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The Florida doctor who died after getting the Pfizer vaccine likely had autoimmune thrombocytopenia triggered in him by the vaccine, and both the Nature article and this NYT article link to the same systematic review showing that infection with the live virus can cause it as well:
What do immunologists, molecular biologists and other experts make of these issues? How great is the risk with the conventional SARS-CoV-2 vaccines, which present the entire spike protein as antigen, of autoimmune reactions, or of the formation of ineffective antibodies (or even ADE)?
These issues surrounding antigen selection are the ones that are causing me the most to take a wait-and-see attitude toward the vaccines that have been released to date, more than possible allergic reactions to their ingredients, or reservations about their novel antigen delivery technologies. I’d appreciate thoughts from you or from any other experts.
Autoimmunogenicity in Covid-19, and via the vaccines?
ggongi - 2021-02-08 00:02:35
Dear Dr. Been,
Below are the questions I've had about the first-generation vaccines, which have been bothering me:
Why have all of the SARS-CoV-2 vaccine candidates approved to date used the entire spike protein as the antigen? It seems like all of the thought has been directed toward clever ways to deliver the antigen, but very little if any thought has been put toward antigen selection. My guess is that the entire spike protein was chosen as antigen to make the vaccines resilient to mutations; or because the designers were in a rush; or a combination of both reasons.
Alternatively, the vaccine makers thus far seem to have assumed that vaccines with the entire spike protein as antigen would produce mostly, or enough, neutralizing antibodies, and thus would not be subject to antibody-dependent enhancement (ADE).
But doesn't that beg the question? Isn't it merely an assumption that a sufficient number of the antibodies to the entire spike protein would be neutralizing? Without a full understanding of SARS-CoV-2's methods of infectivity, how would we know that most, or enough, of the antibodies produced against the entire spike protein are neutralizing, and not subject to ADE? Rather, it seems to me to be largely a matter of chance what type of antibodies (binding or neutralizing) would be formed when presenting the entire spike protein as antigen, and it would be dependent upon which epitopes of the antigen happen to be presented most dominantly to one's immune system.
I ask the above questions because I bookmarked the following paper last spring, and the issues it raises have been nagging at me ever since:
https://www.cambridge.org/core/journals/qrb-discovery/article/biovacc19-a-candidate-vaccine-for-covid19-sarscov2-developed-from-analysis-of-its-general-method-of-action-for-infectivity/DBBC0FA6E3763B0067CAAD8F3363E527#
The authors state that they analyzed the spike protein, and found that it has 78.4% similarity to human-like epitopes, and thus only 21.6% non-human-like epitopes. Further, they state that they selected as antigen for their vaccine candidate only the non-human-like epitopes relevant to SARS-CoV-2's methods of infectivity: i.e. the epitopes residing in the receptor binding domain (RBD), in the furin cleavage site, and in receptor binding sites outside of the main RBD.
Their reasoning for selecting as antigen only these epitopes was that “the immune system will be guided directly to the epitopes which are relevant to virus neutralization.” And further, since their vaccine presents only non-human-like epitopes, and only epitopes relevant to SARS-CoV-2’s methods of infectivity, the risks of: 1) autoimmune reactions and of 2) the formation of ineffective antibodies (and even antibody-dependent enhancement (ADE) on subsequent exposure to the virus) are reduced with their vaccine candidate, vs. the conventionally-designed vaccines, which all present the entire spike protein as antigen.
Alternatively, the vaccine makers thus far seem to have assumed that vaccines with the entire spike protein as antigen would produce mostly, or enough, neutralizing antibodies, and thus would not be subject to antibody-dependent enhancement (ADE).
But doesn't that beg the question? Isn't it merely an assumption that a sufficient number of the antibodies to the entire spike protein would be neutralizing? Without a full understanding of SARS-CoV-2's methods of infectivity, how would we know that most, or enough, of the antibodies produced against the entire spike protein are neutralizing, and not subject to ADE? Rather, it seems to me to be largely a matter of chance what type of antibodies (binding or neutralizing) would be formed when presenting the entire spike protein as antigen, and it would be dependent upon which epitopes of the antigen happen to be presented most dominantly to one's immune system.
I ask the above questions because I bookmarked the following paper last spring, and the issues it raises have been nagging at me ever since:
https://www.cambridge.org/core/journals/qrb-discovery/article/biovacc19-a-candidate-vaccine-for-covid19-sarscov2-developed-from-analysis-of-its-general-method-of-action-for-infectivity/DBBC0FA6E3763B0067CAAD8F3363E527#
The authors state that they analyzed the spike protein, and found that it has 78.4% similarity to human-like epitopes, and thus only 21.6% non-human-like epitopes. Further, they state that they selected as antigen for their vaccine candidate only the non-human-like epitopes relevant to SARS-CoV-2's methods of infectivity: i.e. the epitopes residing in the receptor binding domain (RBD), in the furin cleavage site, and in receptor binding sites outside of the main RBD.
Their reasoning for selecting as antigen only these epitopes was that “the immune system will be guided directly to the epitopes which are relevant to virus neutralization.” And further, since their vaccine presents only non-human-like epitopes, and only epitopes relevant to SARS-CoV-2’s methods of infectivity, the risks of: 1) autoimmune reactions and of 2) the formation of ineffective antibodies (and even antibody-dependent enhancement (ADE) on subsequent exposure to the virus) are reduced with their vaccine candidate, vs. the conventionally-designed vaccines, which all present the entire spike protein as antigen.
Now, if 78.4% of the spike protein's epitopes are human-like, then by injecting in our body an antigen that consists of the entire spike protein, as is the case with all of the vaccines to date, are we not running a high risk of training our immune system to form antibodies and mount other defenses against epitopes that have a high degree of similarity to epitopes found in human tissue?
This Nature article, published January 19, 2021, suggests such autoimmunity is the key to severe Covid-19:
"A way pathogens might trigger autoimmunity is if a part of them coincidentally resembles human cell components"
Doctor’s Death After Covid Vaccine Is Being Investigated
His looks like a very unfortunate case of the immune system forming antibodies against one or more epitopes on the spike protein that happen to be similar to one or more epitopes found on platelets or on the cells in bone marrow that make platelets.
So it seems like the vaccines can trigger autoimmunity in at least some cases. I'm keeping an eye on reports to see just how frequently this happens. When it does happen, it seems like it can be catastrophic, as in that doctor's case. Some or a lot of the 'allergic' reactions reported as a result of these vaccines may in fact be autoimmune reactions. I want to see how frequent, severe and long-lasting such reactions are. And with how much of a lag such reactions can occur.
What do immunologists, molecular biologists and other experts make of these issues? How great is the risk with the conventional SARS-CoV-2 vaccines, which present the entire spike protein as antigen, of autoimmune reactions, or of the formation of ineffective antibodies (or even ADE)?
These issues surrounding antigen selection are the ones that are causing me the most to take a wait-and-see attitude toward the vaccines that have been released to date, more than possible allergic reactions to their ingredients, or reservations about their novel antigen delivery technologies. I’d appreciate thoughts from you or from any other experts.
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Autoimmunogenicity in Covid-19, and via the vaccines?
ggongi - 2021-02-11 16:48:10
More people are developing ITP after getting the mRNA vaccines: https://www.nytimes.com/2021/02/08/health/immune-thrombocytopenia-covid-vaccine-blood.html But the press has not yet put two and two together, and have not yet explored just what it is about the spike protein antigen that is causing this autoimmunity to happen: 78.4% similarity to human-like epitopes. |