Can you speak on this since Alvea has been wound down?

As a layperson, I'm increasingly convinced that we're on a path to a devastating H5N1 pandemic within the next few years, possibly much sooner (writing this in late June 2024). My concern is based on the amount of "biocomputation" that is going towards / will soon go towards parallel search for mutations that have the side effect of triggering a pandemic in humans, plus the risk of viral reassortment with human-native viruses. I've been reading a lot about this over the past few days, and I'm eager to defend this position or revise my opinion in light of new arguments.

Here's my basic reasoning:

• The virus has been adapting for mammals: https://www.nytimes.com/2024/05/03/health/bird-flu-cows-mutations.html

• Grocery store tests suggest it is already very widespread among dairy cattle: https://health.ucdavis.edu/news/headlines/grocery-store-milk-tests-positive-for-bird-flu-why-the-fda-says-its-still-safe-to-drink/2024/04

• I believe this represents a shift from past H5N1 behavior, which did not involve transmission amongst domesticated mammals: https://wwwnc.cdc.gov/eid/article/30/3/23-1098_article

• Adaptations which increase fitness within a dairy cow are also liable to trigger a human pandemic, e.g. added a2,6 SA receptor binding ability: https://nitter.poast.org/richardhirschs1/status/1804830640418025518

• There's a lot of cattle (the US has around 6% of global cattle): https://xkcd.com/1338/

• Lots of cattle biomass = lots of tissue infected with H5N1 = tons of virions (viral density in raw milk is "astronomical" per Nature) = lots of opportunities for a virion to find a mutation that increases fitness in cattle and/or in humans.

• Furthermore, as an influenza virus, it has a high mutation rate (which would appear to both lower mutation barriers, and decrease the effectiveness of vaccination).

• There are multiple vectors for a mutated virus to spread from cattle to humans: raw milk consumption, poor ag worker biosecurity (see milking parlor discussion here), upcoming county fairs. (Pigs might also serve as an intermediary. Part of why I'm so worried is I see various distinct catastrophe stories.)

• For all we know, human-to-human spread is already occurring in states which are doing less testing than Michigan: https://www.michigan.gov/mdhhs/inside-mdhhs/newsroom/2024/05/30/h5n1-updates

• Don't forget about the risk of viral reassortment with ordinary human influenza this fall, given the multiple human/cattle contact vectors I mentioned previously.

• And finally, if an H5N1 pandemic happens, it could be really bad: https://www.nytimes.com/2024/06/17/health/bird-flu-pandemic-humans.html

• On the other hand, perhaps widespread consumption of pasteurized milk could act as "accidental vaccination" (exposure to deactivated virus) and blunt the spread. As a layperson, I am out of my depth here. Could I drink previously-infected pasteurized milk and consume an adjuvant as a method of DIY vaccination?

• Metaculus puts us midway between COVID and the Black Death on a log scale for death rate, perhaps something like the Spanish Flu -- one of the worst pandemics in history? https://www.metaculus.com/questions/23762/h5n1-case-fatality-rate-in-us/

Clarifying my position here, I'm not claiming there will be a pandemic next week or next month. My claim is more that "common in cattle but not common in humans" is an "unstable evolutionary equilibrium" for H5N1, which is unlikely to persist for an extended period of time.

Another way of putting it is that the ambient risk level for H5N1, in the sense of the number of possible-pandemic dice which are getting rolled every day, seems to have gone up a lot recently. The risk level is likely to stay high, because I expect H5N1 to become endemic among cattle (if it isn't already). And regulators seem to be dropping the ball, just like they did for COVID. Calling your congressperson and telling them to ask regulators hard questions could be high-impact.

Thank you, that's very reassuring to hear. It can be hard to tell whether an issue is being overlooked or not

I've spoken to some virologists who think the probability of it becoming a pandemic is low. However even tho there has been limited human spread for years, I am not aware of outbreaks rather than very limited infections among other mammals in past outbreaks like we are seeing now. I'm getting pretty worried, although I haven't yet come up with probabilistic predictions.

Also one thing I am not clear on is the efficacy of tamiflu or whether focusing on increasing tamiflu supplies might help.

The main concern now is that we’re seeing unprecedented likely mammal-to-mammal spread. I don’t know what seems intuitive to most people, but this is the reason for heightened concern around the issue. Whatever your priors were before, this should probably update you towards a bigger risk of human-to-human spread.

Also, with regard to human vaccines, my understanding is they’re in low stock and only tested for seroconversion, since we don’t use them widely enough to get direct data on efficacy. We also have poultry vaccines but don’t use them widely, and it seems their effectiveness is inconsistent. So much to be improved on in the realm of H5N1 vaccine tech.

*H5N1

I don't think I suggested that? Forgive me if the original post was phrased poorly, I wrote it in some fourty minutes.

My point with mentioning 10,000 lives lost was to operationalize the question of whether it becomes a serious pandemic.

Agreed. Here's the account I would give, using my pandemic prediction checklist framework.

• Currently, H5N1 scores a 5/14. COVID scored a 13/14.
• +1 point: You'd have a death toll of > 2,000, 5x beyond when we saw the stock market crash during COVID
• +1 point: Almost certainly, the disease would have altered to be transmitted efficiently from human to human via respiration. Human-to-human H5N1 will lead to a very serious response to contain it, and if we can't contain it at a few poultry/mink farmworkers, that's a sign it spreads very efficiently.
• +1 point: That transmission mechanism would likely mean it has led to community spread
• +1 point: Almost certainly this would be front page news because bird flu is scary even when it's mostly just in birds and animals and sporadically in farmworkers.
• Possible +1 point: Once we get to 10,000 deaths, it's hard to imagine a scenario where that's true but it's contained to a single country. Could happen (a Chinese mink farm leads to efficient human transmission; a Wuhan-on-steroids lockdown isolates it perfectly from the rest of the world), but doesn't seem likely.
• Possible +1 point: If it's limited to one country, they might choose to quarantine the region to contain it. Global spread may see a return to things like travel bans to island nations or other serious containment measures. Pretty easy to imagine a situation with at least one going on.
• Possible +1 point: A 50% CFR from a respiratory infection could easily overwhelm hospitals
• Possible +1 point: If we started to see all these problems, that would almost certainly motivate pharma to rush for mRNA vaccines and other tools

That puts it at anywhere from a 9/14 for the "almost certain to occur by 10,000 deaths" checklist items to a 13/14 (a score that's far more plausible to me).

I'm working with the assumption that we can either test for it sufficiently well, or that given how deadly it is, we just enforce zero tolerance for social contact for any symptoms of illness. If we had testing difficulties, failed to enforce strict social distancing, or had to deal with asymptomatic spread, then I think by the time we're at 10,000 deaths, we're probably already at a full-blown 14/14 situation that, if not already categorized as a pandemic, is well on its way.

It could just be that reason the market isn´t moving is NOT because traders didn´t find it concerning but instead because the market is too low liquidity to be efficient. That´s very much my impression of low liquidity markets at least (I.e. there´s only 20 traders total in this case)

I’m not sure exactly when it became clear that we’re having a bad bird flu year, but it’s possible the mink farm outbreak wasn’t that big an update for the forecasters who were already seeing lots of transmission to mammals, just not among them.

Again this question can be misleading, as in the case of human to human transmission of this H1N1 (which may well happen, 25% chance seems about right to me based on past outbreaks), by far the most likely scenario is one or a few cases of transmission as we have seen in the past - not the kind of human to human transmission which could lead to disaster