Coronavirus

[Daniel in SD]

Good news, it’s getting easier to travel to China:

China relaxes Covid-19 testing rules for travellers from Singapore

Travellers from Singapore to China will need to do fewer pre-departure tests for Covid-19, but quarantine remains. Read more at straitstimes.com.

www.straitstimes.com

BEIJING - Travellers from Singapore to China will need to do fewer pre-departure tests for Covid-19 following changes announced by the Chinese embassy in Singapore on Friday (May 20), even as another district in Beijing went into a semi-lockdown on Saturday.

They will no longer need to do a polymerase chain reaction (PCR) test seven days before flying, nor antibody tests, which used to be required.

The changes will take effect immediately, the embassy added in the notice on its public WeChat account.

But travellers from Singapore will still be required to isolate themselves for seven days - which can be done at home - before departure, and undergo two PCR tests two days before and within 24 hours of departure.

They will need to upload their test results and a letter stating their commitment to self-isolate for seven days to an Internet portal before they can attain a health code, which is necessary for entry into China.

Travellers will also need to do an antigen rapid test (ART) within six hours before boarding, on the day of check-in.


No changes were announced regarding quarantine upon arrival, which is at least two weeks depending on the city travelled to.

"easier" haha. The 2 weeks (I've heard it's 3 weeks for some cities) in a quarantine center is by far the most onerous requirement. That will never be eliminated as long as they're still aiming for zero COVID.

 

[AlanSubie4Life]

Shockingly, it looks like China might actually have gotten things under control in Shanghai (for now). Obviously it's far too early to say if they'll really be able to keep a handle on it, but it sounds like they have found relatively few cases outside of quarantine for quite a few days now.

Omicron not that contagious after all! At least, not enough to beat China! See, Zero COVID is possible! Seriously, though, this does indicate to me that it's relatively easy to avoid infection if you're serious about it and are willing (and able) to take a pass on some activities.

Anecdotally, I see people I know in Shanghai who are now being allowed to recreate and get out (sounds like it was a 4-hour pass), so this is "real" - they wouldn't be making up statistics and calling cases low, but then allowing people out and about (briefly) in most areas.

Determining the actual number of daily cases in Shanghai is impossible though. It sounds like some counts put it at around 50 per day, and others put it at 600 per day or so. Rounding error.

In any case, these numbers are certainly far better and maybe things will really start to free up soon (for consumer spending, Tesla purchases, and whatnot). Not yet, since it sounds like things aren't actually back to normal completely - seems like the entire lockdown in Shanghai is supposed to be released on June 1st (note to readers: this is an actual lockdown, not a "nearly complete lack of restrictions, with no consequences at all for violation" that people call a "lockdown" in some countries) . And maybe China will get serious about vaccinating people soon?

Beijing seems not to be seeing the number of cases as Shanghai did, at least not yet, so maybe they'll have an earlier exit from restrictions? We'll see.

 

[AlanSubie4Life]

I don't expect "adding a 3rd dose" will make much of a difference.

We'll hope that the response is strong enough for the three dose data. I suspect it will be. But we'll know in a few weeks.

We’ll, it took more than a few weeks…but…

They are "hoping" a 3rd dose makes things look better, but given that current vaccines provide only at best moderate coverage for the BA.2 sub-variant (this should really be called it's own variant right now - it's a totally different beast), which will be the dominant variant inside of 3-4 weeks, there is very little chance of the current vaccine being approved for this age group.

We'll see. I wouldn't expect high efficacy against Omicron with two doses, anyway. I think them waiting says it has low efficacy against symptomatic infection, just like it does for adults, with two doses. (Fortunately the third dose cut infections roughly in half, and ~5x better against severe disease [in adults])

I would guess that the vaccine will be approved for young children after the three-dose data is available (I'd expect it to show efficacy above 50%, at least in one of the subgroups),

80% efficacy, but not enough infections yet (only 10 vs 21 required) to make a final efficacy determination. I suspect some cases in the trial go unreported, due to minor symptoms, but not sure how they monitor…

Hopefully by the end of June or in July this thing can actually be approved; even though overall risk is fairly low in this group, 0-4 do have the highest death rates amongst children (CFRs posted above), though the group seems to be faring better with Omicron.

Not bad for a 3-ug dose!

Pfizer-BioNTech COVID-19 Vaccine Demonstrates Strong Immune Response, High Efficacy and Favorable Safety in Children 6 Months to Under 5 Years of Age Following Third Dose

Based on topline data, three doses of the Pfizer-BioNTech COVID-19 Vaccine met all immunobridging criteria required for Emergency Use Authorization The third 3-µg dose was well tolerated among 1,678 children under 5 years of age with a safety profile similar to placebo Vaccine efficacy of 80.3%...

investors.pfizer.com

 

[bkp_duke]

We’ll, it took more than a few weeks…but…





80% efficacy, but not enough infections yet (only 10 vs 21 required) to make a final efficacy determination. I suspect some cases in the trial go unreported, due to minor symptoms, but not sure how they monitor…

Hopefully by the end of June or in July this thing can actually be approved; even though overall risk is fairly low in this group, 0-4 do have the highest death rates amongst children (CFRs posted above), though the group seems to be faring better with Omicron.

Not bad for a 3-ug dose!

Pfizer-BioNTech COVID-19 Vaccine Demonstrates Strong Immune Response, High Efficacy and Favorable Safety in Children 6 Months to Under 5 Years of Age Following Third Dose

Based on topline data, three doses of the Pfizer-BioNTech COVID-19 Vaccine met all immunobridging criteria required for Emergency Use Authorization The third 3-µg dose was well tolerated among 1,678 children under 5 years of age with a safety profile similar to placebo Vaccine efficacy of 80.3%...

investors.pfizer.com

My children won't be getting the booster.

The youngest has already been "boosted" this past week by a natural infection (which any microbiologist will tell you provides a broader antibody response). I'm pretty certain the oldest probably has it as well by now.


This thing is endemic, and the IFR keeps dropping with each variant (duh . . . common in the path to becoming endemic).

 

[AlanSubie4Life]

and the IFR keeps dropping with each variant

It actually seems like the much stronger influence is infections, not variants. The IFR gets lower with each infection. Once we get to 10 billion infections we’ll be doing ok. Unfortunately there is a cost.

The available data suggests Omicron is similar inherent virulence to the original Wuhan strain (perhaps slightly less but confidence intervals overlap), but of course less virulent than Delta.

Many places had more deaths from Omicron than Delta, of course.

We’ll

Is this really that hard for AI? If we can’t do this…. Is it really using the heuristic that more sentences start with “we’ll” than “well?” Mind boggling.

 

[Jeff N]

The youngest has already been "boosted" this past week by a natural infection (which any microbiologist will tell you provides a broader antibody response).

It makes sense to consider an infection to be an approximate stand-in to a booster shot. However, I don’t understand the apparent claim about natural infections always inherently providing a broader antibody response than any vaccination.

It seems clear that antibody immunity response will vary based on which specific variant you are infected or vaccinated with. Exposure to the early Wuhan-era variant resulted in relatively broad protection against many of the subsequent variants derived from it (especially after multiple exposures). But, exposure to some later variants have been shown to not create great antibody responses to some other of the variants (because there is less overlap of common epitopes). It matters which variant you are exposed to.

Right now, exposure to the BA.2.X variant seems likely to be a more useful “booster” off of a base-level vaccination than another Wuhan-era booster shot so, Yay?, but I’m not sure that a natural infection is ever and always a better booster exposure than another vaccine boost.

 

[bkp_duke]

It makes sense to consider an infection to be an approximate stand-in to a booster shot. However, I don’t understand the apparent claim about natural infections always inherently providing a broader antibody response than any vaccination.

The vaccines are ONLY composed of the Spike protein. That's all there is in them (most of them, the mRNA vaccines for sure). By design this limits the antibodies that can be produced to just those that bind the Spike protein.

Naturally, the virus has MANY more proteins than just the Spike protein. And a natural immune response can and will for to all of them that the immune "antigen presenting cells" are exposed to.

Hope this helps you understand.

 

[Jeff N]

The vaccines are ONLY composed of the Spike protein. That's all there is in them (most of the, the mRNA vaccines for sure). By design this limits the antibodies that can be produced to just those that bind the Spike protein.

Naturally, the virus has MANY more proteins than just the Spike protein. And a natural immune response can and will for to all of them that the immune "antigen presenting cells" are exposed to.

Hope this helps you understand.

But the spike protein is where most of the neutralizing antibody epitopes reside. Recent studies seem clear that natural infections with some variants do not provide overall better antibody immunity protection against other variants than the mRNA Wuhan-based vaccines despite the vaccines only covering the spike protein.

 

[AlanSubie4Life]

But, exposure to some later variants have been shown to not create great antibody responses to some other of the variants (because there is less overlap of common epitopes). It matters which variant you are exposed to

Fortunately, when primed by vaccination the neutralizing response even to Omicron seems quite broad, due to immune memory effects, “original antigenic sin”, affinity maturation, etc. Cross neutralization seems good in that case (unlike just an infection by Omicron).

So probably neutralizing response is ok to infection in that situation…but comes with potentially substantial discomfort of infection.

Of course you also end up with antibodies to other portions of the virus too, which may not be neutralizing but at a minimum provide more targets for t-cells, I assume. Not clear to me how much additional benefit over vaccination that has on future infection prevention (which is of course important).

 

[Doggydogworld]

Shockingly, it looks like China might actually have gotten things under control in Shanghai (for now). Obviously it's far too early to say if they'll really be able to keep a handle on it, but it sounds like they have found relatively few cases outside of quarantine for quite a few days now.

Not that shocking to me. Lock up and test enough people for long enough and you can get to zero. China did it in Wuhan. The NBA did it with their "bubble".

Brutal lockdowns have a deterrent effect on humans, too. You better believe other local governments and populations are applying extreme legal and social pressure on any remaining freedumb types to avoid an outbreak and ensuing Shanghai/Wuhan-style lockdown in their own city.

 

[bkp_duke]

But the spike protein is where most of the neutralizing antibody epitopes reside. Recent studies seem clear that natural infections with some variants do not provide overall better antibody immunity protection against other variants than the mRNA Wuhan-based vaccines despite the vaccines only covering the spike protein.

Key word there "most". And when the when the vaccine is the original Wuhan strain, not the new variants that have accumulated dozens of mutations in that spike protein, those antibodies to the old epitopes are not as good at neutralization as they were against the original strain.

Ancillary antibodies do help in viral neutralization. Always have, always will.

 

[AlanSubie4Life]

those antibodies to the old epitopes are not as good at neutralization as they were against the original strain.

Fortunately the immune system finds and creates some of these antibodies to the new epitopes anyway (through somatic hypermutation over time), which is why the booster works quite a bit better against Omicron than two doses. Requires the boost though! Or at least that’s how I understand it.

Ancillary antibodies do help in viral neutralization.

Which (additional) structures provide the epitopes for neutralizing antibodies and how do they interfere with this coronavirus? I guess I could see enough antibodies glomming on to just muck everything up, but not sure it works that way. My understanding is that t-cells will be recruited to target other portions of the virus though…is that true? (But that’s not neutralization.)

 

[bkp_duke]

Fortunately the immune system finds and creates some of these antibodies to the new epitopes anyway (through somatic hypermutation over time), which is why the booster works quite a bit better against Omicron than two doses. Requires the boost though! Or at least that’s how I understand it.



Which (additional) structures provide the epitopes for neutralizing antibodies and how do they interfere with this coronavirus? I guess I could see enough antibodies glomming on to just muck everything up, but not sure it works that way. My understanding is that t-cells will be recruited to target other portions of the virus though…is that true? (But that’s not neutralization.)

Second comment first:
Nucleocapsid is one protein, there are many more.

Frontiers | Anti-spike, Anti-nucleocapsid and Neutralizing Antibodies in SARS-CoV-2 Inpatients and Asymptomatic Individuals

A better understanding of the anti-SARS-CoV-2 immune response is necessary to finely evaluate commercial serological assays but also to predict protection ag...

www.frontiersin.org

(the above is a REALLY good article that shows anti-S antibodies are not necessarily the best - people in the ICU had higher anti-S titers, but they were not necessarily protective)

First comment - whoever told you that is full of it. How are you going to make antibodies to epitopes you are not exposed to. If an epitope changes, to create an antibody to it, you MUST have an exposure (either naturally via infection, or via a changed sequence in the vaccine booster).

Right now, boosters are still against the original Wuhan S-protein. They are ONLY boosting efficacy because they are increasing the number of antibodies that can still bind (to varying degrees) and neutralize the S-protein. The other antibodies to epitopes that have changed are useless and don't cause neutralization, even though the booster increases their numbers as well.

This is why the more proteins you can have an immune response (i.e. a broader immune response), the better you are protected against future variants.

Every study I have looked at showed that those people with "superimmunity" were a combination of vaccine+natural exposure. I have yet to see any supperimmune individuals that were vaccine only, without the exposure to the virus to boost their antibody and T-cells to have a broader array.

 

[AlanSubie4Life]

First comment - whoever told you that is full of it.

Primarily Shane Crotty, though I have seen other papers (posted previously here). One of several threads he has had on it:
(This was the wrong link, as it does not address impact of boosters.)

https://twitter.com/x/status/1468390479280574472

A correct one (a search in this thread will yield other references):

https://twitter.com/x/status/1484568504787345414

I have yet to see any supperimmune individuals that were vaccine only, without the exposure to the virus to boost their antibody and T-cells to have a broader array.

The claim isn’t super immunity with booster. The claim was only better protection against infection (because they have a broader array of antibodies after the boost). Some people are not well protected after the boost, and possibly most boosted people would be infected, with sufficient inoculum.

 

[bkp_duke]

Primarily Shane Crotty, though I have seen other papers (posted previously here). One of several threads he has had on it:

https://twitter.com/x/status/1468390479280574472

The claim isn’t super immunity with booster. The claim was only better protection against infection (because they have a broader array of antibodies after the boost). Some people are not well protected after the boost, and possibly most boosted people would be infected, with sufficient inoculum.

The link you put doesn't say that. It doesn't "broaden" the antibody response. By definition, that means new epitopes.

All it does is increase the numbers of existing antibodies (which has value, not discounting that).

 

[AlanSubie4Life]

The link you put doesn't say that. It doesn't "broaden" the antibody response. By definition, that means new epitopes.

All it does is increase the numbers of existing antibodies (which has value, not discounting that).

Sorry wrong thread (I will add this one above too). Anyway there are many posts previously in this thread with links to videos and papers talking about affinity maturation, which is a key feature of the boosters (not just the antibody levels - that is why the booster is so important for Omicron as I understand it). That long time delay of 5 months gives time for germinal centers to work their magic (as I understand it).

https://twitter.com/x/status/1484568504787345414

“And with 3 doses of vaccine your immune system makes neutralizing antibodies that recognize Omicron, a dramatically divergent variant that isn’t in the vaccine! I mean, it’s really brilliant work by your immune system.”

 

[bkp_duke]

Sorry wrong thread (I will add this one above too). Anyway there are many posts previously in this thread with links to videos and papers talking about affinity maturation, which is a key feature of the boosters (not just the antibody levels - that is why the booster is so important for Omicron as I understand it).

https://twitter.com/x/status/1484568504787345414

“And with 3 doses of vaccine your immune system makes neutralizing antibodies that recognize Omicron, a dramatically divergent variant that isn’t in the vaccine! I mean, it’s really brilliant work by your immune system.”

Again, you are reading something into it which is not stated by that author.

The "affinity maturation" is simply ramping up of antibodies to ORIGINAL STRAIN epitopes of the S-protein - SOME OF WHICH cross-react to Omicron.

There are NO NEW epitopes generated because . . . the way the immune system works that would REQUIRE exposure of those novel epitopes of the Omicron-specific variant to be exposed to the immune system. SOME of those existing antibodies already recognized Omicron, but the booster IS NOT selecting them out over other antibodies. It's simply ramping up production of ALL antibodies that were produced during the first 2 shots (the very definition of what a booster does).



I recommend if you really want to dig deep into how the immune system works in this regard, go read the latest edition of Kuby et al. "Immunology". Great college textbook that is kept up to date by the authors.


EDIT - to be specific - the booster is performing affinity maturation against the ORIGNAL strain. It's unfortunately not able to select out antibodies against the Omicron variant because those Omicron-specific sequences are not present (just sequences common to Omicron and the original strain).

 

[AlanSubie4Life]

Again, you are reading something into it which is not stated by that author.

I wasn’t claiming that it was generating antibodies to new epitopes (my statement about antibodies recognizing new epitopes is confusing though!). However, my point with that statement is that the breadth of the antibodies after the boost incidentally “covers” some of the new epitopes (as I understand it).
The core claim I made (which is just based on what I have read) was that antibody breadth is substantially greater after a boost. I don’t fully understand how the process works, and it’s possible that technically all of these antibodies existed at low levels after two doses, but that is not my understanding of how somatic hypermutation works. It sounds to me like the hypermutation occurs over several months, and then when the boost comes it “amplifies/selects” some of these NEW candidates. So there is actually more breadth of effective antibodies after the boost. Which match well to the original spike, but ALSO match Omicron well enough to neutralize. Whether they partially match the new epitopes or just interfere enough with Omicron at non-mutated sites to neutralize, I do not know - this seems like a complicated question of molecular modeling.

In any case, the boost improves cross-neutralization capacity (as you said). What the exact mechanism is to me is somewhat less important (though I definitely would like to understand) - the data just show the booster is a dramatic improvement against Omicron.

I certainly agree it is not a direct response to the new Omicron epitopes, and thanks for that clarification and the reference to the additional material. Feel free to fix up any additional misinformation I have added here!

 

[bkp_duke]

I wasn’t claiming that it was generating antibodies to new epitopes (my statement about antibodies recognizing new epitopes is confusing though!). However, my point with that statement is that the breadth of the antibodies after the boost incidentally “covers” some of the new epitopes (as I understand it).

No, this is not how it works. A booster of the SAME sequence or design can ONLY boost EXISTING antibodies. The key is that the original protein has OVERLAPPING epitopes that somewhat cross-react with Omicron. Antibodies to THOSE epitopes are boosted (as are many other NOT reactive to Omicron).

EDIT - let me put this a different way: an Omicron-specific booster would be probably 2-5X more effective than just boosting with the original sequence. It would select BOTH common epitopes between the two strains, AND Omicron-specific epitopes. It would be a win-win.

 

[AlanSubie4Life]

No, this is not how it works.

Got it. Agreed. So the boost improves the breadth. Should have stuck with that! This is why the booster is so good and of crucial importance. (And I guess “existing antibodies” includes those (from b-cells?) in the germinal centers that are really not amplified until the boost?)

an Omicron-specific booster would be probably 2-5X more effective than just boosting with the original sequence. It would select BOTH common epitopes between the two strains, AND Omicron-specific epitopes. It would be a win-win.

Right. When used as a booster, agreed, win-win. The issue they are considering now is that it is quite poor at neutralizing earlier lines (cross immunity is quite poor going the other way as posted in papers earlier) so the risk of a significant escape/miss if they only use Omicron spike as a boost is significant. So they’ll likely do a mix as insurance. Since it won’t be used only as a boost.

I’d guess (just a WAG) we’d see 70-80% efficacy against Omicron and sub variants vs. 50% with the old boost. So about twice as good, if that is how it works out. For symptomatic illness. Harder to say on severe disease - hopefully miraculous.