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Old 07-03-2022, 11:56 PM   #561
activeStick
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An article in the Vancouver Sun which is a bit concerning predicting rapidly rising cases coming to the Lower Mainland by mid-July and August and concerns about the fall. A fourth dose isn't being offered right now here by Dr. Henry saying that what they have on hand needs to be reserved for those who haven't gotten their 2nd dose or third dose yet. But not sure it would help anyway as it sounds like the sub variants are getting past the current vaccines.

https://vancouversun.com/health/loca...o-grow-rapidly
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Old 07-04-2022, 12:33 AM   #562
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Eric Topol also doesn't have a bright outlook below

https://erictopol.substack.com/p/the-ba5-story
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Old 07-04-2022, 09:28 AM   #563
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Remember the good ole days when we use to debate about herd immunity.
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Old 07-04-2022, 11:09 AM   #564
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In Topals article it sounds like we just need a 4th booster for over 50 and we will get good protection from hospitalization.

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Boosters would help, and it is noteworthy that for people age 50+ there is a substantial (14-fold) reduction for mortality as recently documented by the CDC for a 4th shot (previously published by the Israel investigators in multiple observational studies). That is 99% reduction in mortality for 4-shots vs 86% for 3 shots. But only 1 in 4 Americans age 50+ have had a fourth shot!
So in terms of limiting severe disease the same strategy looks to be effective. We need to deal with the endemic disease line we do with flu shots.
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Old 07-04-2022, 11:20 AM   #565
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Originally Posted by opendoor View Post
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.


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.


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.



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).


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.



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.
You're fundamentally misinterpreting the way viruses spread in the body. It's not a slow spread. Each one of the initial cells that gets infected will then make hundreds of thousands of copies and all the vulnerable cells are exposed within 1-4 days (depending on strain), at which point the a full blown immune response typically kicks in.


By this time, the body will have been at full viral load, and the vast majority of the cells that are going to be infected, are already infected. With Covid-19, between 1-10% of lung cells are considered vulnerable, and only a small percentage of those ever become infected. No one is sure why some cells get infected and other don't.

Clean up, also doesn't refer to how long replications go on for, but how long the active virus particles, that have already been produced, remain in the body. With a targeted immune response, the clean up of these existing virus particles happens quicker. However, even then it's pretty marginal.

It's not like the virus is slowly spreading through the body and you're dealing with new cells getting infected.

I also don't know what you're talking about in terms of proof of new variants. The new variants started to explode in number around the time that more people were getting infected. Once again, past the first 4-6 months there was no real advantage to infection against protection by vaccination. A dangerous variant is just as likely to arise in an unvaccinated/vaccinated person, but only a person with existing immunity is likely to create a variant that evades immunity.

I agree with your point about functional mutation, you're most likely looking at requiring several base mutations. Although, that's not entirely certain, as it could be just a single base mutation, that's unlucky that could result in non-binding of some immune cell. Single base mutations can, for example, change the 3-dimentional structure of a protein (or RNA/DNA strand). Also I don't get where you're getting the idea that it takes more mutations to have an immunity evading mutation than one that affects how deadly the virus is. You're literally just making that up. For example, a mutation that results in faster replication or binding to a different tissue in the body, could require
a somewhat fundamental change to the virus. There could also actually even be a single mutation that results in both a deadlier and more evasive virus.
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Old 07-04-2022, 11:34 AM   #566
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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).
For the record, I was in no way arguing against vaccination. It's an excellent form of immunity and has been proven to decrease the severity of infections. Once again, the acquired immune response from vaccination has been shown to be far less deadly than the purely innate immune response you see in those with no pre-existing immunity.

This is a great article that talks about how the roles of the various parts of the immune system:

https://www.nature.com/articles/s41418-022-01015-x

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Pro-inflammatory macrophages are the major immune cell type that expresses high levels of ACE2 [38]. Upon SARS-CoV-2 infection, these macrophages release inflammatory cytokines and chemokines including C-C motif chemokine ligand 7 (CCL7), CCL8 and CCL13 to recruit and activate T cells. In turn, T cells produce IFN-γ and other cytokines to further activate macrophages [39]. This positive feedback loop drives the elevation and continuation of the pathological inflammation. Epidemiological data show that older adults and people with underlying health conditions exhibited a dramatically high rate of severe disease and mortality [17]. Along with aging, there is a tendency of increasing inflammatory macrophages [40]. This not only explains why chronic inflammatory disease occurrence is more prevalent but also provides a possibility accounting for the high incidence of severe COVID-19 cases in older people. Along with this scenario, it is reasonable to comprehend why SARS-CoV-2 infection in those with underlying medical conditions also exhibited a higher prevalence in severe disease and mortality [12].
Basically you want ot avoid a high inflammatory response in favor of a targeted immune response.

Doesn't change the fact that the next strain that needs to spread, will have to be one that mutates to avoid existing immunity, and that is only likely to occur in someone with existing immunity.
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Old 07-04-2022, 01:24 PM   #567
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In Topals article it sounds like we just need a 4th booster for over 50 and we will get good protection from hospitalization.



So in terms of limiting severe disease the same strategy looks to be effective. We need to deal with the endemic disease line we do with flu shots.
I assume they will just open it up to everyone but much like the flu shot - the impact will be bigger for older people, immunocompromised, and other higher risk people (obese, smokers, diabetic, etc).

The waiting to tweak the formulation to point towards current variants has been odd as well. One would hope a better targeted vaccine may be more effective in lower risk of catching it.
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Old 07-04-2022, 02:15 PM   #568
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Doesn't change the fact that the next strain that needs to spread, will have to be one that mutates to avoid existing immunity, and that is only likely to occur in someone with existing immunity.
Not necessarily. Immunity against infection wanes in coronaviruses, and other coronaviruses continue to spread year to year without significant mutations that result in immune escape. For instance, OC43 (the most common human coronavirus pre-COVID) has had single genotypes dominate for up to a decade.

And even if it is the case that immune evasion is the only path it can take, based on the evidence from other viruses, the process will most likely slow down (and it probably already has as I've said above). Recently emerged viruses will tend to display a much more rapid mutation rate that more closely matches their rate of substitution, and this is even more true when there's extremely rapid growth in infection numbers. Only when they are subject to more evolutionary pressures will purifying selection tend to quash deleterious mutations. That has been shown in previous flu epidemics as well as with the limited evidence we have from SARS-CoV-2.

So over time, evolutionary pressures will point mutations in a certain direction (i.e. immune evasion), but they will also significantly reduce the viability of most mutations that do occur, slowing down the overall rate of deleterious mutations.
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