
Thank you for the response! I’m gonna jump in to places where we might disagree, and that disagreement might be productive for readers.
I’m pretty sure that mortality “in the wild” will be less than 3% even in populations without insurance, without a doctor, and without high enough intelligence to manage their own care competently using internet lookups and OTC meds and so on.
The biology here just seems plain to me:
I’m pretty sure that the cousin strains of OUTBREAK_2022 have a mortality of roughly 1% just from like… wikipedia and so on.
This looks like a variant of the “West Africa” strain (not the scary strain, that had 10% mortality).
In general: most infectious diseases tend towards higher R_t (because duh).
In general: they also tend (under normal circumstances with no superspreader events in ICUs) towards lower mortality/morbidity over time because it makes them “less scary” and so people don’t do big mitigations (and that buys any virus a bit more R_t which is what the viral evolution process (modeled using the intentional stance) “actually wants”).
ALSO, I’m pretty sure that mortality in a competent/expensive clinic will be pretty low. They’ll simply be able to just look at the patient, and notice problems starting to arise, and have antibody therapies ready to titrate the disease effects down, and so on.
For all the above reasons: I’m just quite confident that a challenge trial with monkey pox would not be a big scary thing. Maybe a person or two might have weird genes, and react in a weird way, and have a doctor that isn’t actually clinically competent, and then tragically die in a 500 person trial? But very very likely: NOT.
Then, if the information is valuable to society (which IT IS VALUABLE and if someone disagrees on that score I’m happy to unpack how and why there is high VoI here) then you could pay the people retrospectively once group assignments are unblinded.
So, for example, maybe everyone who got “a placebo vax, then challenged with monkeypox, and likely case of the pox, and some scars maybe from the blisters” as part of the control group gets $30k in payment (or whatever their cheerful price probably is).
Basically: the humans in a challenge trial are grownups, and this wouldn’t be that dangerous, and the residual danger/sadness is their own business which a competent ethical infectious disease fighting institution (which I grant does not currently exist in the US) would get informed consent about, and then just PAY FOR WITH MONEY. More risk? More pay. Then “competent informed consent by grownups” is ethical pixie dust to make it OK <3
So under my models and under my ethical system, challenge trials are all of (1) safe-ish and (2) deontically permitted and (3) insanely valuable.
The reason they probably won’t happen is because our institutions cannot actually reason coherently about value or probability or ethics or any of it. They’re just idiots basically, and that’s why we can’t have nice things.
...
Maybe you have evidence that I lack that OUTBEAK_2022 has a CFR around 10%? If that is true I would ask for that evidence!
What are the observations? What are the statistical summaries? Do you have links please?
(Also, just to mention this: if CFR>9% for OUTBREAK_2022 then I would update pretty strongly towards “OUTBREAK_2022 was caused by either (1) GoF research or (2) some sort of nosocomial disaster where a clinic was spreading the worst variants to diseases to new patients in some sort of morbidity amplification process, and either way it would be good to start looking for the guilty parties, to correct them, if they can be found”.
An increase in mortality is not how diseases normally evolve, and would thus require some surprising/unusual cause to be true of an actual disease.)
...
SEPARATELY WHERE I HAVE LOW CONFIDENCE:
For a disease where R seems to be not much above 1 … I would say, even if we had a competent and well-funded pandemic prevention authority, they might pass on the challenge trials this time around.
You seem to have assumed a low R, but my current state of knowledge here is: wide error bars and therefore maybe R is high?
A competent publicly funded infectious disease fighting system would have a pro-active responsibility to clearly falsify the bad parts of the plausible range very fast.
Then once the falsification of “bad possibilities” has occurred, they could properly BACK OFF on the “correct pre-emptive measures that one should take in the absence of coherent knowledge that we are very very very likely to be in the safe regime”.
I don’t personally currently have evidence that “the bad possibilities are clearly false based on definite observations”. If you know for sure that R is low, that would be a pleasant relief <3
Could you drop a link to thorough reasoning over adequate observations that makes it very clear that R_t < 1.15? :-)
Thanks for your thorough response. It is well-argued and as a result, I take back what I said. I’m not entirely convinced by your response but I will say I now have no idea! Being low-information on this, though, perhaps my reaction to the “challenge trial” idea mirrors other low-information responses, which is going to be most of them, so I’ll persist in explaining my thinking mainly in the hope it’ll help you and other pro-challenge people argue your case to others.
I’ll start with maybe my biggest worry about a challenge trial: the idea you could have a disease with an in-the-wild CFR of ~1%, that you could put 500 people through a challenge trial, and “very likely” none of them would die. With a CFR of 1%, expected fatalities among 500 people is 5. If medical observation and all the other precautions applied during a challenge trial reduces the CFR by a factor of 10, to 0.1%, your expected deaths is only 0.5, but that still seems unacceptably high for one trial, to me? To get the joint probability of zero deaths across all 500 people above 95%, you need closer to 0.01% CFR, (1−0.01%)500=0.951. Is it realistic to think all the precautions in a challenge trial can reduce CFR by a factor of 100 from 1% to 0.01%? I have no idea, perhaps you do, but I’d want to know before being feeling personally comfortable with a challenge trial.
Regaring R values and monkeypox generally, my understanding on this topic doesn’t go much beyond this post and the group of responses to it, so I’m pretty low-confidence on anything here. Thus, if you say the R is potentially quite high, I believe you.
Monkeypox virus is transmitted from one person to another by close contact with lesions, body fluids, respiratory droplets and contaminated materials such as bedding.
I’d have to guess it’s going to be less infectious than covid, which had an R around 5? On the other hand, since OP asked the question, there’s more speculation about chains of transmission that seem to indicate a higher R. I acknowledge “lower than 5” is a high error!
Having said that, to my mind, I now feel very conflicted. Having read AllAmericanBreakfast’s comment and their headline, I felt reassured that monkeypox wasn’t much for the public to be worried about, and the CDC and WHO would figure it out. But on my own understanding, if R is high (as you say) and CFR is anywhere much above 0.1%, and there’s a widespread outbreak, that is pretty scary and we should all be much more on the alert than we already are?
And that would affirm your conclusion that challenge trials would be a good idea, as long as we have confidence the risk to participants is low.
Why is it assumed that diseases evolve towards lower mortality? Every new disease is an evolved form of an old disease, so if that trend were true we’d expect no disease to ever have noticeable mortality.
Lower mortality is just generally more efficient, even from the disease perspective. Typhoid Mary was a great success for the typhoid, precisely because it didn’t take her out or slow her down.
Over the long run, most diseases find a balance. The balance is almost never “kill the host really fast”. Your gut microbiome is basically made out of a bunch of “infectious diseases” that play nicely with their host. That’s the normal thing. Symbiosis is efficient and normal. Depending on how you count, there are 10s or 100s or 1000s of essentially friendly bacteria species in a modern human GI tract.
When a bat virus, like SARS or Ebola, jumps to humans, the species it came from often wasn’t even really bothered by it any more… but the disease does not start out in evolutionary equilibrium with humans.
Its is usually only only when you have high enough mixing (or a new kind of mixing over barriers of separation that previously kept things separate (or some idiot not inside a BSL5 does GoF research and mixes biological reality with their scary imaginations)) that ancient equilibriums of default symbiosis seriously break down.
Ah, so mortality almost always trends downwards except when it jumps species, at which point there can be a discontinuous jump upwards. That makes sense, thank you.
I agree that this is probably an overreaction.
I don’t think challenge trials are warranted. There’s real harm arising from doing challenge trials. They made sense for Covid because hundreds of millions of people caught it, thousands were dying every day, and getting an effective vaccine or treatment just one day sooner could save thousands of lives. So accepting a level of harm during testing is warranted. For a disease where R seems to be not much above 1, but CFR might be as high as 10%, I would say, even if we had a competent and well-funded pandemic prevention authority, they might pass on the challenge trials this time around.
Thank you for the response! I’m gonna jump in to places where we might disagree, and that disagreement might be productive for readers.
I’m pretty sure that mortality “in the wild” will be less than 3% even in populations without insurance, without a doctor, and without high enough intelligence to manage their own care competently using internet lookups and OTC meds and so on.
The biology here just seems plain to me:
I’m pretty sure that the cousin strains of OUTBREAK_2022 have a mortality of roughly 1% just from like… wikipedia and so on.
This looks like a variant of the “West Africa” strain (not the scary strain, that had 10% mortality).
In general: most infectious diseases tend towards higher R_t (because duh).
In general: they also tend (under normal circumstances with no superspreader events in ICUs) towards lower mortality/morbidity over time because it makes them “less scary” and so people don’t do big mitigations (and that buys any virus a bit more R_t which is what the viral evolution process (modeled using the intentional stance) “actually wants”).
ALSO, I’m pretty sure that mortality in a competent/expensive clinic will be pretty low. They’ll simply be able to just look at the patient, and notice problems starting to arise, and have antibody therapies ready to titrate the disease effects down, and so on.
For all the above reasons: I’m just quite confident that a challenge trial with monkey pox would not be a big scary thing. Maybe a person or two might have weird genes, and react in a weird way, and have a doctor that isn’t actually clinically competent, and then tragically die in a 500 person trial? But very very likely: NOT.
Then, if the information is valuable to society (which IT IS VALUABLE and if someone disagrees on that score I’m happy to unpack how and why there is high VoI here) then you could pay the people retrospectively once group assignments are unblinded.
So, for example, maybe everyone who got “a placebo vax, then challenged with monkeypox, and likely case of the pox, and some scars maybe from the blisters” as part of the control group gets $30k in payment (or whatever their cheerful price probably is).
Basically: the humans in a challenge trial are grownups, and this wouldn’t be that dangerous, and the residual danger/sadness is their own business which a competent ethical infectious disease fighting institution (which I grant does not currently exist in the US) would get informed consent about, and then just PAY FOR WITH MONEY. More risk? More pay. Then “competent informed consent by grownups” is ethical pixie dust to make it OK <3
So under my models and under my ethical system, challenge trials are all of (1) safe-ish and (2) deontically permitted and (3) insanely valuable.
The reason they probably won’t happen is because our institutions cannot actually reason coherently about value or probability or ethics or any of it. They’re just idiots basically, and that’s why we can’t have nice things.
...
Maybe you have evidence that I lack that OUTBEAK_2022 has a CFR around 10%? If that is true I would ask for that evidence!
What are the observations? What are the statistical summaries? Do you have links please?
(Also, just to mention this: if CFR>9% for OUTBREAK_2022 then I would update pretty strongly towards “OUTBREAK_2022 was caused by either (1) GoF research or (2) some sort of nosocomial disaster where a clinic was spreading the worst variants to diseases to new patients in some sort of morbidity amplification process, and either way it would be good to start looking for the guilty parties, to correct them, if they can be found”.
An increase in mortality is not how diseases normally evolve, and would thus require some surprising/unusual cause to be true of an actual disease.)
...
SEPARATELY WHERE I HAVE LOW CONFIDENCE:
You seem to have assumed a low R, but my current state of knowledge here is: wide error bars and therefore maybe R is high?
A competent publicly funded infectious disease fighting system would have a pro-active responsibility to clearly falsify the bad parts of the plausible range very fast.
Then once the falsification of “bad possibilities” has occurred, they could properly BACK OFF on the “correct pre-emptive measures that one should take in the absence of coherent knowledge that we are very very very likely to be in the safe regime”.
I don’t personally currently have evidence that “the bad possibilities are clearly false based on definite observations”. If you know for sure that R is low, that would be a pleasant relief <3
Could you drop a link to thorough reasoning over adequate observations that makes it very clear that R_t < 1.15? :-)
Thanks for your thorough response. It is well-argued and as a result, I take back what I said. I’m not entirely convinced by your response but I will say I now have no idea! Being low-information on this, though, perhaps my reaction to the “challenge trial” idea mirrors other low-information responses, which is going to be most of them, so I’ll persist in explaining my thinking mainly in the hope it’ll help you and other pro-challenge people argue your case to others.
I’ll start with maybe my biggest worry about a challenge trial: the idea you could have a disease with an in-the-wild CFR of ~1%, that you could put 500 people through a challenge trial, and “very likely” none of them would die. With a CFR of 1%, expected fatalities among 500 people is 5. If medical observation and all the other precautions applied during a challenge trial reduces the CFR by a factor of 10, to 0.1%, your expected deaths is only 0.5, but that still seems unacceptably high for one trial, to me? To get the joint probability of zero deaths across all 500 people above 95%, you need closer to 0.01% CFR, (1−0.01%)500=0.951. Is it realistic to think all the precautions in a challenge trial can reduce CFR by a factor of 100 from 1% to 0.01%? I have no idea, perhaps you do, but I’d want to know before being feeling personally comfortable with a challenge trial.
Regaring R values and monkeypox generally, my understanding on this topic doesn’t go much beyond this post and the group of responses to it, so I’m pretty low-confidence on anything here. Thus, if you say the R is potentially quite high, I believe you.
I do have additional uncertainty about R. From public reports about the means of transmission that [say](https://www.who.int/emergencies/disease-outbreak-news/item/2022-DON385) things like
I’d have to guess it’s going to be less infectious than covid, which had an R around 5? On the other hand, since OP asked the question, there’s more speculation about chains of transmission that seem to indicate a higher R. I acknowledge “lower than 5” is a high error!
Having said that, to my mind, I now feel very conflicted. Having read AllAmericanBreakfast’s comment and their headline, I felt reassured that monkeypox wasn’t much for the public to be worried about, and the CDC and WHO would figure it out. But on my own understanding, if R is high (as you say) and CFR is anywhere much above 0.1%, and there’s a widespread outbreak, that is pretty scary and we should all be much more on the alert than we already are?
And that would affirm your conclusion that challenge trials would be a good idea, as long as we have confidence the risk to participants is low.
Why is it assumed that diseases evolve towards lower mortality? Every new disease is an evolved form of an old disease, so if that trend were true we’d expect no disease to ever have noticeable mortality.
Lower mortality is just generally more efficient, even from the disease perspective. Typhoid Mary was a great success for the typhoid, precisely because it didn’t take her out or slow her down.
Over the long run, most diseases find a balance. The balance is almost never “kill the host really fast”. Your gut microbiome is basically made out of a bunch of “infectious diseases” that play nicely with their host. That’s the normal thing. Symbiosis is efficient and normal. Depending on how you count, there are 10s or 100s or 1000s of essentially friendly bacteria species in a modern human GI tract.
When a bat virus, like SARS or Ebola, jumps to humans, the species it came from often wasn’t even really bothered by it any more… but the disease does not start out in evolutionary equilibrium with humans.
Its is usually only only when you have high enough mixing (or a new kind of mixing over barriers of separation that previously kept things separate (or some idiot not inside a BSL5 does GoF research and mixes biological reality with their scary imaginations)) that ancient equilibriums of default symbiosis seriously break down.
Ah, so mortality almost always trends downwards except when it jumps species, at which point there can be a discontinuous jump upwards. That makes sense, thank you.