1/3 IgG4 conversion after XBB booster

Plus, combined visualization of studies to date, and study roll

A summary and synthesis of IgG4 studies to date (to be updated as more are added)

Before reviewing the new preprint looking at post-XBB-booster IgG4, here are two new resources which gather up previous (and future) IgG4 studies and combine their results into one graph:

Study index, and raw data for graph: https://docs.google.com/spreadsheets/d/1DEdwm9swrjwoHSiBWWGB3NLIicSMyJBKSmfJg4QhqHU/edit?usp=sharing

Graph:

Combining studies requires the blending of different vaccine and infection histories. For example, the dip in the “pre XBB booster” IgG4 ratio (from the new preprint) can reflect anything from a lower rate of 3rd-doses, previous infections, or Moderna vs. Pfizer mRNA vaccination (Moderna amplifies IgG4 conversion). I have limited this graph to those studies which measure antibody against the whole (Wuhan) spike protein, leaving out results for antibodies against the Receptor Binding Domain or the composition of B cells.

Still, the overall trend is clear: More mRNA, more IgG4.

A new preprint looks at post-XBB-booster IgG4

The preprint:

Jain, et al.

Background

For an introduction to the IgG4 issue, see, as always, my post from 2022. The tl;dr is that the B Cells that make antibodies to the spike protein after mRNA Covid vaccination begin, some point after the second dose, to switch irrevocably to a “model” of IgG that switches off the immune system’s attack of infected cells that have spike protein on the surface, replacing a normal antiviral response with a “tolerance” response usually induced by long term allergen exposure. (This doesn’t prevent the same antibodies from neutralizing free viral particles, and may not interfere with infected-cell-killing responses prompted by non-spike viral proteins.) As an added insult, IgG4 antibodies can form complexes with IgG1 antibodies, further increasing the overall portion of “dud antibodies” in the pool at a given moment.

A new study examining post-XBB-booster IgG4 is a bit exciting in principle, given that previous “replications” of the original findings by Irrgang, et al. have not kept up with the march of time — where are Covid vaccine recipients now, in terms of IgG4? Since this new mRNA formulation came out in September of last year, the results of this preprint add a good two years to the prior window of observation. (Before this, a few studies looking at B Cell dynamics have enabled a prediction of what would be observed — no or very little “refreshing” of the IgG1 pool after Omicron boosters or infections.)

The new study comes from Jens Wrammert and colleagues at Emory. Wrammert is a prominent name in the last two decades of American immunology research, though mainly for a failed attempt to unlock a universal influenza vaccine and “solve imprinting” (which is not a real problem; but even so, what does this new paper say of the problem in terms of the XBB booster? — that it is not occurring).

Participants in this study are a mix of prior vaccine and infection histories; all have had at least 2 mRNA vaccines before, some have also had other boosters, some have had infections before and after their original vaccination.

Results

Unsurprisingly, tolerance-inducing (anti-spike) IgG4 is still increasing as a portion of IgG1. As a portion of both types together (we do not care about IgG2 or IgG3), IgG4 represents almost a third of antibodies binding to the original-recipe Wuhan spike. The portion for antibodies binding to XBB, which is more interesting from the perspective of future real-life infections, is similar, and has been multiplied to a far greater extant than prior IgG1 antibodies.

Jain, S. et al. Fig 3 - with annotations.

Reasons for the greater increase in IgG4 against XBB could include that the antibodies most likely to increase at all are those which cross-react to XBB — which is to say, those antibodies made by B Cells that will be further “overstimulated” by exposure to XBB spike. Whereas, B Cells that do not cross-react to XBB are not further overstimulated and do not convert to IgG4 due to the booster.

Interpretation: Trend and variation

It would seem clear from Fig 3 that some vaccinees are, at this point, IgG4-dominant. Likewise, the “group IgG4 conversion level” before and after the latest booster is still lower than some individual results from circa dose 3 in Irrgang, et al. (the original IgG4 paper).

In that sense these results may be considered not too alarming. Mostly, the booster has raised the group IgG4 conversion rate by bringing prior “IgG4 stragglers” on board.

These group results therefore have ambiguous implications for any individual person (especially in light of the mixed bag of prior vaccine and infection events).

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