Final insight into the IgG4 farce

Even with seven doses, IgG4 levels plateau at where they were in original studies

Introduction (skip if simply interested in the new results and some theoretical discussion).

It is pretty clear, five years later, that most health-scares regarding the experimental mRNA Covid vaccines — ideas of covert harms beyond initially experienced injuries — have failed to pan out in any perceptible way among their recipients, aside perhaps for cancer (but we may still be another five years out from having any statistics to show it). Among said health-scares, the one most surprising to turn out to be seemingly harmless is perhaps the aberrant, widespread development of pro-“tolerance”, IgG4 antibodies to spike protein after the second dose, which was reported in pre-print in mid-2022 (see my original post if you would like) and subsequently confirmed in multiple published studies.

In short, the IgG4 “bombshell” was something totally unique to mRNA vaccination, almost universally an outcome of it within the first six months, potentially (and later confirmed to be) irreversible, and carrying obvious theoretical disadvantages to immune responses to future infections among the vaccinated. But a new study appears to confirm that the whole thing was a nothing-burger. Since the story was the topic of my most popular post, I obviously ought to publish a report on this “news that there was no news all along,” even if doing so is hardly an exception to the fact that everything about the vaccines is now old news.

IgG4 after mRNA vaccines still has safety implications for future targeted pathogens — but it seems too late to still be worrying about SARS-CoV-2 manifesting some awful disease enhancement among the vaccinated. So, “what ever happened” to that scary IgG4 stuff? If it turned out to be irrelevant all along, then, uh, why?

Tune in at 6:30! Mundanely satisfy your mild curiosity!

The new results

The new study, Sano et al., reports on IgG4 dynamics in 19 healthcare workers whose mRNA antibody responses were previously reported up to the days of XBB boosters, but now have been tracked up until dose 7.

Sano, K. et al..

The results are simply that… nothing really changes after the initial IgG4 explosion of the second and third doses! The initial “wave” of class-switching B cells makes its home in the roster of anti-spike antibody-producing cells as if possessed by a mad fad sure to sweep up all the others, only for it to remain contained to the first wave, as if all the “normal” cells develop an immunity to the craze (initial converts never go away, but they do not “infect” the rest of their kin).

This study demonstrates that S-specific IgG4 levels plateau after the third COVID-19 mRNA vaccination and remain stable through the seventh dose. Although previous reports have raised concerns regarding progressive IgG4 elevation and potential immune tolerance following repeated mRNA vaccination [3], [4], our findings indicate that IgG4 class switching does not progress indefinitely.

The paper is short and does not appear worth paying for access, so I will just use a simulated mock-up of the reported result:

Good news — IgG4 isn’t going to spell accidental future doom for the mRNA Covid vaccinated! But… why?

Wait but how? (Discussion)

What happens to halt the response which starts off so strongly among the first wave of “converts” — why do remaining IgG1 cells in the anti-spike B cell roster not respond the same way to future boosters? Why, ironically, do these cells develop a “tolerance” for future encounters with mRNA-generated spike (by not developing the literal IgG4 tolerance response)?

The plateauing of IgG4 class-switching suggests that affairs reach an equilibrium after a certain threshold; I have already been thinking this must be the case just because Covid vaccinated people haven’t developed any mortal infection-enhancement effect over the last three years. The presence of high (but not dominant) IgG4 antibody levels must relieve the over-stimulation effect of (presumably) excessive mRNA-derived spike in future boosters.

A plausible cause for this is that IgG4-switched cells ironically become more avid responders to future encounters with spike, essentially leaving the IgG1 share behind in future “fights” by possessing more refined receptors and antibodies to begin with (they have more somatic hypermutation¹ in general, meaning they probably bond more avidly) and staying more up-to-date with variant spike boosters (even more SHM, reinforcing the first effect; as observed by Jain, et al. in the case of the XBB booster). The IgG1 faction is “left behind” once the IgG4 share is high enough to have the “first pick” at binding to spike, and thus no longer receives enough stimulation to join the elite (whether or not that stimulation is partially mediated by T cells).

IgG4 does, when binding to spike, dampen immune cell- and complement-mediated destruction of cells that are transfected with mRNA or infected with the virus (those helpful antibody functions essentially being turned off by class-switching), but it is not otherwise “defective” in binding to spike and, in the latter case, neutralizing the virus (in theory). Rather than dropping out of the hunt due to over-stimulation as would be intuitive, IgG4 cells become the “winners who take all” of future over-stimulation.

1. It’s what you think it is, modifying the design of antibodies to stick even better; this is how B cell populations specific for a given antigen also diversify genetically with different binding targets and antibody effectiveness.