Something wicked this way comes (and by something, I mean mRNA immune system dysregulation)

Why the paper reporting an explosion in IgG4 antibodies after the mRNA boosters is so unsettling - in a hopefully easy to understand Q+A

Hope you enjoyed the last week of 2022… and now back to business.

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Time for a story in Q+A format. Why?

By now, you have probably heard about the Science Immunology paper showing that people who have received mRNA Covid vaccines produce more of an unusual antibody called IgG4 over time. A number of mRNA skeptics, including me, wrote about it last week.

But the reasons why the paper is so troubling may still not be clear. So here’s a (with luck) digestible explanation, starting with what is probably the most important question: what’s the worst-case scenario?

1: What’s the worst-case scenario?

Glad you asked.

The worst-case scenario: the mRNA shots lead to a doom loop, robbing vaccinated people of a crucial immune system tool against the coronavirus in a way that worsens with each new infection.

Thus, over time, the average severity of Covid infections will increase. People will take longer to get better once they’re infected. Hospitalizations and deaths will rise. The health-care system will come under worsening strain.

Oh, and some people may suffer nasty autoimmune side effects too, including pancreatitis, kidney disease, and even aneurysms.

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(ALL THE NEWS YOU NEED… EVEN IF YOU WISH YOU DIDN’T.)

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2: Is that all?

Not quite. The truly worst-case scenario would come if those changes combine with a new, more dangerous Sars-Cov-2 variant that our weakened immune systems cannot clear.

3: Seriously? How likely is all that?

Yes, seriously.

How likely? No one knows. The good news is that we are probably relatively safe from a more dangerous variant as long as Omicron subvariants predominate. Since Omicron first appeared in late 2021, it has gone through many mutations but remained less dangerous than the original or Delta variants.

As for the “doom loop?” It is probably not very likely, but does “not very” mean 3 percent chance? 20 percent ? 40 percent? Anyone who claims to know is lying. We know much less about the immune system than we pretend, and even less about how these specific changes might affect people in the long run.

As the researchers who found this anomaly noted, it has not yet been proven to cause worse disease in the people it affects. But it hasn’t been disproven either. Researchers simply have not looked at real-world outcomes in enough people who have these changes to know.

4: So what are the changes again?

Our immune systems make antibodies against “antigens,” invaders like the coronavirus. Those antibodies attach to the antigens and play two crucial roles - they “neutralize” them by keeping them out of our cells, and they recruit other parts of the immune system to destroy them.

Vaccinations like the mRNA shots accelerate this process by pre-exposing people to the antigen, so that our bodies know how to respond to it before they are infected. The mRNA shots do so by causing our cells to make a part of the coronavirus called the spike protein. They are very effective at making us make spike proteins. In response, our immune systems make very high levels of anti-spike protein antibodies.

5: That’s good, right?

Well, yes and no. We clear those vaccine-generated antibodies much more quickly than “natural” antibodies we make in response to infection. This fact became clear within months of the original two-dose vaccination series. Thus the push for boosters, which (briefly) cause another rise in antibodies.

But the Science Immunology paper showed something else, something unusual and unexpected. People who have received mRNA shots make more of an antibody called IgG4, which doesn’t try very hard to destroy the invaders. That process accelerates sharply in people who have received a booster, a third shot.

It accelerates further in people who are infected after being jabbed. Thus the potential doom loop, leaving vaccinated people with only these IgG4 antibodies.

6: And then they would totally unprotected from the coronavirus?

No. IgG4s could still offer some protection through their ability to “neutralize” the Sars-Cov-2 viral particles - preventing them from entering our cells and replicating. (Unlike bacteria, viruses cannot reproduce on their own - they need our own cellular machinery to do so.)

The problem is that the Omicron coronavirus spike has a different shape than the spikes of earlier coronavirus variants. The anti-spike protein antibodies we generate - either after infection or vaccination - already have a harder time neutralizing it.

So we could be facing a double whammy; our immune systems would have antibodies that would still attach to the virus, but they would do a bad job both destroying it and keeping it from entering our cells.

7: That sounds bad.

It is. We would still have protection through our T-cells, which form a final line of defense. But other research has shown that T-cells don’t match up as well against Omicron as against earlier variants, though they lose their potency relatively slowly compared to antibodies. Research has also shown that additional boosting doesn’t help the T-cell response.

8: So if boosters don’t help T-cells, and they cause this IgG4 issue, and the antibodies disappear in a matter of months, and they don’t work very well against Omicron anyway, we have absolutely no reason to give anyone more mRNA shots?

Bingo. Correct. Yes. (Except for vaccine company profits.)

At this point, the long- and medium-term downsides clearly outweigh whatever short-term increase in antibodies boosters provide.

9: So what can vaccinated people do, if more shots are off the table?

Mask up!

I jest. At this point, vaccinated people do not have any real options to stop the IgG4 process. However, being infected with Sars-Cov-2 could provide some protection -

10: I thought you said that was part of the doom loop?

Hold on!

- by helping the immune system create antibodies to another part of the virus called the nucleocapsid. These anti-nucleocapsid antibodies will not stop future infections, but they may help stop severe disease. (Yes, more infections might both help and hurt. The immune system is tricky.)

11: Do you have any good news?

Since the paper came out, certain aggressive anti-vaccine writers have offered horrifying scenarios, for example claiming the IgG4 changes might hurt our ability to fight the flu and other viruses. Those theories are vanishingly unlikely. But the real issues are plenty serious.

12: But this is all speculative, right?

Yes. Except that it explains the growing divergence between the countries that used mRNA and those that did not in the last few months. China aside, the mRNA countries have performed far worse than the the rest of the world since early 2022. The mRNA countries have had huge numbers of Covid infections and reinfections that seem divorced from any seasonality. Covid hospitalizations and deaths have been relatively low, but those are now rising too. And overall excess mortality has been stubbornly high.

13: So scientists and health authorities and the vaccine companies are now going to launch an all-hands investigation to figure out how serious this finding might be?

You’re funny.

14: Seriously -

Seriously has anything in the last two years suggested such an investigation is coming?

15: Right. Okay. Speaking of the companies, shouldn’t they have known about this IgG4 stuff?

Yes. This finding is vitally important, and should have become part of the discussion around boosters more than a year ago.

16: Did they? Did they say anything?

Did they? It’s not clear. They certainly didn’t say anything publicly (as far as I can tell). Did they privately tell regulators? Probably not, because even the most industry-captured regulatory agency would have had to make this information public.

17: What now?

Hopefully some independent and honest academics will investigate both the changes that are occurring on the cellular level and how they may be impacting people’s response to the virus. And we all wait and hope that the ugly trends that countries like Japan - which is very highly mRNA vaccinated and just had its worst month for coronavirus deaths since the epidemic began - do not continue.

18: Wait? That’s the best you got? Wait?

Not waiting - wanting medicine at Warp Speed - is what got us into this mess to begin with.