Coronavirus

[AlanSubie4Life]

Watched the CEO on CNBC just now. Currently $30 a test. They expect price to come down with increased production volume.

Way too expensive, of course. Anyone dig up the actual performance (specificity/sensitivity) and sample size for this test?

We should target $1-$5.

Unfortunately currently there is no way to understand the residual risk after vaccination. We can guess that it is lower than before vaccination - that doesn't help us make informed decisions.

Yep. Need some patience here to get the data. And medical establishment needs to be careful to not be too conservative with guidance, and also caveat the guidance with the uncertainty limits, they have so people can make their own decisions, based on personal risk tolerance. Rather than a rigid one size fits all approach.

And of course keep pushing N95 for everyone. Have a mandatory doctor’s appointment today. Everyone only wearing surgical masks. Really unbelievable; we apparently like failure. Hopefully N95 plus surgical plus safety glasses plus face shield is good enough (P100 with vent tightly covered not allowed, of course, because of “reasons” (that was expected). Even though it would probably be safer for everyone.). Guess I will know in about 10-14 days!

 

[AlanSubie4Life]

Have a mandatory doctor’s appointment today. Everyone only wearing surgical masks. Really unbelievable; we apparently like failure.

It’s entirely possible this is not actually why we are failing, and that proper surgical mask use by everyone works great in nearly all circumstances. We still don’t know!

 

[JRP3]

It’s entirely possible this is not actually why we are failing, and that proper surgical mask use by everyone works great in nearly all circumstances. We still don’t know!

When I watch videos of people in public they are often constantly playing with their masks which constantly slip down off their nose. The rest of the time the mask is a chin guard or neck warmer

 

[AlanSubie4Life]

https://twitter.com/kakape/status/1356359522177179662?s=20
In some ways, this is good news. To me it shows that this is kind of a stable point for the virus - everything converges to this! It may not change much further from here if it's biologically optimal. So not only do the existing vaccines work for the most part on this mutation (though not as effective), any future booster may be targeting something that's less likely to mutate to something else.

 

[EVCollies]

Great NEJM Fauci podcast.

 

[EVNow]

View attachment 633119

https://twitter.com/kakape/status/1356359522177179662?s=20
In some ways, this is good news. To me it shows that this is kind of a stable point for the virus - everything converges to this! It may not change much further from here if it's biologically optimal. So not only do the existing vaccines work for the most part on this mutation (though not as effective), any future booster may be targeting something that's less likely to mutate to something else.

It might be optimal given the context. These are what Richard Dawkins calls "local maxima", IIRC. You change the context (or environment) a different maximum may result.

I think ultimately if this is a potent virus - we should try to eliminate it, rather than just contain it. A lot of people seem to be hoping that this turns into another strain of flu and we'll all be back to normal. But its also possible it remains dangerous and we need to eliminate it with strict isolation + vaccine.

One thing is clear - the whole "let it run and we'll get herd immunity" people are dead wrong.

 

[AlanSubie4Life]

These are what Richard Dawkins calls "local maxima", IIRC. You change the context (or environment) a different maximum may result.

Yep. One particular change in environment that would be of concern would be a population which is heavily vaccinated against something close to what it is right now. That is definitely going to push evolutionary drive in a different direction. The questions are: how many avenues of attack does the immune system have? It is going to take a LOT to escape a multi-faceted immune response, with antibodies which neutralize in at least two places on the protein, and more glommed all over the protein which fire up a pre-primed killer T cell response. Another question is, practically, how would a virus evolve to evade antibodies that prevent it from latching onto the ACE2 receptor...without creating a conformation of the protein which is wholly incompatible with said receptor?

A lot of people seem to be hoping that this turns into another strain of flu and we'll all be back to normal.

Yeah, not going to happen, since it is nothing like flu. Doesn't change rapidly like flu (which has a segmented genome, allowing shuffling, with no proofreading), which is both good (much more effective vaccines) and bad (unlikely to quickly become less virulent to people for whom it is novel).

we need to eliminate it with strict isolation + vaccine.

Yep.

the whole "let it run and we'll get herd immunity" people are dead wrong.

Yes, that was abundantly obvious to everyone who was paying attention in January 2020! It's amazing to me that they were still talking about it in November 2020. Probably STILL are talking about it, lol.

 

[TEG]

People previously infected with Covid-19 may only need one vaccine dose, study suggests

 

[AlanSubie4Life]

People previously infected with Covid-19 may only need one vaccine dose, study suggests

Came here to post this.

Plot.

Note 1: semi log scale
Note 2: See how natural infection results in a mean antibody response (with a geometric average, which is appropriate here) that is ~10x weaker than vaccination. One reason why vaccinations are so effective, and can prevent reinfection even by different strains. (And kind of looks like infection followed by two vaccinations makes you nearly indestructible, though it can be quite unpleasant indeed. And you may be vulnerable to new strains, still.)
Note 3: surprised by the relatively small shift in titer after the second dose in the seronegative group. I thought there was more of a shift between first and second doses. Maybe not. Not sure how long they waited, to measure - this is a preprint and they may be moving fast. I would expect it to go up to above 10000. Second dose could also be better priming systems not measured by antibodies.
Note 4: you can see the response to boosting is a few days faster than it is for the first dose. Basically complete before day 9, while response to first dose takes as long as 21 days, though is mostly complete in most people by day 12. (3-4 day difference with some huge outliers).

Paper.
https://www.medrxiv.org/content/10.1101/2021.01.29.21250653v1.full.pdf

It’s probably worth antibody testing people (or at least asking if they had a positive PCR test!), and suggest only one dose for these people as an option - especially if they have a strong reaction to the first dose.

Seems pretty safe, but of course not tested in the trials, so there is a risk it might not work as well for people getting one dose (despite evidence to the contrary). The only real danger would be some risk if any people were misidentified as previously COVID+. You could tell people who have no reaction to the first dose to feel free to get the second.

Anyway, could save 25 million doses this way with PCR, and about 100 million if you used antibody tests (but they can have false positives which would be the risk here).

 

[JRP3]

Doesn't change rapidly like flu

All the variants we are seeing aren't rapid changes?

 

[AlanSubie4Life]

All the variants we are seeing aren't rapid changes?

No. There are very few changes to the coronavirus genome, unlike with influenza, which changes individual nucleotides very frequently, and additionally can completely reshuffle its genome, making it very hard for the immune system to keep up.

Looks like so far our immune system is doing very well with COVID - it’s possible a booster may be necessary for the “optimal” sequence to really crush it, but it also may not be needed, as the vaccines tested against those variants seem to remain extremely effective (no hospitalizations).

We will see. Definitely need to keep crushing the virus with all measures available to us. The worry is that as many are vaccinated it might find a way around. But note that the best it has been able to do so far is the South African variant (South Africa got hit hard early, and a lot of people with the variant were reinfected), which is still strongly suppressed by the vaccines used against it (more than 50%, and 100% for hospitalization). P.1 is an unknown so far - we’ll know more soon I am sure.

I’m not saying there are no worries. Just that this is all occurring very slowly, and are (mostly) point mutations (there are segment deletions too), which still allow the immune system to provide substantial protection in people picking up the new strains. Unlike influenza.

Uh-oh! @bkp_duke disagrees! This is good; we will learn something.

(I do know that the mutation rate for coronavirus is slower than for influenza - that is factual, which was my point. The speculation about immune response is a guess - as I make clear.) Also to be clear: there is almost certainly going to be a modified booster - possibly more than one. Because we can, and they will be better.

 

[bkp_duke]

No. There are very few changes to the coronavirus genome, unlike with influenza, which changes individual nucleotides very frequently, and additionally can completely reshuffle its genome, making it very hard for the immune system to keep up.

Looks like so far our immune system is doing very well with COVID - it’s possible a booster may be necessary for the “optimal” sequence to really crush it, but it also may not be needed, as the vaccines tested against those variants seem to remain extremely effective (no hospitalizations).

We will see. Definitely need to keep crushing the virus with all measures available to us. The worry is that as many are vaccinated it might find a way around. But note that the best it has been able to do so far is the South African variant (South Africa got hit hard early, and a lot of people with the variant were reinfected), which is still strongly suppressed by the vaccines used against it (more than 50%, and 100% for hospitalization). P.1 is an unknown so far - we’ll know more soon I am sure.

I’m not saying there are no worries. Just that this is all occurring very slowly, and are point mutations, which still allow the immune system to provide substantial protection in people picking up the new strains. Unlike influenza.

Sorry, but this is wrong.

The "rapidity" at which you see new mutations in viruses are due, primarily, to two variables:
1) How quickly the virus mutates (SARS-CoV-2 has a mutation rate less than 1/2 of seasonal influenza) - which is determined by how well or if it has proof-reading enabled in it's replication mechanism (SARS-CoV-2 does, influenza does not).
2) The "generational" rate of the virus - i.e. how many generations we see during a given time period. This variable is directly proportional to how widespread this virus is.

OVERALL, SARS-CoV-2 is mutating faster than seasonal influenza RIGHT NOW because variable #2 is so much larger than variable #1. If the virus were less widespread, we would be doing better and seeing fewer new variants of the virus.

We are not even close to seeing the end of mutations from this thing, and B.1.1.7 and B.1.351 are only the beginning. Seeing them swap mutations is, sadly, expected, and does not indicate a localized minimum for viral evaluation at all.

The REAL fun begins when vaccination is widespread, because just a few more mutations and this bugger is going to completely change the shape of the S-protein and further reduce effectiveness of our vaccines. Our only chance to suppress this virus is for an extremely rapid vaccination, world-wide. Each viral generation gives the virus opportunity to mutate further and adapt to the environmental pressure we are placing upon it with vaccines.

 

[AlanSubie4Life]

OVERALL, SARS-CoV-2 is mutating faster than seasonal influenza RIGHT NOW because variable #2 is so much larger than variable #1. If the virus were less widespread, we would be doing better and seeing fewer new variants of the virus.

I agree with that for a particular flu strain. But flu reshuffles and recombines its genome, right (HxNy)? That’s a key distinction, no? It’s why we have tons of different strains. I feel like people think: this is like the flu, we will have to update it every year with quadrivalent vaccines and then it might only be 30-50% effective - but coronavirus does not appear to be like that at all. It’s fundamentally different, as you point out.

(And for SURE flu isn’t changing much at all right now since it is nearly non-existent - that pretty much goes without saying but I guess I had to say it! )

Of course, you cannot have mutation without infection. More infections, more mutations (have said this several times previously).

The REAL fun begins when vaccination is widespread, because just a few more mutations and this bugger is going to completely change the shape of the S-protein and further reduce effectiveness of our vaccines. Our only chance to suppress this virus is for an extremely rapid vaccination, world-wide. Each viral generation gives the virus opportunity to mutate further and adapt to the environmental pressure we are placing upon it with vaccines.

That may be true. It’ll be interesting to see how the P.1 does. That arose (allegedly) in a population with 75% immunity so you would expect a “fit” protein change to evade immunity. If the vaccine is still more than 50% effective (and near 100% for hospitalizations), the question would be - is that all it has got? It’s perhaps sort of a proxy for what would happen with vaccination (a somewhat pessimistic proxy since natural infection gives a weaker immune protection than vaccination).

CERTAINLY - we should crush this virus via all means necessary, as I have made clear repeatedly since March/April here. And we must vaccinate as rapidly as possible while applying mitigation measures to stop the spread and continued emergence of variants. It is playing with fire.

 

[bkp_duke]

I agree with that for a particular flu strain. But flu reshuffles and recombined its genome, right (HxNy)? That’s a key distinction, no? It’s why we have tons of different strains.

That may be true. It’ll be interesting to see how the P.1 does. That arose (allegedly) in a population with 75% immunity so you would expect a “fit” protein change to evade immunity. If the vaccine is still more than 50% effective (and near 100% for hospitalizations), the question would be - is that all it has got?

CERTAINLY - we should crush this virus via all means necessary, as I have made clear repeatedly since March/April here. And we must vaccinate as rapidly as possible while applying mitigation measures to stop the spread and continued emergence of variants. It is playing with fire.

All viruses reshuffle their genome. The HxNy distinction shows that (when a host is infected with two strains, they swap DNA in those regions (but also other regions, which are less important). With the B.1.1.7 combination with B.1.351, this virus (not surprisingly) shows us it also can "recombine" (that's the proper term - shuffle is not exactly correct) during co-infection in a host.


We are only now starting to put environmental / evolutionary pressure on SARS-CoV-2 with vaccines. That can have a profound effect on the selection force for new viral variants. The S-protein is a big protein, there are plenty of potential mutations that can occur still which will reduce vaccine effectiveness.


And yes, I'm jaded and pissed off. I had to fly to Wash D.C. for work, and the level of dumbassary regarding masks, hand washing, etc. observed (in all states visited, blue or red) was disheartening. People are mentally exhausted from this thing, and many just don't care anymore if they get it or not.

 

[AlanSubie4Life]

With the B.1.1.7 combination with B.1.351, this virus (not surprisingly) shows us it also can "recombine" (that's the proper term - shuffle is not exactly correct) during co-infection in a host.

Is this right? As far as I have read, this is the (expected) single nucleotide polymorphism (I’m not sure it is a SINGLE mutation, to be clear - it may take a couple, I’d have to review the sequence) being introduced into the pre-existing B.1.1.7. It happened in the absence of B.1.351 - it wasn’t like two viruses recombined.

Everything I read says this is an example of convergent evolution.

Detailed discussion:

https://twitter.com/_b_meyer/status/1356516699672092673?s=21

 

[bkp_duke]

Is this right? As far as I have read, this is the (expected) single nucleotide polymorphism (I’m not sure it is a SINGLE mutation, to be clear - it may take a couple, I’d have to review the sequence) being introduced into the pre-existing B.1.1.7. It happened in the absence of B.1.351 - it wasn’t like two viruses recombined.

Everything I read says this is an example of convergent evolution.

Detailed discussion:

https://twitter.com/_b_meyer/status/1356516699672092673?s=21

It could be convergent, no one can ever look and say for certain because it is a single amino acid mutation. But there is absolutely nothing that prevents recombination of two completely separate viral strains/variants in an individual co-infected.

B.1.1.7 and B.1.351 are not the first 2 variants of the original virus we have seen. They are like the 8th and 9th. This sucker is constantly evolving.

 

[AlanSubie4Life]

. But there is absolutely nothing that prevents recombination of two completely separate viral strains/variants in an individual co-infected.

How does that happen? I thought that happened in flu because of the segmented genome. Which does not exist for coronavirus (as I understand it - correct me if wrong)...

My impression was that mutations in SARS2 are being driven by mostly SNPs, which occur in spite of the proofreading. And also, sometimes, there are deletions of segments of the genome which code the spike.

I guess I could envision rarely some really big screw up (have no idea physically how this would occur) where a random piece of RNA from another strain gets stuck into another strain during transcription, but is there any evidence this has happened or actually drives the mutation to date? I get the impression from all discussion I have read on this that that is not happening (specifically: it is not thought to be the proximate cause of any of the current known mutations). There are some very long branches on the phylogenetic tree, but these are thought to be due to long infections in immunocompromised individuals, and are still apparently a compilation/jumble of many SNPS.

Am I missing something in the observed data? I’m not talking about theoretical possibilities here - I am talking about what we think has happened with the key mutations to date.

I don’t doubt that we could get something worse, based on theory, if we keep letting this thing multiply. But have we seen that yet?

I guess I don’t understand the mechanism whereby coinfection with two SARS2 strains can lead to recombination, automatically. It seems straightforward with influenza (it seems to do this as a matter of course since all these segments can be floating around concurrently). Is it straightforward for SARS2?

I’ve really been trying to understand the exact differences here lately, so any light you can shed is certainly appreciated.

The answer will likely allow us to better assign probability to certain outcomes (like the outcome where we are living with this forever, like influenza - my understanding is that this is unlikely - in spite of our incompetence and in fact our joy in infecting others with SARS-CoV-2 - but maybe I am wrong).

 

[bkp_duke]

How does that happen? I thought that happened in flu because of the segmented genome. Which does not exist for coronavirus (as I understand it - correct me if wrong)...

My impression was that mutations in SARS2 are being driven by mostly SNPs, which occur in spite of the proofreading. And also, sometimes, there are deletions of segments of the genome which code the spike.

I guess I could envision rarely some really big screw up (have no idea physically how this would occur) where a random piece of RNA from another strain gets stuck into another strain during transcription, but is there any evidence this has happened or actually drives the mutation to date? I get the impression from all discussion I have read on this that that is not happening (specifically: it is not thought to be the proximate cause of any of the current known mutations). There are some very long branches on the phylogenetic tree, but these are thought to be due to long infections in immunocompromised individuals, and are still apparently a compilation/jumble of many SNPS.

Am I missing something in the observed data? I’m not talking about theoretical possibilities here - I am talking about what we think has happened with the key mutations to date.

I don’t doubt that we could get something worse, based on theory, if we keep letting this thing multiply. But have we seen that yet?

I guess I don’t understand the mechanism whereby coinfection with two SARS2 strains can lead to recombination, automatically. It seems straightforward with influenza (it seems to do this as a matter of course since all these segments can be floating around concurrently). Is it straightforward for SARS2?

You don't have to have "segmentation" to have recombination. It's not "automatic", it's just a statistical event. If there are enough co-infected cells, you have opportunity for homologous recombination.

For your (deep dive) reading pleasure:
Viral genome evolution ~ ViralZone page
https://jvi.asm.org/content/84/7/3134

The 2nd article is particularly good, but very technical, about how viruses like SARS-CoV-2 come into existence through various genetic recombinations in other species.

 

[TEG]

And yes, I'm jaded and pissed off. I had to fly to Wash D.C. for work, and the level of dumbassary regarding masks, hand washing, etc. observed (in all states visited, blue or red) was disheartening. People are mentally exhausted from this thing, and many just don't care anymore if they get it or not.

Along with all the usual careless crap (denial, uninformed, not thoughtful, exhausted, etc.) I think there is a newish force at work with the people who got vaccinated or already had COVID. Some people with immunities may feel they can slack off on the safety protocols now. So you have a mix of that to contend with as well.

 

[AlanSubie4Life]

You don't have to have "segmentation" to have recombination. It's not "automatic", it's just a statistical event. If there are enough co-infected cells, you have opportunity for homologous recombination.

For your (deep dive) reading pleasure:
Viral genome evolution ~ ViralZone page
https://jvi.asm.org/content/84/7/3134

The 2nd article is particularly good, but very technical, about how viruses like SARS-CoV-2 come into existence through various genetic recombinations in other species.

Thanks! The first link laid out the huge differences between influenza and coronaviruses pretty clearly, which was helpful.

Dove deep into the second paper:

Second identified mechanism (which results in substitutions (recombination) of “cassettes” of the spike protein as far as I could understand):
“Coronaviruses have demonstrated a marked capacity to employ homologous recombination, a process by which viruses exchange genetic material in the context of a coinfection (65, 66). This process often takes advantage of the transcription regulatory network (TRN), a virus-specific series of 5- to 7-nt sequences (transcription regulatory sequences, or TRSs) situated at the 5′ end of each ORF that function to facilitate the incorporation of the viral leader sequence on subgenomic RNAs in the context of normal infection (7, 65, 116, 157). Multiple lines of evidence implicate homologous recombination and host shifting in the phylogenetic history of SARS-CoV. ”

HOWEVER: Frequency seems less well defined:
“Of note, analysis of Bat-SCoV sequences has led to speculation that Bat-SCoV may have originated from a recombination event between the ORF1- and ORF2 (Spike)-coding sequences and that this recombination event may have occurred about 4 years before the SARS epidemic (51). A similar study involving the human coronavirus HCoV-NL63 likewise demonstrated that HCoV-NL63 exhibited signs of having arisen from multiple recombination events from its nearest relative over the course of hundreds of years (106). Further, a recent study identified a group 1 bat CoV that shared ancestry with HCoV-229E, which diverged about 200 years ago (104).”

Does not sound like this sort of homologous recombination is occurring all the time. Though hundreds of millions of infections around the world can’t be a good thing.

Additionally the paper refers to the third mechanism - persistence in a host which can allow it to find another receptor to bind (after a LOT of searching and a bit of luck was my impression). That is scary, and would definitely make things difficult. Frequency also unclear for this mechanism - but presumably fairly rare.

The good news (to me at least) is that neither of these two additional mechanisms seem to be dominating current mutations. We are dealing with (apparently) RdRP-error-dominated mechanisms in known variants.

But there is always a chance we will get unlucky - or RdRP-error induced changes will be sufficient to *effectively* escape vaccination (has not happened yet, apparently, but we will see!).

To me it seems we are dealing with RdRP influenced genome changes primarily, and while we should certainly worry about these other mechanisms (no more transmission please!), there’s some hope that we may be able to stamp this out before those other mechanisms crop up and create something which is both just as infectious and equally dangerous (or more dangerous). But it is a race against time.