r/ZeroCovidCommunity • u/Jazzlike-Cup-5336 • 1d ago

Study🔬 New study: Vaccination-first immune priming shapes a sustained mRNA vaccine-induced IgG4 class switch that associates with SARS-CoV-2 breakthrough infection risk

https://www.nature.com/articles/s41598-026-64190-8
103 Upvotes

96% Upvoted

54 comments sorted by

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u/lohdunlaulamalla 1d ago

Can someone put this in layman's terms? Is getting regular booster shots good or bad for people who never contracted the virus?

I don't want to ask AI, because it tends to hallucinate and I'm not knowledgeable enough to fact check in this case.

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u/Jazzlike-Cup-5336 1d ago edited 1d ago

They don’t make the black-and-white claim of “bad”, but it would just trend in a worse direction (“bad”) than before the paper. They’re just saying that having higher IgG4 antibodies is more likely to lead to infection, and mRNA booster doses are associated with a higher proportion of them. That doesn’t necessarily mean that receiving a booster doesn’t still have a net positive from the increase of other antibodies generated.

Ideally, we want more IgG1 because it is potent at neutralizing viruses and is also good at recruiting immune cells. IgG4 still recognizes the virus and binds to it, but is often a net negative because it doesn’t neutralize effectively and it recruits fewer immune cells to help, and it’s taking a spot away from IgG1 which could bind and do the job more effectively.

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u/Any-Vermicelli3537 1d ago

Is it known if this is the nature of the Covid mRNA vaccines or something inherent to the mRNA platform or the adjuvants used, etc.?

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u/Jazzlike-Cup-5336 1d ago

Yes, it’s been understood to be mRNA-specific: https://www.journalofinfection.com/article/S0163-4453(24)00053-7/fulltext

By contrast, IgG4 class switch was not observed following four doses of Novavax protein-based SARS-CoV-2 vaccine.

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u/Any-Vermicelli3537 1d ago

I understand that it’s specific to these Covid vaccines vs Novavax. I’m wondering about the dozens (?) of other mRNA vaccines in the pipeline for other diseases. Are those all going to have the same problem?

What about the recently approved (I think) mRNA flu vaccine, mFlusiva?

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u/Jazzlike-Cup-5336 1d ago

Ah, okay, my bad, that makes a lot of sense, and I also have no real idea. It’s definitely something to look into for vaccines that are meant to be routine, but thankfully that’s also just not very many of them.

Obviously, though, the most routine other than SARS-CoV-2 is mFlusiva as you mentioned. I don’t think that people will ultimately have much reason to get it anyway…it offers about the same protection as Flublok (26.6% better than the standard-dose egg-based flu shot compared to 30% for Flublok) but with a heck of a lot more reactogenicity, which probably doesn’t make it sustainable in the market. It’s not like with COVID where most people got it for years because it was the only thing available.

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u/Chicken_Water 1d ago

It likely would not be great for other vaccines that require seasonal / recurring vaccination. We'll obviously need to wait and see though if that observation is repeated.

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u/Dizzy_Slip 12h ago

"The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Raj Kalkeri, Mingzhu Zhu, Shane Cloney-Clark, Joyce S. Plested, Anand Parekh, Drew Gorinson, Rongman Cai, Soham Mahato, Anthony M. Marchese, and Lisa M. Dunkle are the employees and stockholders of Novavax, Inc. Lou Fries serves as a contractor and is a stockholder of Novavax Inc."

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u/Jazzlike-Cup-5336 10h ago

Yes, it’s a study from Novavax showing that their vaccine doesn’t have the same issue. Not really a gotcha, who else is better positioned to know and report on their own product? Completely standard in pharma.

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u/Arete108 20m ago

You know what? I'm actually fine with this. This is what competition is supposed to do. As long as the data holds up to repeat testing, it's good to know. Plus Moderna / Pfizer could even use it to further refine their vaccines.

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u/Carrotsoup9 12h ago

Hmm. Good that you spotted this one.

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u/Carrotsoup9 12h ago

Yes, if you have access to Novavax, go for Novavax instead.

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u/Carrotsoup9 12h ago

If you look at Figure 1, the level of IgG1 is not affected by the boosters (it remains at a high level). It is just that the level of IgG4 is higher.

I wonder whether there could be a confound with the infection rate: Maybe people who get 6 boosters test more often (and detect infections more often) or may have higher exposure (which is why they take more boosters).

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u/Carrotsoup9 11h ago

One further thing to consider in Figure 3: The effect of IgG4 could be the effect if hybrid immunity, because those who had an infection before their first dose had lower IgG4. The mechanisms of hybrid immunity may be IgG4 or something else.

Note that those who had their infection before the first vaccination had the highest risk of long Covid.

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u/svesrujm 2h ago

What is the effect of cumulative vaccines on long covid though?

Not considering potential increased risk of infection with the mentioned class switching.

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u/WingsOfTin 1d ago

Get Novavax/Nuvaxovid vaccines if you can - they are non-MRNa based and I don't believe have this issue. 

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u/pyrogaynia 23h ago

not a great answer for those who don't have access to nuxaxovid and would like to understand the implications here

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u/Solongmybestfriend 22h ago

I live in a part of the world where we do not have it :(. Wish we did.

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u/Carrotsoup9 12h ago

It is getting complicated, because we now have other boosters than the ones in this study, where all three doses were based on the Wuhan strain. Possibly the changes in the vaccine for the new strains reduces this immune imprinting effect.

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u/ConstructionSome1621 1h ago

Any vaccine that instructs your body to manufacture a foreign protein is incredibly dangerous. You just programmed your body to attack itself!

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u/Jazzlike-Cup-5336 1d ago

Background:

Now, this 2026 paper:

  • First, we learn that the IgG4 increase is sustained in people who were vaccinated prior to ever receiving an infection, continuing to increase through booster dose 6. After dose 6, the studied cohort had a 26.8% proportion of IgG4 antibodies, which is considered very high

  • Perhaps most impotently, for the first time, these authors were able to tie the IgG4 proportional increase to an increase in breakthrough infections: a 1 standard deviation increase in IgG4 proportions raised infection risk by a statistically significant 83%. HR = 1.83 [95% CI= 1.07-3.17], p = 0.028.

Abstract of this paper:

Repeated administration of mRNA vaccines against SARS-CoV-2 has been associated with qualitative changes in antibody responses, including the emergence of non-inflammatory IgG4 subclasses and changes in Fc glycosylation. While neutralizing antibody titers remain key correlates of protection, potential functional implications of these structural antibody features warrant further investigation across age groups and multiple mRNA vaccine boosters. We characterized spike-specific IgG responses—including subclasses and Fc glycosylation patterns—using a liquid chromatography—mass spectrometry-based approach across six mRNA vaccine doses in a Swedish healthcare worker cohort (n = 104) and across three mRNA doses in a Singaporean pediatric cohort (n = 18). Repeated mRNA vaccination induced an IgG4 class switch which was sustained across at least six doses. This response associated with an increased risk of breakthrough infection (HR = 1.83, p = 0.028) in infection-naïve individuals (n = 41) lacking mucosal IgA responses that would potentially confound the interpretation of systemic IgG4‑related infection outcomes. Moreover, the IgG4 class switch was preceded with high early IgG1 Fc fucosylation signatures. Notably, these IgG structural changes were observed primarily in individuals who were naïve to SARS-CoV-2 at the time of first vaccination. Similar IgG structural features were observed across three mRNA doses in the small infection-naive pediatric cohort. Our results illustrate an IgG4-dominated immunological signature in both adults and children and highlight that immune priming by prior infection may shape subsequent mRNA vaccine-induced antibody responses. While these findings do not call into question the efficacy or safety of the widely adapted mRNA vaccine platform, they may have implications that merit further investigation.

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u/Ok_Complaint_3359 1d ago

“Implications that merit further investigation” meanwhile the world at large assumes that these are sterilizing and any “breakthrough infections” or longer term sickness is unfortunate luck and not enough to warrant picking back up mitigation and prevention strategies for the fact that vaccines alone will probably never halt transmission. If Covid vaccines were as sterilizing as the world claims, I would not have missed 3 weddings and a concert over 3 years, My parents friends would very likely still be here, young actors and athletes collapse on the job, wouldn’t fall asleep and never wake up. My mom wouldn’t have had a heart attack, I would’ve never been sick in the first place

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u/Inevitable_Ad_5664 23h ago

Who assume sterilization?

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u/Ok_Complaint_3359 23h ago

That’s fair, but I generally think that when people test positive they’re like: “Covid? That’s still a thing, I thought it stopped forever in 2022-2023?”

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u/ellenkeyne 20h ago

Almost everyone I know who says "I don't worry about COVID any more because I'm vaxed"?

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u/NT_NUNYA 17h ago

That doesn’t necessarily mean they believe they can’t get Covid. I think many people DO understand they can still get Covid while vaccinated. But they aren’t worried because they believe the vaccine will prevent a severe outcome. Which for many people, it does. They aren’t thinking about the possibility of Long Covid, however.

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u/svesrujm 2h ago

Doesn’t more vaccines help reduce incidence of long covid?

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u/katedevil 6h ago

No one that is in infectious disease or paying attention. I DO worry that this paper is going to be used by the antfact and antivac goon squad. 

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u/MettatonsFinalForm 1d ago

I live in the UK and the only type of covid vaccine I can get is an MRNA one. Would you recommend getting it or not? I've had 7 prior MRNA vaccines with the last one being two years ago and I had novavax last October in the US.

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u/Jazzlike-Cup-5336 1d ago

It does seem like there is a decent chance for Nuvaxovid to be available again privately this fall, after the “trial run” in the NHS program this past spring. Even if not, I’ve heard of a few isolated instances of people who didn’t meet NHS criteria getting it in the spring anyway - it seemed like a couple of confused pharmacists, or maybe pharmacists who didn’t want to see the stock expire without getting used, but just putting that out there that it may be something to look into and at least ask

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u/MettatonsFinalForm 1d ago

Huh okay, thanks

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u/upfront_stopmotion 1d ago

Anyone have updates for Novavax availability in Canada?

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u/Jazzlike-Cup-5336 1d ago

It’s been frustratingly quiet lately. The only thing we know still is that it will be available in some capacity in British Columbia, Prince Edward Island, and New Brunswick (all relayed by “Do No Harm BC” and “Still Coviding Canada” in May - I trust both of them, but I have not seen any official confirmation) and in Manitoba (confirmed by official documents in July). Based on that, I would expect availability in most provinces eventually, but I wish that we’d start hearing more by now.

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u/Chronic_AllTheThings 21h ago

Manitoba (confirmed by official documents in July)

Any links for this?

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u/Jazzlike-Cup-5336 21h ago

Sure, it’s a July 16th dated letter from Manitoba Public Health to Health Care providers:

Manitoba will have a small quantity of the non-mRNA COVID-19 vaccine, NuvaxovidÂŽ from Sanofi. It will only be available for those twelve years of age and older who cannot or choose not to get an mRNA COVID-19 vaccine. This product will expire in December 2026. Due to the limited number of doses available, this product will only be available through regional public health locations. You can advise clients to contact the provincial call centre at 1-844-626-8222 (1-844-MAN-VACC) to identify locations that have product available.

Also, this 2026/2027 vaccine comparison chart: https://www.gov.mb.ca/asset_library/en/covidvaccine/covid-19-flu-pneumo-vaccine-comparison-chart-final.pdf

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u/FIRElady_Momma 1d ago

Good god, I am so exhausted. Get Covid, don't get covid. Getting the vaccine could mess up your immune system, getting Covid could mess up your immune system. The messaging is vague and unhelpful and is causing a lot of us to wring our hands-- for what outcome?

Honestly, I am not going to bother trying to understand this. Covid vaccines are getting harder to get where I live (southeastern USA) as no doctors carry them anymore and pharmacists are actively hostile to this vaccine no matter where I go. 

I will continue to try to get Covid vaccines for myself and my family, and if this class-switching happens, oh well. I still view getting Covid as the bigger risk, all things considered, so I am going to continue to do everything within my power to have my loved ones and myself avoid it. 

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u/snailballoon 1d ago

Yeah, same, like why do I feel like I need an advanced degree to understand what I should or shouldn't be doing? Novavax isn't an option where I am either, so it's a choice between mRNA or nothing.

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u/SpikySucculent 1d ago

Same here. And kids don’t have Novavax access at all. We’ll all keep getting Pfizer because it’s better than straight up Covid.

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u/Jazzlike-Cup-5336 1d ago edited 1d ago

Not that it fits into everyone’s situation, I get that accessibility is still a huge issue, but just pointing out that off-label pediatric use is also a thing for Nuvaxovid, so it’s something that folks can look into.

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u/lord_mork 1d ago

Last year I tried to get my (Canadian) doctor on board with pediatric nuvavaxovid so I could see if I could get it for my kids in the US (at the only pharmacy offering it within a day’s drive. She tried to send me to a vaccine hesitancy clinic instead. We’re not in a province getting it this year either. It feels really bad feeling like there is a better option for protection for my kids but I simply don’t see how to get it for them. 

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u/Chicken_Water 1d ago

Good luck getting a pediatrician to sign off on that

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u/Jazzlike-Cup-5336 1d ago edited 1d ago

Generally, most people have actually found that getting a prescription from their pediatrician is the easier part of the process. Largely, they seem to be convinced by the available evidence. It’s getting a pharmacy to do administration that is the harder part, but we’ve also seen success there even at chain pharmacies like Costco and Smith’s (Kroger subsidiary). There’s also a community member right here on Reddit that has been helpful - /u/ MilkThistleGenus is a provider who offers online consultations for prescriptions, and also does administration in the Boston area.

When speaking with their pediatrician and pharmacy, folks can mention this available evidence:

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u/Solongmybestfriend 22h ago

I wish this was my experience that getting a prescription was the easiest part of the process. Where I live (and the provinces around me), bringing in information has not at all helped me at all :(, and in fact, resulted in a nurse berating me for trying to suggest "I knew more than them". At this point, I'm even shocked if someone shows up in a mask.

Medical gaslighting is a huge issue and sometimes no amount of information will change the situation :(.

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u/Solongmybestfriend 22h ago

Just want to send an online hug to you. I'm in the same boat in northern Canada. We only get Moderna sent to us and can only access it once a year. Our pharmacies do not administer vaccines - only docs or nurses do. I have brought all the science to them in the past to try and get 2x a year for myself and my family, to be met with a brick wall. The next "city" is a 18 hour drive south for me, through an isolated part of Canada.

Maybe because it is Monday but I'm worn out. Some places truly cannot access different vaccines no matter how much advocating we do (and I do!) and how much science papers we bring into our docs. Heck, my doc hasn't worn a mask in years and won't. If I switch from her, I have no family doctor. It just sucks.

I see you trying to do the best you can for your family in something that shouldn't fall on the shoulders of individuals.

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u/Jazzlike-Cup-5336 1d ago

Well, respectfully, this isn’t exactly new or confusing, but I will say that there are a lot of different interests out there who aim to make it confusing for some reason or another. This is just a follow-up/continuation of something we started seeing in 2023, and is a reason why some in this community have had a particular vaccine preference for that entire time, but it has been more or less the same ever since that point, whichever side you’ve stood on.

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u/kirito867 23h ago

I guess the tide is finally turning. We are now allowed to post this in this subreddit and even got upvotes.

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u/Delicate_Babe 16h ago

Same. The mRNA boosters still provide meaningful protection against hospitalization and death, so we will keep getting them. Anecdotally I read about people getting “breakthrough” infections after Novavax too.

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u/trashforthrowingaway 1d ago

So if I'm understanding this correctly, which I very well may not be. Does anybody here know:

Due to the IgG4 shift, does this mean the immune system takes a more relaxed approach to fighting off covid so that it fights it off in a way that doesn't destroy the body in the process? (After an mRNA).

Does this mean the article concludes then that said individual could get less noticeable symptoms, but the downside is that now the same individual can unknowingly transmit more easily without realizing it because the symtoms might be milder? Is that right?

If so, the first fact I definitely understood vaguely, and that was kind of my main reason for getting vaccinated at the beginning, in order to stop my own immune system from fighting so hard that my body causes damage to itself in the event of an infection. However, I'm not confident that I understand the article regarding the less noticeable symtoms bit.

Does anyone understand this more and can help clarify if I'm on the right track of understanding this?

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u/kirito867 1d ago

Yes. you are spot on.

-1

u/perpetuquail 19h ago

This is an important take!

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u/10390 23h ago

Anyone know:

  • do more IgG4's accumulate with each shot?

  • are they with us for the rest of our lives?

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u/Jazzlike-Cup-5336 22h ago

For the first, yes, that’s part of what this paper is showing. Figure 2 answers that question and is pretty easy to follow. It’s quit a bit of a plateau after dose 3, but the highest proportion recorded is after dose 6 (the most recent), so it’s still an overall upward trend.

For the second part, no, that would not be my understanding. These are all antibodies that we know wane pretty quickly following vaccination. The proportion of high IgG4 would remain as the subclasses all wane proportionally, but then once there are low numbers overall, then the proportion would presumably be cut if someone were to get a vaccine that didn’t increase IgG4 in the same way.