I wish I had recorded my thoughts the week before they removed most of their remaining restrictions. They were something like “only 20% of adults haven’t been vaccinated, they’re working down the age distribution, and they’re infecting as fast as the winter. At some point, they just have to run out of people.” I thus vaguely expected things to drop, especially as they had turned around before.
One, they’re just running out of susceptibles, two, a shorter serial interval means that everything up and down happens faster and the R value is likely not as higher as it would be if you did not take this into account, and three… a good bet has been to expect authorities to be wrong.
I don’t even understand what Thiel is trying to say, which is pretty typical.
The ‘not a half life’ graph is an IgM graph, not an IgG graph. IgG is the one produced in large amounts for long periods, IgM is always transient. When anyone is talking about half lives, they’re probably talking about IgG.
The ‘effectiveness drop’ data from Pfizer, from what I understand, is confounded by changes in the dominant lineages infecting people over time.
Endorsed by someone who has been reading the literature obsessively. The NTD can still get some mileage but most of the really interesting stuff has happened.
Not yet, I used the Google project where they are posting predicted structures of every known human and yeast gene.https://alphafold.ebi.ac.uk/
The example that made me laugh:
Personally, I can confirm that every yeast protein I work with that does not have a structure, when fed through alphafold produces absolute garbage with mean predicted errors on the order of ten or twenty angstroms and obvious nonsense in the structure.
Granted I work with a lot of repetitive poorly structured proteins which, in as model-system of an organism as yeast, are the only ones without structures and someone has to get unlucky… but still.
Honestly I think it’s quite the opposite. There is no particular reason that lineages that escape immune reactions would be more likely to be driven into existence in a population largely vaccinated or largely infected, and you don’t talk about this in the context of people who have been naturally infected.
We are pulling the inevitable, the time that everyone has immune memory, closer in time to the present and ensuring that we get there with fewer rounds of viral replication in the mean time.
Could the fact that both anecdotes involve large groups simultaneously support the model of correlation and clustering presumably from single extremely infectious sources?
Combined with observations of significantly decreased contagiousness from vaccinated people I would expect such events to become much rarer when completely naive people are rare. Consider the dynamics here, ~6 apparently infected in one event and then only two of those continuing to pass it on at all, a sub-replacement chain in that different context.
I would VERY strongly argue this place also lacks brakes.
There have been some reports that it’s not necessarily just the R value that is changing for the delta lineage, but also maybe a faster serial interval. Both of these would result in faster spread, but only the R change would affect the immunity you need to damp spread, the interval just means everything happens faster.
It should be noted, for your contagion calculations, that people infected through immune memory are almost certainly not NEARLY as infectious to others on average as completely naive people who are infected.
Israeli healthcare workers who are vaccinated who test positive have a much decreased viral RNA level in their samples, circa a factor of thirty, with the difference increasing as time from vaccination increases. There is a wide range but the whole range moves down so way fewer people will have the obscene viral levels that can do things like infecting sixty people in a room all at once. They also go from 80% showing up positive on an antigen test to 30% showing up positive on an antigen test—which has been a reasonable binary proxy for infectiousness in the past.
This makes sense. You never hear about 60 people all getting the flu at once in one place except in very special circumstances (things like an airplane sealed for two hours without air circulation and filtration), presumably because everyone has at least some anti-flu memory even if it isn’t good enough to completely stop everything in its tracks. The disease dynamics when there are lots of totally naive people running around is going to be completely different from the dynamics when everyone has memory, be it from vaccines or infection.
Everything said here is wrong, I am pretty sure.
I am super skeptical of that whole brain damage thing. Brains change, from all kinds of things. I can’t help but notice that everywhere they see statistically significant differences is downstream of smell and taste, and actually closely resembles previously described brain changes in people with chronic rhinitis that blocks the sense of smell through ordinary means.
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’.
Insertions and deletions happen all the time rather than being some kind of rare freak event. They can be random gobbeldygook or they can be short sequence insertions from something else.
Lots of other coronaviruses have insertions and deletions at the same spot rather than it being something rare, just the creation of this particular type of cleavage site is rare. However, this cleavage site is known to increase host breadth and cell type breadth, so if you are conditioning on seeing something that jumped species it’s more likely. Other less closely related viruses have furin sites, but the SARS-like viruses are severely undersampled.
I honestly don’t even know what the codon choice people are arguing. You are creating a new insertion, not looking at the rest of the genome, why would the content of the rest of the genome be relevant to the odds of using a particular codon? Also, these codons are not selected against, they have kept up fine in the human population.
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...