So some initial digestion of this bombshell study...

We probably now have to redo nearly all the vaccine designs and serology assays.

But it gets worse. The immune system is mostly recognizing viral proteins involved *after* replication meaning they won’t neutralize the virus.

What I’m guessing is happening is the immune system is noticing ORF3b/ORF8 on viral-infected cells & inducing cytotoxic response. The infected host cell is torn apart and out spills a ton of the viral N protein, used to pack the viral RNA. This strongly induces more cytotoxicity.

That may be creating the necrosis and buildup of cell lysate in the lungs as there’s N spilling all over the place and the body has no neutralizing function to fall back on. But it gets worse.

Because the immunity can only happen *after* viral replication we are automatically behind the game before we start. Dosing theory might work along these lines as if there is a large enough dose—even for someone already immune!—the disease condition could restart via cytotoxicity

And since we can only be reactive not proactive, in some pts replication may be so efficient they get a large internal dose from any size external dose. Thus another way in which some pts would have worse cases: perhaps their replication is faster or antigen presentation slower.

And we see the body takes very little time to raise immunity to these components but a long long time to eliminate active virus from the body. This means the virus is replicating in places the body can’t or won’t mount enough cytotoxic response to. Or if it does, patient dies.

Regardless, it seems we have to conclude people are in fact dying who have been immune for weeks already! Which means a vaccine needs to be strong enough to win the race against the virus. In elderly whose immune systems stuggle to even make the more effective neutralizing ABs!

So this gives us enough information to solve the puzzle Alex. The virus sugar-coated itself enough to escape our efforts to block it. If we attack it, we attack ourselves. It’s a foot race who finishes off who. And elders have increasing trouble winning that race of course.

Can a vaccine work then? Perhaps not much. Maybe 25% or something protection vs unvaccinated? This places even more emphasis on antivirals. We go all out on those.

What about blocking the cytotoxic immune response as a way of surviving the disease rather than the virus? Perhaps.

This article nicely summarizes some relevant points as to how SARS1 and SARS2 *specifically* differ at ORF3B and ORF8 and how those trigger inflammasome activation. This might be much of why these diseases are different.

The nifty new Roche serology test already uses N protein so that thankfully doesn’t need to be redone. And that is the test I want, stat! Where do I send some blud?

This is an early glimpse of info suggesting a lot of anti-N Ig doesn’t portend well for survival. Which underscores my argument that it’s clearly a lot of cytotoxicity liberating all that N as the patient digests themselves to oblivion. Anti-S would help.

In an NIH webinar on Friday Galit Alter showed data suggesting that presence of IgG and IgM against S was more common among survivors and early response to N was more common among those who did not. N could be immunodominant non neutralizing epitope.

Now how then might we use this new knowledge for a treatment? My crazy-ass idea is to competitively inhibit the antibodies triggering the immune overreaction. This would be titrating in ORF3 and/or ORF8 now we know this. Would let virus grow but save body.

And this is why I tweeted this too, because who knows if the fatal cases are raising antibodies to spike. Maybe they are targetting E or the protease or who knows what, and that is the problem. And in that design, the cure...titer in those instead of spike https://twitter.com/ExcludedMuddle/status/1240766234649432065?s=20

I didn’t find any vaccine candidates targeting ORF3b or ORF8 though it’s possible those could be neutralizing. But if not, monoclonals targeting them might have a shot, especially if those monoclonals would *not* trigger the rest of the immune system but instead block that.

I think what people don’t understand about my analysis is: I see the virus as a harmless common cold, EXCEPT it sets off a snowballing immunopathology ending in cytokine storm/ARDS. I’m primarily interested in tripping up the snowball...the virus might not otherwise be a problem.

My belief fwiw is the spike protein is so coated in sugars by the host that the immune system can’t target it...except for the receptor binding domain, which may look like host protein anyway. May not be true in all pts though.
https://twitter.com/excludedmuddle/status/1252262970500853760?s=21

Like a sugar-coated poison pill, it may make it harder for the immune system to recognize the virus. There is the exposed receptor binding domain, but it’s possible that also looks like angiotensin itself, which would make that hard to recognize as an invasive antigen.

Cheers anrc. It all ties right back into my autoimmune idea, precisely because the viral export proteins are targeted to the cell membrane. Thus the body’s only response is to destroy its own cells...leading to a self-accelerating cascade of Pandora’s box popping.