Thread by @kischober

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

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

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

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

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…

Great Focus article @SciImmunology by @ShivPillai4 on our IgG4 study with some deeper considerations on IgG4 biology and potential functional consequences.