Coronavirus All Purpose Thread: moving on?

[GGG]

Originally Posted by photon

https://www.nature.com/articles/d41586-022-00912-y

The discussion around confounding variables is fairly interesting in that study.

[darockwilder]

Originally Posted by Firebot

My wife's luck has finally run out today. After going through the whole pandemic without covid and made it through my bout with it earlier this year without so much as a cough, she is now extremely sick and barely able to move. It came quite suddenly. Will see how long it lasts for her.



On a side note, my complications finally nearly all subsided last few weeks, but it took about 5 months. Just over a month ago it was still so bad I ended up going to the hospital as I thought I had pneumonia, prescribed steroids and a puffer which eventually cleared it up as it wouldn't on its own. It will be interesting to see if I get it again from her.



Triple vaccinated (moderna / 2x pfizer) and me as well. Even the 'invincible' ones like my wife eventually get it.



Perhaps if you get the new multivalent moderna vaccine when it is out in a year or two, there may be a real point where you can be truly protected from omicron, but at this point you just roll the dice each time you are out.

My sister in Vancouver tested positive today too for the first time! She's full of mucus (gross) and sleeping a lot. Very unfortunate, she can hardly get out of bed. Also triple vaccinated.

[nickerjones]

Originally Posted by photon

https://www.nature.com/articles/d41586-022-00912-y

I've caught Covid twice.... but I've been diabetic for 22 years.

[activeStick]

The annoying thing about this is until the rest of the unvaccinated world gets vaccinated, it's only a matter of time before a vaccine resistant variant appears and infects people. And then we get a new vaccine for that, and then we snag it all up leaving none for the poor countries (preferring to throw our excess away than spare some for them) and on we go.

[Dan02]

Originally Posted by activeStick

The annoying thing about this is until the rest of the unvaccinated world gets vaccinated, it's only a matter of time before a vaccine resistant variant appears and infects people. And then we get a new vaccine for that, and then we snag it all up leaving none for the poor countries (preferring to throw our excess away than spare some for them) and on we go.

Estimates are 95+% of people have antibodies, either through vaccination or exposure. There aren't many immunologically naïve people left.

[Scroopy Noopers]

Originally Posted by Dan02

Estimates are 95+% of people have antibodies, either through vaccination or exposure. There aren't many immunologically naïve people left.

…….95% of the world???

[ikaris]

Originally Posted by activeStick

The annoying thing about this is until the rest of the unvaccinated world gets vaccinated, it's only a matter of time before a vaccine resistant variant appears and infects people. And then we get a new vaccine for that, and then we snag it all up leaving none for the poor countries (preferring to throw our excess away than spare some for them) and on we go.

Huh? It seems the mutations and evolution of the virus is actually occurring in immunocompromised people so I’m not sure what this has to do with unvaccinated people?

[activeStick]

On ourworldindata, they're showing that 33% of the world population still hasn't received a single dose and that only 17% of people in low income countries have received at least one dose. I'm assuming given these numbers, covid will continue to spread in those countries, leading to more variants popping up. Or am I wrong?

[blankall]

Originally Posted by activeStick

The annoying thing about this is until the rest of the unvaccinated world gets vaccinated, it's only a matter of time before a vaccine resistant variant appears and infects people. And then we get a new vaccine for that, and then we snag it all up leaving none for the poor countries (preferring to throw our excess away than spare some for them) and on we go.

Vaccinated people have been catching this for a while now. They are just as likely to spread it at this point. The unvaccinated are still more likely to fill up hospitals though. Although by this point almost all people in Canada, vaccinated and unvaccinated, have likely been exposed and have some kind of immunity.

[blankall]

Originally Posted by activeStick

On ourworldindata, they're showing that 33% of the world population still hasn't received a single dose and that only 17% of people in low income countries have received at least one dose. I'm assuming given these numbers, covid will continue to spread in those countries, leading to more variants popping up. Or am I wrong?

Covid is spreading here and new variants are popping up. Vaccines are poor at stopping spread and having immunity actually encourages mutations, for the same reason that antibiotics breed mutations.

[opendoor]

Just to clarify, immunity doesn't encourage mutations; mutations are totally random. The only impact it has is that whatever mutations do randomly occur, the ones that are capable of evading existing immunity will have a competitive advantage over ones that aren't.

But in the aggregate, existing immunity to will tend to reduce the level of mutations that do occur for two reasons:

1) it reduces the number of replications that happen vs. the same spread in an immunologically naive population. It does this both by preventing infection in the first place (as we saw pre-Omicron) and by equipping your body to neutralize the virus faster (studies have repeatedly shown that the quantity of virions is significantly lower in vaccinated/previously infected people).

2) it limits the ways in which the virus can mutate and still spread through the population. With low levels of immunity, basically anything can happen to the virus and it can have a chance becoming dominant. But with existing immunity through vaccinations and infections, certain mutations aren't going to go anywhere because they'll be neutralized. So the number of mutations that are required to give it a competitive advantage will likely be higher. And because mutations are random, that will tend to take a longer time than with low levels of immunity.

And the evidence has borne that out. Alpha, Beta, Delta, Gamma, etc. all came about in the first 100-200 million worldwide infections during the first year of the pandemic when there was little immunity. Whereas in the hundreds of millions (or even billions) of infections post-Omicron, the level of mutation is more muted, even while the number of infections is many times higher.

[blankall]

Originally Posted by opendoor

Just to clarify, immunity doesn't encourage mutations; mutations are totally random. The only impact it has is that whatever mutations do randomly occur, the ones that are capable of evading existing immunity will have a competitive advantage over ones that aren't.

But in the aggregate, existing immunity to will tend to reduce the level of mutations that do occur for two reasons:

1) it reduces the number of replications that happen vs. the same spread in an immunologically naive population. It does this both by preventing infection in the first place (as we saw pre-Omicron) and by equipping your body to neutralize the virus faster (studies have repeatedly shown that the quantity of virions is significantly lower in vaccinated/previously infected people).

2) it limits the ways in which the virus can mutate and still spread through the population. With low levels of immunity, basically anything can happen to the virus and it can have a chance becoming dominant. But with existing immunity through vaccinations and infections, certain mutations aren't going to go anywhere because they'll be neutralized. So the number of mutations that are required to give it a competitive advantage will likely be higher. And because mutations are random, that will tend to take a longer time than with low levels of immunity.

And the evidence has borne that out. Alpha, Beta, Delta, Gamma, etc. all came about in the first 100-200 million worldwide infections during the first year of the pandemic when there was little immunity. Whereas in the hundreds of millions (or even billions) of infections post-Omicron, the level of mutation is more muted, even while the number of infections is many times higher.

I agree with your first paragraph.

The main issue is selective pressure. So within a given genome the odds of having a mutation that incurs any kind of benefit are extremely low. Only when there is a selective pressure does that random mutation get propagated.

So for example, a person with no immunity and a person with immunity both have a mutation that occurs 1/1,000,000 replications (realistically meaninfull mutation probably occurs 1/trillions or more). Assuming it's not harmful (which the vast majority of mutations are) the person without immunity would expect to have only 1/1,000,000 viral particles would have the mutation, and if you're exposed to that person, the odds of you coming into contact with that mutation would be low. Meanwhile, the person with immunity and a mutation that carries evasion of that immunity would quickly have that new virus take over, and any further transmissions would be entirely that new evasive virus.

This is why the virus spreads in waves of strains the way it does. There is selective pressure to do so, amongst a population that already has significant immunity. This is especially true with our system of vaccines that no longer protect from actual infection.

I don't know where you are getting this "more muted" mutation thing from? Are you talking about death rate and severity of symptoms? That has more to do with people having cross-over immunity and natural selective evolutionary pressures for viruses not to kill their hosts.

[opendoor]

Originally Posted by blankall

I agree with your first paragraph.

The main issue is selective pressure. So within a given genome the odds of having a mutation that incurs any kind of benefit are extremely low. Only when there is a selective pressure does that random mutation get propagated.

So for example, a person with no immunity and a person with immunity both have a mutation that occurs 1/1,000,000 replications (realistically meaninfull mutation probably occurs 1/trillions or more). Assuming it's not harmful (which the vast majority of mutations are) the person without immunity would expect to have only 1/1,000,000 viral particles would have the mutation, and if you're exposed to that person, the odds of you coming into contact with that mutation would be low. Meanwhile, the person with immunity and a mutation that carries evasion of that immunity would quickly have that new virus take over, and any further transmissions would be entirely that new evasive virus.

This is why the virus spreads in waves of strains the way it does. There is selective pressure to do so, amongst a population that already has significant immunity. This is especially true with our system of vaccines that no longer protect from actual infection.

But you need to be careful with how you put it. Yes, vaccines or prior immunity generate selective pressure on mutations that evade immunity, simply because anything that doesn't evade immunity is dead in the water. However, because mutations are random, prior immunity reduces the number of problematic mutations that are viable.

With little to no existing immunity, a virus just needs to mutate to become more severe without impacting its ability to spread and then you have a very real risk of a more severe variant taking over. That's what happened with prior variants. Once you have widespread immunity though, the virus needs to mutate to become more severe AND mutate in ways that it can evade immunity. That's a significantly higher threshold to clear, as immune evasion requires a fairly significant number of mutations generated through an iterative process of cumulative errors.

And this isn't just a theoretical thing; studies have found an inverse correlation between vaccination rates and the mutation frequency in SARS-CoV-2. As well as a significantly reduced mutation frequency in people with prior immunity, as immunologically naive people who get infected exhibit more mutational variance than vaccinated/previously infected people.

So yes, immunity will favor selection of immune evasive variants; that's obvious and it would be the case even vaccines were 100% effective. But the threat of more severe variants popping up is reduced with a higher level of immunity.

I don't know where you are getting this "more muted" mutation thing from? Are you talking about death rate and severity of symptoms? That has more to do with people having cross-over immunity and natural selective evolutionary pressures for viruses not to kill their hosts.

I mean less diversity. Alpha, Beta, Delta, and Gamma all existed by September of 2020, after there were ~100 million cumulative infections. Since Omicron took over, we've probably had 10-20x that many infections (including a vast number in people with some form of prior immunity), yet the currently circulating variants are still less distinct than the variants that popped up in the first 6-8 months of widespread infections.

[blankall]

Originally Posted by opendoor

But you need to be careful with how you put it. Yes, vaccines or prior immunity generate selective pressure on mutations that evade immunity, simply because anything that doesn't evade immunity is dead in the water. However, because mutations are random, prior immunity reduces the number of problematic mutations that are viable.

With little to no existing immunity, a virus just needs to mutate to become more severe without impacting its ability to spread and then you have a very real risk of a more severe variant taking over. That's what happened with prior variants. Once you have widespread immunity though, the virus needs to mutate to become more severe AND mutate in ways that it can evade immunity. That's a significantly higher threshold to clear, as immune evasion requires a fairly significant number of mutations generated through an iterative process of cumulative errors.

And this isn't just a theoretical thing; studies have found an inverse correlation between vaccination rates and the mutation frequency in SARS-CoV-2. As well as a significantly reduced mutation frequency in people with prior immunity, as immunologically naive people who get infected exhibit more mutational variance than vaccinated/previously infected people.

So yes, immunity will favor selection of immune evasive variants; that's obvious and it would be the case even vaccines were 100% effective. But the threat of more severe variants popping up is reduced with a higher level of immunity.

I mean less diversity. Alpha, Beta, Delta, and Gamma all existed by September of 2020, after there were ~100 million cumulative infections. Since Omicron took over, we've probably had 10-20x that many infections (including a vast number in people with some form of prior immunity), yet the currently circulating variants are still less distinct than the variants that popped up in the first 6-8 months of widespread infections.

What studies have shown that Covid is likely create a more deadly virus in an unvaccinated person? That was likely true back in 2021, when the unvaccinated were far more likely to catch covid. Now with the current strains vaccinated people are just as likely to catch covid.

https://www.healthline.com/health-ne...s-unvaccinated

“They play a huge role. If everyone is vaccinated, eventually infections drop to zero and so do variants,“ Parikh said. “But if the virus has an easy host, such as an unvaccinated individual, then it is easy for it to mutate into a more contagious and virulent form.”

This simply is not true anymore as vaccination provides only a very small amount of protection against actually catching current Covid strains.

Also, what evidence is there to show that Covid will mutate into a more deadly strain. The evolutionary pressure is for the opposite. Also viruses that are extremely similar to Covid-19 account for about 15% of common colds. Why is Covid-19 more likely than these existing viruses, that infect us all the time, to revert into some ultra deadly strain?

[opendoor]

Originally Posted by blankall

What studies have shown that Covid is likely create a more deadly virus in an unvaccinated person? That was likely true back in 2021, when the unvaccinated were far more likely to catch covid. Now with the current strains vaccinated people are just as likely to catch covid.

https://www.healthline.com/health-ne...s-unvaccinated

This simply is not true anymore as vaccination provides only a very small amount of protection against actually catching current Covid strains.

For the reasons I outlined above:

1) Fewer replications in people with prior immunity means fewer opportunities for mutations.

2) Fewer pathways for it to mutate and be viable. For a mutation to thrive now, it has to overcome existing immunity, which is a pretty significant threshold to clear. With an immunologically naive population, that's not a concern. It just has to be able to spread effectively and it can potentially become the dominant variant.

This study is from 2021, but it's comparing infected vaccinated vs infected unvaccinated (e.g. immunologically naive), so any protection against infection is irrelevant. We're talking about what happens after being infected:

Prospective validation of these macroscale evolutionary patterns using clinically annotated SARS-CoV-2 whole genome sequences confirms that vaccine breakthrough patients indeed harbor viruses with significantly lower diversity in known B cell epitopes compared to unvaccinated COVID-19 patients (2.3-fold, 95% C.I. 1.4-3.7).
...
This study presents the first known evidence that COVID-19 vaccines are fundamentally restricting the evolutionary and antigenic escape pathways accessible to SARS-CoV-2.

https://www.medrxiv.org/content/10.1....01.21259833v1

Also, what evidence is there to show that Covid will mutate into a more deadly strain. The evolutionary pressure is for the opposite. Also viruses that are extremely similar to Covid-19 account for about 15% of common colds. Why is Covid-19 more likely than these existing viruses, that infect us all the time, to revert into some ultra deadly strain?

There isn't really any evolutionary pressure to become less severe in a disease that takes as long as COVID does to debilitate. People die weeks after infection, so if it kills 0.1% of those it infects or it kills 5%, it doesn't really affect its ability to spread other than through how we mitigate it in response to its severity. Or to put it another way, why would the less severe variant out-compete a more severe one if both were circulating at the same time?

As to why other coronaviruses don't mutate to become deadly, there are a couple of reasons:

1) They're not as transmissible and they're not nearly as severe. So fewer opportunities to mutate and when they do, they would have to become essentially a fundamentally different coronavirus to get anywhere near the severity of COVID. The only likely way that would happen is through recombination with a more severe coronavirus, but the chances of that are very, very slim.

2) Decades/centuries of prior immunity which helps slow down the rate of mutations for the reasons outlined above (which is my whole point).

To get back to my main point, I was responding what you said here:

Originally Posted by blankall

having immunity actually encourages mutations, for the same reason that antibiotics breed mutations.

That's simply not correct. Immunity (whether through infection or vaccination) does not encourage mutations. There is selective pressure to evade immunity (as there is with any virus), but that doesn't mean it happens at an increasing rate. Overall, widespread immunity tends to reduce the rate and diversity of mutations.

[blankall]

Originally Posted by opendoor

For the reasons I outlined above:

1) Fewer replications in people with prior immunity means fewer opportunities for mutations.

Vaccination does not affect viral load:

https://www.medrxiv.org/content/10.1....31.21261387v1

Originally Posted by opendoor

2) Fewer pathways for it to mutate and be viable. For a mutation to thrive now, it has to overcome existing immunity, which is a pretty significant threshold to clear. With an immunologically naive population, that's not a concern. It just has to be able to spread effectively and it can potentially become the dominant variant.

Exactly...it has to overcome existing immunity, which is what we don't want, and only likely to occur in someone who already has immunity. Once again, without immunity, there's no selective pressure to overcome immunity.

Originally Posted by opendoor

This study is from 2021, but it's comparing infected vaccinated vs infected unvaccinated (e.g. immunologically naive), so any protection against infection is irrelevant. We're talking about what happens after being infected:

https://www.medrxiv.org/content/10.1....01.21259833v1

There isn't really any evolutionary pressure to become less severe in a disease that takes as long as COVID does to debilitate. People die weeks after infection, so if it kills 0.1% of those it infects or it kills 5%, it doesn't really affect its ability to spread other than through how we mitigate it in response to its severity. Or to put it another way, why would the less severe variant out-compete a more severe one if both were circulating at the same time?

Very wrong. People with severe infections go to the hospital and are isolated. People with very mild or no symptoms walk around, go to work, get on transit etc....

Originally Posted by opendoor

As to why other coronaviruses don't mutate to become deadly, there are a couple of reasons:

1) They're not as transmissible and they're not nearly as severe. So fewer opportunities to mutate and when they do, they would have to become essentially a fundamentally different coronavirus to get anywhere near the severity of COVID. The only likely way that would happen is through recombination with a more severe coronavirus, but the chances of that are very, very slim.

Being less severe would increase the chance of a mutation, as it increases the chance of spread. These viruses have been around for centuries, so your argument about having less mutations due to less transmissions is non-sensical.

Originally Posted by opendoor

2) Decades/centuries of prior immunity which helps slow down the rate of mutations for the reasons outlined above (which is my whole point).

No. People are still catching them. They still have large viral loads. The viruses have been around for centuries, as you state, that's a lot of transmissions over that time.

Originally Posted by opendoor

To get back to my main point, I was responding what you said here:



That's simply not correct. Immunity (whether through infection or vaccination) does not encourage mutations. There is selective pressure to evade immunity (as there is with any virus), but that doesn't mean it happens at an increasing rate. Overall, widespread immunity tends to reduce the rate and diversity of mutations.

Immunity encourages the bad mutations, which relate to immunity evasion. And, once again, there's no evidence to show that vaccinated people have decreased viral load. That's simply not the way vaccines work. Another paper on the subject:

https://www.thelancet.com/journals/l...ted%20contacts.

Vaccination reduces the risk of delta variant infection and accelerates viral clearance. Nonetheless, fully vaccinated individuals with breakthrough infections have peak viral load similar to unvaccinated cases and can efficiently transmit infection in household settings, including to fully vaccinated contacts. Host–virus interactions early in infection may shape the entire viral trajectory.

Vaccination does not decrease replications, it just helps your body clean them up quicker and with less dangerous elements of the immune system. For example, someone without immunity would rely more on fevers, inflammation, mucus, inflammatory systems, cytokines, etc...which can be quite damaging, and, in fact with Covid are likely the cause of most deaths. People with immunity will rely more on B-Cells, anti-bodies, T-Cells, etc...which can be less damaging (obviously there are exceptions, see HIV).

[opendoor]

Originally Posted by blankall

Vaccination does not affect viral load:

https://www.medrxiv.org/content/10.1....31.21261387v1

PCR cycle counts aren't really a great proxy for viral load or replication levels. They pick up dead and neutralized virions, which is why you can test positive for months after recovery. Only culture tests which determine the level of live virus are useful for determining this, and they have repeatedly shown that immunologically naive people have significantly higher viral levels.

And of course, even if peak viral load was similar, the duration of infection (and replication) is shorter with prior immunity, so the total number of replications is lower.

Exactly...it has to overcome existing immunity, which is what we don't want, and only likely to occur in someone who already has immunity. Once again, without immunity, there's no selective pressure to overcome immunity.

It has to overcome it, but it doesn't make it more likely. Mutations are random, so the threshold for a new variant to spread is higher with immunity. So yes, there is evolutionary pressure to evade immunity, but because immune evasion generally requires a fairly significant number of mutations, the bar is higher.

And ultimately, partially overcoming immunity isn't necessarily a big deal, as long as there isn't a corresponding increase in severity. That's what we see with other coronaviruses.

Very wrong. People with severe infections go to the hospital and are isolated. People with very mild or no symptoms walk around, go to work, get on transit etc....

It normally takes a week or so of someone being infectious before they end up with a severe infection, and for much of that period there is little distinction between mild and severe COVID. That and pre-symptomatic spread are things that make COVID so infectious.

Being less severe would increase the chance of a mutation, as it increases the chance of spread. These viruses have been around for centuries, so your argument about having less mutations due to less transmissions is non-sensical.

You're misunderstanding what I said. You asked why other coronaviruses haven't randomly become deadly, and why COVID would be more likely to do that than the other circulating coronaviruses. I said, that's because they're far less severe. To become deadly like COVID is, they'd have to become vastly more severe as a result of a mutation, which is basically impossible for any coronavirus, barring a recombination with a more severe variant (which is exceedingly unlikely in humans).

No. People are still catching them. They still have large viral loads. The viruses have been around for centuries, as you state, that's a lot of transmissions over that time.

But the rate of mutation is lower for the reasons I outlined (immunity reducing the genetic diversity and allowing the body to neutralize the virus faster).

They also may be inherently more stable too, but it's hard to know that so early into SARS-CoV-2's existence. Though it is speculated that the Russian Flu in 1889-1890 was actually the introduction of the OC43 coronavirus into the human population. But once it circulated enough, there were no longer immunologically naive people (other than infants) so the burden dropped significantly over the years.

Immunity encourages the bad mutations, which relate to immunity evasion. And, once again, there's no evidence to show that vaccinated people have decreased viral load. That's simply not the way vaccines work. Another paper on the subject:

https://www.thelancet.com/journals/l...ted%20contacts.

Vaccination does not decrease replications, it just helps your body clean them up quicker and with less dangerous elements of the immune system. For example, someone without immunity would rely more on fevers, inflammation, mucus, inflammatory systems, cytokines, etc...which can be quite damaging, and, in fact with Covid are likely the cause of most deaths. People with immunity will rely more on B-Cells, anti-bodies, T-Cells, etc...which can be less damaging (obviously there are exceptions, see HIV).

Think about the bolded for a second. So vaccinated/previously infected people are infected for a shorter period of time, yet that doesn't lead to fewer replications? How does that make any sense?

Again, the proof is really in what we're seeing. If immunity encourages dangerous mutations, then why was the rate of new variants of concern per infection vastly higher in the first year of the pandemic compared to now? We should have seen 10-20 changes equivalent to Alpha, Delta, or Beta based on the number of post-Omicron infections. And why haven't we seen significant mutations in the other circulating coronaviruses over the decades?

The answer is, an immunologically naive population is like a blank canvas. The virus will mutate and basically any type of mutation has the chance to become dominant. So if it mutates to become more severe, well there's nothing to really stop that as long as it can spread effectively. But with immunity, if it randomly mutates to become more severe, chances are it will die out almost immediately (and before being detected) as it hits a wall of immunity.

[jayswin]

opendoor has been incredible to read throughout this pandemic.

[opendoor]

I will say, blankall's original point (at least what I think he was getting at) is a fair one. At this point, unvaccinated people aren't going to be the population that drives mutations, because most of them have had COVID already. So the idea of the unvaccinated being variant factories is more of a relic of pre-Omicron when they were basically the only ones getting infected in any real numbers.

And yes, it's true that widespread immunity will put evolutionary pressure on mutations to get past that; that's just the reality. But ultimately, high levels of immunity will tend to depress the the rate of troublesome variants, potentially significantly. In the 7 months that Omicron has been dominant, we've seen probably 10-20x as many infections as we saw in the period that resulted in Alpha, Beta, Delta, and Gamma coming about, but so far there hasn't been a significant level of change in either severity or immune escape. And that's with a relatively large portion of the world's population still being immunologically naive before Omicron took over (about 40% of the world's population isn't vaccinated).

And beyond that, there's no real option in the matter like there is with antibiotics. We can be stricter with antibiotic use in order to delay antibiotic resistance and generally have similar health outcomes (i.e. by only using antibiotics when necessary and by following the full course). There's no other path we can take with a circulating respiratory virus. We're all going to be repeatedly exposed to it and will generate immunity one way or another (whether that's through infection, vaccination, or a combination of both).

[TorqueDog]

It would be nice if we could start expanding availability of Paxlovid and other COVID-19 antivirals going forward.