Douglas_Knight

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Covid 2/4: Safe and Effective Vaccines Aplenty

All the modeling efforts talked about in the write-up are doomed because they don’t understand the role of the control system

Is that a forward-looking prediction? What consequences was UIUC doomed to? The article ends its coverage of UIUC in early September, declaring it a failure. But, in fact, it achieved its goal of keeping infections below 5k. You could credit that to "the control system," the panic caused by the early spike that got all the news coverage, but it's still a success.

Making Vaccine

If it's so cheap and easy to make vaccines, why aren't commercial ones made this way? In particular, the Novavax vaccine sounds similar, so why wasn't that the first vaccine to market?

Added: Specifically, the ultimate purpose of a vaccine is to get protein into the body. Traditional vaccines grow the virus using its own reproductive apparatus. Fancy new vaccines, like the adenovirus and mRNA vaccines inject instructions and induce the subject to manufacture proteins. But if it's so easy to just print proteins, why don't we do that? That's what Novavax does, unlike the ~7 vaccines that beat it to market.

Added: one difference is that all the vaccines that made it to market, including, I think, Novavax, used the whole spike protein, whereas this proposal uses short peptides. Identifying the right short snippets takes time, while using the whole protein is simpler and more likely to work. The cost of peptides is probably super-linear in length. Still, I remain confused about Novavax.

Covid 1/28: Muddling Through

By default, we should expect viruses to become less deadly over time rather than more severe, but more severe is always a risk. We also believe the new strain carries generally higher viral loads, which could plausibly be a cause of higher severity.

That is the consensus among biologists, or maybe even evolutionary biologists, but the consensus among people who study the evolution of parasites is exactly the opposite. Theory predicts and observation agrees that parasites evolve to become more virulent over time, especially ones that have just jumped from one host to another. See Paul Ewald, for example.

Covid: Bill Gates and Vaccine Production

I suspect that Gates had a long-standing specific plan for manufacturing old-fashioned vaccines, but was unable to pivot to funding new vaccines. It's a lot harder to spend money to speed up deployment of new technologies, especially at arm's length.

AZ claims this week that the EU negotiations being delayed for a couple months delayed their factories. Why couldn't they just start earlier? This is a clear claim that money would have mattered. But maybe there is a lot more to this than physical construction. The EU is currently threatening to confiscate AZ vaccine, so maybe AZ didn't see any point in building factories in countries that hadn't pre-paid.

Covid: Bill Gates and Vaccine Production

Why is the Gates foundation a charity, as opposed to just a non-profit? If he wants to take Buffett's money and give him a tax benefit, then it has to be charity, but for spending his own money, he doesn't need this status.

Covid 1/21: Turning the Corner

Given the high dimension of the search space, I think (b) is negligible and the linear model (a) of your first comment is better. In low dimension the boundary of the unit sphere is small and you can have a lot of copies on the inside, having to pass through the sphere to reach new terrain. Whereas, in high dimensions, the population will quickly thin out and all be unique, so what matters is the total volume of space explored, not how long it takes to get anywhere.

Covid 1/21: Turning the Corner

Dynamically, that predicts that the advantage would rise over time, as a substantial proportion of the population got infected by the original strain. I think we've been monitoring the UK variant enough to see that this is not a large portion of its advantage.

Even statically, I think it's difficult to make the numbers work out. The idea that the population has heterogeneous risk makes a lot of sense, but it doesn't seem born out by the basic prediction that HIT is much lower than predicted by initial R. I suppose the control system might make it hard to observe how close we are getting to HIT, but I'm skeptical. And you need zero cross-immunity. But then wouldn't the observed reinfections skyrocket and be obvious? Maybe if the reinfections are asymptomatic, but just as contagious. I guess that this very specific scenario predicts that the new variant has passed through the riskiest portion of the London population and no longer has an advantage there.

Covid 1/21: Turning the Corner

My (highly speculative!) hypothesis is that the emergence of these variant viruses arises in cases of chronic infection during which the immune system places great pressure on the virus to escape immunity and the virus does so by getting really good at getting into cells. 11/19

That’s plausible, but doesn’t explain why the chronic infections hadn’t done this earlier, and the English strain doesn’t escape immunity in this way (and we don’t know about the others) so I notice it doesn’t feel like it explains things.

That isn't plausible to me. Not only does it not explain everything, I don't think it explains anything. There are two traits, immune escape and infectiousness, which is pretty much the same as fitness. It makes sense that chronic infection causes immune escape, but we aren't looking at immune escape. There might be tons of strains with immune escape out there, but we won't notice until we achieve substantial herd immunity, at which point they will have increased fitness. If that happens, and we need to explain immune escape in future strains, then this is a possibility. But I see no reason to believe it about these strains. We are filtering by increased fitness, so we need to explain increased fitness. Immune escape is probably a side effect of increased fitness, because it's a potential side effect of any change.

Fitness is fitness. There is no need for a weird environment to explain selection for fitness, because it's the main story. In fact, this is exactly backwards. If there is any trade-off between reproduction between hosts and reproduction in hosts, then selection by chronic infection will favor the latter at the expense of the former and probably move away from optimal fitness. Whereas it appears, as Bedford claims, that these mutations are a free lunch. This is quite plausible for a young parasite that hasn't finished adapting to its new host. But then what does a weird selection pressure explain? Every infection should be an opportunity to develop this. What matters is the number of roughly the number of virus-host-days. A virus trapped in one individual for 100 days is under roughly the same selection pressure as a virus passing through 20 individuals under the same time. I've seen a lot of people call that "fast evolution" because 20x as much selection happens in the host, but it's not any faster in time.

Bedford seems to allude to this view, but he also uses similar points to make a different argument, which is that the UK variant appeared out of nowhere with a lot of mutations, without the intermediate forms being observed. Arising from a chronic infection would explain this. But we also know that all the mutations have arisen before, without seeming to do much on their own. So we know that it only took off when it reached the magic combination, which explains why we didn't see the intermediate forms. I don't think chronic infection adds much to this, although I could imagine a scenario in which the individual changes happen to be selected for in chronic infection at the slight expense of general fitness. So it needs the different landscape of a chronic infection to cross the valley and reach the final form. But this seems like excess detail to me.

Covid 1/7: The Fire of a Thousand Suns

I don't believe that every infected cell is killed.

Covid 1/7: The Fire of a Thousand Suns

This is about the change that is shared between UK and SA, not about the change in the SA variant that is uniquely worrisome.

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