Kilian Schober Profile picture
Dec 22, 2022 13 tweets 4 min read Read on X
We observed an unexpected rise in IgG4 antibodies after repeated SARS-CoV-2 mRNA vaccination. This work is now published @SciImmunology. The 🧵👇 will point to my tweetorial of the original preprint as well as new data in the peer-reviewed version. 1/11science.org/doi/10.1126/sc…
Re-cap: There are 4 IgG subclasses dependent on the Fc part (so the antigen-binding Fab is the same). However, effector functions (antibody-dependent phagocytosis, complement deposition, cellular cytotox) are different. Also see preprint 🧵👇2/11
In the peer-reviewed manuscript, relative numbers (panel c) of IgG4 highlight that shortly after 3rd vaccination, about 20% of IgG is IgG4, which is further boosted through breakthrough infections (grey circles) at follow-up (FU) to up to 40-80%. This is very unusual. 3/11 Image
We wanted to be really sure about this. Next to confirmation of this class switch by single-cell RNA seq, we also looked at IgG subclasses of spike-binding memory B cells by flow cytometry. High frequencies of IgG4+ B cells are already present late after 2nd vax. 4/11 Image
So what? Fab function is unchanged. We, as many others, saw improved antibody avidity and cross-neutralization after 3rd vs. 2nd vaccination. However, Fc effector functions are indeed deteriorated (!). Next to phagocytosis, we now also report this for complement deposition. 5/11 Image
What does this mean for mRNA vaccination schemes? Our preprint had "gone viral" among some anti-vax circles, because it would supposedly show that mRNA vaccines are inducing "tolerance". This view is certainly too simplistic. mRNA vaccines have saved millions of lives. 6/11
Again, Fab functions like neutralization are fully preserved upon class switch to IgG4. So is the class switch irrelevant in terms of consequences on subsequent infections? We don't know. Fc effector functions could be critical for viral clearance (sterile immunity)... 7/11
...however, it is also conceivable that non-inflammatory Fc-mediated effector functions prevent immunological over-activation while virus is still being neutralized via high-avidity antibody variable regions. 8/11
Given the enormous potential of mRNA vaccines for the fields of infectious diseases, autoimmunity and cancer, the induction of IgG4 antibodies clearly requires further investigation. Deciphering the precise immunological mechanism underlying this class switch will be fun! 9/11
Special thanks go to first authors Pascal Irrgang (lab of Matthias Tenbusch), Juliane Gerling (lab of Thomas Winkler) & Katharina Kocher (our lab) @UniFAU. There couldn't be a better christmas present for them than this reward of their hard work. Here's us celebrating. 10/11 Image
We are also grateful to @BMBF_Bund @Covim_Netzwerk @dfg_public @DZIF_ and @EKFStiftung for supporting this work. Funders had no influence on the study design and data interpretation. Lastly, thanks go to editor @IforRWilliams and our 4 critical, but constructive reviewers. 11/11
That was quick. Colleagues from Lübeck, Germany, confirmed our findings on IgG4 induction long after second mRNA vaccination. Yes, mRNA vaccination, because with Moderna they see even higher levels of IgG4 than with Biontech/Pfizer. frontiersin.org/articles/10.33…
Image
Great Focus article @SciImmunology by @ShivPillai4 on our IgG4 study with some deeper considerations on IgG4 biology and potential functional consequences.

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More from @kischober

Jun 14
On my way to @badw_muenchen, and as often then finding time and inspiration to read stuff that I should know, but actually don’t. Here’s a short history of the discovery of the T cell receptor. 🧵
In 1982, @JimAllisonPhD, McIntyre & Bloch described @J_Immunol a molecule that is expressed on T cell lymphomas. Searching for immunotherapy targets, they noticed an antibody (Mab 124-40) bound T cell lymphomas (but not normal splenocytes!). It was disulfide-bonded, 2x40k m.w. Image
In T cells and thymocytes, a similar structure was present. It took a massively clonally expanded individual clonotype to discover a surface receptor with similar (but not identical) sister molecules that were specifically expressed on T cells. journals.aai.org/jimmunol/artic…
Image
Read 15 tweets
Mar 5
What would happen if you got vaccinated against the same antigen over and over again? In @TheLancetInfDis, we now report on a hypervaccinated individual from Magdeburg (HIM) who received 217 vaccinations within 29 months against SARS-CoV-2. 👇 1/19 thelancet.com/journals/lanin…
When, in 2022, the media reported about a man from Germany who received at least 90 vaccinations against SARS-CoV-2, we (as many others) wondered what kind of consequences such hypervaccination would have on the immune system. 2/19 Image
HIM underwent hypervaccination for private reasons outside of a clinical study context & against national vaccination recommendations. The public prosecutor of Magdeburg opened an investigation of HIM's case with the allegation of fraud, but criminal charges were not filed. 3/19
Read 20 tweets
May 9, 2023
Did you ever wonder what the avidity landscape of an antigen-specific T cell population is before antigen encounter? And how it's recruited as a polyclonal population into immune responses? I certainly did. Here's what we found, now out @ImmunityCP: authors.elsevier.com/c/1h2me3qNrUu3… 🧵/18
Before an organism "sees" an antigen for the first time, already hundreds of T cell clones exist that recognize this epitope. Upon antigen exposure, these precursors expand and differentiate, forming immunological memory. 2/18
In this process, clonal selection occurs & is thought to be driven by high-avidity T cell receptors. However, also low-avidity TCRs have been shown to be of relevance. But it's methodologically difficult to follow a polyclonal TCR repertoire from scratch & over time. 3/18
Read 18 tweets
Jul 11, 2022
NEW PREPRINT by the labs of Tenbusch, Winkler and ourselves @UniFAU. We made the surprising observation that later after 2° SARS-2 mRNA vax non-inflammatory IgG isotypes are coming up, which are boosted by 3° vax and/or breakthrough infections. This may be pretty relevant. 🧵 1/n
Early after (mRNA) vax, pro-inflammatory IgG1 and IgG3 isotypes are induced. This is well documented also by many others. Pro-inflammatory means good Fc-mediated effector function (phagocytosis, complement, ADCC). But: Late after 2° vax, IgG4 suddenly pops up. This is unusual 2/n Image
Late after 2x vax, IgG4 is only induced after 2x mRNA vax and not after heterologous or homologous vax involving adenoviral ChAd (Astra Zeneca). Therefore, this phenotype seems to be specific for mRNA vax and/or short time intervals between 1° and 2° vax. 3/n Image
Read 15 tweets

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