Thread by @johnjljacobs

Time for a deep dive into SARS-CoV-2 immunology after vaccination and infection. I’ll try to explain it also for non immunologists.
New observation: Booster mRNA vaccines induce antibody switch to IgG4, what does this mean?
science.org/doi/epdf/10.11…
pubmed.ncbi.nlm.nih.gov/36548397/
1/

It is known that immune responses could either protect against disease or exacerbate disease.
Early non-neutralizing, afucosylated IgG1 antibody responses are associated with COVID-19 severity.
pubmed.ncbi.nlm.nih.gov/35040666/
pubmed.ncbi.nlm.nih.gov/36385627/
2/

Previously it was shown that the afucosylated IgG1 antibodies are only found after the first vaccination.
ncbi.nlm.nih.gov/pmc/articles/P…
ncbi.nlm.nih.gov/pmc/articles/P…
3/

Evidence for enhanced efficacy of afucosylated therapeutic IgG1 in vivo in antibody dependent cellular cytotoxicity by macrophages or neutrophils.
pubmed.ncbi.nlm.nih.gov/35844552/
4/

IgG4?
B-cells make antibodies and during affinity maturation the type of antibodies changes – it matures too. Different antibodies have different functions.
It starts of with IgM (coded by μ) and then switches with stronger binding antibodies to IgG1-IgG4 (γ1-
5/

IgA1 (α1), IgA2 (α2), and IgE (ε). The IgAs are mucosal antibodies that could protect from infections, IgE is known from type 1 (acute) allergy, but what is the difference between those different forms of IgG?

That raises some questions on the role of IgG4 in COVID-19.
6/

The authors note a reduced capacity of the spike-specific antibodies to mediate antibody-dependent cellular phagocytosis (by neutrophils) and complement deposition. #neutrophils will be less activated by IgG4 antibodies.
7/

IgG4 reduces exacerbations of immune reactions e.g., by IgE, and thus unwanted immune responses. IgG4 might be predicted to have similar effects than dexamethasone that saves lives of patients at the ICU. researchgate.net/publication/32…
8/

Is less neutrophil activation a good or a bad thing for immunity against COVID-19?
Another study shows that the activation of myelopoietic responses #neutrophils is associated with disease severity.
pubmed.ncbi.nlm.nih.gov/36208629/
9/

The switch to IgG4 would fit with the contradictory results seen after the fourth vaccine dose. The 4th booster increased antibody titers but less than earlier boosters, yet was effective in reducing the rate and severity of disease.
pubmed.ncbi.nlm.nih.gov/36367927/
10/12

Thus, the immune response seems to become less harmful for the person and more effective against the virus with subsequent vaccinations and class switching from IgG1 to IgG4 might be part of this.
11/12

The route in immune maturation after repeated mRNA vaccination would be
IgM -> IgG1 afucosylated -> IgG1 fucosylated -> IgG4 with
-less activation of neutrophils
-Less severe disease

However this does NOT occur after infection & other vaccines.

@UnrollThread

It should noted that this thread completely ignores the cellular immune system which might be more important in protection from disease.

@UnrollThread Updates to my 🧵
afucosylated IgG promotes inflammation by lung macrophages
pubmed.ncbi.nlm.nih.gov/33979301/
And is a prothrombotic stimulus for platelets
pubmed.ncbi.nlm.nih.gov/34315173/

unrollthread.com/t/160637570838…

https://twitter.com/johnjljacobs/status/1606379212369121280

afucosylated IgG is transient up after mRNA vaccination, but remains high after infection.
The latter could be a mechanism of excess mortality by thrombosis after infection.