In the 18th century, Daniel Bernoulli—the son, nephew and brother of mathematicians Johann, Jacob and Nicolaus II Bernoulli, respectively—made one of the first great mathematical contributions to infectious disease control. While formally trained in medicine, Bernoulli is known for his research in biomechanics, hydrodynamics, economics, and astronomy. He also played an important role in the eradication of smallpox from Europe, which was likely introduced there in the early 16th century and was endemic (maintained constantly) by the 18th century. Variolation is an inoculation technique whereby a scab or pus from an individual with a mild smallpox infection is introduced into the nose or mouth of healthy individuals. This practice began as early as 1000 AD in China and India and was introduced into England in 1717, where it was initially controversial. While variolation reduced the mortality probability of infected individuals from 30% to 1%, there was a small chance that the procedure would lead to death from a full-blown case of smallpox.
I mean the reason people say "it seems to be extremely unlikely" is because "viruses" (the prevailing variant from a throat swab or whatever) are pretty well conserved, because they more or less had exhausted all the most probable improvements mutations can make.
I see what you're saying - the patient gets infected, infects others outside of home while not yet ill.
The study also says that this was observed in children 0..11 months old. So the dose dependence may also be specific to maternal antibodies.
In any case, while it is plausible that there may be dose dependence in general, jumping to it as explanation for variolations seems very silly. They dried the scabs and let them sit for a while.
General rule of thumb for chemical reactions is something like 2x faster at every 10 K temperature increase.
So basically they would have had extreme variation in the number of still viable virions from one sample to next depending on temperature.
Also, the first truly "man made" vaccine for a viral disease, rabies vaccine, was made by drying neural tissue from rabbits. That one we know was a dead virus vaccine, because we kept making those all the way into 20th century (if not till now in countries that can't make a better vaccine).
So there's a far more plausible explanation that variolation worked like a badly made dead virus vaccine, with a bunch of live virus present / maybe a bunch of knock-out variants / etc. (And another highly plausible explanation that it used the less lethal strain, which we know had mortality rate similar to mortality rate of variolation)
That's not the issue. Many types of virus change their selective environment frequently, as they move from one patient to another. Here the idea is that spreading within families could be different from spreading between families. The host genotypes have a different relationship to one another, and making the patient bedridden has a different cost to the virus. Bedridden patients are bad for spreading between families, but good for spreading within families, since the patient stays at home 24/7, and the virus gets to suck more resources from its host and turn them into more viral particles. Short-term evolutionary improvement can be very easy if it just consists of knocking out genes that were useful in a previous environment that is now no longer present.
They dried the scabs for a week or so. And if you look at the first artificial viral vaccine, for rabies, it also used dried infectious tissue.
Bottom line is, he'd need to determine the therapeutic dose somehow, and demonstrate safety and efficacy exactly the same as for a vaccine except with extreme biohazard around everything. I honestly don't even get what he thinks he gets to skip compared to a vaccine. Just because the patients get over a very mild case of the "real" disease doesn't mean you don't need to demonstrate they actually are immune to re-infection.
If you could simply log into God's online store and place an order of perfectly titred, stabilized ampoules of the virus itself, sure, but here in the real world it's the same as manufacturing a live virus vaccine except worse.
Vaccines aren't magic, the dead virus vaccines are sort of a variolation-derived idea too, except with more emphases on "dried the scabs" and less emphasis on "some will die".
What would have helped convince me (I ultimately shifted my view when I got this info) is more basic science as to why this is plausible in theory grounds. In particular, that means something like a comparison of variation in initial number of infecting virus particles compared to replication rate.
I think many people naturally assume that the doubling time of the virus multiplied by log_2 of variance in viruses people are exposed to is a small number (eg a big dose gives virus only an hour or two head start). Finding out that wasn’t true was what shifted my views (and that medical experts find the mech plausible).
The data is just to messy to be that convincing on its own.
I found another hypothesis about this effect on the Wikipedia article about "optimal virulence" - again involving adaptation to local conditions by the virus:
"If the pathogen's virulence kills the host and interferes with its own transmission to a new host, virulence will be selected against. But as long as transmission continues despite the virulence, virulent pathogens will have the advantage. So, for example, virulence often increases within families, where transmission from one host to the next is likely, no matter how sick the host."
There are only two strains at this point, and probably one of them would be dominant in any area. However, healthcare workers do have a higher risk of being exposed to more dangerous bacteria, which might cause a superinfection on top of covid. I'm not sure that is a major factor associated with mortality, though.
As well as the initial dose, there is also the question perhaps of where the infection takes hold. Some people report diarrhoea as a symptom. Might this mean there is a milder form of the disease if the infection is gastric or esophegal not in the lungs? You don't have to infect people via aerosol.
The New Yorker has some pretty weak evidence. It says healthcare workers have some of the worst cases for their age. Wouldn't that be more likely due to getting the sickest patients, and hence the worst strains (assuming strains significantly differ, and it isn't all down to host difference)
Sorry, but your theory fails to describe the data. CFR in Italy varies wildly from region to region, and the most important factor affecting CFR is... the number of tests.I know, it's very surprising that the denominator can affect so much the result of a ratio...Veneto tested immediately with broad criteria, identifying and isolating mild cases before they could spread the virus.Lombardia did not and is failing to do that even now. Official medical sources are saying that not enough people are getting tested in Lombardia, they can't keep up with the high rate, so of course the number of positive cases is grossly underestimated.The health care system is overwhelmed, both the hospitals and the testing labs.And this is the other big factor: saturation of hospital beds and ICUs lead obviously to more deaths.In some areas there are not enough ambulances to go pick up sick people and bring them to the hospitals.But that's not all: even within Lombardia CFR is very different in different counties/cities, for example Milan vs Bergamo.If lockdown was the main culprit, then you would expect the same results in all locked areas, but that's not the case.Of course, when people are locked down, the main channel of viral transmission is through family or in the hospital, but this doesn't say anything about what would have happened without the lockdown.There are already more trivial and proved explanations for the variability of CFR between different countries (age distribution, testing, contact tracing).The viral dose is just a theory, there's no data that proves it for this specific virus, all other data can be explained without it, so Occam disfavors it.Certainly, I wouldn't base any strategy on it.
Oh, you ‘ re so cute! You know that ‘ s not what was meant.
Good point, perhaps I was unclear.
I mean the reason people say "it seems to be extremely unlikely" is because "viruses" (the prevailing variant from a throat swab or whatever) are pretty well conserved, because they more or less had exhausted all the most probable improvements mutations can make.
I see what you're saying - the patient gets infected, infects others outside of home while not yet ill.
The study also says that this was observed in children 0..11 months old. So the dose dependence may also be specific to maternal antibodies.
In any case, while it is plausible that there may be dose dependence in general, jumping to it as explanation for variolations seems very silly. They dried the scabs and let them sit for a while.
General rule of thumb for chemical reactions is something like 2x faster at every 10 K temperature increase.
So basically they would have had extreme variation in the number of still viable virions from one sample to next depending on temperature.
Also, the first truly "man made" vaccine for a viral disease, rabies vaccine, was made by drying neural tissue from rabbits. That one we know was a dead virus vaccine, because we kept making those all the way into 20th century (if not till now in countries that can't make a better vaccine).
So there's a far more plausible explanation that variolation worked like a badly made dead virus vaccine, with a bunch of live virus present / maybe a bunch of knock-out variants / etc. (And another highly plausible explanation that it used the less lethal strain, which we know had mortality rate similar to mortality rate of variolation)
That's not the issue. Many types of virus change their selective environment frequently, as they move from one patient to another. Here the idea is that spreading within families could be different from spreading between families. The host genotypes have a different relationship to one another, and making the patient bedridden has a different cost to the virus. Bedridden patients are bad for spreading between families, but good for spreading within families, since the patient stays at home 24/7, and the virus gets to suck more resources from its host and turn them into more viral particles. Short-term evolutionary improvement can be very easy if it just consists of knocking out genes that were useful in a previous environment that is now no longer present.
They dried the scabs for a week or so. And if you look at the first artificial viral vaccine, for rabies, it also used dried infectious tissue.
Bottom line is, he'd need to determine the therapeutic dose somehow, and demonstrate safety and efficacy exactly the same as for a vaccine except with extreme biohazard around everything. I honestly don't even get what he thinks he gets to skip compared to a vaccine. Just because the patients get over a very mild case of the "real" disease doesn't mean you don't need to demonstrate they actually are immune to re-infection.
If you could simply log into God's online store and place an order of perfectly titred, stabilized ampoules of the virus itself, sure, but here in the real world it's the same as manufacturing a live virus vaccine except worse.
Vaccines aren't magic, the dead virus vaccines are sort of a variolation-derived idea too, except with more emphases on "dried the scabs" and less emphasis on "some will die".
I think the issue is, people confuse mutations with evolutionary improvement (which is generally slow when in an equilibrium).
Then I'd appreciate it if you or someone else could compile this info into a persuasive form. Inciuding cites to med lit.
What would have helped convince me (I ultimately shifted my view when I got this info) is more basic science as to why this is plausible in theory grounds. In particular, that means something like a comparison of variation in initial number of infecting virus particles compared to replication rate.
I think many people naturally assume that the doubling time of the virus multiplied by log_2 of variance in viruses people are exposed to is a small number (eg a big dose gives virus only an hour or two head start). Finding out that wasn’t true was what shifted my views (and that medical experts find the mech plausible).
The data is just to messy to be that convincing on its own.
I found another hypothesis about this effect on the Wikipedia article about "optimal virulence" - again involving adaptation to local conditions by the virus:
"If the pathogen's virulence kills the host and interferes with its own transmission to a new host, virulence will be selected against. But as long as transmission continues despite the virulence, virulent pathogens will have the advantage. So, for example, virulence often increases within families, where transmission from one host to the next is likely, no matter how sick the host."
Sure, that's a fine variation to try when we are ready to experiment.
When people are telling you that offering money to someone is "coercing" them, it's safe to say rational discussion is impossible.
There are only two strains at this point, and probably one of them would be dominant in any area. However, healthcare workers do have a higher risk of being exposed to more dangerous bacteria, which might cause a superinfection on top of covid. I'm not sure that is a major factor associated with mortality, though.
As well as the initial dose, there is also the question perhaps of where the infection takes hold. Some people report diarrhoea as a symptom. Might this mean there is a milder form of the disease if the infection is gastric or esophegal not in the lungs? You don't have to infect people via aerosol.
healthcare workers are probably also overstressed and overworked which may be a confounding variable. The idea overall however is an interesting one.
The New Yorker has some pretty weak evidence. It says healthcare workers have some of the worst cases for their age. Wouldn't that be more likely due to getting the sickest patients, and hence the worst strains (assuming strains significantly differ, and it isn't all down to host difference)
Sorry, but your theory fails to describe the data. CFR in Italy varies wildly from region to region, and the most important factor affecting CFR is... the number of tests.I know, it's very surprising that the denominator can affect so much the result of a ratio...Veneto tested immediately with broad criteria, identifying and isolating mild cases before they could spread the virus.Lombardia did not and is failing to do that even now. Official medical sources are saying that not enough people are getting tested in Lombardia, they can't keep up with the high rate, so of course the number of positive cases is grossly underestimated.The health care system is overwhelmed, both the hospitals and the testing labs.And this is the other big factor: saturation of hospital beds and ICUs lead obviously to more deaths.In some areas there are not enough ambulances to go pick up sick people and bring them to the hospitals.But that's not all: even within Lombardia CFR is very different in different counties/cities, for example Milan vs Bergamo.If lockdown was the main culprit, then you would expect the same results in all locked areas, but that's not the case.Of course, when people are locked down, the main channel of viral transmission is through family or in the hospital, but this doesn't say anything about what would have happened without the lockdown.There are already more trivial and proved explanations for the variability of CFR between different countries (age distribution, testing, contact tracing).The viral dose is just a theory, there's no data that proves it for this specific virus, all other data can be explained without it, so Occam disfavors it.Certainly, I wouldn't base any strategy on it.
I think those are more likely recurrence than reinfection.