Guest Post — By Edward Nirenberg: mRNA Vaccines and Antibody Induction

Taylor Nichols, MD
4 min readDec 22, 2022
COVID-19 Spike Proteins

So this paper in Science is an interesting paper with important findings that I think merit discussion:

Class switch towards non-inflammatory, spike-specific IgG4 antibodies after repeated SARS-CoV-2 mRNA vaccination

Here’s the gist: everyone thinks of neutralization when it comes to antibodies (that is — stopping viruses from infecting cells) and while that’s important, that’s not all that antibodies do. Antibodies also signal to other components of the immune system to instruct their responses, and this depends on many factors.

One of these is the antibody class (isotype) and some antibodies also have subclasses (IgG isotype in humans has IgG1, IgG2, IgG3, and IgG4). You can have the situation where a given pair of antibodies recognizes the same exact antigen but has different classes or subclasses and thus produces a different effect inside the body. For example, IgG1 and IgG3 are generally considered promoters of inflammation, which as the authors point out can be very important in controlling viral infections.

IgG3 in particular is a relatively rare subclass and has a very flexible hinge that makes it better at binding two sites at the same time (called bivalent binding) and also activating proteins in the blood called complement which can recruit other components of the immune system to respond to an infection. In contrast, IgG4 is a bit of a mystery but is known to be much less potent in eliciting these effector functions than either IgG1 or IgG3.

In fact, in allergen desensitization therapy, the presence of IgG4 is correlated with the successful induction of tolerance to the allergen and IgG4 is sometimes seen with immune responses to antigens we are repeatedly exposed to (as is the case here with mRNA vaccination after 3 doses but notably not 2 and not with mixed series).

So the big question that we are left to wonder here is what this means — is this good, bad, or neither?

We don’t really know yet — but the authors note that the importance of effector functions in COVID-19 is well established and that in a retrospective study of Brazilian patients, those exhibiting a response to SARS-CoV-2 enriched in IgG4 had worse outcomes.

Taylor Nichols, MD

Humanist. Emergency Medicine and Addiction Medicine Physician. Health policy enthusiast. Views are my own. (He/Him)