本文探讨了当前H5N1禽流感潜在风险，尤其关注奶牛群体持续感染带来的威胁。奶牛群体成为H5N1病毒的理想变异温床，与人类接触频繁，且正值人类流感季节，存在病毒重组风险。此外，加拿大出现不明来源感染病例，疑似野生H5N1病毒发生突变，增强了对人体受体的结合能力。作者认为，虽然目前风险尚不明确，但需密切关注病毒变异和传播情况，并做好应对准备。文章还讨论了疫苗研发、社会政治反应以及潜在疫情的严重程度等方面，提醒我们关注潜在风险并做好准备。

🤔 **奶牛群体持续感染H5N1病毒：**奶牛群体成为病毒的理想变异温床，因为它们数量众多、全年存在且与人类接触频繁，增加了病毒发生变异并传播给人类的可能性。

🦠 **加拿大不明来源感染病例：**加拿大出现一例不明来源的H5N1感染病例，疑似野生H5N1病毒发生突变，增强了对人体受体的结合能力，增加了人类感染风险。

🐷 **关注病毒是否传播至猪群：**猪群是流感病毒的混合载体，如果H5N1病毒传播至猪群，可能发生病毒重组，增加疫情暴发的风险。

😷 **密切关注病毒的传播途径：**需关注H5N1病毒是否发生变异，导致在奶牛群体中出现气溶胶传播，以及更多类似加拿大病例的出现，这些都可能预示着疫情风险的上升。

💉 **疫苗研发及储备：**美国政府已预先储备了禽流感疫苗，并投入资金支持疫苗研发，但现有疫苗储备量有限，且可能无法有效应对新的变异毒株，疫苗研发和生产需要一定时间。

Published on December 5, 2024 9:11 PM GMT

Epistemic status: a few people without any particular expertise in epidemiology spent an afternoon in a coffee shop discussing and reading about H5N1, with a focus on how an individual should orient towards this (as opposed to say, the government). This is a write-up of what I took away from that exercise, written from my perspective. 

Some ideas were generated in collaboration with Claude but generally spot checked. This post was also sanity-checked by a friend who works in epidemiology. I feel ok about the ideas presented but would not be surprised if someone with more expertise has a significantly different conclusion. Any mistakes are mine.

I went into this exercise with a prior of “I’ve been hearing about bird flu for years, and it’s always been nothing, it’s probably nothing again this time.” The main upshot is that I walked away from the exercise thinking “I don’t know if this is going to be something or not.” As far as updates go, that seems directionally bad. My current orientation towards this is something like “watch and wait, and spend appropriately more effort on this if / when certain milestones happen (and also make some trades).”

What’s different this year?

One main thing that seems to generate a heightened level of ongoing risk is sustained infections in dairy cow populations. This is already bad because it’s mammal-to-mammal transmission in a population that hasn’t historically had problems with bird flu, and it would be worse if it becomes endemic in farmed cows. As long as it is sustaining infections in farmed cows, H5N1 has a convenient breeding ground for mutations that is:

In a high density populationYear round (bird flu is seasonal among birds)In regular contact with humans

The last point gets a bonus with the human flu season coming up. If a dairy worker gets sick with both bird flu and human flu simultaneously, the two strains might share their genetic information and mutate into a pandemic-worthy strain.

Another thing being talked about is the teen in Canada who got sick from an unknown source. I suspect that at least some of the attention here is because scary things generate ad revenue, but there is also evidence that a wild strain of H5N1 has a mutation that improves binding to human receptors.

These seem to represent two distinct threat vectors to me; the Canadian teen seems to be very sick, whereas dairy workers have generally had mild symptoms (although in the case of the 1918 Spanish flu (also avian), younger people had higher fatality rates). A jump from birds directly to humans would be mostly independent of whatever is happening in dairy farms, and vice versa.

I don’t have a concrete prediction here, but I notice that Polymarket being at 14% doesn’t feel wild to me. I would tentatively assign more probability to something coming from the cow situation than directly from birds.

What to watch for

As I said above, my plan is to watch and wait, but what to watch for? There are a few key things IMO:

A (sustained) jump to pigs. Pigs are traditionally considered a mixing vessel for flu viruses, since they are apparently susceptible to them and are able to host avian, human, and swine flus. This is how the 2009 H1N1 pandemic mutations happened. There has been one confirmed case in a pig, but that was over a month ago now with no more news that I've seen.A mutation to airborne transmission among cows. Seems self-explanatory, indicates that the virus is undergoing significant mutations in the cow population. Also airborne bad.Whether it continues to infect cows / becomes endemic (see previous section on why this creates elevated risk).A lot more cases like the teen in Canada, with evidence that the suspected mutation that makes it easier to bind to human receptors is common in wild H5N1.Of course the big one is human to human transmission, with each of the previous points being plausible stepping stones.

Something speculative is watching how pharma companies are reacting. As I understand it, to some crude approximation pharma companies take a hits-based approach to investing in drugs. In the venerated tradition of pulling numbers out of my ass, if O($100M) is an appropriate amount to spend on pre-empting a pandemic, and they expect to make O($1B) on a hit, then this indicates an O(10%) belief that some kind of pandemic happens in the near future? 

The US government has paid Moderna $176M to work on H5N1 vaccines (which impacts the above speculation, since this de-risks the investment for Moderna), Pfizer is working on it as well (though I didn’t find anything indicating a federal grant), and the government has also paid $72M to manufacturers to make existing vaccines ready to use.

Vaccine response

The US government has a strategic reserve of bird flu vaccines. Given that pharma companies are also preemptively working on a vaccine, what could we expect in terms of immediate response and an eventual bespoke vaccine for the pandemic strain?

The strategic reserve of bird flu vaccines is small relative to the population and seems basically intended for emergency / essential workers. The above link about paying $72M to manufacturers mentions that this would double the strategic reserve from 5 million to 10 million doses, which is already far from the total US population before accounting for multiple doses per person. Furthermore, these vaccines are based on known strains and may only provide limited protection against a new pandemic strain.

So we probably aren’t going to get an immediate bail out of a pandemic. How long would it take to develop and ramp up a vaccine for the full population? For reference, widespread availability of the covid vaccine took around a year, while H1N1 took around 6 months. Why was H1N1 so much faster? Basically we’re really good at making flu vaccines because we make them every year and there are mature platforms for this, whereas the coronavirus vaccine used fairly novel technology (mRNA vaccines). 

So we could plausibly move as fast as with H1N1, but here are some serially bound steps that need to happen to make a pandemic-strain-specific vaccine, so much faster than H1N1 sounds hard. Something like 4-6 months seems plausible to me, not accounting for any political friction.

Sociopolitical response

We didn’t spend much time thinking about the political response and I don’t super feel qualified to shoot from the hip here, but some potentially important factors to note:

Pandemic fatigue seems real, and it might be hard to coordinate effectively a second time.AFAIK RFK is pretty anti-vax (and is the nominee for HHS) and vaccines are super politicized now. Not really sure how to game this out – if a hypothetical pandemic was bad enough, would it moderate everyone’s views?Individual reactions might be modeled by a bimodal distribution? Seems plausible to me that some people overreact while others underreact.

How bad would a pandemic actually be?

Wikipedia has a page on past influenza pandemics. I was somewhat surprised to learn that the seasonal flu already kills hundreds of thousands of people every year (!), and is in fact typically more lethal each year than 2009 H1N1 was. I don’t really understand the HXNY labeling, but it seems like H1N1-like strains have caused three pandemics, each time less bad than the last, which makes sense if you no longer have a naive population.

Our base case might look more like H2N2 or H3N2 then. The case fatality rate for these is very low compared to the observed fatality rate in some H5N1 strains (~50%?), but the H5N1 strain that is infecting dairy cows and workers hasn’t killed anyone yet and seems much more mild than a coin-flip death sentence (and an effective pandemic strain is unlikely to have a 50% fatality rate – being too lethal causes a virus to burn out before spreading widely, in addition to motivating a stronger response). H2N2 and H3N2 happened before we figured out how to surveil these diseases before a jump to humans, so it’s not clear whether these looked like H5N1 does today or if they were much milder even before the jump. 

For another point of reference, covid had an original reproduction number of around 3 and a case fatality rate of around 1% (on top of other “lucky” features, like being contagious during a long asymptomatic incubation period).

We also already have antivirals for the flu like Tamiflu, in contrast to covid where it took a long time to develop things like Paxlovid. There’s no guarantee that it would be super effective, but so far it seems like it has some effect and is currently being used to treat human H5N1 cases.

My best guess is that we should expect an H5N1 pandemic to look much more like a (possibly more lethal) H2N2 or H3N2 pandemic than a covid pandemic, though we shouldn’t rule out something worse. This would be bad, but not incredibly bad. 

What else?

I’d be interested in hearing more takes and especially places where I might have gotten something wrong or missed something important. My guess is that there are also trades that are more profitable than buying Yes shares on Polymarket if they hit, though I'm not sure about publicly speculating about this.

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Thanks for ideas, discussions, feedback: Maggie, James, Linda

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