Immune system fatigue from repeated boosters?

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Wm. Stewart

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Dec 27, 2021, 7:57:58 AM12/27/21
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Hi folks, I came across an interesting exchange on the Askscience forum on Reddit, copied below.  Unfortunately, the forum moderators quickly locked the thread from further posts, likely out of concern the information might reduce willingness to vaccinate.  Now, I am double vaccinated plus boosted with the Pfizer vaccine, and as previously communicated am a big vaccine supporter.  However, I know that scientists are very, very human, and susceptible to the same human weaknesses as everyone else, particularly to the temptation to group think, and resentment of being challenged.  While the risk might be small, the potential for harm if there are issues with this vaccine or the way it is prescribed could be very large.  Therefore, the existence of this mailing list, to help provide an outlet to explore any potential issues with this very new situation and technology.  Any expert thoughts on the concerns outlined below?  Please forward to others in your network that might also have knowledgeable feedback. 

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https://www.reddit.com/r/askscience/comments/rnpcoy/why_do_some_israeli_scientists_say_a_second/

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Why do some Israeli scientists say a second booster is "counterproductive," and may compromise the body’s ability to fight the virus? Israel recently approved a fourth dose for the vulnerable citing waning immunity after the first boost. Peter Hotez endorsed a second boost for healthcare workers in the LA Times. This excerpt confuses me though:

Article: https://archive.md/WCGDd

The proposal to give a fourth dose to those most at risk drew criticism from other scientists and medical professionals, who said it was premature and perhaps even counterproductive. Some experts have warned that too many shots eventually may lead to a sort of immune system fatigue, compromising the body’s ability to fight the virus.  A few members of the advisory panel raised that concern with respect to the elderly, according to a written summary of the discussion obtained by The New York Times.

A few minutes googling didn't uncover anything. I'm concerned because I heard Osterholm mention (37:00) long covid may be the result of a compromised immune system. Could the fourth shot set the stage for reinfection and/or long term side effects? Or is it merely a wasted shot?


I hold a PhD in immunology and work in a lab studying mechanisms of antibody production after vaccination.

The primary mechanism I hear about is something called "original antigenic sin." It's the concept that if you immunize with a protein of 3 parts (let's say A, B, C), the immune system learns to respond to this. If you then come back and immunize with something similar but slightly different (A, B, D), the immune system dominantly responds against A and B, and suppresses responses against D.

In the context of COVID, the worry is that we're still re-immunizing with the original spike protein (A, B, C in my earlier example), which could lock in that specificity and keep it from responding as well to Omicron or an Omicron-specific vaccine later (A, B, D).

I’m also an immunologist, and my postdoc was on immune exhaustion. The fatigue mentioned in the quote differs from original antigenic sin. The concern is that the immune cells will get worn out and few stem cell memory cells remain to work with boosters. I’m more familiar with T cells, cancer/chronic infection, and checkpoint inhibitors but the same logic likely holds for B cells.

OAS is definitely a factor of concern, although the quote may not have been addressing it specifically.

Generally speaking, B-cells don't deal with fatigue in the same way as T, since chronic antigen exposure can induce differentiation to long-lived plasma cells. A non-germinal extra follicular response definitely burns itself out, although it can seed memory cells for later.

Would you think that 4 doses (and presence of transient antigen from the vaccine for all of about 8 total weeks) would be chronic enough to induce exhaustion? I've always thought of it in the context of years-long responses, but it's not my field.

The takeaway in my mind is that the breadth of the quoted statement holds even more because of the number of "exhaustion" or mechanisms of poor response that can exist, even if the person being quoted wasn't referring to them specifically.

Thanks for this insight.

B cells and the nuance of recall responses aren’t my specific expertise either. Wish I could get some former colleagues on this thread who would know. In the meantime Shane Crotty, Alessandro Sette, and Chris Goodnow are world experts and sometimes speak publicly on such topics.

FWIW, I don’t think a 4th dose is likely going to cause an issue. However dosing every 3 months will eventually have negative consequences on long term immunity. Thus the scientific concern for too frequently dosing is something I considered. I don’t know what dose will tip that risk/ reward balance for a particular group.

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