Okay, what the variolation concept needs most now is a trial/test/experiment ASAP. So to help get the ball rolling, let me sketch a tentative plan. I’m NOT saying this plan is now good enough. I’m saying let’s talk together about how to make it better. (Not so interested here in those ever popular “this can never work” comments.)
Keep in mind that whatever viruses you select to use, you are having a huge impact on the virus's evolution -- giving this particular variation a huge leg up on the others. So this selection should be made very carefully.
Note that one factor the virus seems to have evolved differences in is exactly one you care about -- viral load.
"Ultra deep sequencing of 11 Chinese patient-derived viral isolates from a single hospital in Hangzhou ("average coverage exceeding 2,000,000 X)"...."These patients therefore constitute 1st and 2nd generations of the viral victims based on their epidemiological history"... "We observed diverse mutations in these viral isolates, including 6 different mutations in the spike glycoprotein (S protein), and 2 of which are different SNVs that led to the same missense mutation. Importantly, these viral isolates show significant variation in cytopathic effects and viral load, up to 270-fold differences, when infecting Vero-E6 cells. Therefore, we provide direct evidence that the SARS-CoV-2 has acquired mutations capable of substantially changing its pathogenicity." https://www.medrxiv.org/con...
The receptor for the virus is ACE-2 in the lungs. However, this receptor is also expressed in the gastro-intestinal tract. Taking the innocuous in pill form might even spare the lung for viral replication.
Sure. It's a chicken and egg problem. You may need money to attract good people. You may need good people to attract money. Solving either one could resolve the bottleneck. I agree that finding people who care about the project beyond money is ideal, just saying there's another method in a pinch.
Natural experiments are fun and as we get better surveillance and better machine intelligence we will be able to squeeze more and more juice out of them. However, you may find that they don't entirely substitute for RCTs when it comes to establishing safety.
Most vaccines have the potential to wipe out their corresponding disease. Natural reservoirs tend to make this process harder, though. It seems as though this time there are multiple species and natural reservoirs involved.
Yes the idea of making attenuated viruses is not new - using genomics to find attenuated virus in the field and using epidemiology to prove they are safe is new.
The major advantage of my proposal is that we can speed up development of making an attenuated virus vaccine, actually speed up the development of any vaccine since we can use the "trial" nature has done for us to do experiments that will take at least 12 months to get to with conventional lab derived vaccines.
Oh and there is the small issue that my proposal can potentially be used to drive the dangerous strain to extinction.
Yes, people are allowed to argue with the dictionary. It doesn't always reflect well on their proposals, however. In this case, calling using small doses "variolation" also seems confusing and misleading because other effects besides dose size were likely more important in how historical variolation worked .
Also the young people's herd immunity saving the old people may not work because 1: old people tend to hang out with other old people, 2: the "young people" (as in the segment with less than 0.1% risks) aren't even a sufficient percentage of the population to get herd immunity.
edit: it is interesting that after coming up with the post about infecting young to get herd immunity for protecting the old, the thing Hanson does is noticing that the lowering of R may not protect sub-populations, but only applies that insight to distancing but not to herd immunity.
Well I think there is merit to trawling pre existing data for findings of safety, as opposed to deleting segments of the genome and then facing the (low) odds of making a massively more dangerous disease.
One problem here is that this is not a very deadly disease, so for all prophylaxis done in people who hadn't contracted it, the "utility" calculations are dominated by the risk of making it worse. Also it being mild, size of trials is proportionally larger.
If it was rabies with ~99% mortality rate, it would be a lot easier to identify a vaccination approach.
Yes, it is horrible on the world scale, and it is so much worse than the regular flu, but it is still more or less within the "first, do no harm" segment (dominated by risks of treatment) and not in the "literally bit by a zombie, try anything" segment (risks of treatment negligible). People panic and imagine it is the latter, but it is objectively not.
We've always been facing odds of that magnitude, such as a couple years worth of fatal cancer risk.
edit: on the other hand the problem with real world strains is that they would have to be virulent enough to actually propagate themselves. While lab created variants do not.
Most homoeopathy involves putting labels on sugar and not doing dilution due to liability issues.
That does not define it.
The general principle of homeopathy is to "treat like with like", it was supported by referring to vaccinations via a very similar argument as Hanson's (see my cite), and Hanson's proposal with freezing has exactly the same hazard (not diluting it reliably enough due to poor understanding of physics). There are very useful parallels to make here with regards to how he is likely to end up with an unsafe experiment.
Hanson is trying to misrepresent his proposal by referring to it as variolation. I objected to it multiple times on the grounds that it is a harmful misrepresentation. Hanson and many others were defending it with some variation of a "it is just a matter of semantics". Fine. Then it is also a matter of semantics to refer to it as viral homeopathy.
Funny how when the words chosen do not lend undue credence to someone's argument, but do the opposite, that suddenly it stops being a mere matter of semantics.
I'm still not sure what parts you think are novel. There's certainly a fair volume of literature covering making vaccines from live viruses using sequence deletion of virulence-related traits to produce safety. You seem to emphasize combing the population for benign variants - as opposed to making them in the lab. Maybe that is novel - and it might save some time. Or maybe you are ignoring potentially-useful options for finding benign variants.
Variance is one factor, and ability to sample from the end of the distribution is another. Variation increasing virulence is unimportant. Variation decreasing virulence is likely to be fairly large due to deleterious mutations that knock out the capabilities of the virus being common. However you don't want to "weight by the number of cases". We are looking for variants that die out through not spreading. Seek them in virus particles a long way (in viral generations) from the last spreading event - e.g. in patents who have been asymptomatic for a while. Some of those variants should hopefully cause around zero new cases.
There is no historical evidence that smallpox used a weaker strain as this is like asking if people in the 17th C used general relativity to describe gravity - the concept of strain variation in smallpox pathogenicity was unknown at the time.
What is known is that patients with mild forms of smallpox were used as the source material for variolation. Quoting from Daniel Suttons' The Inoculator [1] makes it clear how the source material was selected (I have corrected the terrible OCR text manually).
Of Subjects most proper to Supply the Matter for Inoculation — Time of Day, Season of the Year, and the heft Age for the Operation.
HITHERTO people in general, and even the majority of inoculators, have confined their hopes of success, so far as concerns the choice of proper matter for inoculation, to the good natural date of health of the subject from whom the matter is to be collected; preferring a mild, benign sort to a copious, malignant, ill-conditioned species...
Viriolation success was the result of using a small inoculum of a mild strain. Now of course what releivance this has to SARS-CoV-2 is another question.
This is just trolling.You cannot demonstrate what you call “actual variolation” involved a weaker strain.Even if it did, your syllogistic conclusion that Hanson’s proposal “has no resemblance to actual variolation” is a logical fallacy.That *some* homeopathic formulations have not been diluted beyond Avogadro’s number does not disprove the general proposition that *mostly* homeopathy involves dilutions that would render pharmacodynamic effect of the “active” impossible. This is no place for an argument about homeopathy - aside from observing that argument-by-analogy here is too confounder-ridden to be of any use in a positivist sense: it appears you are using it as an attempt to slander the proposal.
Tim it is quite a different proposal than the other vaccine approaches. You might find my follow up post on how my proposal can be put into practice helpful in understanding it.
Daniel, it seems as though you want a lot of heathy people to deliberately expose themselves to save a bunch of old smokers. For people to go for that, the risk has to be pretty low, which is likely to require considerable safety testing - which takes time. We are likely talking about well after the current projected peak. As you point out, this is how some vaccines already work. I am not all that clear on how this is different from some of the established vaccine production approaches. I think people also use genetic engineering and artificial evolution to produce/find candidates.
Keep in mind that whatever viruses you select to use, you are having a huge impact on the virus's evolution -- giving this particular variation a huge leg up on the others. So this selection should be made very carefully.
Note that one factor the virus seems to have evolved differences in is exactly one you care about -- viral load.
"Ultra deep sequencing of 11 Chinese patient-derived viral isolates from a single hospital in Hangzhou ("average coverage exceeding 2,000,000 X)"...."These patients therefore constitute 1st and 2nd generations of the viral victims based on their epidemiological history"... "We observed diverse mutations in these viral isolates, including 6 different mutations in the spike glycoprotein (S protein), and 2 of which are different SNVs that led to the same missense mutation. Importantly, these viral isolates show significant variation in cytopathic effects and viral load, up to 270-fold differences, when infecting Vero-E6 cells. Therefore, we provide direct evidence that the SARS-CoV-2 has acquired mutations capable of substantially changing its pathogenicity." https://www.medrxiv.org/con...
The receptor for the virus is ACE-2 in the lungs. However, this receptor is also expressed in the gastro-intestinal tract. Taking the innocuous in pill form might even spare the lung for viral replication.
Sure. It's a chicken and egg problem. You may need money to attract good people. You may need good people to attract money. Solving either one could resolve the bottleneck. I agree that finding people who care about the project beyond money is ideal, just saying there's another method in a pinch.
Natural experiments are fun and as we get better surveillance and better machine intelligence we will be able to squeeze more and more juice out of them. However, you may find that they don't entirely substitute for RCTs when it comes to establishing safety.
Most vaccines have the potential to wipe out their corresponding disease. Natural reservoirs tend to make this process harder, though. It seems as though this time there are multiple species and natural reservoirs involved.
Yes the idea of making attenuated viruses is not new - using genomics to find attenuated virus in the field and using epidemiology to prove they are safe is new.
The major advantage of my proposal is that we can speed up development of making an attenuated virus vaccine, actually speed up the development of any vaccine since we can use the "trial" nature has done for us to do experiments that will take at least 12 months to get to with conventional lab derived vaccines.
Oh and there is the small issue that my proposal can potentially be used to drive the dangerous strain to extinction.
Yes, people are allowed to argue with the dictionary. It doesn't always reflect well on their proposals, however. In this case, calling using small doses "variolation" also seems confusing and misleading because other effects besides dose size were likely more important in how historical variolation worked .
Also the young people's herd immunity saving the old people may not work because 1: old people tend to hang out with other old people, 2: the "young people" (as in the segment with less than 0.1% risks) aren't even a sufficient percentage of the population to get herd immunity.
edit: it is interesting that after coming up with the post about infecting young to get herd immunity for protecting the old, the thing Hanson does is noticing that the lowering of R may not protect sub-populations, but only applies that insight to distancing but not to herd immunity.
Well I think there is merit to trawling pre existing data for findings of safety, as opposed to deleting segments of the genome and then facing the (low) odds of making a massively more dangerous disease.
One problem here is that this is not a very deadly disease, so for all prophylaxis done in people who hadn't contracted it, the "utility" calculations are dominated by the risk of making it worse. Also it being mild, size of trials is proportionally larger.
If it was rabies with ~99% mortality rate, it would be a lot easier to identify a vaccination approach.
Yes, it is horrible on the world scale, and it is so much worse than the regular flu, but it is still more or less within the "first, do no harm" segment (dominated by risks of treatment) and not in the "literally bit by a zombie, try anything" segment (risks of treatment negligible). People panic and imagine it is the latter, but it is objectively not.
We've always been facing odds of that magnitude, such as a couple years worth of fatal cancer risk.
edit: on the other hand the problem with real world strains is that they would have to be virulent enough to actually propagate themselves. While lab created variants do not.
Most homoeopathy involves putting labels on sugar and not doing dilution due to liability issues.
That does not define it.
The general principle of homeopathy is to "treat like with like", it was supported by referring to vaccinations via a very similar argument as Hanson's (see my cite), and Hanson's proposal with freezing has exactly the same hazard (not diluting it reliably enough due to poor understanding of physics). There are very useful parallels to make here with regards to how he is likely to end up with an unsafe experiment.
Hanson is trying to misrepresent his proposal by referring to it as variolation. I objected to it multiple times on the grounds that it is a harmful misrepresentation. Hanson and many others were defending it with some variation of a "it is just a matter of semantics". Fine. Then it is also a matter of semantics to refer to it as viral homeopathy.
Funny how when the words chosen do not lend undue credence to someone's argument, but do the opposite, that suddenly it stops being a mere matter of semantics.
I'm still not sure what parts you think are novel. There's certainly a fair volume of literature covering making vaccines from live viruses using sequence deletion of virulence-related traits to produce safety. You seem to emphasize combing the population for benign variants - as opposed to making them in the lab. Maybe that is novel - and it might save some time. Or maybe you are ignoring potentially-useful options for finding benign variants.
Variance is one factor, and ability to sample from the end of the distribution is another. Variation increasing virulence is unimportant. Variation decreasing virulence is likely to be fairly large due to deleterious mutations that knock out the capabilities of the virus being common. However you don't want to "weight by the number of cases". We are looking for variants that die out through not spreading. Seek them in virus particles a long way (in viral generations) from the last spreading event - e.g. in patents who have been asymptomatic for a while. Some of those variants should hopefully cause around zero new cases.
There is no historical evidence that smallpox used a weaker strain as this is like asking if people in the 17th C used general relativity to describe gravity - the concept of strain variation in smallpox pathogenicity was unknown at the time.
What is known is that patients with mild forms of smallpox were used as the source material for variolation. Quoting from Daniel Suttons' The Inoculator [1] makes it clear how the source material was selected (I have corrected the terrible OCR text manually).
Of Subjects most proper to Supply the Matter for Inoculation — Time of Day, Season of the Year, and the heft Age for the Operation.
HITHERTO people in general, and even the majority of inoculators, have confined their hopes of success, so far as concerns the choice of proper matter for inoculation, to the good natural date of health of the subject from whom the matter is to be collected; preferring a mild, benign sort to a copious, malignant, ill-conditioned species...
Viriolation success was the result of using a small inoculum of a mild strain. Now of course what releivance this has to SARS-CoV-2 is another question.
1. https://archive.org/stream/...
This is just trolling.You cannot demonstrate what you call “actual variolation” involved a weaker strain.Even if it did, your syllogistic conclusion that Hanson’s proposal “has no resemblance to actual variolation” is a logical fallacy.That *some* homeopathic formulations have not been diluted beyond Avogadro’s number does not disprove the general proposition that *mostly* homeopathy involves dilutions that would render pharmacodynamic effect of the “active” impossible. This is no place for an argument about homeopathy - aside from observing that argument-by-analogy here is too confounder-ridden to be of any use in a positivist sense: it appears you are using it as an attempt to slander the proposal.
Huh? If there's not much variance then gains are small from picking from the low tail.
Tim it is quite a different proposal than the other vaccine approaches. You might find my follow up post on how my proposal can be put into practice helpful in understanding it.
https://www.tillett.info/20...
Daniel, it seems as though you want a lot of heathy people to deliberately expose themselves to save a bunch of old smokers. For people to go for that, the risk has to be pretty low, which is likely to require considerable safety testing - which takes time. We are likely talking about well after the current projected peak. As you point out, this is how some vaccines already work. I am not all that clear on how this is different from some of the established vaccine production approaches. I think people also use genetic engineering and artificial evolution to produce/find candidates.