FWIW I expect the equilibrium severity in the absence of continued immunization and presence of continued drift whenever it manages to slip through preexisting memory to be rather worse than the other human coronaviruses, at least for a while. This bugger has a clutch of fancy accessory proteins that help hide from and screw up immune reactions, and for other reasons is very good at forming syncytia and infects such a wide range of cell types. But NOTHING like what happens when people get it never having seen anything like it. Think closer to flu on the cold and flu spectrum. But we deal with that, and the antigenic drift after this explosive adaptation-to-humanity phase should be slower than we are dealing with now. All the evolution we have seen lately is about becoming better able to infect human cells, with mild immune evasion from previous memory a side effect. It is even possible that once the primary selective pressure is for immune evasion, the infectivity declines again due to the different set of trade-offs encountered—the best analysis I have seen of the D614G mutations that took over the world in the first half of 2020 suggests that it increased the avidity of the protein to human cells at the expense of making the S1 domain more open to neutralization and immune deactivation by immune memory, but this did not matter because all the infections were directed towards those with no memory.
Decent possibility that over the coming decades the fancy accessory proteins (which are very necessary for infection in bats, less so for humans) start falling to bits due to Muller’s Ratchet, as mutations that degrade them hitchhike along for the ride with spike and nucleocapsid mutations that actually allow infection of those with immune memory. This already sort of happened once in the Alpha lineage, where accessory protein ORF8 that hides T-cell epitopes from the immune system broke but got dragged along for the ride linked with a spike that was better at attacking human cells.
Most of what is said about all of that suggesting it is suspicious is truly ‘not even wrong’.
The other side is not using that reasoning.
Because there is no evidence that they mean any of that.
The mechanisms stopping growth in vitro at obscene concentrations I agree are probably not operative in vivo, or at the very best not in the same way. However there are other bits of data regarding the drug as an immunomodulator in other viral infections, and this virus in particular has much of its pathogenesis having to do with badly regulated immune reactions.
Basically I am at the awkward position where I think the risk to potential reward ratio is favorable and that good research is needed while thinking most of the existing research is super shoddy.
While I agree that there is insufficient attention paid to ivermectin as a possible treatment in Western nations, I have seen far too much shoddy and conflicting data in the studies that are brought forward proposing it as prophylaxis and think the hype is a spiral that has amplified nonsense into prominence. People LOVE the idea of a panacea. While there is quite possibly something interesting going on there it has been hyped to the moon and back in a way it should not be.
The animal data I have seen that I trust the most (since it avoids many of the pitfalls of observational trials, and few people are doing randomized trials that are actually good and not shoddy as hell after chloroquine sucked all the oxygen out of the room) suggests there could be something there, but not in a way that would block epidemics. Animals that are infected and then dosed have no difference in viral levels but recover their sense of smell significantly faster and when you take tissue samples the levels of inflammatory and tissue-destroying signaling molecules are lower while the ones that are more classically associated with antiviral responses are higher. Leans me towards the idea that it could decrease severity and odds of falling into downwards spirals. I have been following the in vitro work on this from the beginning and my conclusion is that you’re probably looking at immunomodulatory effects that can help you not fall into the pathological attractors, and deal with long infections better, rather than doing anything about viral binding or replication, if any of it pans out.
See, as an example, https://www.biorxiv.org/content/10.1101/2020.11.21.392639v1.full
This being said, given the safety profile of the drug I say the risk to reward ratio is pretty good if you pay close attention to contraindications and I see no reason for it to not be used and studied more.
With regards to repurposing drug studies being almost impossible, I am much much more angry that there are no good studies, and no studies at all outside India, for indomethacin. A much more promising and well defined antiviral mechanism there against cytoplasmic RNA viruses via host factors that works STUNNINGLY well on canine intestinal coronaviruses in vivo, and sars and sars-2 in culture, and when you dig carefully through the literature being already on it by prescription is associated with much lower covid hospitalization risk.
I should try to dig up an essay I remember reading a few years ago, that argued that American social innovation and engagement regularly swings back and forth between the religious and the political on generational timescales...
I continue to state that most of what is being said by absolutely anyone about furin (and synonymous codon choice, in this case) to support lab ideas is simply nonsense. There is nothing particularly interesting at all about the genetics.
Sounds like something to look for antibodies (or more functionally, T-cells) in the population at large and see if they are correlated with autoimmune diseases, and sounds like something to look for a mouse equivalent of and see what happens when you immunize them against a sometimes-expressed transposase.
They’re also never exactly at high levels.
I actually care a lot less about ‘never getting it’ now, since I will never have to deal with that first burn though me when I have never seen anything like it at all since I am vaccinated. Any memory is good, even in the face of drift or waning.
I couldn’t tell you if there will be updated boosts over time. If so, they’ll certainly help...
I expect it to return as an endemic seasonal virus, especially in areas of low vaccination uptake, with continued antigenic drift allowing occasional mild infection of those with immune memory after enough time has passed. It’s the first infection of a naive set of lungs that matters though.
If you aren’t vaccinated you WILL be infected eventually.
Indeed, it does not.
Opposite. Them getting to your immune system from slightly different ‘directions’ likely increases effectiveness slightly, especially for the adenoviral vector vaccines where vector immunity might be an issue.
I am pretty sure the FDA thing is just simply completely factually wrong, actual fake news in the original sense of the phrase.
It is a small change that only applies to bulk drugs in compounding pharmacies and is being widely misinterpreted… near as I can tell they are reviewing four supplements including melatonin for inclusion on the 503A Bulk List, which would make it legal for compounding pharmacies to use them, with that long list shown being things they are continually looking at for ADDING TO AUTHORIZATION FOR COMPOUNDING PHARMACIES. List two (not pictured, later in the document) is for things that are anti-recommended for compounding pharmacy approval, and list 3 is things that were recommended but they don’t think they have enough evidence for approving for compounding pharmacies. No banning of supplements anywhere, nothing going away at all in any way shape or form in that document. In fact, it means the OPPOSITE of what is being implied here!
N-acetyl cysteine does not appear anywhere in that document and appears to be an entirely separate and self-contained matter that refers to that substance and that subestance alone. Seems to have been going on for a year now having to do with them enforcing something that was technically true but unenforced before, that it was marketed as a drug decades ago before people started selling it as a supplement. Stupid and definitely an error but not a new regulation and companies are covering their butts.
Nobody is regulating parsley, sesame seeds, ribose sugar, and yeast as drugs. This list should have been a dead giveaway and I am flabbergasted that anyone can take it seriously as some kind of ban list. The referenced twitter accounts appear to be simply forwarding falsehoods and some seem to be kind of… interesting.
That… seems like almost precisely the opposite metaphor one would use to compare to reality? Instead we are looking at something that happens naturally ALL THE TIME and you need special effort to sometimes maybe replicate if you really wanted to?
A hell of a lot of what they say about furin is simply wrong. Insertions and deletions happen ALL THE TIME in nature and while rarer than SNPs are not uncommon, around the cleavage site loop there are other indels in related viruses, the furin site is DECIDEDLY suboptimal for cleavage such that all the fun lineages that are more contagious are optimizing it and creating actual canonical sites rather than something just good enough, it is generated out of frame in in a way that no sane biologist ever would, and the glycosylation pattern nearby weakly suggests it appeared in the context of an actual immune system rather than cell culture.
The alignments they point to arguing for other differences in the cleavage sites in other viruses being due to SNPs rather than insertions are laughable, and from people who I have found to have a poor grasp of the underlying science.
On top of all that when conditioning on something that successfully changes species you will enrich for things that broaden their tropism, which that kind of cleavage site will do, so of course things that are rarer but helpful will pop up more than if you were looking at the space of all possible mutations without conditioning.
There is absolutely nothing about the biology of the virus that suggests laboratory anything. Anyone who says it does does not know what they are talking about. If anyone says something about furin being suspicious or indels being unlikely, or recombination patterns being odd, they can safely be ignored and their opinions discounted. Yes, this includes David Baltimore.
One cannot exclude the possibility that someone had a stock in a lab being studied somewhere and it got into a lab worker by sheer bad luck. That would look quite similar to the utterly normal zoonotic spillovers that happen all the time, especially for something like this that is a tenth as deadly as SARS classic such that the early thin transmission chains are effectively invisible to public health infrastructure.
SARS classic has infected lab workers before, but as something that caused a previous global issue it was being studied by many people in many places while in the scenario of a novel zoonotic transfer having occurred in a lab, you almost certainly just have one poorly characterized sample of something with no published sequence data someone happens to be growing for a quick one-off experiment spilling over such that the rate would presumably be much much lower.
I see no reason to think that this is particularly likely over and above utterly normal outside-world zoonotic spillover that happen all the freaking time (several percent of Chinese villagers tested for antibodies against SARS-like viruses that live near bat caves have them in previous literature), especially since the invisibility of early thin overdispersed transmission chains mean the first big outbreak could occur somewhere quite different than the location of the initial zoonotic event. Even SARS-classic had its first big internationally-noticeable explosion happen thousands of miles away from the initial site of zoonotic spillover, and if it were not as deadly as it was that initial spillover in southern China could potentially have gone unnoticed outside of local authorities and you could’ve been talking about SARS as originating in Hong Kong.
All this being said given the state of recombinant DNA technology and its power I do see the value in most virology work using reconstituted sequence in pseudovirus systems rather than infectious particles.
Returns on performance being pareto distributed is emphatically NOT the same thing as performance being pareto distributed.
Optionality, to echo Nassim Taleb?