Escape Mutant is of little relevance since naive innate immunity and memory immunity are not exclusively or even predominantly defined by antibodies to spike. There might be some marginal loss of protection for at-risk+recovered who truly “need” durable sterilizing immunity, but the virus was going to go through antigenic drift eventually anyway. For most this is not a problem - T Cell immunity targets the whole spectrum of epitopes associated with viral replication, etc.
Marek’s would be bad for everyone, but has to “be possible” first.
Superspreader (with high viral loads) would still be a crapshoot (how much time spent with an asymptomatic “superspreader”, etc.) that might not matter for most people, but would be bad for everyone who does get a high viral dose. Again, this has to “be possible” first. There may be a natural limit to possible dose - depletion of available TMPRSS2, etc.
Forever spike would be worst for the young, who have the most to lose (innate immune competence) due to sensitization/tolerance to spike; whereas the elderly might be less likely to form any reaction. Here, too, “is possible” is questionable, now that the waves in the southern US and Israel are history. The ball is still circling the rim in Europe and the northern US, so we’ll see...
Many thanks, interesting. In Europe (all-cause) excess deaths have been persistently elevated since vaccination programmes began (throughout the summer in 2021, but not in 2020), for the middle aged, but not the elderly.
It's hard to know what to make of the by-age data, since the by country data shows a much messier picture - be nice if Ukraine, with its low vaccination rate and heavy autumn wave (perhaps due to not being hit has hard last year), and UK, with its bizarre summer-autumn wave, were excluded...
I think it was a mistake to discard your original hypothesis in the UK. In all age groups but Under 18 and 40-49, the overall case rates are declining. It's just that the Unvaccinated case rates are declining faster. I think this can entirely be explained by the actually non-immune portion of the "Unvaccinated" denominator being a very small portion of the overall number.
Using the UK Sero Prevalence data, I show that overall immunity in the population is over 90% in all groups and 96% or higher in the 80+ group and moreover the truly non-immune (no prior infection) make up between 5-20% of their "Unvaccinated" age group cohorts. Part one is here https://justguy.substack.com/p/what-does-unvaccinated-mean and consider it bait for vaccine proponents (while also being correct). Part two sets an lower bound on prior-infection case rates and part two attempts to tease out the cases rates among those with no vaccination but prior infection and those who are truly non-immune.
None of this means the vaccines cannot ALSO be losing efficiency, but it puts negative efficiency into a much more plausible arena - it is paradoxical for vaccines to have negative efficacy but hospitalizations and deaths still show efficacy if the vaccines were ACTUALLY causing more disease. This is an outcome I think isn't at all impossible in the future - I'm more or less expecting it - but it doesn't appear to be the case currently.
So as I make it out, your approach essentially subtracts the "unvaccinated + previously infected" from the "unvaccinated" denominator? Whereas it the previously infected are left in for the vaccinated. But when looking at "real-time" efficacy, the previously infected should be included on both sides, even if that is a handicap against the Covid-vaccinated since they were "out of play" for a ~4 month stretch and now have to catch up. (Hence why "real-time" efficacy is of limited significance.) Otherwise I think a much safer way to adjust for prior infection (as in, without overcorrecting) would be comparative N protein sampling.
I like the idea of comparing the ratio of rates over time but note that by using absolute difference instead of ratio, there's "relative" changes that aren't actually "relative" - they just match the receding of the summer wave in older groups.
It is not paradoxical if you think of the Covid-vaccine immune response as essentially reaching a resting point akin to having "pre-loaded monoclonal antibodies." They don't prevent infection, but they prevent severe outcomes. But, the difference is that with the vaccines there is also some impact on mucosal immunity. From that conservative set of conclusions, I am venturing just what that impact is.
Hmm, I'm not sure I follow how the previously infected in the vaccinated side would be a negative there. I'd expect them to have better overall immunity than just vaccinated (at a minimum it should act as a booster shot). Maybe I'm reading what you are saying incorrectly. I would argue that their effect, whatever it is, on the vaccinated side has to be much smaller than on the Unvaccinated side because of they become a clear minority there. I'll need to run some numbers to quantify this, but we should be able to at least back out the remaining N protein immunity from the vaccinated group as a whole on a very generous basis.... But I'd expect that group to be reducing the case rate on the vaccinated side.
As to relative vs absolute rates, that's an interesting point I'll need to look at. The interesting part here is that even with changing case counts, the rate of change between the two groups is mostly constant. This would be true if the three coefficient of immunity between the groups is at a fairly fixed ratio... Then for any X cases in the population, the distribution will be by ratio, regardless of the raw numbers.
Both groups have a certain amount of previously infected. It could be 18% for the Covid-vaccinated and 20% for the unvaccinated, for example. Removing them from only one group and not the other, as I think your method ends up doing, is the same as multiplying the case rate by 1.25 for one side. However, that doesn't get to your end results, so maybe you've uncovered that the official vaccination rates are several points lower than they should be. Or it could be a sampling bias toward the vaccinated in the seroprevalence surveys. It's something to look into.
As far as "negative efficacy" the best argument against it is probably Israel. "0 infection efficacy" was already really close to becoming legible in Israel in July, right before the boosters messed up the stats (https://unglossed.substack.com/p/midsummer-maladies#footnote-anchor-14). But even with the changing definition of "partially vaccinated" to include un-boosted, it's significant that the current dashboard still never shows negative efficacy for that group - https://datadashboard.health.gov.il/COVID-19/general
Here I show the relative proportions of my calculated Prior-Infected and Non-Immune in the "Unvaccinated" group and more directly how I got them. I will follow up with N Protein immunity numbers backed into the Vaccinated group - but it seems that the majority are in this group by size.
My solution was to use the S protein and the entire population as defined on the Vaccination report in the data pages of the Flu and COVID-19 Weekly Report. I calculated what the S Protein positive population should be and subtracted the single dose population from that number. The remaining number is the population that is not in any way vaccinated, but has S immunity - logically that must be those with prior infections (which can be subtracted from the N protein population to give a good estimate of the number of prior infections in the vaccinated cohort as a whole). But that population is around 90% of the Unvaccinated population as defined by UK HSA. It's not a small portion.
Right, but it (seemingly) can't be at 90% if N protein seroprevalence is still low in younger groups (though, the testing thresholds could simply be too high). It's definitely a question I'll have to look into before my next hop across the pond.
In the most recent report, in all age groups but 18-29 and 30-39, there is excess N Protein population left after subtracting out the S Positive Unvaccinated from the total N Protein population.
For both 18-29 and 30-39 there end up being negative 200-300k remaining population. Out of roughly 10m overall population in each group.
I'm not sure the best way to deal with this - should I clamp S positive cases to no more than available N positive? Or is there some possibility that younger, more aggressive innate immune responses might reduce the likelihood of ever generating N Antibodies after infection? I would suspect I should run with both and see how much difference it makes to the results.
Thanks for sharing these, and I'm pleasantly surprised to see my hypothesis incorporated into your thinking. My thought is that if the genetic vaccines truly are inducing negative efficacy via immune tolerance, the consequences for the vaccinated will become disastrously obvious at some point and the responsible vaccines will disappear from use in a giant scandal - and perhaps will be replaced by Novavax-type or even inactivated-virus vaccines. Tolerance will presumably fade eventually, so I don't think it will truly be a "forever spike" situation inducing tolerance in unvaccinated people.
If the superspreader hypothesis is real, the vaxxed/unvaxxed illness/death differential should disappear once a majority of unvaxxed have natural immunity. At that point (probably sometime in the next few months in the US) we will see whether the differential reverses which would indicate tolerance/immune suppression, original antigenic sin, antibody-dependent enhancement, or some other issue specific to the vaccines.
I won't be 100% convinced of negative-efficacy data until I see a chart that separates unvaccinated-naive from unvaccinated-prior-immunity people. It seems like people with prior immunity would self-select into the unvaccinated group, and given that we know natural immunity is superior that alone could lead to lower infection levels in that group.
I like your graphic - that is about what I would expect from immune tolerance. I'm also interested in understanding the degree to which induced tolerance might be protective against severe illness due to immune dysfunction/overreaction - in which case it might appear superficially as a feature rather than a bug.
I've never been convinced by the Marek's disaster scenario. For one, it is much more of an exception than a rule - much as was true of smallpox in terms of being eradicable through vaccination. For another, there are many important factors that are true of Marek's in chickens that are not true of SARS-CoV2 in humans. Below is a response I recently posted to another forum on this issue.
-------------
Although I'm certainly not an expert on the level of Geert Vanden Bossche, I find the Marek's scenario unlikely for several reasons.
1. Natural immunity is superior to vaccine immunity, and we are rapidly reaching a point at which a majority of unvaccinated people have natural immunity. This is in contrast to the situation in chickens, in which the entire population turns over on average several times per year and so there is a constant influx of disease-naive birds and natural immunity plays a smaller role.
2. The concern is that a vaccine that reduces symptoms without blocking infection could select for more virulent strains that are capable of causing symptoms in vaccinated people - but that then are deadly to unvaccinated people. This is more likely if symptoms are required for spread - e.g. a virus that spreads through lesions or pustules. In the case of covid, which spreads through breathing and talking, suppression of symptoms may actually increase transmission as asymptomatic people are more likely to be out and about. So there should not be much selection for more virulent strains among vaccinated people.
3. The selective pressure for respiratory viruses to become endemic through increased transmissibility and decreased virulence over time is very strong, and while vaccination may interfere with this trajectory in harmful ways I would not expect it to destroy it entirely. Natural immunity against coronaviruses and influenza viruses is also "leaky" and of limited duration, and so leaky vaccination is not so much a special case as an inferior version of natural immunity. I would be much more concerned about a Marek's scenario if we had a leaky vaccine against Ebola, polio, or smallpox - diseases with a naturally high virulence and for which natural immunity is typically sterilizing (non-leaky) and lifelong.
4. We have been vaccinating with leaky flu vaccines for years without creating new lethal strains, and SARS-CoV2 is much more similar to influenza than to the carcinogenic herpes virus that causes Marek's in chickens.
5. Vaccine efficacy is rapidly waning to the point at which they are not merely "leaky" but might better be called "ineffective against everything except severe illness." In this circumstance there should be little if any selective pressure for increased virulence among vaccinated people. The primary selective pressure will be for evasion of vaccine-induced neutralizing antibodies, and these antibody-escape mutants should not in general cause more severe illness in unvaccinated people. (Although if leaky vaccines increase the total amount of virus in circulation, they will increase the overall mutation rate, which could lead to new strains emerging more frequently and potentially causing more frequent reinfection among both vaccinated and unvaccinated people. This is a problem but not on the level of Marek's.)
6. The Marek's scenario unfolded relatively slowly. It was not so much that the vaccines selected *for* hotter (more virulent) strains but rather that they failed to select *against* them. Because the vaccines suppressed symptoms, strains that would have been eliminated in unvaccinated populations because they killed birds too quickly were allowed to evolve and persist if they also increased transmissibility even slightly. Thus Marek's disease gradually became more deadly to unvaccinated birds over several decades of widespread leaky vaccination. So even if widespread leaky vaccination against influenza or SARS-Cov2 does have the effect of increasing virulence, I would expect this to occur over a years-to-decades timescale - whereas many of the other crisis scenarios we have been discussing could easily unfold over the next few months.
As a smallhold farmer who raises free-range chickens for both meat and eggs (and never vaccinates my birds), I'm not certain Marek's Disease is a good comparison to humans and SARS-CoV-2. On the whole this disease affects chickens raised commercially--crowded, unhealthy conditions that lack any access to the open air, sunlight, and nutritious feed that supports the immune system. Oh wait! I've just described most of the population of the US. Never mind.
I want to love your comment multiple times. Free range chooks that are truly free range, and what we should have done instead of lock down ad infinitum.
"I won't be 100% convinced of negative-efficacy data until I see a chart that separates unvaccinated-naive from unvaccinated-prior-immunity people"
And this, of course, would only select for people with strong and persistent "dark matter" immunity to SARS-CoV-2. For example if the Cleveland Clinic study is still tracking results, the "unvaccinated / not previously infected" healthcare worker set (there were 17,000 of them still in May; they were not targeted by mandates before but have just fallen under Biden's mandate) must have all of those individuals by now. There's no way to sort them out or measure them except to spray the virus right into everyone's nose. Nothing can be measured without being changed - suppression of innate immunity via a year of lockdown stress/inactivity is just as plausible for explaining a higher summer wave, for example, though I doubt it would have gotten us to winter levels as turned out.
RE "If the superspreader hypothesis is real, the vaxxed/unvaxxed illness/death differential should disappear once a majority of unvaxxed have natural immunity." I should have done a separate crude chart for changes to convalescent challenge outcomes. The unvaccinated+recovered side should look similar but with the severe outcomes gone, maybe a bit greater "asymptomatic" share toward the top but I think really it will just be that "mild" changes to "really mild." Natural "sterilizing" immunity is meant to wane, to avoid incentivizing immune evasion - similar to how you phrase it in point 3. That still leaves me with the (now enumerated in an update) reservations about converting from seasonal challenge to perpetual challenge.
I agree with everything in your list overall. Re tolerance, I agree that it, along with antibody fade-out, are part of the important "amendability" of the immune system. I am not aware of enough natural precedents for antibody dependent enhancement to argue that there is a necessary role for tolerance in avoiding it; unless, of course, it is doing so to such perfection that it is impossible to measure the role.
Thanks for enriching my post with your well though-out remarks.
Many thanks for such an informative post. I was wondering how the four hypotheses would affect different age groups.
For unvaccinated per age,
Escape Mutant is of little relevance since naive innate immunity and memory immunity are not exclusively or even predominantly defined by antibodies to spike. There might be some marginal loss of protection for at-risk+recovered who truly “need” durable sterilizing immunity, but the virus was going to go through antigenic drift eventually anyway. For most this is not a problem - T Cell immunity targets the whole spectrum of epitopes associated with viral replication, etc.
Marek’s would be bad for everyone, but has to “be possible” first.
Superspreader (with high viral loads) would still be a crapshoot (how much time spent with an asymptomatic “superspreader”, etc.) that might not matter for most people, but would be bad for everyone who does get a high viral dose. Again, this has to “be possible” first. There may be a natural limit to possible dose - depletion of available TMPRSS2, etc.
Forever spike would be worst for the young, who have the most to lose (innate immune competence) due to sensitization/tolerance to spike; whereas the elderly might be less likely to form any reaction. Here, too, “is possible” is questionable, now that the waves in the southern US and Israel are history. The ball is still circling the rim in Europe and the northern US, so we’ll see...
Many thanks, interesting. In Europe (all-cause) excess deaths have been persistently elevated since vaccination programmes began (throughout the summer in 2021, but not in 2020), for the middle aged, but not the elderly.
https://www.euromomo.eu/graphs-and-maps
It's hard to know what to make of the by-age data, since the by country data shows a much messier picture - be nice if Ukraine, with its low vaccination rate and heavy autumn wave (perhaps due to not being hit has hard last year), and UK, with its bizarre summer-autumn wave, were excluded...
I think it was a mistake to discard your original hypothesis in the UK. In all age groups but Under 18 and 40-49, the overall case rates are declining. It's just that the Unvaccinated case rates are declining faster. I think this can entirely be explained by the actually non-immune portion of the "Unvaccinated" denominator being a very small portion of the overall number.
Using the UK Sero Prevalence data, I show that overall immunity in the population is over 90% in all groups and 96% or higher in the 80+ group and moreover the truly non-immune (no prior infection) make up between 5-20% of their "Unvaccinated" age group cohorts. Part one is here https://justguy.substack.com/p/what-does-unvaccinated-mean and consider it bait for vaccine proponents (while also being correct). Part two sets an lower bound on prior-infection case rates and part two attempts to tease out the cases rates among those with no vaccination but prior infection and those who are truly non-immune.
None of this means the vaccines cannot ALSO be losing efficiency, but it puts negative efficiency into a much more plausible arena - it is paradoxical for vaccines to have negative efficacy but hospitalizations and deaths still show efficacy if the vaccines were ACTUALLY causing more disease. This is an outcome I think isn't at all impossible in the future - I'm more or less expecting it - but it doesn't appear to be the case currently.
So as I make it out, your approach essentially subtracts the "unvaccinated + previously infected" from the "unvaccinated" denominator? Whereas it the previously infected are left in for the vaccinated. But when looking at "real-time" efficacy, the previously infected should be included on both sides, even if that is a handicap against the Covid-vaccinated since they were "out of play" for a ~4 month stretch and now have to catch up. (Hence why "real-time" efficacy is of limited significance.) Otherwise I think a much safer way to adjust for prior infection (as in, without overcorrecting) would be comparative N protein sampling.
I like the idea of comparing the ratio of rates over time but note that by using absolute difference instead of ratio, there's "relative" changes that aren't actually "relative" - they just match the receding of the summer wave in older groups.
It is not paradoxical if you think of the Covid-vaccine immune response as essentially reaching a resting point akin to having "pre-loaded monoclonal antibodies." They don't prevent infection, but they prevent severe outcomes. But, the difference is that with the vaccines there is also some impact on mucosal immunity. From that conservative set of conclusions, I am venturing just what that impact is.
Hmm, I'm not sure I follow how the previously infected in the vaccinated side would be a negative there. I'd expect them to have better overall immunity than just vaccinated (at a minimum it should act as a booster shot). Maybe I'm reading what you are saying incorrectly. I would argue that their effect, whatever it is, on the vaccinated side has to be much smaller than on the Unvaccinated side because of they become a clear minority there. I'll need to run some numbers to quantify this, but we should be able to at least back out the remaining N protein immunity from the vaccinated group as a whole on a very generous basis.... But I'd expect that group to be reducing the case rate on the vaccinated side.
As to relative vs absolute rates, that's an interesting point I'll need to look at. The interesting part here is that even with changing case counts, the rate of change between the two groups is mostly constant. This would be true if the three coefficient of immunity between the groups is at a fairly fixed ratio... Then for any X cases in the population, the distribution will be by ratio, regardless of the raw numbers.
Both groups have a certain amount of previously infected. It could be 18% for the Covid-vaccinated and 20% for the unvaccinated, for example. Removing them from only one group and not the other, as I think your method ends up doing, is the same as multiplying the case rate by 1.25 for one side. However, that doesn't get to your end results, so maybe you've uncovered that the official vaccination rates are several points lower than they should be. Or it could be a sampling bias toward the vaccinated in the seroprevalence surveys. It's something to look into.
As far as "negative efficacy" the best argument against it is probably Israel. "0 infection efficacy" was already really close to becoming legible in Israel in July, right before the boosters messed up the stats (https://unglossed.substack.com/p/midsummer-maladies#footnote-anchor-14). But even with the changing definition of "partially vaccinated" to include un-boosted, it's significant that the current dashboard still never shows negative efficacy for that group - https://datadashboard.health.gov.il/COVID-19/general
Here I show the relative proportions of my calculated Prior-Infected and Non-Immune in the "Unvaccinated" group and more directly how I got them. I will follow up with N Protein immunity numbers backed into the Vaccinated group - but it seems that the majority are in this group by size.
https://justguy.substack.com/p/showing-my-work
My solution was to use the S protein and the entire population as defined on the Vaccination report in the data pages of the Flu and COVID-19 Weekly Report. I calculated what the S Protein positive population should be and subtracted the single dose population from that number. The remaining number is the population that is not in any way vaccinated, but has S immunity - logically that must be those with prior infections (which can be subtracted from the N protein population to give a good estimate of the number of prior infections in the vaccinated cohort as a whole). But that population is around 90% of the Unvaccinated population as defined by UK HSA. It's not a small portion.
Right, but it (seemingly) can't be at 90% if N protein seroprevalence is still low in younger groups (though, the testing thresholds could simply be too high). It's definitely a question I'll have to look into before my next hop across the pond.
In the most recent report, in all age groups but 18-29 and 30-39, there is excess N Protein population left after subtracting out the S Positive Unvaccinated from the total N Protein population.
For both 18-29 and 30-39 there end up being negative 200-300k remaining population. Out of roughly 10m overall population in each group.
I'm not sure the best way to deal with this - should I clamp S positive cases to no more than available N positive? Or is there some possibility that younger, more aggressive innate immune responses might reduce the likelihood of ever generating N Antibodies after infection? I would suspect I should run with both and see how much difference it makes to the results.
I confirmed by replication that UK HSA uses total population - single dose population to calculate Unvaccinated
Thanks for sharing these, and I'm pleasantly surprised to see my hypothesis incorporated into your thinking. My thought is that if the genetic vaccines truly are inducing negative efficacy via immune tolerance, the consequences for the vaccinated will become disastrously obvious at some point and the responsible vaccines will disappear from use in a giant scandal - and perhaps will be replaced by Novavax-type or even inactivated-virus vaccines. Tolerance will presumably fade eventually, so I don't think it will truly be a "forever spike" situation inducing tolerance in unvaccinated people.
If the superspreader hypothesis is real, the vaxxed/unvaxxed illness/death differential should disappear once a majority of unvaxxed have natural immunity. At that point (probably sometime in the next few months in the US) we will see whether the differential reverses which would indicate tolerance/immune suppression, original antigenic sin, antibody-dependent enhancement, or some other issue specific to the vaccines.
I won't be 100% convinced of negative-efficacy data until I see a chart that separates unvaccinated-naive from unvaccinated-prior-immunity people. It seems like people with prior immunity would self-select into the unvaccinated group, and given that we know natural immunity is superior that alone could lead to lower infection levels in that group.
I like your graphic - that is about what I would expect from immune tolerance. I'm also interested in understanding the degree to which induced tolerance might be protective against severe illness due to immune dysfunction/overreaction - in which case it might appear superficially as a feature rather than a bug.
I've never been convinced by the Marek's disaster scenario. For one, it is much more of an exception than a rule - much as was true of smallpox in terms of being eradicable through vaccination. For another, there are many important factors that are true of Marek's in chickens that are not true of SARS-CoV2 in humans. Below is a response I recently posted to another forum on this issue.
-------------
Although I'm certainly not an expert on the level of Geert Vanden Bossche, I find the Marek's scenario unlikely for several reasons.
1. Natural immunity is superior to vaccine immunity, and we are rapidly reaching a point at which a majority of unvaccinated people have natural immunity. This is in contrast to the situation in chickens, in which the entire population turns over on average several times per year and so there is a constant influx of disease-naive birds and natural immunity plays a smaller role.
2. The concern is that a vaccine that reduces symptoms without blocking infection could select for more virulent strains that are capable of causing symptoms in vaccinated people - but that then are deadly to unvaccinated people. This is more likely if symptoms are required for spread - e.g. a virus that spreads through lesions or pustules. In the case of covid, which spreads through breathing and talking, suppression of symptoms may actually increase transmission as asymptomatic people are more likely to be out and about. So there should not be much selection for more virulent strains among vaccinated people.
3. The selective pressure for respiratory viruses to become endemic through increased transmissibility and decreased virulence over time is very strong, and while vaccination may interfere with this trajectory in harmful ways I would not expect it to destroy it entirely. Natural immunity against coronaviruses and influenza viruses is also "leaky" and of limited duration, and so leaky vaccination is not so much a special case as an inferior version of natural immunity. I would be much more concerned about a Marek's scenario if we had a leaky vaccine against Ebola, polio, or smallpox - diseases with a naturally high virulence and for which natural immunity is typically sterilizing (non-leaky) and lifelong.
4. We have been vaccinating with leaky flu vaccines for years without creating new lethal strains, and SARS-CoV2 is much more similar to influenza than to the carcinogenic herpes virus that causes Marek's in chickens.
5. Vaccine efficacy is rapidly waning to the point at which they are not merely "leaky" but might better be called "ineffective against everything except severe illness." In this circumstance there should be little if any selective pressure for increased virulence among vaccinated people. The primary selective pressure will be for evasion of vaccine-induced neutralizing antibodies, and these antibody-escape mutants should not in general cause more severe illness in unvaccinated people. (Although if leaky vaccines increase the total amount of virus in circulation, they will increase the overall mutation rate, which could lead to new strains emerging more frequently and potentially causing more frequent reinfection among both vaccinated and unvaccinated people. This is a problem but not on the level of Marek's.)
6. The Marek's scenario unfolded relatively slowly. It was not so much that the vaccines selected *for* hotter (more virulent) strains but rather that they failed to select *against* them. Because the vaccines suppressed symptoms, strains that would have been eliminated in unvaccinated populations because they killed birds too quickly were allowed to evolve and persist if they also increased transmissibility even slightly. Thus Marek's disease gradually became more deadly to unvaccinated birds over several decades of widespread leaky vaccination. So even if widespread leaky vaccination against influenza or SARS-Cov2 does have the effect of increasing virulence, I would expect this to occur over a years-to-decades timescale - whereas many of the other crisis scenarios we have been discussing could easily unfold over the next few months.
As a smallhold farmer who raises free-range chickens for both meat and eggs (and never vaccinates my birds), I'm not certain Marek's Disease is a good comparison to humans and SARS-CoV-2. On the whole this disease affects chickens raised commercially--crowded, unhealthy conditions that lack any access to the open air, sunlight, and nutritious feed that supports the immune system. Oh wait! I've just described most of the population of the US. Never mind.
I want to love your comment multiple times. Free range chooks that are truly free range, and what we should have done instead of lock down ad infinitum.
These scientists claim that lysine prevents Marek's disease in unvaccinated chickens (or at least protects them while they develop natural immunity).
YouTube interview:
https://www.youtube.com/watch?v=nmox2RbLKeo
Research papers:
https://www.researchgate.net/publication/344210822_Lysine_Therapy_for_SARS-CoV-2
https://www.researchgate.net/publication/312115736_D_L-lysine_acetylsalicylate_glycine_Impairs_Coronavirus_Replication
Lysine was also found to help a small set of test humans, too. https://www.researchgate.net/publication/344210822_Lysine_Therapy_for_SARS-CoV-2
"I won't be 100% convinced of negative-efficacy data until I see a chart that separates unvaccinated-naive from unvaccinated-prior-immunity people"
And this, of course, would only select for people with strong and persistent "dark matter" immunity to SARS-CoV-2. For example if the Cleveland Clinic study is still tracking results, the "unvaccinated / not previously infected" healthcare worker set (there were 17,000 of them still in May; they were not targeted by mandates before but have just fallen under Biden's mandate) must have all of those individuals by now. There's no way to sort them out or measure them except to spray the virus right into everyone's nose. Nothing can be measured without being changed - suppression of innate immunity via a year of lockdown stress/inactivity is just as plausible for explaining a higher summer wave, for example, though I doubt it would have gotten us to winter levels as turned out.
RE "If the superspreader hypothesis is real, the vaxxed/unvaxxed illness/death differential should disappear once a majority of unvaxxed have natural immunity." I should have done a separate crude chart for changes to convalescent challenge outcomes. The unvaccinated+recovered side should look similar but with the severe outcomes gone, maybe a bit greater "asymptomatic" share toward the top but I think really it will just be that "mild" changes to "really mild." Natural "sterilizing" immunity is meant to wane, to avoid incentivizing immune evasion - similar to how you phrase it in point 3. That still leaves me with the (now enumerated in an update) reservations about converting from seasonal challenge to perpetual challenge.
I agree with everything in your list overall. Re tolerance, I agree that it, along with antibody fade-out, are part of the important "amendability" of the immune system. I am not aware of enough natural precedents for antibody dependent enhancement to argue that there is a necessary role for tolerance in avoiding it; unless, of course, it is doing so to such perfection that it is impossible to measure the role.
Thanks for enriching my post with your well though-out remarks.