B Cells do not stem from a singular, centralized "immune response." For this reason, Francis's obsession never made sense to begin with. (OAS lit review supplement.)
Glad to hear that - and that's partly why I am so engaged on the subject. Baseless fearmongering should be confronted if it also has a dumb name is my rule.
I was fascinated by the graphic with the baby wearing the Viking helmet and the sunglasses. I checked all the articles cited in footnote 2 and did not find it. What was the source? I'd love to see if my guess about what the various icons represent was even close.
Edit to add: OK, it looks like that's your own illustration. I'd still like a legend just out of curiosity.
Just a stray thought. One of your references in footnote 2 is "B cell memory: building two walls of protection against pathogens" and states at one point "The findings from these studies are most relevant to antibody-mediated development of vaccines to induce protective immunity in naive individuals. However, there is an urgent need for vaccines for individuals who have chronic infections, including AIDS, malaria and hepatitis virus infections. The development of such vaccines may be highly challenging as current evidence indicates that such chronic infections have a profound impact on the memory B cell compartment...we may be quite a distance from designing vaccines for chronic infections."
Could repeated boosters of Spike be creating what is essentially a chronic infection? If so, the statement "we may be quite a distance from designing vaccines for chronic infections" becomes Ouroboros-like.
Yeah, "vaccine" doesn't make sense against chronic infection since "just get some antibodies in there" doesn't lead to improvement, and all vaccines are good for is loading up antibodies. But focusing instead on the difficulty of programming an antibody response when there's already constant antigen encounter is a good way to get your unproductive HIV research funded.
I would say that boosters mimmic chronic infection. The question would remain whether this advantages the virus and what effect that has on community exposure or on viral fitness (creating an attenuated strain incapable of besting innate immunity in the unvaxxed) as was partially discussed in "Forever Spike"
Isn't the memory B cell response more rapid than generating new antibodies? I imagine that the immune system, on encountering a new strain, would quickly pump out antibodies from the last strain while also developing new antibodies particular to the new strain. So the mix of new vs. old antibodies would vary over time, with the new antibodies gradually displacing the old as new B cells are formed and the new antibodies out-compete the old in binding to the new pathogens.
For the repeatedly vaccinated, I can imagine a worst-case scenario where they have not only massive banks of old memory B cells, but also excessive old IgG antibodies circulating in the bloodstream. An infection with a new strain thus triggers a massive ramp-up of old stain antibody production before the IgM and the germinal centers have a chance to develop new antibodies. There might also be a sort of positive feedback loop, where the old antibodies keep stimulating the old B cells, and the new antibodies are effectively suppressed by the sheer volume of old antibody production.
The rosiest outcome would be that multi-dosing doesn't result in any new (Wuhan-redundant) Germinal Center -> Memory B Cell pools, thanks to the IgG->No Response pathway pictured in "Routing Logic." So baseline percentage of Wuhan-spike-geared B Cells doesn't actually increase. But there's no longitudinal study of germinal center responses anywhere so I'm basically blowing smoke here.
Obviously baseline is irrelevant if the virus is encountered while antibodies are still high, especially in pre-Omicron where said antibodies inhibited viral shedding. So that's where you get both the tropes that breakthrough infections have lower viral loads and don't lead to N antibodies, both tropes are based on rare early spring 2021 breakthrough infections.
Baseline is also irrelevant if dosing every 3 months, artificially keeping the b cell / antibody response jacked up. As with severe efficacy it becomes impossible to understand long-term effects of any "dose X" if everyone keeps jumping to "X+1".
But in general the "bank" of Wuhan-specific Memory B Cells should stay close to some sort of equilibrium, and IgG antibodies fade, the same way that boosting with other vaxxes is like filling a leaky bucket with sand.
OTOH there's the crazy emergence of IgG4 after triple-dosing in the paper linked by Jim H below. That seems to clearly show a detriment to repeat-dosing. I'm doing a post on it now.
Thanks once again. Very enlightening post. So much smoke-and-mirror squawking about OAS. Thank you for going to the trouble to clarify things. If you ever have any physics questions just let me know.
There is a new twist to the story in the case of those >/= 2X transfected with mRNA.. and that is IgG class switching toward "non-inflammatory" IgG4 antibodies. This is discussed in a new paper out of
Germany that I feel has gotten too little attention by those oriented toward immunology;
IgG4 antibodies no longer fight the infection - rather they are a sign that the immune system is tapping out due to overstimulation by an antigen. "Vaccines" are not supposed to do this. The mRNA is clearly hanging around way too long..................
Ok, that one definitely deserves attention. That’s funny because I was listing alternate explanations for higher infections in a comment on Part 1 and tolerance was an afterthought. But looks like it might be here. I’ll have to appraise the paper. Wow!
Thank you for acknowledging this Brian.. you are certainly better equipped to digest the paper and start connecting the dots than I. I see this as another layer in the overall addling of our immune systems. First you have OAS (or whatever you want to call it) whereby the immune system naturally wants to recall, upon reinfection, the antibodies specific to the Wuhan spike.. then you have class conversion to IgG4 on top of that.. what a mess the mRNA causes.
I was a little concerned when you actually prefaced this post with a "nitty & gritty" remark. I thought we were going to be taken through an entire year of medical school!
I ended up looking up Frances' OAS argument, which appeared in early 1960s (possibly 1960 itself? Although your post of 1953 likely aligns with his initial research timeline). Much of the B-cell research appear to have happened a few years after, with many research coming about during the late 1960s to the 1990s (and onward, really) if the timeline from this article is to be believed.
And so that would really line up with the notion that antibodies and OAS were decided before much was known about B and T cells as we do today, and why there are many issues with what we are having right now.
I wonder if much of the talk of OAS has overridden people's conceptions about the adaptive immunity. It is, in essence, a requirement that the adaptive immune system rely on recall in order to tackle a pathogen that shares some similarities to prior ones. So now we have prior immunity recalling a response, and it's assumed to be immediately bad. I even remember reading a part of one of the first mouse studies on OAS where the researchers even commented that the recall would have been a good thing.
I also guess this is all a consequence of everyone just focusing on antibodies and nothing else. The whole immune system is complex and can't be boiled down to the antibodies sticking once, and if they continue to stick again.
I look forward to the Frances portion and see what you write about that!
Burnet appears to have been the one ahead of the game in the 50s. In 57 he came up with clonal selection (affinity maturation) and negative selection for lymph cells as how antibodies are refined, pretty much nailed it.
When it comes to "immune imprinting" it definitely seems like a lot of scientists have lost the plot. We're supposed to remember viruses, that's literally the whole idea.
I'm still very naive to much of immunology, so much of this has been a really slow burn. However, there's always been a nagging feeling that just didn't sit right with me in regards to OAS. When I wrote about it months ago I didn't see your Substack at the time. However, framed my response around all of the responses to a certain person's Substack that appeared to serve as the progenitor of OAS on this site.
I'm just jokingly referring to this as the sin of OAS, or the original sin of OAS. Something along those lines.
I'm starting to think my friend who called all of this the frat guy presentation of the immunology world actually had it spot on. A lot of show but not much substance.
"The suggestion, in the context of SARS-CoV-2, that the Memory B Cells and Plasma Cells generated in reply to the Covid vaccine-induced spike proteins can somehow forbid the body from initiating a new immune memory response in any Germinal Center, anywhere, is without merit." So what you are saying is that OAS is not an issue, and the reason the vaccinated are getting covid multiple times and apparently getting sicker is due to something else?
I was getting this idea in hearing a study shared by Dr. John Campbell...my layman's interpretation is that the shots don't seem to be blocking new antibodies, the antibodies are just lesser...
RE your theory that "antibodies are just lesser" the paper linked by Jim H above is right on the money, shows immune-suppressing IgG4 emerging after third dose.
Is this related to the idea that people getting mRNA vaccines are developing "spike protein tolerance" because the spikes are being produced too much, to the extent to which the body needs to downregulate the response to them to avoid autoimmunity?
This is really important to understand...I have many loved ones wanting to continue on the booster train and I'm hoping that Novavax won't have these problems because it does not use mRNA to generate the spikes.
That was my first guess but they find the class switching is not related to a change in T Cells, it seems to be in an uncharted territory. Might be more of an allergic response pathway.
I mean to me that specific mechanism is a funny idea (like imagine vax-spike-induced plasma cells in the bone marrow calling up your lymph nodes and threatening to get the whole staff fired if they touch anything else on the virus), and since that's what it would take for OAS to be true, OAS is by extension an idea without merit.
ADE is still a possible explanation for higher rates of infection, like there's https://www.nature.com/articles/s41586-022-04702-4 as far as true ADE, and then there's GvB's natural antibody interference theory which I think is more plausible and have mentioned in a few posts. And then RE reinfection there's the question of whether post-vax infection "corrects" the vax response by doing more than just throwing on new antibodies - does it program cellular immunity, including tissue resident T Cells etc.
I don't know about the vaxxed getting sicker - as with other stuff that's an anecdote that doesn't seem highly reflected here in California, but who knows if the shots were consistently manufactured / perserved here vs elsewhere
You have to remember that neutralizing assays never tell "which" antibodies stick around (literally!) and which ones do not. We just know how much are still sticking. That's why I wrote about the association between monoclonal antibodies and variants in my post from last week.
For example, we know that the E484K mutation in many variants led to a large level of loss of neutralizing antibodies, which tells us that many neutralizing antibodies require the use of the E484 amino acid residue to bind. If it mutates, they don't bind and fewer antibodies stick. However, when you look at an assay you just see how much are still sticking, not which antibodies and which epitopes are targeted. It's the relationship between the two that we have to remember when we look at an assay.
And so it could be that new immune responses aren't super robust, it may just be good enough to do its job with the prior old responses leading the charge.
With repeat illness, it depends on the timeframe. The Wuhan lineage are so different than Omicron that nobody with any prior immunity would be protected- the antigens are far too different to have a good recall, and so another response needs to happen. With Omicron from Omicron, my argument was that the variants may have been circulating together and popped up whenever a niche appeared in the immunity landscape. Because they were already around, we didn't need to wait months for a new escape variant to come around- we just needed everyone's immune system to be trained towards Ba.1. Then Ba.2 pops up and is different enough to escape the Ba.1 immunity landscape and then eventually we reach Ba.4/Ba.5. So there isn't necessarily a slow move towards other variants, but it was really a giant leap from Delta -> Omicron and we are just playing hopscotch in between each Omicron sub-lineage.
At least that's all my perspective. Plenty of holes in my perspective as well 🤷♂️
I'm so ambivalent about OAS. About the only thing I can say for sure is that the appellation of "sin" was the true sin.
As someone who stopped after the first Moderna shots, it's encouraging to read your take. To channel Fox Mulder, I Want To Believe.
Glad to hear that - and that's partly why I am so engaged on the subject. Baseless fearmongering should be confronted if it also has a dumb name is my rule.
I was fascinated by the graphic with the baby wearing the Viking helmet and the sunglasses. I checked all the articles cited in footnote 2 and did not find it. What was the source? I'd love to see if my guess about what the various icons represent was even close.
Edit to add: OK, it looks like that's your own illustration. I'd still like a legend just out of curiosity.
Good suggestion - will add when I have a chance.
Just a stray thought. One of your references in footnote 2 is "B cell memory: building two walls of protection against pathogens" and states at one point "The findings from these studies are most relevant to antibody-mediated development of vaccines to induce protective immunity in naive individuals. However, there is an urgent need for vaccines for individuals who have chronic infections, including AIDS, malaria and hepatitis virus infections. The development of such vaccines may be highly challenging as current evidence indicates that such chronic infections have a profound impact on the memory B cell compartment...we may be quite a distance from designing vaccines for chronic infections."
Could repeated boosters of Spike be creating what is essentially a chronic infection? If so, the statement "we may be quite a distance from designing vaccines for chronic infections" becomes Ouroboros-like.
Yeah, "vaccine" doesn't make sense against chronic infection since "just get some antibodies in there" doesn't lead to improvement, and all vaccines are good for is loading up antibodies. But focusing instead on the difficulty of programming an antibody response when there's already constant antigen encounter is a good way to get your unproductive HIV research funded.
I would say that boosters mimmic chronic infection. The question would remain whether this advantages the virus and what effect that has on community exposure or on viral fitness (creating an attenuated strain incapable of besting innate immunity in the unvaxxed) as was partially discussed in "Forever Spike"
Isn't the memory B cell response more rapid than generating new antibodies? I imagine that the immune system, on encountering a new strain, would quickly pump out antibodies from the last strain while also developing new antibodies particular to the new strain. So the mix of new vs. old antibodies would vary over time, with the new antibodies gradually displacing the old as new B cells are formed and the new antibodies out-compete the old in binding to the new pathogens.
For the repeatedly vaccinated, I can imagine a worst-case scenario where they have not only massive banks of old memory B cells, but also excessive old IgG antibodies circulating in the bloodstream. An infection with a new strain thus triggers a massive ramp-up of old stain antibody production before the IgM and the germinal centers have a chance to develop new antibodies. There might also be a sort of positive feedback loop, where the old antibodies keep stimulating the old B cells, and the new antibodies are effectively suppressed by the sheer volume of old antibody production.
The rosiest outcome would be that multi-dosing doesn't result in any new (Wuhan-redundant) Germinal Center -> Memory B Cell pools, thanks to the IgG->No Response pathway pictured in "Routing Logic." So baseline percentage of Wuhan-spike-geared B Cells doesn't actually increase. But there's no longitudinal study of germinal center responses anywhere so I'm basically blowing smoke here.
Obviously baseline is irrelevant if the virus is encountered while antibodies are still high, especially in pre-Omicron where said antibodies inhibited viral shedding. So that's where you get both the tropes that breakthrough infections have lower viral loads and don't lead to N antibodies, both tropes are based on rare early spring 2021 breakthrough infections.
Baseline is also irrelevant if dosing every 3 months, artificially keeping the b cell / antibody response jacked up. As with severe efficacy it becomes impossible to understand long-term effects of any "dose X" if everyone keeps jumping to "X+1".
But in general the "bank" of Wuhan-specific Memory B Cells should stay close to some sort of equilibrium, and IgG antibodies fade, the same way that boosting with other vaxxes is like filling a leaky bucket with sand.
OTOH there's the crazy emergence of IgG4 after triple-dosing in the paper linked by Jim H below. That seems to clearly show a detriment to repeat-dosing. I'm doing a post on it now.
Thanks once again. Very enlightening post. So much smoke-and-mirror squawking about OAS. Thank you for going to the trouble to clarify things. If you ever have any physics questions just let me know.
Haha, thanks. I might wade into that zone one day, for now I keep a wide berth
Trust me on this: what you're doing is far more difficult.
There is a new twist to the story in the case of those >/= 2X transfected with mRNA.. and that is IgG class switching toward "non-inflammatory" IgG4 antibodies. This is discussed in a new paper out of
Germany that I feel has gotten too little attention by those oriented toward immunology;
https://www.medrxiv.org/content/10.1101/2022.07.05.22277189v1.full.pdf
IgG4 antibodies no longer fight the infection - rather they are a sign that the immune system is tapping out due to overstimulation by an antigen. "Vaccines" are not supposed to do this. The mRNA is clearly hanging around way too long..................
Ok, that one definitely deserves attention. That’s funny because I was listing alternate explanations for higher infections in a comment on Part 1 and tolerance was an afterthought. But looks like it might be here. I’ll have to appraise the paper. Wow!
Thank you for acknowledging this Brian.. you are certainly better equipped to digest the paper and start connecting the dots than I. I see this as another layer in the overall addling of our immune systems. First you have OAS (or whatever you want to call it) whereby the immune system naturally wants to recall, upon reinfection, the antibodies specific to the Wuhan spike.. then you have class conversion to IgG4 on top of that.. what a mess the mRNA causes.
I was a little concerned when you actually prefaced this post with a "nitty & gritty" remark. I thought we were going to be taken through an entire year of medical school!
I ended up looking up Frances' OAS argument, which appeared in early 1960s (possibly 1960 itself? Although your post of 1953 likely aligns with his initial research timeline). Much of the B-cell research appear to have happened a few years after, with many research coming about during the late 1960s to the 1990s (and onward, really) if the timeline from this article is to be believed.
https://www.nature.com/articles/nri3801
And so that would really line up with the notion that antibodies and OAS were decided before much was known about B and T cells as we do today, and why there are many issues with what we are having right now.
I wonder if much of the talk of OAS has overridden people's conceptions about the adaptive immunity. It is, in essence, a requirement that the adaptive immune system rely on recall in order to tackle a pathogen that shares some similarities to prior ones. So now we have prior immunity recalling a response, and it's assumed to be immediately bad. I even remember reading a part of one of the first mouse studies on OAS where the researchers even commented that the recall would have been a good thing.
I also guess this is all a consequence of everyone just focusing on antibodies and nothing else. The whole immune system is complex and can't be boiled down to the antibodies sticking once, and if they continue to stick again.
I look forward to the Frances portion and see what you write about that!
That's a good link, thanks!
Burnet appears to have been the one ahead of the game in the 50s. In 57 he came up with clonal selection (affinity maturation) and negative selection for lymph cells as how antibodies are refined, pretty much nailed it.
When it comes to "immune imprinting" it definitely seems like a lot of scientists have lost the plot. We're supposed to remember viruses, that's literally the whole idea.
I'm still very naive to much of immunology, so much of this has been a really slow burn. However, there's always been a nagging feeling that just didn't sit right with me in regards to OAS. When I wrote about it months ago I didn't see your Substack at the time. However, framed my response around all of the responses to a certain person's Substack that appeared to serve as the progenitor of OAS on this site.
I'm just jokingly referring to this as the sin of OAS, or the original sin of OAS. Something along those lines.
I'm starting to think my friend who called all of this the frat guy presentation of the immunology world actually had it spot on. A lot of show but not much substance.
"The suggestion, in the context of SARS-CoV-2, that the Memory B Cells and Plasma Cells generated in reply to the Covid vaccine-induced spike proteins can somehow forbid the body from initiating a new immune memory response in any Germinal Center, anywhere, is without merit." So what you are saying is that OAS is not an issue, and the reason the vaccinated are getting covid multiple times and apparently getting sicker is due to something else?
I was getting this idea in hearing a study shared by Dr. John Campbell...my layman's interpretation is that the shots don't seem to be blocking new antibodies, the antibodies are just lesser...
https://wholistic.substack.com/p/evidence-of-immune-escape-geert-was
I also realize OAS is not ADE but how does ADE fit into this picture?
RE your theory that "antibodies are just lesser" the paper linked by Jim H above is right on the money, shows immune-suppressing IgG4 emerging after third dose.
Is this related to the idea that people getting mRNA vaccines are developing "spike protein tolerance" because the spikes are being produced too much, to the extent to which the body needs to downregulate the response to them to avoid autoimmunity?
This is really important to understand...I have many loved ones wanting to continue on the booster train and I'm hoping that Novavax won't have these problems because it does not use mRNA to generate the spikes.
That was my first guess but they find the class switching is not related to a change in T Cells, it seems to be in an uncharted territory. Might be more of an allergic response pathway.
I mean to me that specific mechanism is a funny idea (like imagine vax-spike-induced plasma cells in the bone marrow calling up your lymph nodes and threatening to get the whole staff fired if they touch anything else on the virus), and since that's what it would take for OAS to be true, OAS is by extension an idea without merit.
ADE is still a possible explanation for higher rates of infection, like there's https://www.nature.com/articles/s41586-022-04702-4 as far as true ADE, and then there's GvB's natural antibody interference theory which I think is more plausible and have mentioned in a few posts. And then RE reinfection there's the question of whether post-vax infection "corrects" the vax response by doing more than just throwing on new antibodies - does it program cellular immunity, including tissue resident T Cells etc.
I don't know about the vaxxed getting sicker - as with other stuff that's an anecdote that doesn't seem highly reflected here in California, but who knows if the shots were consistently manufactured / perserved here vs elsewhere
You have to remember that neutralizing assays never tell "which" antibodies stick around (literally!) and which ones do not. We just know how much are still sticking. That's why I wrote about the association between monoclonal antibodies and variants in my post from last week.
For example, we know that the E484K mutation in many variants led to a large level of loss of neutralizing antibodies, which tells us that many neutralizing antibodies require the use of the E484 amino acid residue to bind. If it mutates, they don't bind and fewer antibodies stick. However, when you look at an assay you just see how much are still sticking, not which antibodies and which epitopes are targeted. It's the relationship between the two that we have to remember when we look at an assay.
And so it could be that new immune responses aren't super robust, it may just be good enough to do its job with the prior old responses leading the charge.
With repeat illness, it depends on the timeframe. The Wuhan lineage are so different than Omicron that nobody with any prior immunity would be protected- the antigens are far too different to have a good recall, and so another response needs to happen. With Omicron from Omicron, my argument was that the variants may have been circulating together and popped up whenever a niche appeared in the immunity landscape. Because they were already around, we didn't need to wait months for a new escape variant to come around- we just needed everyone's immune system to be trained towards Ba.1. Then Ba.2 pops up and is different enough to escape the Ba.1 immunity landscape and then eventually we reach Ba.4/Ba.5. So there isn't necessarily a slow move towards other variants, but it was really a giant leap from Delta -> Omicron and we are just playing hopscotch in between each Omicron sub-lineage.
At least that's all my perspective. Plenty of holes in my perspective as well 🤷♂️