Interesting Brian! I was actually thinking of breaking down that Science article, probably within the same vein as you have done with other papers (i.e. who are these dots?!) although the researchers answered that question. I think it's a very interesting article since it at least measured B and T cell response, but to the extent that there is robust evidence or good conclusions is where it becomes difficult (the transgenic mice with the Class II HLA DRB1*04:01 Haplotype honestly seemed weird to me).
You've mentioned problems with that article before, and I'm glad you made a comment there to at least provide some discourse.
Jul 1, 2022·edited Jul 1, 2022Liked by Modern Discontent
The T cell anti-BA.1 nonresponse in the Wuhan + 3vax + BA.1 “wave” infection is interesting but impossible to extrapolate anything from, particularly given the authors’ moronic and inexplicable exclusion of results for unvaxxed ie the control group. And obviously could be a result of the “wave” infections actually not being BA.1, since no individual infections had sequencing / PCR strain designation.
Well it's interesting because the mice were homozygous for the DRB1 haplotype, yet we don't know the haplotypes of any of the participants so how are we to know whether the haplotypes are playing a big role in varied T-cell responses. Apparently the DRB1*04:01 haplotype supposedly leads to less severe/ asymptomatic COVID and is found in predominately high latitude, Caucasian populations.
I didn’t interrogate the methods there. That section was a bit self-reflexive in that it wanted to show that Wuhan / BA.1 spike are recognized differently by force-feeding chopped up bits instead of the whole antigen...
My comments were RE the “ T cell immunity after B.1.1.529 (Omicron) infection” section
Yes I'm aware, I suppose my background made me focus on that study. This is interesting since I was noticing a few pieces but I think based on what you've said I'll look back and see what makes sense (or doesn't make sense). Your insight is very helpful finding points to examine further!
I never commented on the control part, but it does appear this is a huge consequence of the massive vaccination campaign in which we have artificially removed the control group. The go-to reference group now appears to be "X vaccinated, uninfected" now.
I believe one section of the study made it seem as if they collected sera of some of the Wuhan/Alpha infected participants then they got jabbed and were put into the vaxxed category at that point. I'll try looking at it again and see if I misread it.
"the authors’ moronic and inexplicable exclusion of results for unvaxxed ie the control group."
Yes! Ha ha. That's what I thought when I read Malone's article on it (in fact, I saw your comment and almost commented on the lack of an unvaxxed control group).
I'm neutral about the whole OAS debate in regards to these vaccines. I see both sides of the argument. However, I'm wondering about the repeated nature of these shots--will 3 or 4 shots (of the the same mRNA produced Wuhan spike/antigen) eventually trigger OAS when the highly vaxxed immune system is exposed to some variant in the future? With the talk of another jab in the Fall (which will likely be bivalent, containing the same Wuhan spike mRNA plus BA4 and 5 spike), I wonder if that's when undeniable OAS will manifest itself? It seems to me that repeated exposure in a short time frame (4-6 times in less than 24 months) will prime the adaptive immune system in a way that will encourage OAS to occur when it is then exposed to a wild variant.
Well repeat exposure would not necessarily point to OAS. Like I stated somewhere else in the comments, that would be more akin to maybe being called something such as immune priming. It'd be a semantics game, but in science terminology is important and the technical differences are important.
It would be interesting to see if this is more of a consequence of repeat exposure. Again, that probably wouldn't be considered OAS. There's an issue where antibody titers appear to be the end goal when that hardly explains everything else going on.
I think we also need to keep in mind that for us we are looking at things with the foresight and knowledge to make assumptions and sometimes personify what we think is going on with our immune system. Even if repeat vaccinations may cause it to not respond to these newer variants, is it because our immune system is acting in a complete detrimental way, or is it behaving in a manner we should expect for something that is being told to always be on the lookout for [this] (Wuhan) antigen, and when it doesn't we appear surprised because we assumed it should have.
Right! Perhaps "OAS" is not the correct technical term. Perhaps I should use the term, "immune imprinting" when relaying my concern/query about repeated exposures to the same Wuhan spike/antigen.
My concern/query is how will immune imprinting be affected by priming the immune system 3+ times with the original Wuhan spike/antigen AND THEN priming it again with the original Wuhan spike/antigen PLUS a BA4 or 5 spike/antigen--ALL WITHIN 18-24 MONTHS TIME?
I think the answer is "we don't know for sure." Has there ever been a time in medical history where people's immune systems were repeatedly (3+ times) inoculated with the same viral antigen in such a short period of time while simultaneously being exposed to wild variants of said viral antigen? And, are there studies on the effects of such a practice on immune imprinting and subsequent immune responses? Not to my knowledge.
So, it seems to me this is all one big experiment in which no one knows for sure what's going to happen. And, it's experimental scenarios like this where theories of OAS and ADE become plausible. Please correct me if I'm wrong.
Well, I kind of threw out immune imprinting although I'm not sure that would be the right term either 🤷♂️, just a bit of speculation. If only the literature would try to find alternatives rather than chasing after the trendy hypothesis.
There is likely to be a concern with forced, constant exposure to the virus to such a degree. We're likely to come across viruses all the time, yet we generally aren't being vaccinated to the degree we are. It's interesting that a few months back there was some retroactive thought that they probably should have spaced the 2nd dose out even further than 1 month (I believe a month or even a few more weeks; was it 1 month between doses? I can't even remember now!)
But all of this is really an experiment. I think so much of this is entering into a territory in which we have no evidence of and just speculating as we go along.
ADE is interesting because prior animal studies looking for a coronavirus vaccine showed ADE occurring- Dr. Fauci even mentioned it I believe in the late Spring/early Summer of 2020 as a reason for the vaccines taking several years. But in general, in this area of uncertainty many ideas are likely to arise, and there is an issue as to why certain ideas persist. It could be a result of following the cult of personality, it could be people searching for a light in the darkness.
The whole Dr. Ardis debacle makes me lean towards the latter: people want an answer and they will follow ideas that appear to be the answer, even if the evidence is not likely to hold up when various factors are taken into account. I think an issue of OAS is that there's been a general idea that you start at OAS then find ways of validating it's existence rather than examine the evidence and see if OAS is a viable hypothesis. It's why the idea that lack of antibody formation against the nucleocapsid protein somehow is an example of OAS, even though OAS absolutely does not tell us what is occurring with other antigens.
I understand the difference between OAS and ADE. In my non-medical opinion, it does appear that we are observing OAS. Originally, when I was learning in Feb. 2021, I was more concerned re: ADE. Yet here we are.
Re: comment, "What am I seeing?" I get bogged down with statistical graphs/data, in the absence of a conclusion or guiding statements. I like stats, but when posters assume a level of understanding or present too many different figures, some beyond my scope, then a guiding statement/conclusion/hypothesis is needed.
Many of us are suffering from information overload.
Thanks for commenting! I'm always curious to see what others think.
Can I ask you what evidence supports OAS for you? I think that's the most important thing to consider.
There absolutely is information overload. In one of my posts I commented that we are in an "infodemic", although that term appears to have been co-opted to refer to anti-vaccine ideas. Graphs/data can be really difficult to parse since it may require knowing special methodologies to analyze specific studies. Usually the figures should at least provide some help. The best way I've learned (if looking at papers) is to look at the Discussion section since that at least provides the researcher's explanation. Then look at the Results and the figures and see if it makes sense with the Discussion, or if something seems egregious.
Good topic...I don't have time right now to write up answers to all your questions...if I am so inspired, I'll write them up in an article. The short version is that I know OAS is an issue with some diseases like dengue fever, in which your body making antibodies to one strain inadvertently makes you more vulnerable to another strain, because the original antibodies are essentially getting in the way of any newer antibodies that are needed to fight the new strain. Whether this can happen due to covid vaccines is not clear.
So that actually is an example of Antibody Dependent Enhancement which is the question TheGreatAwakening asked, so I suppose there may be a good deal of confusion going on!
Interesting idea Stephanie. I'd look forward to that article. I've mostly decided to write this post because I wanted to see what people thought/knew out there. I think there's a real issue of lack of understanding for many readers who may just read things and take what they read at face value even if they aren't sure what they read. My questions were a few things I think about when looking at OAS, and so I wonder if a few people consider the same.
It is ADE but also frequently cited as an example of OAS. This is essentially OAS “carpetbagging” on another theory because otherwise there is literally zero natural real world relevance for the myth.
Carpetbagging?? Well, I never Brian! I tried to at least provide some possible explanation, although I'll admit I haven't looked too deep into the situation.
I mean that when researchers are droning on about OAS, and they want to list some example that isn’t just flu vaccines (so “OAS” doesn’t have to be renamed “the constant vaccine update problem” and give away the game) they cite Dengue, which is an example of ADE as best currently understood.
I see. That makes sense, although I'll admit I haven't looked too extensively into dengue. It does line up with the same antibodies from a different variant binding to conserved regions of the a different variant and leading to the enhanced infection.
How surprised are you that OAS appears to be the go-to response from everyone now. There's a ton of immune imprinting studies in the literature and so I wonder if this is a consequence of scientific groupthink in which people are trying to find any explanation and turning to OAS.
Maybe it’s like string theory. Wrong ideas attract attention in science because mediocre talent can “advance” the theory by spewing nonsense and get cited by others. Mix in a little Dunning Krueger or whatever it is called (I am working on iPhone at the moment), an ignorance of their own evident stupidity.
Isn't some of this just semantics then? If we're talking about a type of antibody that was there first (by whatever mechanism, infection or vaccine), causing problems in whatever manner (blocking better antibodies, or enabling a virus to more easily infect cells) then that's the "original sin" that's causing problems...sounds to me that people are just using the term OAS a bit loosely, but I'm not sure I understand the objection to that.
Actually, the use of the term loosely has been one of my gripes. The term was never intended to argue adults getting infected/vaccinated, but argued that children's first response to an infection is what affects immune learning down the road. When you look at the elderly, there's a general argument that their immune system has been trained for select epitopes, but that this training is what has provided them both diversity and selectivity that helps protect the elderly. So for me I see a general issue in how OAS is defined as well as how it is applied.
There's generally been a big issue as to how flu studies define OAS, how they apply them, and whether they are actually measuring the effects of OAS. I think there's been a big issue in that the literature has been inundated with a good deal of noise while also groupthink bias. I've come across a few OAS articles that kind of stated on some way, "well, there ARE some who disagree with OAS, but they're probably wrong".
The comments here aren't necessarily to state "OAS is not happening" but to really see people's general understanding and compare it to my own and see where those differences lie.
Jul 1, 2022·edited Jul 1, 2022Liked by Modern Discontent
As opposed to the null hypothesis that flu shots are just useless, and only appear to work by random chance or user bias, which then flips whenever you track the users through multiple years? What have you seen to eliminate that from the realm of possibility? There’s nothing. OAS is just a placeholder, petulant “vaccines don’t work because nature stupid” assumption on the part of moronic humans in lab coats; it’s not science.
*edit: And even regarding flu vax studies, 1/3 of them refute OAS (and the other half are super poorly controlled) in the Yewdell review of the dumpster fire that is “the research” http://m.perspectivesinmedicine.cshlp.org/content/11/5/a038786.long— the most robust study cited in OAS research is Gostic et al 2016 which found that the “sin” is that early exposure to given subgroups confers lifelong protection, ie immunity, normal positive connotation.
I actually looked it up when I responded and found OAS connected with dengue in a Wikipedia article...granted, that's a crappy source but I did do a quick double check. I think OAS and ADE are related anyway if I am not mistaken, in other words, you need the OAS to get the ADE. You could have OAS without ADE as well probably.
They actually are, in a sense that different variants will be comprised of both unique and conserved epitopes. One aspect of OAS is that cross-creactive antibodies which target conserved epitopes across variants will supposedly be "back-boosted" and target these conserved regions which may or may not neutralize the virus.
I believe ADE comes in when the conserved region that is targeted by cross-reactive antibodies actually leads the immune system to aid this virus/antibody complex into entering the cell.
So I suppose OAS would lead to favoring cross-reactive antibodies, and ADE would suggest that those cross-reactive antibodies help the virus.
This is at least from the basic premise presented by OAS, although I could be very wrong!
Jul 1, 2022·edited Jul 1, 2022Liked by Modern Discontent
I find it challenging to read the current literature, to understand what are the conflicts of interest of any of the authors or publishers, yet seem to have a critical skeptical eye recognizing that, as Buffalo Springfield sang: "Something Happening Here, what it is ain't exactly clear." So I appreciate writing that exhibits a cautious thought process rather than a headline banner shout out.
So whichever it is called, I recognized that this jab, flu vaccines, etc. create downstream unintended consequences, and that this one is worse for lack of transparency.
The acknowledgements/conflict of interest is usually something I avoid looking at even though you can get a good deal of information from it. Sometimes the conflicts may be a whole page itself.
There are some things that we can argue are highly questionable (just like the vaccines), but that doesn't mean we use random papers or bad science to bolster our arguments.
And just to be clear, I am definitely not immune to that and I'm pretty sure I've used studies that may have had methodological flaws. I think the issue is that we all should be able to provide good-faith criticism to one another in order to find the truth. But if we prevent ourselves from criticizing others or providing different opinions then we enter into our own echo chambers.
Thanks Paul, based on this I may try a few more of these and see what people know going down the line.
The one I’m referring to is HCW and immune boosting from his 2nd post (part2 maybe?) It was very technical and obviously a difficult paper for most non-scientists to read, but I was also confused by DR.M’s purpose for writing, although he may have just been informing with no implications to be taken. I could see in the comments that others were also perhaps reading more into what Dr. M had written than he may have intended. So, I guess that supports the point you are making.
Well, I did see a video with Dr. Malone I believe in another hearing with Sen. Ron Johnson in which he referenced the article. I think Dr. M is using it as an argument that OAS is being caused by the vaccines, although the study argued that vaccines alone had broader immunity (note that this is based on the author's remarks, not something I believe) compared to an initial infection with Alpha or Wuhan. It's a bit of an issue because he sort of glossed over it and made a comment that vaccines are causing OAS even though there's a lot more context needed.
I think there's been an issue in which a few people have been extrapolating too much from studies. I'll admit I am likely to have done the same sometimes (although I try to avoid doing so), but it is a difficult situation when many readers may take what they see at face value rather than question the actual veracity of the argument.
One of the reasons I wanted to try this post is to test the waters and see if people are reading all of these articles on different Substacks and really able to discern what they read, or do they just boil it down into one phrase of "vaccines bad" or "we're all doomed!". I was wondering how to go about it but I thought it would be fitting just to ask everyone and see how much they knew.
David Martin is sure millions will die, but I’m praying that’s not the case although strange things are happening to many people. The only thing I’m sure about is that it’s very strange that so many so called scientists are not questioning any of these flags raised with the jabs.
That's the type of thing I usually avoid thinking of, mostly because it really does no good to make such predictions. And even if it was true, would you live your life any differently knowing that there may be an end near? If it leads to us becoming fearful to live, then all we're doing is staying alive. Remember that those in power have utilized fear to try to get many to kowtow to their demands. When people we align with make such bold predictions be careful in letting it fill you with fear and anxiety- there's plenty of people trying to prey on that vulnerability already.
Jul 1, 2022·edited Jul 1, 2022Liked by Modern Discontent
My basic understanding is that upon first exposure to a new family or type of virus we produce various forms of immunity, one of which is the creation of antibodies.
Because we all tend to experience different viruses at different times, and the things are always evolving anyway, we have huge diversity of both viruses and antibodies. That is what stops any one virus being able to spread far and wide without some compromise, such as reduced symptoms and a very low death count.
We can create entirely new antibodies for entirely new viruses or variants but if presented with a virus that is too similar to the first one we ever saw, we just throw those original antibodies at it, which may not work. So basically a security loophole we have is any virus that is both too different but looks too similar - like thinking you recognize a friend, call Hi! but it's a total stranger.
Flu vaccines have shown OAS in effect, because we can see that older generations have no defense against the reemergence of very similar-but-different variants to those going around when they were young. When they come around older people are likely to die, in part because they are throwing the antibodies for a long-extinct variant and cannot adapt to the new one. I don't have scientific names or studies at hand but my understanding is this effect was spotted and known about a very long time ago, and flu vaccines have further proved the point.
OAS is very real.
If it is a concern with coronaviruses is not so clear, ditto with COVID-19. However the fact vaccinated people are proving MORE vulnerable to infection with variants suggests that the vaccines are indeed creating some OAS effects, and even driving the variants towards that end-result.
As anything vaccine-related is treated as Religious Scripture it's not so easy to find mainstream articles, especially in this era. It does however seem a well-established and proven effect, so why you or Mowrey are declaring it some myth that never existed and the research on it is all bogus I dunno?
Perhaps in real simple terms you could explain how they're wrong?
If you cannot explain it simply then you don't understand it either, is my general take.
My understanding if ADE is that not only does the default antibody fail to prevent binding/infection but actually helps unlock the cell's defenses. That would be in the same kind of category of problem, but not the same thing.
Well I believe one of the issues with the 3rd paragraph is really what happens after. I think from the perspective of OAS there's an assumption that you're either a sitting duck or you hope that your primary immune response will deal with the infection. There's usually no nuanced discussion that suggests if your immune system mounts another secondary response that actually learns more about the pathogen. It's difficult because most studies aren't going to provide a window into the immune process- we only assume what happened based on what results we get.
Flu studies have been referenced as a major example of OAS, but there is a real problem in the literature in which many researchers have either improperly defined OAS (not taking into account that it's a matter of age-related immune imprinting) or may be improperly looking at their results and extrapolating information that may not be there.
There's also an argument as to whether OAS is occurring, or if a more fitting term would be something like antigenic seniority, such that the first antigen we respond to is gets priority in future responses, but that each successive infection and its antigen has some position in the immunity line. It's a bit of a muddy hypothesis as well but at least suggests that more is going on that just exclusion.
Then that also leaves us with questions about the role of other infections. If we assume that there's a strong correlation between cross-reactive antibodies and conserved epitopes across different viruses, we should then ask how infections with viruses from similar families such as betacoronaviruses would influence OAS or immune imprinting. Even further than that, there are several viruses that may not share many similarities that may also produce cross-reactive antibodies. What role would these play in OAS, considering that a coronavirus infection one gets as a child should, in theory, alter the way their body responds to SARS-COV2 as well. Usually this piece is not included in the discussion as well. In fact, many discussions about OAS act as if the pandemic was the initial timepoint of OAS, and not any years prior. Remember that OAS being age-related means that our immune system is the sum of our prior infection history, not something that started arbitrarily as soon as the pandemic hit.
With vaccines leading people to being MORE vulnerable, that begs the question as to how we are measuring more vulnerable. Are we using cases as a measure? That doesn't provide anything but weak correlations in which we assume that there's a general trend of higher cases in areas with higher vaccination rates. We know nothing about the individual person's behavior, their prior history which would be needed to argue OAS, as well as their overall health status.
It also brings up the argument as to whether these people have any protective immunity where it's needed. I've argued that it's strange we take swabs from the nose to measure infection, yet we take blood samples to measure antibody levels. There's hardly any literature on the effect of mucosal immunity/innate immunity, and prior evidence with the flu vaccine suggests that vaccine injections into the deltoids do not stimulate B cell memory in places such as the nose and throat where it would be needed the most to fight off respiratory infections. So even if these people are testing positive, is it because the vaccines are leading to OAS and are preventing them mounting a new immune response, or is it that they never had prior immunity where it was needed (and where they get tested)?
But even in all of this, we still have not discussed the role of OAS in those who have been infected with prior variants and what would happen if they got reinfected. Should we expect backboosting of cross-reactive antibodies? That would at least go in line with OAS. Or maybe this is all a consequence of constant exposure, such that those who have received the vaccine are constantly exposing themselves to an old, outdated antigen and are incorrectly training their immune system. However, that wouldn't actually be OAS more than some form of immune priming (I'm speculating here).
Lastly, I'm not declaring OAS as a myth, but something that people should be more hesitant to ascribe to rather than going along with whatever is out there. Not to say that this is happening, but I wrote my first piece on OAS because so many people were somehow trying to relate the lack of N-antibodies as some example of OAS, which is a complete misuse of the hypothesis to begin with. And from there a lot of this eventually just built upon itself.
I try not to see myself as a contrarian, but I at least wanted to provide a different perspective to push back and have people reevaluate how much they know of their position.
And I am learning a lot of this as I go along, so maybe I can't explain it well because I don't understand it, but I certainly won't argue that I'm at least trying to put in a good-faith effort to see what's out there, see what the literature says, see what is going on now and trying to tie loose ends together, and I want others to do the same rather than to just follow along with whatever they see out there.
Maybe at the end of the day the scientific consensus says that OAS is right, but I'm not writing this to prove myself right, and if that's the general takeaway people are getting then there's probably a lot they're missing in my writing. I'm trying to follow the facts and make sense of a world that doesn't want us to have it make sense, and if it means being the odd one out in the discourse then so be it.
Second, the fact it needed to be such a long response sums up what you admitted at the end of of - "..maybe I can't explain it well because I don't understand it..." ;)
Your good-faith efforts are appreciated and in truth my irritation is more with Mowrey, who seems to be basically declaring the entire concept as a myth.
When you say "maybe this is all a consequence of constant exposure, such that those who have received the vaccine are constantly exposing themselves to an old, outdated antigen and are incorrectly training their immune system. However, that wouldn't actually be OAS more than some form of immune priming (I'm speculating here)" - to me, that IS what I view OAS to be, not so much repeated exposure but that initial "priming" exposure. Hence the "original" part of OAS, which itself is a vague term borrowed from religion.
The entire point of a vaccine is that the body will remember the 1st exposure, correct? So it's not a huge leap to accept it could make a mistake if a new variant or strain looks similar enough.
Again I do appreciate your good-faith efforts, and totally agree regarding mucosal versus blood-borne markers. Indeed this is why I knew such vaccines could never stop transmission and infection, and the drug companies knew that too. It was the talking heads who claimed they would, and I deeply hope they both get held accountable for that deliberate deception.
Well, there's a few things to say about what it means to "understand" something. There's a problem in boiling down science to such a simplistic degree that it loses all nuance and subtlety needed to examine the information. You also need to figure out to what level someone must become knowledgeable on a specific topic in order to have some form of "understanding". I may read many articles but have difficulties relaying information, but for those who may only get a superficial glance into the topic is it viable for them to argue that they have an "understanding"? I think a lot of this will be heavily subjective, but I want to at least see how much people actually understand and how they came to the conclusions that they have.
And that's the issue with the 3rd paragraph. It may appear that that is OAS, but that actually isn't the technical hypothesis of OAS. OAS does not refer to just the narrow window of repeat exposure, but it relies on the initial exposure to the antigen and the downstream supposed effects from that initial exposure. That's different than continuous exposure to the same antigen- actually, I doubt any studies on OAS has ever looked into that repeat exposure because we've never artificially forced people to become exposed to the same antigen over the period of a few months.
I don't like the religious connotations since it's generally what people use reference as if it provides any additional validity to the hypothesis. Scientists refer to it both by OAS and immune imprinting, but when doing so they don't belabor the point of it's religious backstory since there really is no need to do such a thing.
1st exposure is highly subjective- into what window are we looking at 1st exposure, and relative to what? Again, that brings up that additional issue of where exactly we mark the initial point of the sin. When does the original antigen arise? Does it need to be from SARS-COV2, or are any coronaviruses good enough? Or to expand it even further if any cross-reactive antibodies can bind to SARS-COV2 then would that be considered the original antigen? Would that affect the immune system's initial response to SARS-COV2?
One thing that Dr. Malone greatly overlooked in his post was that the researchers were suggesting broader immunity in the triple vaccinated group compared to the Wuhan infected then vaccinated group. Not to say I find those results valid, but wouldn't that instead argue that this would cast blame on those who initially got infected and incorrectly led their immune system to go down a path of poor immune responses? This is all hypothetical. Remember that the study cited by Dr. Malone never looked at people who were naturally infected several times- they didn't even bother having a proper control in their studies.
To steelman Brian's point, I do understand why he can be frustrated with the whole OAS issue has it has emerged on Substack- this actually points to the topic of understanding.
As I know it, the first instance of OAS on Substack came from Alex Berenson and his reading of the UK report making this one comment that those who were vaccinated did not produce anti-N antibodies, then went with it and used it as an example of OAS.
On that front, that was a completely inappropriate use of OAS- OAS is never meant to explain what happens with other antigens, so right off the bat that was completely improper and bad science.
However, other people began to piggy-back off of Alex's post and began to write about OAS as well, referencing the religious subtext and pointing to the anti-N protein one-liner rather than examine the information for themselves. I wrote my series on OAS BECAUSE I saw people referencing the N protein when there absolutely was no reason to. And from there it just snowballed and escalated, to the point where many people on Substack just continued to build off of that horrible interpretation and have OAS take on a life of its own nearly devoid of its initial intentions.
I've remarked that, ironically, OAS appears to suffer from its own original sin, and one of a poorly analyzed and deeply flawed analysis that just built upon itself. With such a poor foundation, can we consider everything else that was built on top of it to be of high merit as well?
And I believe that's why Brian pushes back to the extent that he has. I personally am so enthused to find so many people becoming interested in science. But there's a big difference between knowing the science and assuming to know the science. I think we're running into an issue in which many people are not properly reading the science, and when you try to rebut improper analyses you may come across as either being a contrarian, or you may begin to experience some form of in-group bias.
It's one of the reasons I bring up someone like Dr. Ardis a lot. He's allowed to say whatever he wants, but he'd better be damn well sure that his information is well-researched before he makes claims that we're being poisoned with snake venom in the water. So many people clung to that argument, even when there were so many holes in Dr. Ardis' theory that it was easily made defunct, and yet the idolatry surrounding Dr. Ardis and the ingroup dynamics became so entrenched in such a short period that it was rather astonishing to see.
Because of all of that I can empathize with Brian. When there are so many claims about OAS being made, when OAS is being misused or grossly misapplied and it just continues to build upon itself can you necessarily blame someone who at least attempts to provide some nuance?
Well, sorry for the wall of text again. Even if Brian may come off abrasive, he- at least from my perspective- is doing a lot more to understand the literature and parse the information. He actually reads the supplemental material for studies! So for me that comes with a good deal of respect compared to others who may just read the title of a paper and assume that they know what the paper is about (no one in particular, but I have a feeling this happens a lot more often than it should in general).
Priming populations with 2 year old viral stain is like antigen fixation for a strain different from evolving circulating strains. This can result in OAS. Recent Nature article reported infected monocytes in some COVID-19 patients. If the infections develop from Fc receptor bound to antibody viral uptake, I consider this one type of ADE. Hypothesis: many critical COVID-19 patients with high SARS-CoV-2 antibodies likely have this type of ADE.
Hypothesis 2: MIS-C and MIS-A patients with higher than primary antibody titers and histamine intolerance have a second type of ADE with hyperactivated mast cells releasing histamine
That's interesting Darrell (Dr. Ricke?). Thanks for your insights! I suppose my question pertains to what extent we argue that antigen fixation is occurring, and whether that fixation is a negative consequence. I think that's one of the issues I have with OAS since I believe it serves as a bit of a general argument that sort of obfuscates certain factors.
I think you first hypothesis is interesting. I can't remember where but I believe there is a general argument that a specific immune response has been associated with more severe COVID. Actually, I think your second hypothesis points to what I was asking. I did a quick search and there appears to be a lot of research going on into histamine and long COVID, so that's really interesting.
For some models, OAS antibodies may contribute to ADE. An article by Wan etc al. describes a concentration affect were ADE in the cells being evaluated needed sufficient antibody level to enable ADE that was followed by higher concentrations blocking ADE - too many antibodies may block the membrane fusion mechanism of the virus. Hence, very high titers are protective until the durability decline of antibody titer.
For some long COVID-19 patients, one of my hypotheses is persistent infections - this fits with an ongoing role for histamine release from mast cells.
I am happy with being called either Darrell or Dr. Ricke. I am a Molecular Biologist/ Computational Biologist in training.
That's interesting. Do you know if the study examined shared epitopes among the antibodies and whether there was a factor of needing to outcompete ADE-biased antibodies?
The persistent infection thing is very interesting. It's a shame we have no actual data on that. Some have argued persistent viral load within the gut due to high ACEII receptors, but I wonder what role the microbiome and mucosal immunity would play there.
Thanks for the background! I'm a curmudgeon in training so we'll see how well that goes!
SARS-CoV-2 appears to be able to persist in GI for some individuals, perhaps CNS in others ( autopsy evidence), etc. I can more details next week - I am on travel.
I'm not too good with immunology so there's a bit of a steep learning curve for me, but that's an interesting idea that I'll try looking into.
The CNS is interesting since I was wondering what role the nose and the entryway into the CNS from there plays in CNS invasion. I did see a paper on the microbiome and COVID, so it'd be interesting to see if a dysfunctional microbiome may have some relationship between both immune function and viral persistence.
Matschke, J., et al., Neuropathology of patients with COVID-19 in Germany: a post-mortem case series. Lancet Neurol, 2020. 19(11): p. 919-929.
Meinhardt, J., et al., Olfactory transmucosal SARS-CoV-2 invasion as a port of central nervous system entry in individuals with COVID-19. Nat Neurosci, 2021. 24(2): p. 168-175.
Nauen, D.W., et al., Assessing Brain Capillaries in Coronavirus Disease 2019. JAMA Neurol, 2021.
Lukiw, W.J., A. Pogue, and J.M. Hill, SARS-CoV-2 Infectivity and Neurological Targets in the Brain. Cell Mol Neurobiol, 2020.
De Melo, G.D., et al., COVID-19-associated olfactory dysfunction reveals SARS-CoV-2 neuroinvasion and persistence in the olfactory system. bioRxiv (Preprint), 2020.
Guedj, E., et al., 18 F-FDG brain PET hypometabolism in patients with long COVID. Eur J Nucl Med Mol Imaging, 2021.
Sollini, M., et al., Long COVID hallmarks on [18F]FDG-PET/CT: a case-control study. Eur J Nucl Med Mol Imaging, 2021.
Also immune complexes have been recently reported, etc.
Thank you! I'll try taking a look later. I'm sure MIS is likely to occur from many different factors, but for the vaccines there's likely to be some association. Inflammation is expected, but considering there's many questions as to the actual circulation of the LNPs and spike protein there's a lot of question about if this would lead to systemic inflammation.
Hypothesis for MIS: the Fc receptor on mast cells have a low affinity for IgG antibodies; so, higher than primary immune response level is required to hyperactivate mast cells. Most individuals can process the excess histamine and no MIS will develop. Some foods, drugs, etc can lower the histamine tolerance level and these individuals are at risk - explains the rare frequency. Most MIS-C patients appear to have persistent GI infections, explaining delayed onset pattern after COVID-19 surges. For MIS-V, driving excess any protein will also work nicely.
Jun 30, 2022·edited Jul 1, 2022Liked by Modern Discontent
Is OAS/Immune Imprinting the same as Antibody Dependent Enhancement/Pathogenic Priming? If so, why are there so many names for it? 😫 Someone just published something to do w/OAS. I know you haven't seen evidence of it for the Covid injections, so I was thinking of sending you the link, but I didn't know how to DM you :).
No: so Antibody dependent enhancement suggests that some antibodies you form against something such as a virus may facilitate the immune system to increase viral entry. It essentially enhances the virus' ability to enter cells. OAS/Immune printing are different.
Interesting, if it's something that doesn't have to kept discrete you can post a link here. If not, I believe you can send me an email through Substack. I will be honest though and state that I am VERY bad at checking my emails! Mostly because I'm not sure where Substack sends them in posts 😅
We all have bias behavior, seeking that which reinforces our established perceptions. Mostly I am blind to my own bias, and rely upon others to point it out. It's why I enjoy reading perspectives that don't fit mine, though I have to say I have stopped reading the Washington Post halfway through the pandemic. My bs meter was tweaking too much!
There's no greater indication of cognitive bias than to argue that you don't have any bias! Like you stated Paul, we all have biases, and even if we don't know what they are specifically we should understand that it exists somewhere. The best way to understand your own position is to see other perspectives- how else will you know if your arguments will stand the test of (cognitive) battle?
Nearly all outlets were horrible during COVID. The information was all over the place, or they were clearly coming from people with no understanding of science itself. I kind of figured we were in trouble when a local news station was covering convalescent plasma therapy and the segment had a chyron that stated "antibodies help to fight off viruses".... OK? Thanks for telling us something we should already know?
I don't know what would be worse: that there are people that don't understand how antibodies work, or that the media thought it was necessary for them to make such a report with an assumption that their audience is completely ignorant.
Lots of Qs. Some background first: I have a BSc in organic chemistry, but didn’t fancy a PhD as I wanted to earn money., fast. I have worked in the pharma sector for years. I don’t even have a biology O level though (U.K. based) so I feel a bit out of my depth on immunology. These questions are making me think though. Consider them the responses of an interested & curious lay person.
Do you know what Original Antigenic Sin/ Immune Imprinting is?
What do you know about OAS?
I have a vague idea, from what I’ve read over the past year. It is the phenomenon whereby a person on encountering a pathogen responds by producing an antibody type that it first generated on encountering a similar prior pathogen.
Do you think the vaccines are leading to immune imprinting/ OAS?
Looks as if that is possible, given higher infection rates in the vaccinated. Alternatively they could be damaging innate immune responses.
What role would natural immunity play in OAS?
Not sure I understand this Q. Natural immunity would produce a greater array of antibodies, so I would assume unless all of the antigens of the new pathogen were meaningfully different, at least some of them would work to neutralise it, so OAS would be less of a problem. If that’s what you are asking.
How far back does OAS go? Does the issue of OAS start when we are born, or is it only a phenomenon when we are older?
Not clear. I would assume it becomes more of an issue once we start to rely less on innate immunity and more on adaptive immunity, which happens as we age.
If OAS is based on prior immune responses, what role would other infections play?
See above on natural immunity.
If we caught a coronavirus infection when younger, would that lead to some form of immune imprinting and thus affect our response to both SARS-COV2 and the COVID vaccine? Or is the response to both SARS-COV2 and the vaccine wholly separate?
See the above Q on natural infection. It could be a problem, but presumably only if ALL the antigens involved in the adaptive immune response mutated enough to be “similar but different” to the same degree. Vaccine is more problematic because of the very narrow spectrum of antibodies it produces vs natural infection.
Would there be any benefit to OAS? Or is it completely detrimental?
It would allow for faster adaptive immune response. Which could be beneficial if there is a lot of that variant circulating, in a deadly pandemic.
What role would cross-reactive antibodies play in explaining OAS/Immune Imprinting?
Poor cross reactivity of antibodies from immune imprinted individuals leads to lack of neutralising effect.
Are there other alternatives to OAS that may explain the effects of prior antigen exposure on immune response?
ADE is an alternative but I would imagine that this would lead to a more virulent course of illness than we are seeing, so if this is happening, it would seem to be at the margins. For now at least.
Does OAS apply to only one antigen, or does it affect other antigens as well?
Not sure I understand this. On one antigen in the virus? In any antigen in any virus? Or just the S1 antigen?
How would you measure OAS/Immune Imprinting in a study? What would be some limitations of such studies?
I would measure antibody types and amounts on exposure to a pathogen in both disease naive (vaxxed & unvaxxed) and disease experienced (both groups again), and also record severity of any resulting infection. All kinds of problems doing that IRL, unless you know what prior variants previous infections were, when they were caught, and that everybody in your sample experiences the same variant when reexposed. Massive sample needed to get controls right.
How often do you check links in posts? Sometimes
Do you generally do additional research, or do you take information at face value? Usually a bit more googling
What factors do you use to gauge the veracity of the information you read? Whether it makes logical sense is the main one. So much really doesn’t.
How do you find other sources of information? Pubmed. Following references. Usual literature search techniques I learned at uni in the pre internet days.
Oh that's interesting! I have a B.S. in Biochemistry but I took a lot of courses related to drugs so that's generally my wheelhouse. Just like you I have trouble with Immunology.
Your definition of OAS is interesting, as it would actually relate to the first ever exposure to the antigen, and not the prior response. I think many people may consider this to be a semantic argument (not you specifically) but there is a big difference between the two.
The infection rates is interesting, since it begs the question of whether we can predict immune function based on infection alone. That enters into a lot of speculative territory, and it's usually why I don't like to look at infections rates as an indicator for OAS since so many other factors are at play than what is usually provided.
Naturally immunity does produce greater array of antibodies, but different antigens is not part of the definition of OAS. Remember that OAS refers to one antigen in specific and the exposure of that antigen's role on all other immune responses to variations of the antigen. For SARS-COV2 we may look specifically at the spike (more specifically maybe the S1 subunit, although S2 is included as well I believe). OAS' hypothesis tells us that we cannot look at other antigens as a prediction for how the immune system will respond to the intended antigen. That means we can't look at the N protein of SARS-COV2 and predict anything about the S protein and antibodies.
My question about whether it's important when we are older is actually at the crux of OAS. OAS is defined to be an age-related phenomenon, such that the very first exposure to an antigen should shape all future exposures to variations of that antigen. So when we look at OAS in the elderly, there's an assumption that their antibodies and their immune system have behaved over decades based on that very first exposure they got when they were little. Most people tend to not include this aspect of OAS into their analysis, and it opens a host of other things to consider that muddies the waters of OAS.
For the benefits of OAS, it is assumed that OAS is a heuristic approach to targeting variations of an antigen by mounting an already learned immune response to clear out an infection rather than rely on the delayed time between exposure and adaptive immunity that can be even more detrimental. But like with any heuristic, shortcuts can have it's faults. However, if prior immune responses is "good enough" then that would at least argue some evolutionary benefit to mounting an improper immune response.
For the cross-reactive antibodies, I actually suggested that question as a way to relate variations of antigens. Cross-reactive antibodies are assumed to target conserved epitopes of an antigen, such that if antibodies formed from the exposure to one spike protein can cross-react with another spike we can assume that those antibodies target regions that have not mutated. A good example is Sortrovimab, one of the mAB in use against COVID that was isolated from a 2003 SARS-COV patient. Its ability to target the spike of SARS-COV2 means that it targets a conserved region of the spike. As it relates to OAS, the idea here is that mounting a previously learned immune response will cause many antibodies to not bind due to antigenic drift while those that do bind are likely to target conserved epitopes. Then it becomes a question as to whether targeting these regions can clear out the virus, or if it may enhance infectivity akin to ADE.
As to if OAS applies to one antigen, that question was one to see whether people generally consider other antigens when evoking OAS. For SARS-COV2, many people relate the anti-N antibody response to the Spike's response, but OAS is not intended to define the behaviors across different antigens- it only explains what happens when exposed to one specific antigen.
It's a shame we can't really conduct any studies on people who have only been infected and not vaccinated, especially for people who have continuously been infected with COVID without the vaccine. There's a huge gap in knowledge because the current policies have essentially removed a critical cohort, because it would at least provide more evidence if we are to assume OAS is occurring.
And thanks for answering the last few questions! On Substack we get metrics on whether people click links and it's quite astonishing when you find out those clicks are likely to be in the low single digits. I always encourage other people to read studies themselves to see if anyone, including myself, has misread a study but I think it highlights that some people may not look further than what is presented to them.
The logical sense answer is interesting. I suppose it's a matter of whether the logical sense is objective or subjective. Of course, logic should be objective but you do have to wonder whether people conflate the two (obj vs subj). We may believe we are being logical when we may have some biases that get in the way of critical thinking and reasoning.
Thanks for providing your answers! I always appreciate seeing what other people say! The response to this is making me think I should do a few more of these in the future.
I have a general understanding of OAS and ADE, but sometimes I need to refresh my memory as I’m reading about each. Somehow, I had read Dr. Malone’s 2nd article, but had missed the first, so I went back to it. I even went to the original article Dr. M was writing about.
There was way too much information packed together in the original article for me to unpack in one reading , especially as I’m a non-scientist, but this is what I got from the original article:
If you had an early form of Covid and the shots, the shots protect you from those first strains only and not so much from later ones.
If you had an early form of Covid, it does not protect you from later strains.
If you didn’t have Covid, the shots protect you against something, maybe, but now I’m confused about what and will have to go back again.
If you have the shots first then Covid, something, something.
Dr. M’s report on article is also confusing to me. I couldn’t discern if he was agreeing with the conclusions of the article or not. Is Dr. Malone saying to take the shots? To take one shot? Then later in his article he seems to contradict himself.
Maybe if I had the hard copy of both the original study and Dr. Malone ‘s paper I could make some sense of everything because I could write on a hard copy and draw pictures, highlight etc.
My take away:
You can have Covid more than once, just like the flu, because having Covid, the shots, or both cannot protect you forever because of variants.
Guess that’s why we need early treatment.
Background: Retired, widowed 5th grade teacher, mother, and grandmother.
Thanks for your comment Canny. I think it's good to always at least see whether what you're reading makes sense or not. I've come across a lot of papers that I just don't know anything about, and usually it becomes an issue of whether you should do more research and come back, or if you sort of "brute force" going through the paper until it makes sense. Like I stated, most people don't have time for either so usually it's a good idea to say "I'm not sure exactly what I'm reading, so I'll remain a bit skeptical of the conclusions".
Which original paper are you referring to? Is it the cell one?
If it's the cell article, it's actually one of my biggest gripes with that first post he made, mostly because he took the abstract summary. If you actually read the paper, it explains that the authors don't believe OAS is the proper term, but more something along the lines of antigenic seniority.
"Is it really a ‘sin’ to have immune memory and pre-existing antibodies to the first influenza virus
strain an individual is exposed to? It would only be a true sin if nothing good comes from it, and
although Francis used this term, he also suggested that the concept of OAS could be employed
to induce broader immunity [12]. Perhaps the term ‘antigenic seniority’ better describes the
phenomenon. This more recent model of OAS dictates that strains from childhood are given a
more ‘senior’ antigenic position in our immune repertoire, and that each subsequent strain
takes a more junior position in the response [26–28]. Thus, the relative response to each
individual strain will be determined by its hierarchal position, and previously encountered strains
will be boosted by encounter with strains of the same subtype. Over time, these responses
accumulate, resulting in the highest antibody titers against the strains of childhood. It is also
possible that the response to primary exposure is simply larger than that to subsequent
exposures [21]. A key distinction of this new model is that every new strain gets a place in
the hierarchy, not only the strain of first exposure (Figure 1)."
So I'm not exactly sure why he included this paper as the pivotal OAS paper, but like I stated above I think it's a matter of people not clicking on links.
If not this paper, could you point out which original paper you are referring to?
Or maybe you're referring to the Science article! That article has a lot going for it, but it's unfortunately a paper that is very technical. Many of the points you made above require a bit of nuance, mostly because the study itself was created in such a strange way. We don't know what exactly is happening in those who are unvaccinated but have continuous infections. The science article never measured that, and the political atmosphere right now would likely have one labeled for even daring to go unvaccinated this late in the game and appear in a study.
So the general, very loose argument made from the paper is that those who were first infected before being vaccinated tended to show greater antibody proclivities to prior strains rather than Omicron. Those who were never infected but heavily fascinated had some "better" neutralizing capabilities compared to those who were initially infected with Wuhan, and this was suggested as an indication that Wuhan infection may have left some imprinting to Omicron's response. What imprinting? Well, that's a lot more nuanced, and it doesn't exactly explain the role that the 3 doses of the vaccine played.
There's generally a lot going on with the study, and the main issue is understanding what context this paper works in. It's setup is so convoluted that it really just really provides a narrow window into what "may" be happening.
We can assume that Dr. M's position is against the vaccinations, since he has that in big bold letters at the end of his post. The issue is that, in many of these papers coming out about immune imprinting, you'll notice the authors suggesting that vaccines are needed due to lower severity of illness. So even if their paper suggests immune imprinting is occurring, they still support vaccinations. This is one of those good times where you can get a bit of perspective from the researchers in the Discussion section. I kind of read it feeling as if it was some slight castigation at those who dared to get infected before vaccines arrived, as if these people were too naughty and had to go out and break the new social norms and get themselves ill and now must live with an imprinted immune system.
Hopefully that provides a bit more context from my perspective. I think your last point is important since I think we should made well aware that COVID is not going to be a one and done situation, therefore best to protect ourselves through better overall health.
I believe the coronavirus trials never made it past animals due to ADE. I believe Dr. Fauci even mentioned it early on when talking about why vaccines would not come for years (I believe this was late spring 2020?) so there is a lot of concern that this could happen. I do agree that we are entering into unknown territory with science right now, and there's a lot of concerns that the science as it is is likely to plague the field for years to come.
I think there's a big issue as to what/if ADE is happening here. I believe prior evidence suggests that greater precaution should be taken. As for now it's hard to discern, and it's made more difficult since the science probably wouldn't want to look deep into ADE and find out that something has gone terribly wrong if that appears to be the case.
Do you remember which videos of his were the ones you considered misinformation? To be honest, this is a strange area in which we have to keep in mind many people have gotten more wealthy/popular in this era, and so one usually has to wonder if certain biases may lead people to act or behave in a certain manner.
I'm sorry you were banned for asking questions. More questions should be asked rather than fewer.
Malone misinterpreted basic details in the imprinting study. My corrections here https://rwmalonemd.substack.com/p/immune-imprinting-comirnaty-and-omicron-520/comment/7358306
Interesting Brian! I was actually thinking of breaking down that Science article, probably within the same vein as you have done with other papers (i.e. who are these dots?!) although the researchers answered that question. I think it's a very interesting article since it at least measured B and T cell response, but to the extent that there is robust evidence or good conclusions is where it becomes difficult (the transgenic mice with the Class II HLA DRB1*04:01 Haplotype honestly seemed weird to me).
You've mentioned problems with that article before, and I'm glad you made a comment there to at least provide some discourse.
The T cell anti-BA.1 nonresponse in the Wuhan + 3vax + BA.1 “wave” infection is interesting but impossible to extrapolate anything from, particularly given the authors’ moronic and inexplicable exclusion of results for unvaxxed ie the control group. And obviously could be a result of the “wave” infections actually not being BA.1, since no individual infections had sequencing / PCR strain designation.
Stupid paper all around.
Well it's interesting because the mice were homozygous for the DRB1 haplotype, yet we don't know the haplotypes of any of the participants so how are we to know whether the haplotypes are playing a big role in varied T-cell responses. Apparently the DRB1*04:01 haplotype supposedly leads to less severe/ asymptomatic COVID and is found in predominately high latitude, Caucasian populations.
I didn’t interrogate the methods there. That section was a bit self-reflexive in that it wanted to show that Wuhan / BA.1 spike are recognized differently by force-feeding chopped up bits instead of the whole antigen...
My comments were RE the “ T cell immunity after B.1.1.529 (Omicron) infection” section
Yes I'm aware, I suppose my background made me focus on that study. This is interesting since I was noticing a few pieces but I think based on what you've said I'll look back and see what makes sense (or doesn't make sense). Your insight is very helpful finding points to examine further!
I never commented on the control part, but it does appear this is a huge consequence of the massive vaccination campaign in which we have artificially removed the control group. The go-to reference group now appears to be "X vaccinated, uninfected" now.
There were unvaxxed HCWs in the study pool per S1 in the supplemental materials but they appear to simply be excluded after delta era
I believe one section of the study made it seem as if they collected sera of some of the Wuhan/Alpha infected participants then they got jabbed and were put into the vaxxed category at that point. I'll try looking at it again and see if I misread it.
"the authors’ moronic and inexplicable exclusion of results for unvaxxed ie the control group."
Yes! Ha ha. That's what I thought when I read Malone's article on it (in fact, I saw your comment and almost commented on the lack of an unvaxxed control group).
I'm neutral about the whole OAS debate in regards to these vaccines. I see both sides of the argument. However, I'm wondering about the repeated nature of these shots--will 3 or 4 shots (of the the same mRNA produced Wuhan spike/antigen) eventually trigger OAS when the highly vaxxed immune system is exposed to some variant in the future? With the talk of another jab in the Fall (which will likely be bivalent, containing the same Wuhan spike mRNA plus BA4 and 5 spike), I wonder if that's when undeniable OAS will manifest itself? It seems to me that repeated exposure in a short time frame (4-6 times in less than 24 months) will prime the adaptive immune system in a way that will encourage OAS to occur when it is then exposed to a wild variant.
Well repeat exposure would not necessarily point to OAS. Like I stated somewhere else in the comments, that would be more akin to maybe being called something such as immune priming. It'd be a semantics game, but in science terminology is important and the technical differences are important.
It would be interesting to see if this is more of a consequence of repeat exposure. Again, that probably wouldn't be considered OAS. There's an issue where antibody titers appear to be the end goal when that hardly explains everything else going on.
I think we also need to keep in mind that for us we are looking at things with the foresight and knowledge to make assumptions and sometimes personify what we think is going on with our immune system. Even if repeat vaccinations may cause it to not respond to these newer variants, is it because our immune system is acting in a complete detrimental way, or is it behaving in a manner we should expect for something that is being told to always be on the lookout for [this] (Wuhan) antigen, and when it doesn't we appear surprised because we assumed it should have.
Right! Perhaps "OAS" is not the correct technical term. Perhaps I should use the term, "immune imprinting" when relaying my concern/query about repeated exposures to the same Wuhan spike/antigen.
My concern/query is how will immune imprinting be affected by priming the immune system 3+ times with the original Wuhan spike/antigen AND THEN priming it again with the original Wuhan spike/antigen PLUS a BA4 or 5 spike/antigen--ALL WITHIN 18-24 MONTHS TIME?
I think the answer is "we don't know for sure." Has there ever been a time in medical history where people's immune systems were repeatedly (3+ times) inoculated with the same viral antigen in such a short period of time while simultaneously being exposed to wild variants of said viral antigen? And, are there studies on the effects of such a practice on immune imprinting and subsequent immune responses? Not to my knowledge.
So, it seems to me this is all one big experiment in which no one knows for sure what's going to happen. And, it's experimental scenarios like this where theories of OAS and ADE become plausible. Please correct me if I'm wrong.
Well, I kind of threw out immune imprinting although I'm not sure that would be the right term either 🤷♂️, just a bit of speculation. If only the literature would try to find alternatives rather than chasing after the trendy hypothesis.
There is likely to be a concern with forced, constant exposure to the virus to such a degree. We're likely to come across viruses all the time, yet we generally aren't being vaccinated to the degree we are. It's interesting that a few months back there was some retroactive thought that they probably should have spaced the 2nd dose out even further than 1 month (I believe a month or even a few more weeks; was it 1 month between doses? I can't even remember now!)
But all of this is really an experiment. I think so much of this is entering into a territory in which we have no evidence of and just speculating as we go along.
ADE is interesting because prior animal studies looking for a coronavirus vaccine showed ADE occurring- Dr. Fauci even mentioned it I believe in the late Spring/early Summer of 2020 as a reason for the vaccines taking several years. But in general, in this area of uncertainty many ideas are likely to arise, and there is an issue as to why certain ideas persist. It could be a result of following the cult of personality, it could be people searching for a light in the darkness.
The whole Dr. Ardis debacle makes me lean towards the latter: people want an answer and they will follow ideas that appear to be the answer, even if the evidence is not likely to hold up when various factors are taken into account. I think an issue of OAS is that there's been a general idea that you start at OAS then find ways of validating it's existence rather than examine the evidence and see if OAS is a viable hypothesis. It's why the idea that lack of antibody formation against the nucleocapsid protein somehow is an example of OAS, even though OAS absolutely does not tell us what is occurring with other antigens.
I understand the difference between OAS and ADE. In my non-medical opinion, it does appear that we are observing OAS. Originally, when I was learning in Feb. 2021, I was more concerned re: ADE. Yet here we are.
Re: comment, "What am I seeing?" I get bogged down with statistical graphs/data, in the absence of a conclusion or guiding statements. I like stats, but when posters assume a level of understanding or present too many different figures, some beyond my scope, then a guiding statement/conclusion/hypothesis is needed.
Many of us are suffering from information overload.
Thanks for commenting! I'm always curious to see what others think.
Can I ask you what evidence supports OAS for you? I think that's the most important thing to consider.
There absolutely is information overload. In one of my posts I commented that we are in an "infodemic", although that term appears to have been co-opted to refer to anti-vaccine ideas. Graphs/data can be really difficult to parse since it may require knowing special methodologies to analyze specific studies. Usually the figures should at least provide some help. The best way I've learned (if looking at papers) is to look at the Discussion section since that at least provides the researcher's explanation. Then look at the Results and the figures and see if it makes sense with the Discussion, or if something seems egregious.
Good topic...I don't have time right now to write up answers to all your questions...if I am so inspired, I'll write them up in an article. The short version is that I know OAS is an issue with some diseases like dengue fever, in which your body making antibodies to one strain inadvertently makes you more vulnerable to another strain, because the original antibodies are essentially getting in the way of any newer antibodies that are needed to fight the new strain. Whether this can happen due to covid vaccines is not clear.
So that actually is an example of Antibody Dependent Enhancement which is the question TheGreatAwakening asked, so I suppose there may be a good deal of confusion going on!
Interesting idea Stephanie. I'd look forward to that article. I've mostly decided to write this post because I wanted to see what people thought/knew out there. I think there's a real issue of lack of understanding for many readers who may just read things and take what they read at face value even if they aren't sure what they read. My questions were a few things I think about when looking at OAS, and so I wonder if a few people consider the same.
It is ADE but also frequently cited as an example of OAS. This is essentially OAS “carpetbagging” on another theory because otherwise there is literally zero natural real world relevance for the myth.
Carpetbagging?? Well, I never Brian! I tried to at least provide some possible explanation, although I'll admit I haven't looked too deep into the situation.
I mean that when researchers are droning on about OAS, and they want to list some example that isn’t just flu vaccines (so “OAS” doesn’t have to be renamed “the constant vaccine update problem” and give away the game) they cite Dengue, which is an example of ADE as best currently understood.
I see. That makes sense, although I'll admit I haven't looked too extensively into dengue. It does line up with the same antibodies from a different variant binding to conserved regions of the a different variant and leading to the enhanced infection.
How surprised are you that OAS appears to be the go-to response from everyone now. There's a ton of immune imprinting studies in the literature and so I wonder if this is a consequence of scientific groupthink in which people are trying to find any explanation and turning to OAS.
Maybe it’s like string theory. Wrong ideas attract attention in science because mediocre talent can “advance” the theory by spewing nonsense and get cited by others. Mix in a little Dunning Krueger or whatever it is called (I am working on iPhone at the moment), an ignorance of their own evident stupidity.
Isn't some of this just semantics then? If we're talking about a type of antibody that was there first (by whatever mechanism, infection or vaccine), causing problems in whatever manner (blocking better antibodies, or enabling a virus to more easily infect cells) then that's the "original sin" that's causing problems...sounds to me that people are just using the term OAS a bit loosely, but I'm not sure I understand the objection to that.
Actually, the use of the term loosely has been one of my gripes. The term was never intended to argue adults getting infected/vaccinated, but argued that children's first response to an infection is what affects immune learning down the road. When you look at the elderly, there's a general argument that their immune system has been trained for select epitopes, but that this training is what has provided them both diversity and selectivity that helps protect the elderly. So for me I see a general issue in how OAS is defined as well as how it is applied.
What do you mean by "isn't just flu vaccines" because to me that's the biggest clue that OAS is very real.
There's generally been a big issue as to how flu studies define OAS, how they apply them, and whether they are actually measuring the effects of OAS. I think there's been a big issue in that the literature has been inundated with a good deal of noise while also groupthink bias. I've come across a few OAS articles that kind of stated on some way, "well, there ARE some who disagree with OAS, but they're probably wrong".
The comments here aren't necessarily to state "OAS is not happening" but to really see people's general understanding and compare it to my own and see where those differences lie.
As opposed to the null hypothesis that flu shots are just useless, and only appear to work by random chance or user bias, which then flips whenever you track the users through multiple years? What have you seen to eliminate that from the realm of possibility? There’s nothing. OAS is just a placeholder, petulant “vaccines don’t work because nature stupid” assumption on the part of moronic humans in lab coats; it’s not science.
*edit: And even regarding flu vax studies, 1/3 of them refute OAS (and the other half are super poorly controlled) in the Yewdell review of the dumpster fire that is “the research” http://m.perspectivesinmedicine.cshlp.org/content/11/5/a038786.long— the most robust study cited in OAS research is Gostic et al 2016 which found that the “sin” is that early exposure to given subgroups confers lifelong protection, ie immunity, normal positive connotation.
I actually looked it up when I responded and found OAS connected with dengue in a Wikipedia article...granted, that's a crappy source but I did do a quick double check. I think OAS and ADE are related anyway if I am not mistaken, in other words, you need the OAS to get the ADE. You could have OAS without ADE as well probably.
They actually are, in a sense that different variants will be comprised of both unique and conserved epitopes. One aspect of OAS is that cross-creactive antibodies which target conserved epitopes across variants will supposedly be "back-boosted" and target these conserved regions which may or may not neutralize the virus.
I believe ADE comes in when the conserved region that is targeted by cross-reactive antibodies actually leads the immune system to aid this virus/antibody complex into entering the cell.
So I suppose OAS would lead to favoring cross-reactive antibodies, and ADE would suggest that those cross-reactive antibodies help the virus.
This is at least from the basic premise presented by OAS, although I could be very wrong!
I find it challenging to read the current literature, to understand what are the conflicts of interest of any of the authors or publishers, yet seem to have a critical skeptical eye recognizing that, as Buffalo Springfield sang: "Something Happening Here, what it is ain't exactly clear." So I appreciate writing that exhibits a cautious thought process rather than a headline banner shout out.
So whichever it is called, I recognized that this jab, flu vaccines, etc. create downstream unintended consequences, and that this one is worse for lack of transparency.
Thanks for the continuing conversation
The acknowledgements/conflict of interest is usually something I avoid looking at even though you can get a good deal of information from it. Sometimes the conflicts may be a whole page itself.
There are some things that we can argue are highly questionable (just like the vaccines), but that doesn't mean we use random papers or bad science to bolster our arguments.
And just to be clear, I am definitely not immune to that and I'm pretty sure I've used studies that may have had methodological flaws. I think the issue is that we all should be able to provide good-faith criticism to one another in order to find the truth. But if we prevent ourselves from criticizing others or providing different opinions then we enter into our own echo chambers.
Thanks Paul, based on this I may try a few more of these and see what people know going down the line.
Immune boosting by B.1.1.529
The one I’m referring to is HCW and immune boosting from his 2nd post (part2 maybe?) It was very technical and obviously a difficult paper for most non-scientists to read, but I was also confused by DR.M’s purpose for writing, although he may have just been informing with no implications to be taken. I could see in the comments that others were also perhaps reading more into what Dr. M had written than he may have intended. So, I guess that supports the point you are making.
Well, I did see a video with Dr. Malone I believe in another hearing with Sen. Ron Johnson in which he referenced the article. I think Dr. M is using it as an argument that OAS is being caused by the vaccines, although the study argued that vaccines alone had broader immunity (note that this is based on the author's remarks, not something I believe) compared to an initial infection with Alpha or Wuhan. It's a bit of an issue because he sort of glossed over it and made a comment that vaccines are causing OAS even though there's a lot more context needed.
I think there's been an issue in which a few people have been extrapolating too much from studies. I'll admit I am likely to have done the same sometimes (although I try to avoid doing so), but it is a difficult situation when many readers may take what they see at face value rather than question the actual veracity of the argument.
One of the reasons I wanted to try this post is to test the waters and see if people are reading all of these articles on different Substacks and really able to discern what they read, or do they just boil it down into one phrase of "vaccines bad" or "we're all doomed!". I was wondering how to go about it but I thought it would be fitting just to ask everyone and see how much they knew.
David Martin is sure millions will die, but I’m praying that’s not the case although strange things are happening to many people. The only thing I’m sure about is that it’s very strange that so many so called scientists are not questioning any of these flags raised with the jabs.
That's the type of thing I usually avoid thinking of, mostly because it really does no good to make such predictions. And even if it was true, would you live your life any differently knowing that there may be an end near? If it leads to us becoming fearful to live, then all we're doing is staying alive. Remember that those in power have utilized fear to try to get many to kowtow to their demands. When people we align with make such bold predictions be careful in letting it fill you with fear and anxiety- there's plenty of people trying to prey on that vulnerability already.
My basic understanding is that upon first exposure to a new family or type of virus we produce various forms of immunity, one of which is the creation of antibodies.
Because we all tend to experience different viruses at different times, and the things are always evolving anyway, we have huge diversity of both viruses and antibodies. That is what stops any one virus being able to spread far and wide without some compromise, such as reduced symptoms and a very low death count.
We can create entirely new antibodies for entirely new viruses or variants but if presented with a virus that is too similar to the first one we ever saw, we just throw those original antibodies at it, which may not work. So basically a security loophole we have is any virus that is both too different but looks too similar - like thinking you recognize a friend, call Hi! but it's a total stranger.
Flu vaccines have shown OAS in effect, because we can see that older generations have no defense against the reemergence of very similar-but-different variants to those going around when they were young. When they come around older people are likely to die, in part because they are throwing the antibodies for a long-extinct variant and cannot adapt to the new one. I don't have scientific names or studies at hand but my understanding is this effect was spotted and known about a very long time ago, and flu vaccines have further proved the point.
OAS is very real.
If it is a concern with coronaviruses is not so clear, ditto with COVID-19. However the fact vaccinated people are proving MORE vulnerable to infection with variants suggests that the vaccines are indeed creating some OAS effects, and even driving the variants towards that end-result.
As anything vaccine-related is treated as Religious Scripture it's not so easy to find mainstream articles, especially in this era. It does however seem a well-established and proven effect, so why you or Mowrey are declaring it some myth that never existed and the research on it is all bogus I dunno?
Perhaps in real simple terms you could explain how they're wrong?
If you cannot explain it simply then you don't understand it either, is my general take.
My understanding if ADE is that not only does the default antibody fail to prevent binding/infection but actually helps unlock the cell's defenses. That would be in the same kind of category of problem, but not the same thing.
Edited to add the ADE bit and a typo.
Well I believe one of the issues with the 3rd paragraph is really what happens after. I think from the perspective of OAS there's an assumption that you're either a sitting duck or you hope that your primary immune response will deal with the infection. There's usually no nuanced discussion that suggests if your immune system mounts another secondary response that actually learns more about the pathogen. It's difficult because most studies aren't going to provide a window into the immune process- we only assume what happened based on what results we get.
Flu studies have been referenced as a major example of OAS, but there is a real problem in the literature in which many researchers have either improperly defined OAS (not taking into account that it's a matter of age-related immune imprinting) or may be improperly looking at their results and extrapolating information that may not be there.
There's also an argument as to whether OAS is occurring, or if a more fitting term would be something like antigenic seniority, such that the first antigen we respond to is gets priority in future responses, but that each successive infection and its antigen has some position in the immunity line. It's a bit of a muddy hypothesis as well but at least suggests that more is going on that just exclusion.
Then that also leaves us with questions about the role of other infections. If we assume that there's a strong correlation between cross-reactive antibodies and conserved epitopes across different viruses, we should then ask how infections with viruses from similar families such as betacoronaviruses would influence OAS or immune imprinting. Even further than that, there are several viruses that may not share many similarities that may also produce cross-reactive antibodies. What role would these play in OAS, considering that a coronavirus infection one gets as a child should, in theory, alter the way their body responds to SARS-COV2 as well. Usually this piece is not included in the discussion as well. In fact, many discussions about OAS act as if the pandemic was the initial timepoint of OAS, and not any years prior. Remember that OAS being age-related means that our immune system is the sum of our prior infection history, not something that started arbitrarily as soon as the pandemic hit.
With vaccines leading people to being MORE vulnerable, that begs the question as to how we are measuring more vulnerable. Are we using cases as a measure? That doesn't provide anything but weak correlations in which we assume that there's a general trend of higher cases in areas with higher vaccination rates. We know nothing about the individual person's behavior, their prior history which would be needed to argue OAS, as well as their overall health status.
It also brings up the argument as to whether these people have any protective immunity where it's needed. I've argued that it's strange we take swabs from the nose to measure infection, yet we take blood samples to measure antibody levels. There's hardly any literature on the effect of mucosal immunity/innate immunity, and prior evidence with the flu vaccine suggests that vaccine injections into the deltoids do not stimulate B cell memory in places such as the nose and throat where it would be needed the most to fight off respiratory infections. So even if these people are testing positive, is it because the vaccines are leading to OAS and are preventing them mounting a new immune response, or is it that they never had prior immunity where it was needed (and where they get tested)?
But even in all of this, we still have not discussed the role of OAS in those who have been infected with prior variants and what would happen if they got reinfected. Should we expect backboosting of cross-reactive antibodies? That would at least go in line with OAS. Or maybe this is all a consequence of constant exposure, such that those who have received the vaccine are constantly exposing themselves to an old, outdated antigen and are incorrectly training their immune system. However, that wouldn't actually be OAS more than some form of immune priming (I'm speculating here).
Lastly, I'm not declaring OAS as a myth, but something that people should be more hesitant to ascribe to rather than going along with whatever is out there. Not to say that this is happening, but I wrote my first piece on OAS because so many people were somehow trying to relate the lack of N-antibodies as some example of OAS, which is a complete misuse of the hypothesis to begin with. And from there a lot of this eventually just built upon itself.
I try not to see myself as a contrarian, but I at least wanted to provide a different perspective to push back and have people reevaluate how much they know of their position.
And I am learning a lot of this as I go along, so maybe I can't explain it well because I don't understand it, but I certainly won't argue that I'm at least trying to put in a good-faith effort to see what's out there, see what the literature says, see what is going on now and trying to tie loose ends together, and I want others to do the same rather than to just follow along with whatever they see out there.
Maybe at the end of the day the scientific consensus says that OAS is right, but I'm not writing this to prove myself right, and if that's the general takeaway people are getting then there's probably a lot they're missing in my writing. I'm trying to follow the facts and make sense of a world that doesn't want us to have it make sense, and if it means being the odd one out in the discourse then so be it.
Well first, thank you for the long response. :)
Second, the fact it needed to be such a long response sums up what you admitted at the end of of - "..maybe I can't explain it well because I don't understand it..." ;)
Your good-faith efforts are appreciated and in truth my irritation is more with Mowrey, who seems to be basically declaring the entire concept as a myth.
When you say "maybe this is all a consequence of constant exposure, such that those who have received the vaccine are constantly exposing themselves to an old, outdated antigen and are incorrectly training their immune system. However, that wouldn't actually be OAS more than some form of immune priming (I'm speculating here)" - to me, that IS what I view OAS to be, not so much repeated exposure but that initial "priming" exposure. Hence the "original" part of OAS, which itself is a vague term borrowed from religion.
The entire point of a vaccine is that the body will remember the 1st exposure, correct? So it's not a huge leap to accept it could make a mistake if a new variant or strain looks similar enough.
Again I do appreciate your good-faith efforts, and totally agree regarding mucosal versus blood-borne markers. Indeed this is why I knew such vaccines could never stop transmission and infection, and the drug companies knew that too. It was the talking heads who claimed they would, and I deeply hope they both get held accountable for that deliberate deception.
Well, there's a few things to say about what it means to "understand" something. There's a problem in boiling down science to such a simplistic degree that it loses all nuance and subtlety needed to examine the information. You also need to figure out to what level someone must become knowledgeable on a specific topic in order to have some form of "understanding". I may read many articles but have difficulties relaying information, but for those who may only get a superficial glance into the topic is it viable for them to argue that they have an "understanding"? I think a lot of this will be heavily subjective, but I want to at least see how much people actually understand and how they came to the conclusions that they have.
And that's the issue with the 3rd paragraph. It may appear that that is OAS, but that actually isn't the technical hypothesis of OAS. OAS does not refer to just the narrow window of repeat exposure, but it relies on the initial exposure to the antigen and the downstream supposed effects from that initial exposure. That's different than continuous exposure to the same antigen- actually, I doubt any studies on OAS has ever looked into that repeat exposure because we've never artificially forced people to become exposed to the same antigen over the period of a few months.
I don't like the religious connotations since it's generally what people use reference as if it provides any additional validity to the hypothesis. Scientists refer to it both by OAS and immune imprinting, but when doing so they don't belabor the point of it's religious backstory since there really is no need to do such a thing.
1st exposure is highly subjective- into what window are we looking at 1st exposure, and relative to what? Again, that brings up that additional issue of where exactly we mark the initial point of the sin. When does the original antigen arise? Does it need to be from SARS-COV2, or are any coronaviruses good enough? Or to expand it even further if any cross-reactive antibodies can bind to SARS-COV2 then would that be considered the original antigen? Would that affect the immune system's initial response to SARS-COV2?
One thing that Dr. Malone greatly overlooked in his post was that the researchers were suggesting broader immunity in the triple vaccinated group compared to the Wuhan infected then vaccinated group. Not to say I find those results valid, but wouldn't that instead argue that this would cast blame on those who initially got infected and incorrectly led their immune system to go down a path of poor immune responses? This is all hypothetical. Remember that the study cited by Dr. Malone never looked at people who were naturally infected several times- they didn't even bother having a proper control in their studies.
To steelman Brian's point, I do understand why he can be frustrated with the whole OAS issue has it has emerged on Substack- this actually points to the topic of understanding.
As I know it, the first instance of OAS on Substack came from Alex Berenson and his reading of the UK report making this one comment that those who were vaccinated did not produce anti-N antibodies, then went with it and used it as an example of OAS.
On that front, that was a completely inappropriate use of OAS- OAS is never meant to explain what happens with other antigens, so right off the bat that was completely improper and bad science.
However, other people began to piggy-back off of Alex's post and began to write about OAS as well, referencing the religious subtext and pointing to the anti-N protein one-liner rather than examine the information for themselves. I wrote my series on OAS BECAUSE I saw people referencing the N protein when there absolutely was no reason to. And from there it just snowballed and escalated, to the point where many people on Substack just continued to build off of that horrible interpretation and have OAS take on a life of its own nearly devoid of its initial intentions.
I've remarked that, ironically, OAS appears to suffer from its own original sin, and one of a poorly analyzed and deeply flawed analysis that just built upon itself. With such a poor foundation, can we consider everything else that was built on top of it to be of high merit as well?
And I believe that's why Brian pushes back to the extent that he has. I personally am so enthused to find so many people becoming interested in science. But there's a big difference between knowing the science and assuming to know the science. I think we're running into an issue in which many people are not properly reading the science, and when you try to rebut improper analyses you may come across as either being a contrarian, or you may begin to experience some form of in-group bias.
It's one of the reasons I bring up someone like Dr. Ardis a lot. He's allowed to say whatever he wants, but he'd better be damn well sure that his information is well-researched before he makes claims that we're being poisoned with snake venom in the water. So many people clung to that argument, even when there were so many holes in Dr. Ardis' theory that it was easily made defunct, and yet the idolatry surrounding Dr. Ardis and the ingroup dynamics became so entrenched in such a short period that it was rather astonishing to see.
Because of all of that I can empathize with Brian. When there are so many claims about OAS being made, when OAS is being misused or grossly misapplied and it just continues to build upon itself can you necessarily blame someone who at least attempts to provide some nuance?
Well, sorry for the wall of text again. Even if Brian may come off abrasive, he- at least from my perspective- is doing a lot more to understand the literature and parse the information. He actually reads the supplemental material for studies! So for me that comes with a good deal of respect compared to others who may just read the title of a paper and assume that they know what the paper is about (no one in particular, but I have a feeling this happens a lot more often than it should in general).
Priming populations with 2 year old viral stain is like antigen fixation for a strain different from evolving circulating strains. This can result in OAS. Recent Nature article reported infected monocytes in some COVID-19 patients. If the infections develop from Fc receptor bound to antibody viral uptake, I consider this one type of ADE. Hypothesis: many critical COVID-19 patients with high SARS-CoV-2 antibodies likely have this type of ADE.
Hypothesis 2: MIS-C and MIS-A patients with higher than primary antibody titers and histamine intolerance have a second type of ADE with hyperactivated mast cells releasing histamine
That's interesting Darrell (Dr. Ricke?). Thanks for your insights! I suppose my question pertains to what extent we argue that antigen fixation is occurring, and whether that fixation is a negative consequence. I think that's one of the issues I have with OAS since I believe it serves as a bit of a general argument that sort of obfuscates certain factors.
I think you first hypothesis is interesting. I can't remember where but I believe there is a general argument that a specific immune response has been associated with more severe COVID. Actually, I think your second hypothesis points to what I was asking. I did a quick search and there appears to be a lot of research going on into histamine and long COVID, so that's really interesting.
For some models, OAS antibodies may contribute to ADE. An article by Wan etc al. describes a concentration affect were ADE in the cells being evaluated needed sufficient antibody level to enable ADE that was followed by higher concentrations blocking ADE - too many antibodies may block the membrane fusion mechanism of the virus. Hence, very high titers are protective until the durability decline of antibody titer.
For some long COVID-19 patients, one of my hypotheses is persistent infections - this fits with an ongoing role for histamine release from mast cells.
I am happy with being called either Darrell or Dr. Ricke. I am a Molecular Biologist/ Computational Biologist in training.
That's interesting. Do you know if the study examined shared epitopes among the antibodies and whether there was a factor of needing to outcompete ADE-biased antibodies?
The persistent infection thing is very interesting. It's a shame we have no actual data on that. Some have argued persistent viral load within the gut due to high ACEII receptors, but I wonder what role the microbiome and mucosal immunity would play there.
Thanks for the background! I'm a curmudgeon in training so we'll see how well that goes!
See http://www.aimspress.com/article/doi/10.3934/Allergy.2022007 for references; no epitopes examined. I view this as virus leveraging Fc receptor antibody uptake to expand tropism to phagocytic cells.
SARS-CoV-2 appears to be able to persist in GI for some individuals, perhaps CNS in others ( autopsy evidence), etc. I can more details next week - I am on travel.
Thanks for the citations, I'll take a look later!
I'm not too good with immunology so there's a bit of a steep learning curve for me, but that's an interesting idea that I'll try looking into.
The CNS is interesting since I was wondering what role the nose and the entryway into the CNS from there plays in CNS invasion. I did see a paper on the microbiome and COVID, so it'd be interesting to see if a dysfunctional microbiome may have some relationship between both immune function and viral persistence.
Anyways, enjoy your travels!
GI references:
https://doi.org/10.1101/2020.03.24.20042382
https://doi.org/10.3390/pathogens11050556
Relevant CNS articles:
Matschke, J., et al., Neuropathology of patients with COVID-19 in Germany: a post-mortem case series. Lancet Neurol, 2020. 19(11): p. 919-929.
Meinhardt, J., et al., Olfactory transmucosal SARS-CoV-2 invasion as a port of central nervous system entry in individuals with COVID-19. Nat Neurosci, 2021. 24(2): p. 168-175.
Nauen, D.W., et al., Assessing Brain Capillaries in Coronavirus Disease 2019. JAMA Neurol, 2021.
Lukiw, W.J., A. Pogue, and J.M. Hill, SARS-CoV-2 Infectivity and Neurological Targets in the Brain. Cell Mol Neurobiol, 2020.
De Melo, G.D., et al., COVID-19-associated olfactory dysfunction reveals SARS-CoV-2 neuroinvasion and persistence in the olfactory system. bioRxiv (Preprint), 2020.
Guedj, E., et al., 18 F-FDG brain PET hypometabolism in patients with long COVID. Eur J Nucl Med Mol Imaging, 2021.
Sollini, M., et al., Long COVID hallmarks on [18F]FDG-PET/CT: a case-control study. Eur J Nucl Med Mol Imaging, 2021.
Also immune complexes have been recently reported, etc.
Thank you! I'll try taking a look later. I'm sure MIS is likely to occur from many different factors, but for the vaccines there's likely to be some association. Inflammation is expected, but considering there's many questions as to the actual circulation of the LNPs and spike protein there's a lot of question about if this would lead to systemic inflammation.
Hypothesis for MIS: the Fc receptor on mast cells have a low affinity for IgG antibodies; so, higher than primary immune response level is required to hyperactivate mast cells. Most individuals can process the excess histamine and no MIS will develop. Some foods, drugs, etc can lower the histamine tolerance level and these individuals are at risk - explains the rare frequency. Most MIS-C patients appear to have persistent GI infections, explaining delayed onset pattern after COVID-19 surges. For MIS-V, driving excess any protein will also work nicely.
My articcles on Kawasaki Disease and MIS:
https://www.pediatricsresearchjournal.com/articles/kawasaki-disease-multisystem-inflammatory-syndrome-in-children-antibody-induced-mast-cell-activation-hypothesis.html
https://scientonline.org/open-access/etiology-scenarios-for-multisystem-inflammatory-syndrome-in-children-and-adults-associated-with-sars-cov-2.pdf
https://www.qeios.com/read/52A6VH
Thanks Darrell! I'll try to look at these when I have the time. It sucks I can't pin these comments to refer to later.
Is OAS/Immune Imprinting the same as Antibody Dependent Enhancement/Pathogenic Priming? If so, why are there so many names for it? 😫 Someone just published something to do w/OAS. I know you haven't seen evidence of it for the Covid injections, so I was thinking of sending you the link, but I didn't know how to DM you :).
No: so Antibody dependent enhancement suggests that some antibodies you form against something such as a virus may facilitate the immune system to increase viral entry. It essentially enhances the virus' ability to enter cells. OAS/Immune printing are different.
Interesting, if it's something that doesn't have to kept discrete you can post a link here. If not, I believe you can send me an email through Substack. I will be honest though and state that I am VERY bad at checking my emails! Mostly because I'm not sure where Substack sends them in posts 😅
We all have bias behavior, seeking that which reinforces our established perceptions. Mostly I am blind to my own bias, and rely upon others to point it out. It's why I enjoy reading perspectives that don't fit mine, though I have to say I have stopped reading the Washington Post halfway through the pandemic. My bs meter was tweaking too much!
There's no greater indication of cognitive bias than to argue that you don't have any bias! Like you stated Paul, we all have biases, and even if we don't know what they are specifically we should understand that it exists somewhere. The best way to understand your own position is to see other perspectives- how else will you know if your arguments will stand the test of (cognitive) battle?
Nearly all outlets were horrible during COVID. The information was all over the place, or they were clearly coming from people with no understanding of science itself. I kind of figured we were in trouble when a local news station was covering convalescent plasma therapy and the segment had a chyron that stated "antibodies help to fight off viruses".... OK? Thanks for telling us something we should already know?
I don't know what would be worse: that there are people that don't understand how antibodies work, or that the media thought it was necessary for them to make such a report with an assumption that their audience is completely ignorant.
Lots of Qs. Some background first: I have a BSc in organic chemistry, but didn’t fancy a PhD as I wanted to earn money., fast. I have worked in the pharma sector for years. I don’t even have a biology O level though (U.K. based) so I feel a bit out of my depth on immunology. These questions are making me think though. Consider them the responses of an interested & curious lay person.
Do you know what Original Antigenic Sin/ Immune Imprinting is?
What do you know about OAS?
I have a vague idea, from what I’ve read over the past year. It is the phenomenon whereby a person on encountering a pathogen responds by producing an antibody type that it first generated on encountering a similar prior pathogen.
Do you think the vaccines are leading to immune imprinting/ OAS?
Looks as if that is possible, given higher infection rates in the vaccinated. Alternatively they could be damaging innate immune responses.
What role would natural immunity play in OAS?
Not sure I understand this Q. Natural immunity would produce a greater array of antibodies, so I would assume unless all of the antigens of the new pathogen were meaningfully different, at least some of them would work to neutralise it, so OAS would be less of a problem. If that’s what you are asking.
How far back does OAS go? Does the issue of OAS start when we are born, or is it only a phenomenon when we are older?
Not clear. I would assume it becomes more of an issue once we start to rely less on innate immunity and more on adaptive immunity, which happens as we age.
If OAS is based on prior immune responses, what role would other infections play?
See above on natural immunity.
If we caught a coronavirus infection when younger, would that lead to some form of immune imprinting and thus affect our response to both SARS-COV2 and the COVID vaccine? Or is the response to both SARS-COV2 and the vaccine wholly separate?
See the above Q on natural infection. It could be a problem, but presumably only if ALL the antigens involved in the adaptive immune response mutated enough to be “similar but different” to the same degree. Vaccine is more problematic because of the very narrow spectrum of antibodies it produces vs natural infection.
Would there be any benefit to OAS? Or is it completely detrimental?
It would allow for faster adaptive immune response. Which could be beneficial if there is a lot of that variant circulating, in a deadly pandemic.
What role would cross-reactive antibodies play in explaining OAS/Immune Imprinting?
Poor cross reactivity of antibodies from immune imprinted individuals leads to lack of neutralising effect.
Are there other alternatives to OAS that may explain the effects of prior antigen exposure on immune response?
ADE is an alternative but I would imagine that this would lead to a more virulent course of illness than we are seeing, so if this is happening, it would seem to be at the margins. For now at least.
Does OAS apply to only one antigen, or does it affect other antigens as well?
Not sure I understand this. On one antigen in the virus? In any antigen in any virus? Or just the S1 antigen?
How would you measure OAS/Immune Imprinting in a study? What would be some limitations of such studies?
I would measure antibody types and amounts on exposure to a pathogen in both disease naive (vaxxed & unvaxxed) and disease experienced (both groups again), and also record severity of any resulting infection. All kinds of problems doing that IRL, unless you know what prior variants previous infections were, when they were caught, and that everybody in your sample experiences the same variant when reexposed. Massive sample needed to get controls right.
How often do you check links in posts? Sometimes
Do you generally do additional research, or do you take information at face value? Usually a bit more googling
What factors do you use to gauge the veracity of the information you read? Whether it makes logical sense is the main one. So much really doesn’t.
How do you find other sources of information? Pubmed. Following references. Usual literature search techniques I learned at uni in the pre internet days.
Oh that's interesting! I have a B.S. in Biochemistry but I took a lot of courses related to drugs so that's generally my wheelhouse. Just like you I have trouble with Immunology.
Your definition of OAS is interesting, as it would actually relate to the first ever exposure to the antigen, and not the prior response. I think many people may consider this to be a semantic argument (not you specifically) but there is a big difference between the two.
The infection rates is interesting, since it begs the question of whether we can predict immune function based on infection alone. That enters into a lot of speculative territory, and it's usually why I don't like to look at infections rates as an indicator for OAS since so many other factors are at play than what is usually provided.
Naturally immunity does produce greater array of antibodies, but different antigens is not part of the definition of OAS. Remember that OAS refers to one antigen in specific and the exposure of that antigen's role on all other immune responses to variations of the antigen. For SARS-COV2 we may look specifically at the spike (more specifically maybe the S1 subunit, although S2 is included as well I believe). OAS' hypothesis tells us that we cannot look at other antigens as a prediction for how the immune system will respond to the intended antigen. That means we can't look at the N protein of SARS-COV2 and predict anything about the S protein and antibodies.
My question about whether it's important when we are older is actually at the crux of OAS. OAS is defined to be an age-related phenomenon, such that the very first exposure to an antigen should shape all future exposures to variations of that antigen. So when we look at OAS in the elderly, there's an assumption that their antibodies and their immune system have behaved over decades based on that very first exposure they got when they were little. Most people tend to not include this aspect of OAS into their analysis, and it opens a host of other things to consider that muddies the waters of OAS.
For the benefits of OAS, it is assumed that OAS is a heuristic approach to targeting variations of an antigen by mounting an already learned immune response to clear out an infection rather than rely on the delayed time between exposure and adaptive immunity that can be even more detrimental. But like with any heuristic, shortcuts can have it's faults. However, if prior immune responses is "good enough" then that would at least argue some evolutionary benefit to mounting an improper immune response.
For the cross-reactive antibodies, I actually suggested that question as a way to relate variations of antigens. Cross-reactive antibodies are assumed to target conserved epitopes of an antigen, such that if antibodies formed from the exposure to one spike protein can cross-react with another spike we can assume that those antibodies target regions that have not mutated. A good example is Sortrovimab, one of the mAB in use against COVID that was isolated from a 2003 SARS-COV patient. Its ability to target the spike of SARS-COV2 means that it targets a conserved region of the spike. As it relates to OAS, the idea here is that mounting a previously learned immune response will cause many antibodies to not bind due to antigenic drift while those that do bind are likely to target conserved epitopes. Then it becomes a question as to whether targeting these regions can clear out the virus, or if it may enhance infectivity akin to ADE.
As to if OAS applies to one antigen, that question was one to see whether people generally consider other antigens when evoking OAS. For SARS-COV2, many people relate the anti-N antibody response to the Spike's response, but OAS is not intended to define the behaviors across different antigens- it only explains what happens when exposed to one specific antigen.
It's a shame we can't really conduct any studies on people who have only been infected and not vaccinated, especially for people who have continuously been infected with COVID without the vaccine. There's a huge gap in knowledge because the current policies have essentially removed a critical cohort, because it would at least provide more evidence if we are to assume OAS is occurring.
And thanks for answering the last few questions! On Substack we get metrics on whether people click links and it's quite astonishing when you find out those clicks are likely to be in the low single digits. I always encourage other people to read studies themselves to see if anyone, including myself, has misread a study but I think it highlights that some people may not look further than what is presented to them.
The logical sense answer is interesting. I suppose it's a matter of whether the logical sense is objective or subjective. Of course, logic should be objective but you do have to wonder whether people conflate the two (obj vs subj). We may believe we are being logical when we may have some biases that get in the way of critical thinking and reasoning.
Thanks for providing your answers! I always appreciate seeing what other people say! The response to this is making me think I should do a few more of these in the future.
I have a general understanding of OAS and ADE, but sometimes I need to refresh my memory as I’m reading about each. Somehow, I had read Dr. Malone’s 2nd article, but had missed the first, so I went back to it. I even went to the original article Dr. M was writing about.
There was way too much information packed together in the original article for me to unpack in one reading , especially as I’m a non-scientist, but this is what I got from the original article:
If you had an early form of Covid and the shots, the shots protect you from those first strains only and not so much from later ones.
If you had an early form of Covid, it does not protect you from later strains.
If you didn’t have Covid, the shots protect you against something, maybe, but now I’m confused about what and will have to go back again.
If you have the shots first then Covid, something, something.
Dr. M’s report on article is also confusing to me. I couldn’t discern if he was agreeing with the conclusions of the article or not. Is Dr. Malone saying to take the shots? To take one shot? Then later in his article he seems to contradict himself.
Maybe if I had the hard copy of both the original study and Dr. Malone ‘s paper I could make some sense of everything because I could write on a hard copy and draw pictures, highlight etc.
My take away:
You can have Covid more than once, just like the flu, because having Covid, the shots, or both cannot protect you forever because of variants.
Guess that’s why we need early treatment.
Background: Retired, widowed 5th grade teacher, mother, and grandmother.
Thanks for your comment Canny. I think it's good to always at least see whether what you're reading makes sense or not. I've come across a lot of papers that I just don't know anything about, and usually it becomes an issue of whether you should do more research and come back, or if you sort of "brute force" going through the paper until it makes sense. Like I stated, most people don't have time for either so usually it's a good idea to say "I'm not sure exactly what I'm reading, so I'll remain a bit skeptical of the conclusions".
Which original paper are you referring to? Is it the cell one?
https://www.cell.com/trends/immunology/fulltext/S1471-4906(17)30164-3
If it's the cell article, it's actually one of my biggest gripes with that first post he made, mostly because he took the abstract summary. If you actually read the paper, it explains that the authors don't believe OAS is the proper term, but more something along the lines of antigenic seniority.
"Is it really a ‘sin’ to have immune memory and pre-existing antibodies to the first influenza virus
strain an individual is exposed to? It would only be a true sin if nothing good comes from it, and
although Francis used this term, he also suggested that the concept of OAS could be employed
to induce broader immunity [12]. Perhaps the term ‘antigenic seniority’ better describes the
phenomenon. This more recent model of OAS dictates that strains from childhood are given a
more ‘senior’ antigenic position in our immune repertoire, and that each subsequent strain
takes a more junior position in the response [26–28]. Thus, the relative response to each
individual strain will be determined by its hierarchal position, and previously encountered strains
will be boosted by encounter with strains of the same subtype. Over time, these responses
accumulate, resulting in the highest antibody titers against the strains of childhood. It is also
possible that the response to primary exposure is simply larger than that to subsequent
exposures [21]. A key distinction of this new model is that every new strain gets a place in
the hierarchy, not only the strain of first exposure (Figure 1)."
So I'm not exactly sure why he included this paper as the pivotal OAS paper, but like I stated above I think it's a matter of people not clicking on links.
If not this paper, could you point out which original paper you are referring to?
Or maybe you're referring to the Science article! That article has a lot going for it, but it's unfortunately a paper that is very technical. Many of the points you made above require a bit of nuance, mostly because the study itself was created in such a strange way. We don't know what exactly is happening in those who are unvaccinated but have continuous infections. The science article never measured that, and the political atmosphere right now would likely have one labeled for even daring to go unvaccinated this late in the game and appear in a study.
So the general, very loose argument made from the paper is that those who were first infected before being vaccinated tended to show greater antibody proclivities to prior strains rather than Omicron. Those who were never infected but heavily fascinated had some "better" neutralizing capabilities compared to those who were initially infected with Wuhan, and this was suggested as an indication that Wuhan infection may have left some imprinting to Omicron's response. What imprinting? Well, that's a lot more nuanced, and it doesn't exactly explain the role that the 3 doses of the vaccine played.
There's generally a lot going on with the study, and the main issue is understanding what context this paper works in. It's setup is so convoluted that it really just really provides a narrow window into what "may" be happening.
We can assume that Dr. M's position is against the vaccinations, since he has that in big bold letters at the end of his post. The issue is that, in many of these papers coming out about immune imprinting, you'll notice the authors suggesting that vaccines are needed due to lower severity of illness. So even if their paper suggests immune imprinting is occurring, they still support vaccinations. This is one of those good times where you can get a bit of perspective from the researchers in the Discussion section. I kind of read it feeling as if it was some slight castigation at those who dared to get infected before vaccines arrived, as if these people were too naughty and had to go out and break the new social norms and get themselves ill and now must live with an imprinted immune system.
Hopefully that provides a bit more context from my perspective. I think your last point is important since I think we should made well aware that COVID is not going to be a one and done situation, therefore best to protect ourselves through better overall health.
I believe the coronavirus trials never made it past animals due to ADE. I believe Dr. Fauci even mentioned it early on when talking about why vaccines would not come for years (I believe this was late spring 2020?) so there is a lot of concern that this could happen. I do agree that we are entering into unknown territory with science right now, and there's a lot of concerns that the science as it is is likely to plague the field for years to come.
I think there's a big issue as to what/if ADE is happening here. I believe prior evidence suggests that greater precaution should be taken. As for now it's hard to discern, and it's made more difficult since the science probably wouldn't want to look deep into ADE and find out that something has gone terribly wrong if that appears to be the case.
Do you remember which videos of his were the ones you considered misinformation? To be honest, this is a strange area in which we have to keep in mind many people have gotten more wealthy/popular in this era, and so one usually has to wonder if certain biases may lead people to act or behave in a certain manner.
I'm sorry you were banned for asking questions. More questions should be asked rather than fewer.