I want to make sure that I understand OAS. Because I watched the Original Gangstas of Kirk, Spock, McCoy and especially Uhura in a miniskirt, is that why I feel pain when exposed to the supposedly better Next Gen and all the other clones? If that is so, that would explain why I believe that in a confrontation between Kirk and Picard that Kirk's diplomacy of a phaser and a smirk would blast Picard out of existence. If I have this accurately understood, then it would explain others suffering from the same affliction. http://www.comedycorner.org/12.html
Exactly. It's probably impossible to be as "impressed" by TNG if exposed to TO(a)S. But is TNG actually bad, as it seems to be to those of us ruined by high expectations?
I think it's fundamentally a problem with the stilted voices. Little of the acting is great (Dorn's is, almost always; and Wheaton's is surprisingly good sometimes), but *all* of the acting is rendered off-putting by the stodgy inflection, which spikes the occasionally excellent writing in turn. Solution: switch to German or French audio in Netflix. Lot of great voice actors in both languages. The show will come alive.
TO(a)S......Sir, you are clever *and* funny. Tryin' to get the li'l ol' pea-brain to wrap around this new wrinkle. Would the German/French audio act as a sterilizing vaccine or perhaps a new OAS causing ear bleed for all English language programming? If it makes the Frenchman drop the British accent, I'm guessing it acts as a sterilizing vaccine. Dorn does make it watchable.
The Frenchman indeed becomes French in French; every captain's log sounds as if he has just finished guillotining you, and is recording notes. In German, a bit more pleasantly English (as in, with a sort of Monty Python High-T-Energy warble). The first is a pinch of salt, the other a burst of umami: Either way they make the old dish shine.
Mr. Mowrey, you are motivating me to crawl out from under my rock in my cave, forego my neolithic cave wall art project and my recent discovery of this nascent technology I call agriculture and find someone willing to share a Netflix subscription password and binge. I do know someone afflicted with OAS of TNG and I'll advise them of the upgrade. They've watched so many episodes they can lip sync most episodes. A pleasure, sir, a true pleasure. Thanks again.
I stopped to read up on natural antibodies first, since Alexander at first invokes those. But then the rest of the post is a bit all over the map, sort of like my Forever Spike tour of theories but without separation between contradictory stances ("asymptomatic superspreaders" and "getting more sick" all in the same list of possibilities)... Certainly (again as I posit in Forever Spike) getting more sick / dysfunctional innate immunity are plausible to me, not so much superspreaders or Marek's...
This made my head hurt as well and I have a biology degree with a fair amount of time racked up on immunology. Admittedly from an early internet era...
Questioms, if i may?
How do you account for the real world numbers of cov reinfections tending more prevalent in vaccinated?
Depressed immunity post vaccination leading to lower viral load causing disease?
Poor antibodies leading to ADE or similar?
Small antigen target (s) vs whole virus?
Auto immunity from overstimulation?
Statistical artefact of % vaccinate vs not?
I’m struggling with any other explanations…
It would also seem true that antibody measures of waning immunity are totally useless as a reason to give boosters. At this point that would be obvious, with reliance on B/T cells. Would you agree?
Aside from antibody levels, population cohort studies have shown an obvious trend to waning immunity over time.
Is there anything that could reasonably be done from a biology perspective that would answer the question of COVID evolution, and therefore what would actually constitute sensible policy?
Grateful got the perspective.
For me, it’s starting to look like the removal of OAS as a danger, or impact of constant re priming of the immune system, eg to cause auto immunity, leaves few options on the table, which Is worrying when policy seems to err to the most draconian option….
Do you mean higher rates of infection / apparent negative efficacy, or the higher reinfection rate in the Goldberg et al. graph? For the former, I have taken it as a provisional affirmation of the disabling of innate immunity as proposed by vanden Bossche (https://unglossed.substack.com/p/forever-spike#footnote-anchor-13 ), but I’m less certain if “negative efficacy” is actually real).
For the latter, individuals are not groups. If 3% more people have reinfections after the vaccine then that means the vaccine “messed up” natural immunity for those 3% - but not for the other 97. So 97% of the time the vaccine doesn’t impair natural immunity. Of course, all these rates have to be multiplied over time but the August+September period represented a good half-year of exposure risk in Israel.
I have argued that severe efficacy remains durable and the anti-Covid-vax group should emphasize this fact as an argument against boosters (just as the FDA resigners have done). Boosters, despite the short-term increase in antibodies, could be putting the vaccinated into tolerance territory, though that’s really a hypothetical since this is such a novel experiment on nature.
Why is any policy needed RE the virus? Even with waning immunity, whether natural or artificial, severe outcomes become rare. The problem I foresee is economic dysfunction resulting from direct harms from the shot (including autoimmunity).
I think reinfection as per Goldberg is the interesting question re is repeated vaccination causing people to become prone to reinfection, and therefore by what mechanism…that’s where I don’t see many convincing hypotheses.
I do think that data is stark, if only in the degree of difference, which is begging for an explanation.
I had thought that OAS was a good stab, but the antibody / severe disease assays do hint at an objection. Albeit who can say if the tests are of high enough resolution as yet….(?)
I think saying ‘not now’ to boost because of existing protection is churlish as an anti vaccine argument. The simplistic view is immunity wanes, as it obviously does. The counter argument has to be about the greater risk and the subsequent decisions made to mitigate the consequences of the prior mistake. That is why these questions are so very urgent….
I think the policy question is therefore integral. If revaccination leads to disease, that’s ultimately an economic impact. Within this, the scope of debate is wide; from direct harms to hypothetical long term possibilities like auto immunity, which to date I have (mercifully) seen no reports of. But this is a Grand Experiment is it not….?!!!
Are you aware of any literature that points at auto immune disease from over vaccination and the biology of it?
Generally, I think the danger here (of your analysis), is that you’ve raised the flag on the fact that current explanations are wanting.
But that’s not a bad thing….as long as the specificity question isn’t the answer and OAS remains real, as several other people like yourself have indeed suggested…..
The simplest model for potential detriment to post-"breakthrough" memory immunity is failure to correct what was deficient in the first place. This means mucosal immunity, especially resident T Cells imo. Do they migrate to the GI / respiratory tract now that the immune system has "seen" the virus itself, with associated cellular destruction and activation of DAMP pathways, all of which didn't happen in the simulated encounter (injected mRNA transfection)? Lack of mucosal immunity "correction" would not be "OAS", though it is amusingly the mechanism suggested in this article trying to propose a model for OAS https://trialsitenews.com/the-original-antigenic-sin-covid-19-vaccination-and-sub-optimal-initial-immune-priming-deranges-the-antibody-cytotoxic-t-cell-immune-response/
With this simplistic model, I never would have bet money on 90+% "correction" rate (and that's not taking into account how many "breakthrough" infections are before 3 months post 2nd dose, with a higher false positivity and asymptomatic rate than the naturally infected) - so I think the Goldberg et al. results are good news. Presumably if this is a signal for "correction", the folks who get secondary "breakthroughs" will have another chance to join the "correction" crowd.
Vinu Arumugham offers a plausible biology for general autoimmunity from vaccination - it's simple sensitization from residual animal / fungus / etc proteins in vaccine prep. He's now got a sub set up now - https://vinuarumugham.substack.com/ This is his paper on his theory - https://zenodo.org/record/3647593#.YbedaS2cZTY He might know more about existing research but there really isn't much interest in how the immune system responds to injected moth proteins (random example from Novavax); hence why it falls on an engineer / outsider like him to raise these points.
I don’t think it’s unfair to say that, given the scale of the experiment, we might very well be seeing genetic ‘weakness’ in immune response for the given epitopes, resulting in the likelihood of reinfection later. This being purely a statistical fact of life.
Similarly with the potential for auto immunity caused by over exposure to a given protein.
The implication of that is simple, mRNA vaccines, whilst largely experimental, do the job they were designed to do, with a slightly worse safety profile than traditional vaccines.
Further, that whilst governments are adopting authoritarian policy stances, and pharmaceutical businesses are cashing in, and the world is I the grip of a mass psychosis caused by 2 years of fear and propaganda, fundamentally the biology is no more than a risk calculation that those in power are largely correct on. (Even if only by accident).
It wasn’t the answer I thought I’d consider, but at this stage, it doesn’t seem entirely unreasonable….
Many thanks. I will follow your posts with interest and always welcome the discussions.
Only "correct" if and when they pass the ADE hurdle that has dogged previous experimental coronavirus vaccines, which means waiting until more antigenic drift-! But I projected (in an August post) that to be two years down the line, and was optimistic that "correction" would help for those who get breakthrough. Also that still wouldn't be "correct" in my extremely bullish estimations of the direct harms from the shot (1+/10 scale in medium term).
Omicron seems to be either a sign that the ADE black swan was never really going to arrive, or a lateral get-out-of-spike-sensitization-jail card as suggested by vanden Bossche (as always, with his mysterious focus on natural antibodies - https://jessicar.substack.com/p/a-new-piece-by-geert-vanden-bossche)...
This was my thinking in September, especially as I was skeptical of the mainstream "Delta is more contagious" narrative. But then look at Russia, Ukraine, Romania (cases) - very low vaccine uptake, but still had bigger autumn waves this year (w/ pretty consistent test positivity rates). So, I finally accepted the Delta narrative. But that could be a change in the host, not the virus.
Hospitalizations are difficult metric to compare over time (admission standards can change), but Norway, much like Israel in the summer, looks pretty good if you scale for the much higher case rates (assuming 0 infection efficacy in both cases).
Ah - yes, I suppose scaling to cases in y1 v y2 doesn't address the possibly missing "discount" that apparent severe efficacy should be applying to hospitalization. Too bad my low-vax-rate poster countries don't have hospitalization numbers.
Using death rates in Ukraine and Romania at worldometers, "autumn wave cases / all cases" is nearly = "autumn wave deaths / all deaths" - so no discount for the (low) vax. In Israel case ratio is higher than death ratio - so, some discount in deaths thanks the vax.
Hours of math might produce the result that delta, adjusted for no vax severe/death efficacy, was globally more virulent (whether because of the virus or host/environment) by like 10-20%; in fact there were already studies that suggested this in July, from Singapore, Canada, and Scotland, and I wasn't able to dismiss the finding entirely (https://unglossed.substack.com/p/near-t-rock-bottom-out-on-route-23#footnote-15). This, plus reduced standards for hospital admission based on expectations that delta is milder, plus healthy-user-bias factors that lead to a slightly exaggerated severe/deaths efficacy, could get us to the results we see now.
Probably just statistics. If probability is greater numbers are vaxed, then probability is higher numbers of vaxed get sick. We know the vax doesn't last long, and doesn't work well for some with weaker immu e health, which is increasingly large slice of westernized populations, so the biggest revelation of the stats is the vax is irrelevant to most of us.
We should always remember ber that statistical averages only apply directly to a few average people. Most people are above or below average. In the case of immunity, most of us can choose to be above average.
We then need some standardised stats to account for relative numbers of vaccinated vs not for covid infection and reinfection. Know of any that are?
More broadly, it seems to me to be true that there is nothing that effectively represents the real world complexity of this, other than perhaps deaths above average by age and vaccine status, and further elicited as time goes on.
Will look forward to further perspectives on the biology.
I think the Goldberg figures are pretty reliable. They plot out the population changes over time in the study. I’ve also independently back-of-napkined the denominators for the Israel Ministry of Health population rates before, so I’m inclined to trust studies from there - whereas the UK denominators seem totally broken.
The linked graphic at the very beginning of the article doesn't work (tried 2 browsers, turned off add blocker, etc.) So it took me a while to figure out what was going on. I enjoyed the Star Trek/video game structure.
The scroll? All my dividers/spacers are hyperlinked to “null”. Substack doesn’t allow turning off hyperlinks on images; the default is to open the image in a new window but since my dividers have transparent backgrounds, this results in a “blank” tab with a creepy amazon URL. So I edit the URL to null, and am trying to use spacers more sparingly in the OP / email version to reduce accidental link-opens.
If there was a way of sending you an image I could send you a screenshot. It's not your scroll thingy. It looks like there's something missing from the beginning of the article.
Actually, you can reply to emails in substack; it's a little-advertised feature, I've only had one reader use it (and some / most bigger subs probably turn it off).
Sounds like the spacer png - I put one below "Options" and "Start Game" in session 1 and 2 of the "game", respectively. If you mouse-over in web version, the alt-text shows "spacer". You'll notice almost no substacks have white space - or they have to use a _ or similar. Aesthetically unacceptable to me. But like I said, I try to avoid adding the spacers until after the email posts, now - Darmok was an exception.
"taking up some hypothetically zero-sum memory immunity bandwidth"
I'm glad somebody finally brought this up, because I've been scratching my head over how it may be so. Competition for resources? I'm not a rocket scientist or an immunologist, but it seems unlikely, from what I understand of physiology.
One personal hypothesis that I'm fairly confident about is that applying logic to an imperfectly understood situation doesn't work very well. GIGO.
Memory immunity is distributed/collaborative. While we can “see” when it works (protection against infection / illness) and fails (auto-immunity) the underlying reality is a spectrum consisting of billions of “immune responses” initiated by individual antigen-presenting-cells that are all essentially autonomous - none of them is “updated” by the updates of the others; but if enough of them “update” the same way then a durable programmed immune response is produced in T Cell and thymus land, leading to measurable “works”/“fails”. There’s overlap in response times as well. After adolescence, T Cell motifs become more fixed and the thymus less active, but new motifs never stop generating (take adult-onset allergies). That’s my current understanding and I don’t see how B Cells and antibodies can attenuate new durable memory responses initiated by APCs since they are two and three orders downstream; there is no clear “bandwidth” overlap.
We're all wired a little differently. Some are more visual than others. Well done graphs help visualization. Poorly done graphs are sometimes intentionally misleading, sometimes just confusing. All graphs should cite sources.
Right - I feel that even a well done graph is giving me the work of trying to figure out a conclusion that could just be explained in words, without enhancing my ability to scrutinize the conclusion itself.
You may be right that OAS is a myth as originally conceived - some sort of immune defect. But I also keep seeing data suggesting that Omicron preferentially infects vaccinated people.
My best guess is that if an OAS-like phenomenon is real, it is caused primarily by epitope masking by abundant but weakly-binding antibodies. If the antibodies bind more weakly than the receptor target, the antigens will still be able to bind to the target and cause infection, but they will also be effectively "hidden" from the immune system by the attached antibodies, inhibiting the development of strongly-binding variant-specific antibodies.
I was distracted by dinner. More precisely, Cron presents a “problem” for OAS in that OAS gets to declare a win no matter where the signal comes up - Detrimental performance among the previously SC2-spike-exposed (“original” sin is spike exposure) or not (“original” sin is coronavirus exposure, and spike exposure corrects it). It’s a constantly rigged game; memory immunity has to cease existing for OAS to lose.
Cron is an even bigger problem for “viruses want to get milder.” If Cron didn’t come from any previously measured + circulating SC2 then it reveals nothing about what SC2 “wanted.”
Of course, I’m suspicious of genetic clocks - it’s obviously guaranteed that the 1 in 10^20 chance of a cluster of 50 mutations will produce a viable genome _will come about_ if the genome is mis-copied with 50 changes 10^20 times; plus there’s the genomic crisis / transposable element realm that science has ignored for 80 years, which is the only way to account for the INDELS outside of lab creation as far as I can grok...
Other human coronaviruses are sufficiently genetically distinct that I would expect fairly minimal immune modulation of SC2 response whether positive ("cross-protection") or negative ("OAS"). All claimed OAS signals have been statistically very minor and quite possibly artifacts, although a few studies of cross-protective T cell immunity have been more convincing.
Immune interference *between* SC2 lineages is much more plausible. What I gather from your writing is that you question the concept of OAS as originally conceived. Others have done that as well, e.g. https://pubmed.ncbi.nlm.nih.gov/31964645/
I think you are right about that, but I am more interested in outcomes than mechanisms. Increasingly within the alternative media-sphere "OAS" refers to the situation in which vaccinated people get infected at a higher rate while "ADE" refers to the situation in which vaccinated people experience more severe illness. I have argued against this choice of terminology at times but I'm open to this modified outcome-based definition.
As for the origins of Omicron I'm fairly agnostic, though I would consider reverse zoonosis followed by later transfer back to humans to be the leading hypothesis.
It should be remembered that low-affinity antibodies are a lifelong anti-adjuvant, as the tldr on the paper. The immune system is not as easily alarmed by what does not as easily harm. Cross-immunity, again.
And as suggested by Gostic, et al., frequency of childhood exposure to flu subtype confers lifetime higher competence in challenge with that subtype - adults with less childhood exposure cannot hope to develop such refined protection. It’s not “interference” with by the more trained immune response; and there’s still implied cross immunity protection in T Cells. This seems to be the limit of natural immunity relevance to childhood priming with flu; leaving “OAS” as a concern only for vaccnes. However, it is a very dense paper and I need to read it further...
Low affinity antibodies are not a problem so long as they don't trigger ADE and there aren't so very many of them that they get in the way, preventing the adaptive immune system from mounting a de novo antibody response with better mapping to epitopes on the current virus.
The ADE effect seems to be relatively uncommon (except for Dengue and maybe a few others). I would hypothesize that interference/epitope masking is generally avoided by limiting antibody titer. However the current vax-boost strategy of achieving neutralization of partial-escape variants by way of stratospheric antibody titers strikes me as potentially very problematic in an OAS sort of way, and an attempt to brute-force manipulate a delicately adapted system.
I get queasy every time I scroll past Eliakim-Raz, et al. in my study roll - “The median titer level increased significantly after the third dose, from a median of 440 AU/mL (IQR, 294-923) to 25 468 AU/mL (IQR, 14 203-36 618)” I think I would have thrown my computer in the trash if I was looking at those results in a lab.
There’s implicit equilibrium - antibodies that get in the way will result in the virus getting a head start, leading to higher “alarm” and cancelling out the anti-adjuvant. This is, essentially, symptomatic reinfection. There’s probably wear and tear, but if we didn’t give something back to the virus then the existence of temperate non-evading viruses would be impossible. Humans can critique this model and plot out imaginary “delayed, higher” viremia plots all we want but in reality it’s functional coevolution at work.
The cited article is a fun history lesson. The money shot passage seems to be "explication should provide employment for scientific historians and social psychologists for decades to come." One has to wonder how much of research is productive for society and how much is just full employment program for lab rats. Some of both I suppose. As the ladies say, gotta kiss a lot of frogs to find the handsome prince.
Those interested in history might enjoy Code Breaker by Isaacson. History and tutorial of biotechnology, focus on Jennifer Doudna who invented CRSPR gene editing.
Learning to manage what nature gives us is the key to our success. Bacteria figured it out millions of years ago, but it took Jennifer to figure out how to make it work for us.
And rate of post-exposure infection is modulated by cellular immunity after antibodies fade, regardless of whether said exposure is vaccine or infection, in my model. Fending off subsequent challenge without updating antibodies is literally “immunity”; failure to fend off challenge due to lack of resident T Cells post-vaccine is vaccine failure, but does not imply a net-detrimental effect from priming. All non-OPV kids vaccines probably work this way, with breakthrough infections disguised by lessoned symptoms; here the net-detriment is probably second order (lower overall immune competence) but in terms of the target bug the kid gets to “immunity” in the end. If it doesn’t work that well for adults, well, neither does memory immunity overall. The “priming” is redundant.
Thanks for that link! I didn’t want to post RE OAS again until I did a lot more reading into influenza research; this looks like a handy overview. My instinct is that Francis’ OAS was resurrected to blame natural immunity for the failure of the modern revival of adult vaccination, and no one has come to grips with the fact that it doesn't correspond to a single in-nature deficiency in immunity (aside from Dengue)!
“data suggesting that Omicron preferentially infects vaccinated people.”
- also a stupendous refutation of OAS! Since all those “nasty” unvaccinated are such “sinners” by way of previous, “original” non-SC2-relevant coronavirus exposure. Ethical Skeptic is pretty convincing that the LCA for Omicron is early 2018, meaning that all prior immune response to SC2 in 18-20 can be wiped off the board. An OAS signal in Omicron should snap to wild coronavirus antibody, not to SC2 antibody.
Let me see if I can summarize your argument against OAS and please tell me if I have it more or less correct. You don't deny that previous exposure to the spike proteins of similar viruses impedes the development of antibodies that fit the new virus well. You are just saying that neutralizing antibodies are overblown. They are not the most important form of immunity. Previous exposure to similar viruses gives very effective cellular immunity. People with previous exposure to similar viruses do not tend to get more sick, on the contrary they get less sick. The fact that they are not making neutralizing antibodies that are specific to the new virus is not very important. Is this more or less your view? Thanks.
That is pretty much my view in a nutshell. There are no real-life instances where the immune system is at a net negative due to previous encounter with a related virus strain *because* it doesn't produce as many form-fit antibodies to the new strain as it would have in naive encounter - rather, the lower generation of new form-fit antibodies reflects that prior memory immunity worked fine. This is especially the case for flu. Immunity against new strains of childhood-encountered groups is stronger than immunity against unrelated groups - https://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.1008109; presumably even cross-group immunity is stronger than hypothetical "0 childhood flu exposure" but medicine always discounts the positive.
Vaccinology is desparate to find a real-life example of OAS, otherwise it the inability to trick the immune system into X' antibodies for every X antibody is not "a deep flaw in the immune system that only we understand, trust us we've got the links" but simply "an obvious defect in vaccination (against any virus with antigenic drift)."
Hence, Dengue (an injected virus) becoming the poster child. But Dengue is "other strain antibodies enhance infection," not, "can't make new strain antibodies fast enough." It's use to prop up OAS is more sign of the desperation.
The Last Common Ancestor for Omicron being 2018? Wow. Is there a link to Ethical Skeptic's take on that? That would be pretty interesting to read especially as thus far the theories I've seen suggest the last common ancestor for omicron was alpha variant which was last seen in June 2020 and that omicron itself diverged in June 2021, seemingly from leak at a BSL-3 lab in Durban where they were doing the kinds of research on actual samples of alpha that could have led to omicron (rather than doing that research with pseudoviruses which would have been safer)
😄 great post, thank you. I understand oas a little more now, the extra dose of humor and sarcasm is what did it for me.
Haha - thank you. It's difficult to parody OAS without being confusing, since the argument is intrinsically deceptive.
Mr. Mowrey,
Thank you.
I want to make sure that I understand OAS. Because I watched the Original Gangstas of Kirk, Spock, McCoy and especially Uhura in a miniskirt, is that why I feel pain when exposed to the supposedly better Next Gen and all the other clones? If that is so, that would explain why I believe that in a confrontation between Kirk and Picard that Kirk's diplomacy of a phaser and a smirk would blast Picard out of existence. If I have this accurately understood, then it would explain others suffering from the same affliction. http://www.comedycorner.org/12.html
Exactly. It's probably impossible to be as "impressed" by TNG if exposed to TO(a)S. But is TNG actually bad, as it seems to be to those of us ruined by high expectations?
I think it's fundamentally a problem with the stilted voices. Little of the acting is great (Dorn's is, almost always; and Wheaton's is surprisingly good sometimes), but *all* of the acting is rendered off-putting by the stodgy inflection, which spikes the occasionally excellent writing in turn. Solution: switch to German or French audio in Netflix. Lot of great voice actors in both languages. The show will come alive.
TO(a)S......Sir, you are clever *and* funny. Tryin' to get the li'l ol' pea-brain to wrap around this new wrinkle. Would the German/French audio act as a sterilizing vaccine or perhaps a new OAS causing ear bleed for all English language programming? If it makes the Frenchman drop the British accent, I'm guessing it acts as a sterilizing vaccine. Dorn does make it watchable.
If you want to jump into the deep end, start with 2:21 "Peak Performance" in French.
The Frenchman indeed becomes French in French; every captain's log sounds as if he has just finished guillotining you, and is recording notes. In German, a bit more pleasantly English (as in, with a sort of Monty Python High-T-Energy warble). The first is a pinch of salt, the other a burst of umami: Either way they make the old dish shine.
Mr. Mowrey, you are motivating me to crawl out from under my rock in my cave, forego my neolithic cave wall art project and my recent discovery of this nascent technology I call agriculture and find someone willing to share a Netflix subscription password and binge. I do know someone afflicted with OAS of TNG and I'll advise them of the upgrade. They've watched so many episodes they can lip sync most episodes. A pleasure, sir, a true pleasure. Thanks again.
I find the following explanations bio-logically comprehensible, OAS or not:
https://palexander.substack.com/p/mortal-antigenic-sin-original-antigenic
I stopped to read up on natural antibodies first, since Alexander at first invokes those. But then the rest of the post is a bit all over the map, sort of like my Forever Spike tour of theories but without separation between contradictory stances ("asymptomatic superspreaders" and "getting more sick" all in the same list of possibilities)... Certainly (again as I posit in Forever Spike) getting more sick / dysfunctional innate immunity are plausible to me, not so much superspreaders or Marek's...
Will their eyes open?
This made my head hurt as well and I have a biology degree with a fair amount of time racked up on immunology. Admittedly from an early internet era...
Questioms, if i may?
How do you account for the real world numbers of cov reinfections tending more prevalent in vaccinated?
Depressed immunity post vaccination leading to lower viral load causing disease?
Poor antibodies leading to ADE or similar?
Small antigen target (s) vs whole virus?
Auto immunity from overstimulation?
Statistical artefact of % vaccinate vs not?
I’m struggling with any other explanations…
It would also seem true that antibody measures of waning immunity are totally useless as a reason to give boosters. At this point that would be obvious, with reliance on B/T cells. Would you agree?
Aside from antibody levels, population cohort studies have shown an obvious trend to waning immunity over time.
Is there anything that could reasonably be done from a biology perspective that would answer the question of COVID evolution, and therefore what would actually constitute sensible policy?
Grateful got the perspective.
For me, it’s starting to look like the removal of OAS as a danger, or impact of constant re priming of the immune system, eg to cause auto immunity, leaves few options on the table, which Is worrying when policy seems to err to the most draconian option….
So. What do you think?
Do you mean higher rates of infection / apparent negative efficacy, or the higher reinfection rate in the Goldberg et al. graph? For the former, I have taken it as a provisional affirmation of the disabling of innate immunity as proposed by vanden Bossche (https://unglossed.substack.com/p/forever-spike#footnote-anchor-13 ), but I’m less certain if “negative efficacy” is actually real).
For the latter, individuals are not groups. If 3% more people have reinfections after the vaccine then that means the vaccine “messed up” natural immunity for those 3% - but not for the other 97. So 97% of the time the vaccine doesn’t impair natural immunity. Of course, all these rates have to be multiplied over time but the August+September period represented a good half-year of exposure risk in Israel.
I have argued that severe efficacy remains durable and the anti-Covid-vax group should emphasize this fact as an argument against boosters (just as the FDA resigners have done). Boosters, despite the short-term increase in antibodies, could be putting the vaccinated into tolerance territory, though that’s really a hypothetical since this is such a novel experiment on nature.
Why is any policy needed RE the virus? Even with waning immunity, whether natural or artificial, severe outcomes become rare. The problem I foresee is economic dysfunction resulting from direct harms from the shot (including autoimmunity).
I think reinfection as per Goldberg is the interesting question re is repeated vaccination causing people to become prone to reinfection, and therefore by what mechanism…that’s where I don’t see many convincing hypotheses.
I do think that data is stark, if only in the degree of difference, which is begging for an explanation.
I had thought that OAS was a good stab, but the antibody / severe disease assays do hint at an objection. Albeit who can say if the tests are of high enough resolution as yet….(?)
I think saying ‘not now’ to boost because of existing protection is churlish as an anti vaccine argument. The simplistic view is immunity wanes, as it obviously does. The counter argument has to be about the greater risk and the subsequent decisions made to mitigate the consequences of the prior mistake. That is why these questions are so very urgent….
I think the policy question is therefore integral. If revaccination leads to disease, that’s ultimately an economic impact. Within this, the scope of debate is wide; from direct harms to hypothetical long term possibilities like auto immunity, which to date I have (mercifully) seen no reports of. But this is a Grand Experiment is it not….?!!!
Are you aware of any literature that points at auto immune disease from over vaccination and the biology of it?
Generally, I think the danger here (of your analysis), is that you’ve raised the flag on the fact that current explanations are wanting.
But that’s not a bad thing….as long as the specificity question isn’t the answer and OAS remains real, as several other people like yourself have indeed suggested…..
The simplest model for potential detriment to post-"breakthrough" memory immunity is failure to correct what was deficient in the first place. This means mucosal immunity, especially resident T Cells imo. Do they migrate to the GI / respiratory tract now that the immune system has "seen" the virus itself, with associated cellular destruction and activation of DAMP pathways, all of which didn't happen in the simulated encounter (injected mRNA transfection)? Lack of mucosal immunity "correction" would not be "OAS", though it is amusingly the mechanism suggested in this article trying to propose a model for OAS https://trialsitenews.com/the-original-antigenic-sin-covid-19-vaccination-and-sub-optimal-initial-immune-priming-deranges-the-antibody-cytotoxic-t-cell-immune-response/
With this simplistic model, I never would have bet money on 90+% "correction" rate (and that's not taking into account how many "breakthrough" infections are before 3 months post 2nd dose, with a higher false positivity and asymptomatic rate than the naturally infected) - so I think the Goldberg et al. results are good news. Presumably if this is a signal for "correction", the folks who get secondary "breakthroughs" will have another chance to join the "correction" crowd.
Vinu Arumugham offers a plausible biology for general autoimmunity from vaccination - it's simple sensitization from residual animal / fungus / etc proteins in vaccine prep. He's now got a sub set up now - https://vinuarumugham.substack.com/ This is his paper on his theory - https://zenodo.org/record/3647593#.YbedaS2cZTY He might know more about existing research but there really isn't much interest in how the immune system responds to injected moth proteins (random example from Novavax); hence why it falls on an engineer / outsider like him to raise these points.
I don’t think it’s unfair to say that, given the scale of the experiment, we might very well be seeing genetic ‘weakness’ in immune response for the given epitopes, resulting in the likelihood of reinfection later. This being purely a statistical fact of life.
Similarly with the potential for auto immunity caused by over exposure to a given protein.
The implication of that is simple, mRNA vaccines, whilst largely experimental, do the job they were designed to do, with a slightly worse safety profile than traditional vaccines.
Further, that whilst governments are adopting authoritarian policy stances, and pharmaceutical businesses are cashing in, and the world is I the grip of a mass psychosis caused by 2 years of fear and propaganda, fundamentally the biology is no more than a risk calculation that those in power are largely correct on. (Even if only by accident).
It wasn’t the answer I thought I’d consider, but at this stage, it doesn’t seem entirely unreasonable….
Many thanks. I will follow your posts with interest and always welcome the discussions.
Only "correct" if and when they pass the ADE hurdle that has dogged previous experimental coronavirus vaccines, which means waiting until more antigenic drift-! But I projected (in an August post) that to be two years down the line, and was optimistic that "correction" would help for those who get breakthrough. Also that still wouldn't be "correct" in my extremely bullish estimations of the direct harms from the shot (1+/10 scale in medium term).
Omicron seems to be either a sign that the ADE black swan was never really going to arrive, or a lateral get-out-of-spike-sensitization-jail card as suggested by vanden Bossche (as always, with his mysterious focus on natural antibodies - https://jessicar.substack.com/p/a-new-piece-by-geert-vanden-bossche)...
Man your posts hurt my brain X) I feel like I have put too much weight on my squat bar and I BARELY managed to lift em.
Q: How would one calculate the years / amount of antigenic drift necessary to reach ADE ?
This was my thinking in September, especially as I was skeptical of the mainstream "Delta is more contagious" narrative. But then look at Russia, Ukraine, Romania (cases) - very low vaccine uptake, but still had bigger autumn waves this year (w/ pretty consistent test positivity rates). So, I finally accepted the Delta narrative. But that could be a change in the host, not the virus.
I recently offered the UK 1968/69 flu experience as a case study of a virus hitting harder in the second year, not necessarily because of the virus itself - https://unglossed.substack.com/p/being-cron-malkovich
Hospitalizations are difficult metric to compare over time (admission standards can change), but Norway, much like Israel in the summer, looks pretty good if you scale for the much higher case rates (assuming 0 infection efficacy in both cases).
Ah - yes, I suppose scaling to cases in y1 v y2 doesn't address the possibly missing "discount" that apparent severe efficacy should be applying to hospitalization. Too bad my low-vax-rate poster countries don't have hospitalization numbers.
Using death rates in Ukraine and Romania at worldometers, "autumn wave cases / all cases" is nearly = "autumn wave deaths / all deaths" - so no discount for the (low) vax. In Israel case ratio is higher than death ratio - so, some discount in deaths thanks the vax.
Hours of math might produce the result that delta, adjusted for no vax severe/death efficacy, was globally more virulent (whether because of the virus or host/environment) by like 10-20%; in fact there were already studies that suggested this in July, from Singapore, Canada, and Scotland, and I wasn't able to dismiss the finding entirely (https://unglossed.substack.com/p/near-t-rock-bottom-out-on-route-23#footnote-15). This, plus reduced standards for hospital admission based on expectations that delta is milder, plus healthy-user-bias factors that lead to a slightly exaggerated severe/deaths efficacy, could get us to the results we see now.
(That link drops you into what I found the most convincing nugget of the three studies discussed in the entire segment that begins at https://unglossed.substack.com/p/near-t-rock-bottom-out-on-route-23#footnote-anchor-9)
Probably just statistics. If probability is greater numbers are vaxed, then probability is higher numbers of vaxed get sick. We know the vax doesn't last long, and doesn't work well for some with weaker immu e health, which is increasingly large slice of westernized populations, so the biggest revelation of the stats is the vax is irrelevant to most of us.
We should always remember ber that statistical averages only apply directly to a few average people. Most people are above or below average. In the case of immunity, most of us can choose to be above average.
We then need some standardised stats to account for relative numbers of vaccinated vs not for covid infection and reinfection. Know of any that are?
More broadly, it seems to me to be true that there is nothing that effectively represents the real world complexity of this, other than perhaps deaths above average by age and vaccine status, and further elicited as time goes on.
Will look forward to further perspectives on the biology.
I think the Goldberg figures are pretty reliable. They plot out the population changes over time in the study. I’ve also independently back-of-napkined the denominators for the Israel Ministry of Health population rates before, so I’m inclined to trust studies from there - whereas the UK denominators seem totally broken.
* for the perspective….
Nice Star Trek reference
The linked graphic at the very beginning of the article doesn't work (tried 2 browsers, turned off add blocker, etc.) So it took me a while to figure out what was going on. I enjoyed the Star Trek/video game structure.
The scroll? All my dividers/spacers are hyperlinked to “null”. Substack doesn’t allow turning off hyperlinks on images; the default is to open the image in a new window but since my dividers have transparent backgrounds, this results in a “blank” tab with a creepy amazon URL. So I edit the URL to null, and am trying to use spacers more sparingly in the OP / email version to reduce accidental link-opens.
If there was a way of sending you an image I could send you a screenshot. It's not your scroll thingy. It looks like there's something missing from the beginning of the article.
Actually, you can reply to emails in substack; it's a little-advertised feature, I've only had one reader use it (and some / most bigger subs probably turn it off).
Sounds like the spacer png - I put one below "Options" and "Start Game" in session 1 and 2 of the "game", respectively. If you mouse-over in web version, the alt-text shows "spacer". You'll notice almost no substacks have white space - or they have to use a _ or similar. Aesthetically unacceptable to me. But like I said, I try to avoid adding the spacers until after the email posts, now - Darmok was an exception.
"taking up some hypothetically zero-sum memory immunity bandwidth"
I'm glad somebody finally brought this up, because I've been scratching my head over how it may be so. Competition for resources? I'm not a rocket scientist or an immunologist, but it seems unlikely, from what I understand of physiology.
One personal hypothesis that I'm fairly confident about is that applying logic to an imperfectly understood situation doesn't work very well. GIGO.
Memory immunity is distributed/collaborative. While we can “see” when it works (protection against infection / illness) and fails (auto-immunity) the underlying reality is a spectrum consisting of billions of “immune responses” initiated by individual antigen-presenting-cells that are all essentially autonomous - none of them is “updated” by the updates of the others; but if enough of them “update” the same way then a durable programmed immune response is produced in T Cell and thymus land, leading to measurable “works”/“fails”. There’s overlap in response times as well. After adolescence, T Cell motifs become more fixed and the thymus less active, but new motifs never stop generating (take adult-onset allergies). That’s my current understanding and I don’t see how B Cells and antibodies can attenuate new durable memory responses initiated by APCs since they are two and three orders downstream; there is no clear “bandwidth” overlap.
A famous quote comes to mind, "Show me your graph, and I'll show you another graph."
And I distrust graphs in general, and mathematical abstractions especially. All I want is the raw results. The heat-map in Figure 5 is close enough.
We're all wired a little differently. Some are more visual than others. Well done graphs help visualization. Poorly done graphs are sometimes intentionally misleading, sometimes just confusing. All graphs should cite sources.
Right - I feel that even a well done graph is giving me the work of trying to figure out a conclusion that could just be explained in words, without enhancing my ability to scrutinize the conclusion itself.
Me too. Others have trouble with words, pictures seem to help.
Damn. I can't recall a more elegant discussion of immunology.
We should all keep in mind that 100% perfect response is not only unlikely, but unnecessary. Good enough is good enough.
This post made my head hurt...
You may be right that OAS is a myth as originally conceived - some sort of immune defect. But I also keep seeing data suggesting that Omicron preferentially infects vaccinated people.
My best guess is that if an OAS-like phenomenon is real, it is caused primarily by epitope masking by abundant but weakly-binding antibodies. If the antibodies bind more weakly than the receptor target, the antigens will still be able to bind to the target and cause infection, but they will also be effectively "hidden" from the immune system by the attached antibodies, inhibiting the development of strongly-binding variant-specific antibodies.
I was distracted by dinner. More precisely, Cron presents a “problem” for OAS in that OAS gets to declare a win no matter where the signal comes up - Detrimental performance among the previously SC2-spike-exposed (“original” sin is spike exposure) or not (“original” sin is coronavirus exposure, and spike exposure corrects it). It’s a constantly rigged game; memory immunity has to cease existing for OAS to lose.
Cron is an even bigger problem for “viruses want to get milder.” If Cron didn’t come from any previously measured + circulating SC2 then it reveals nothing about what SC2 “wanted.”
Of course, I’m suspicious of genetic clocks - it’s obviously guaranteed that the 1 in 10^20 chance of a cluster of 50 mutations will produce a viable genome _will come about_ if the genome is mis-copied with 50 changes 10^20 times; plus there’s the genomic crisis / transposable element realm that science has ignored for 80 years, which is the only way to account for the INDELS outside of lab creation as far as I can grok...
Other human coronaviruses are sufficiently genetically distinct that I would expect fairly minimal immune modulation of SC2 response whether positive ("cross-protection") or negative ("OAS"). All claimed OAS signals have been statistically very minor and quite possibly artifacts, although a few studies of cross-protective T cell immunity have been more convincing.
Immune interference *between* SC2 lineages is much more plausible. What I gather from your writing is that you question the concept of OAS as originally conceived. Others have done that as well, e.g. https://pubmed.ncbi.nlm.nih.gov/31964645/
I think you are right about that, but I am more interested in outcomes than mechanisms. Increasingly within the alternative media-sphere "OAS" refers to the situation in which vaccinated people get infected at a higher rate while "ADE" refers to the situation in which vaccinated people experience more severe illness. I have argued against this choice of terminology at times but I'm open to this modified outcome-based definition.
As for the origins of Omicron I'm fairly agnostic, though I would consider reverse zoonosis followed by later transfer back to humans to be the leading hypothesis.
It should be remembered that low-affinity antibodies are a lifelong anti-adjuvant, as the tldr on the paper. The immune system is not as easily alarmed by what does not as easily harm. Cross-immunity, again.
And as suggested by Gostic, et al., frequency of childhood exposure to flu subtype confers lifetime higher competence in challenge with that subtype - adults with less childhood exposure cannot hope to develop such refined protection. It’s not “interference” with by the more trained immune response; and there’s still implied cross immunity protection in T Cells. This seems to be the limit of natural immunity relevance to childhood priming with flu; leaving “OAS” as a concern only for vaccnes. However, it is a very dense paper and I need to read it further...
Low affinity antibodies are not a problem so long as they don't trigger ADE and there aren't so very many of them that they get in the way, preventing the adaptive immune system from mounting a de novo antibody response with better mapping to epitopes on the current virus.
The ADE effect seems to be relatively uncommon (except for Dengue and maybe a few others). I would hypothesize that interference/epitope masking is generally avoided by limiting antibody titer. However the current vax-boost strategy of achieving neutralization of partial-escape variants by way of stratospheric antibody titers strikes me as potentially very problematic in an OAS sort of way, and an attempt to brute-force manipulate a delicately adapted system.
I get queasy every time I scroll past Eliakim-Raz, et al. in my study roll - “The median titer level increased significantly after the third dose, from a median of 440 AU/mL (IQR, 294-923) to 25 468 AU/mL (IQR, 14 203-36 618)” I think I would have thrown my computer in the trash if I was looking at those results in a lab.
There’s implicit equilibrium - antibodies that get in the way will result in the virus getting a head start, leading to higher “alarm” and cancelling out the anti-adjuvant. This is, essentially, symptomatic reinfection. There’s probably wear and tear, but if we didn’t give something back to the virus then the existence of temperate non-evading viruses would be impossible. Humans can critique this model and plot out imaginary “delayed, higher” viremia plots all we want but in reality it’s functional coevolution at work.
The cited article is a fun history lesson. The money shot passage seems to be "explication should provide employment for scientific historians and social psychologists for decades to come." One has to wonder how much of research is productive for society and how much is just full employment program for lab rats. Some of both I suppose. As the ladies say, gotta kiss a lot of frogs to find the handsome prince.
Those interested in history might enjoy Code Breaker by Isaacson. History and tutorial of biotechnology, focus on Jennifer Doudna who invented CRSPR gene editing.
Bacteria invented CRSPR, technically.
Learning to manage what nature gives us is the key to our success. Bacteria figured it out millions of years ago, but it took Jennifer to figure out how to make it work for us.
And rate of post-exposure infection is modulated by cellular immunity after antibodies fade, regardless of whether said exposure is vaccine or infection, in my model. Fending off subsequent challenge without updating antibodies is literally “immunity”; failure to fend off challenge due to lack of resident T Cells post-vaccine is vaccine failure, but does not imply a net-detrimental effect from priming. All non-OPV kids vaccines probably work this way, with breakthrough infections disguised by lessoned symptoms; here the net-detriment is probably second order (lower overall immune competence) but in terms of the target bug the kid gets to “immunity” in the end. If it doesn’t work that well for adults, well, neither does memory immunity overall. The “priming” is redundant.
Thanks for that link! I didn’t want to post RE OAS again until I did a lot more reading into influenza research; this looks like a handy overview. My instinct is that Francis’ OAS was resurrected to blame natural immunity for the failure of the modern revival of adult vaccination, and no one has come to grips with the fact that it doesn't correspond to a single in-nature deficiency in immunity (aside from Dengue)!
“data suggesting that Omicron preferentially infects vaccinated people.”
- also a stupendous refutation of OAS! Since all those “nasty” unvaccinated are such “sinners” by way of previous, “original” non-SC2-relevant coronavirus exposure. Ethical Skeptic is pretty convincing that the LCA for Omicron is early 2018, meaning that all prior immune response to SC2 in 18-20 can be wiped off the board. An OAS signal in Omicron should snap to wild coronavirus antibody, not to SC2 antibody.
Let me see if I can summarize your argument against OAS and please tell me if I have it more or less correct. You don't deny that previous exposure to the spike proteins of similar viruses impedes the development of antibodies that fit the new virus well. You are just saying that neutralizing antibodies are overblown. They are not the most important form of immunity. Previous exposure to similar viruses gives very effective cellular immunity. People with previous exposure to similar viruses do not tend to get more sick, on the contrary they get less sick. The fact that they are not making neutralizing antibodies that are specific to the new virus is not very important. Is this more or less your view? Thanks.
That is pretty much my view in a nutshell. There are no real-life instances where the immune system is at a net negative due to previous encounter with a related virus strain *because* it doesn't produce as many form-fit antibodies to the new strain as it would have in naive encounter - rather, the lower generation of new form-fit antibodies reflects that prior memory immunity worked fine. This is especially the case for flu. Immunity against new strains of childhood-encountered groups is stronger than immunity against unrelated groups - https://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.1008109; presumably even cross-group immunity is stronger than hypothetical "0 childhood flu exposure" but medicine always discounts the positive.
Vaccinology is desparate to find a real-life example of OAS, otherwise it the inability to trick the immune system into X' antibodies for every X antibody is not "a deep flaw in the immune system that only we understand, trust us we've got the links" but simply "an obvious defect in vaccination (against any virus with antigenic drift)."
Hence, Dengue (an injected virus) becoming the poster child. But Dengue is "other strain antibodies enhance infection," not, "can't make new strain antibodies fast enough." It's use to prop up OAS is more sign of the desperation.
The Last Common Ancestor for Omicron being 2018? Wow. Is there a link to Ethical Skeptic's take on that? That would be pretty interesting to read especially as thus far the theories I've seen suggest the last common ancestor for omicron was alpha variant which was last seen in June 2020 and that omicron itself diverged in June 2021, seemingly from leak at a BSL-3 lab in Durban where they were doing the kinds of research on actual samples of alpha that could have led to omicron (rather than doing that research with pseudoviruses which would have been safer)
Okay I found it on his twitter feed. And wow!