The following is an incorrect and incomplete post about the recent bird flu, H5N1. I am offering rewards to anyone who helps me improve it. My total budget is up to $5,000, and I commit to spending at least $1,000.*

[ETA: 1/13: bounty no longer available, although reach out if you think you have something especially good]

Payouts are a judgement call. I’ve marked some bullet points below with what I would have awarded them if they’d been suggested here (and would pay out if someone proved incorrect). 

  • Spread
    • The virus has been found in livestock and wild birds across all 50 states, and every continent.
    • H5N1 has been found in 600+ dairy cow herds in CA, which is 45% of all CA herds. This is the first flu known to infect cows.
    • There are 58 confirmed human cases in the US. of those, 2 do not have a known source; the remainder are from poultry and dairy cows.
    • Spread appears to be primarily or exclusively through fluids, at least from cows.
    • A new paper says that H5N1 only needs a single point mutation to switch to human receptors.
      • However given flu’s mutation rate and the number of virons produced by each infection, this should already happen at least once per infected cow, so clearly it’s not sufficient.
      • What does it need to get airborne? ($300)
    • The flu virus taxon has something similar to chromosomes- instead of one strand of RNA it has 8 separate segments. If a cell is co-infected by two different strains it can mix and match segments. If those strains are from different species (e.g. bird and human flu mixing in pigs), this can result in virulent hybrids. ($250 to quantify this)
  • Reference Class
    • Past major epidemic scares in the US:
      • 1976 Swine Flu Scare (small)
      • 2002: SARS (774 deaths worldwide)
      • 2009: Swine Flu H1N1 (151,700 to 575,400 deaths worldwide)
    • Past major epidemics in the US (death count):
      • 1910s-1950s: Repeated Polio epidemics
      • 1918: Spanish Flu (675,000)
      • 1957: Asian Flu H2N2 (116,000)
      • 1968: Hong Kong Flu (100,000)
      • 1980s: AIDS
      • 2020: covid (1,219,48)
  • Treatment
    • Tamiflu
      • … is most effective when taken within 12-48 hours of symptom onset. Starting treatment within 12 hours can reduce illness duration by over 3 days compared to starting at 48 hours
      • When used prophylactically, Tamiflu reduced the risk of developing influenza by 89% in household contacts of infected individuals
    • Xofluza is more effective than Tamiflu but I can’t find anywhere to buy it online
    • Traditional vaccines
      • This year’s flu vaccine contains an H1N1 but not an H5N1
      • For years with good antigenic match between the vaccine and circulating strains, effectiveness estimates are typically around 49% to 60%. However, in years with poor matches, such as the 2014-2015 season, effectiveness dropped to as low as 19% (source)
    • The US does not have over the counter tests available, however you can import Fluorecare tests (flu A and B, RSV, and covid on one cartridge) from Europe for a fraction of the cost of an American covid test.
  • Specific requests:
    • Additional major epidemics or scares that didn’t pan out ($50 for first few, $25 for later).
      • ETA: must have confirmed human cases.
    • Detailed report on the usefulness of tamiflu ($500)
    • How good is national flu monitoring? Should I take comfort in the low prevalence? ($100-$500)
    • How did H5N1 spread from bird to cow if it requires fluids? ($500)
    • What percent of cows in infected dairy herds were actually sick?($50)
    • Is there something better than tamiflu? ($100 for a credible suggestion, $500 for details)
    • Detailed report on cross immunity ($500)
    • Any information that updates my estimates of mortality or human-to-human spread.

*Details on payment: awards will be given over paypal or to a 501c3 of your choice. If you receive >$500 you will need to fill out a 1099 on tax1099.com. This means I won’t have your SSN but tax1099 will.

If the awards total to less than $500, I will double all awards given. If the total comes to between $500 and $1000, I will donate the excess to Lightcone. 

To add legibility without cluttering up the comments, I'm responding to comments with rewards <=100 with 

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I've been researching this topic in my spare time and would be happy to help. Do you have time to clarify a few points? Here are some thoughts and questions that came up as I reviewed your post:

  1. Livestock vs. Wild Birds
    The distinction between livestock and wild birds is significant. Livestock are in much closer contact with humans and are biologically closer as well. How granular of an analysis are you interested in here?
  2. US-specific H5N1 Trends
    It's peculiar that H5N1 seems so prevalent in the US. Could this be due to measurement bias, or does the US simply have more factory farming? How interested are you in exploring the reasons behind this trend?
  3. Citations and Depth
    While most points aren’t cited (which is fine), it might be valuable to compile both a list of key aspects and resources for further reading. Are you looking for a more polished, thoroughly cited document?
  4. Biological Factors of Severity
    Binding to human receptors is just one factor controlling the severity and infectiousness of a virus. Would you like a deeper dive into the biology of respiratory infections and what makes them dangerous?
  5. Tamiflu and Xofluza
    Wikipedia notes that Tamiflu has limited evidence of being worth the side effects. Are you interested in a detailed evaluation of its effectiveness? Similarly, how interested are you in assessing the likelihood of shortages and efficacy of Tamiflu/Xofluza during an H5N1 pandemic?
  6. Over-the-counter Tests
    Is the issue a lack of over-the-counter tests specifically for H5N1, or for flu in general? General flu PCR testing is likely available—should we investigate this?
  7. Trajectory of Illness
    For past H5N1 cases, is there a treatable "window of opportunity" before the infection becomes severe? How critical is it to determine whether mild cases might escalate and require aggressive intervention?
  8. Historical Epidemics
    I could pull together a list of relevant modern epidemics (human-to-human airborne transmission without an animal vector). Are there any specific criteria you'd like to prioritize?
  9. Cross Immunity
    While cross immunity seems important, determining decision-relevant information may be challenging. Would you like a summary of existing knowledge or only actionable insights?
  10. Respiratory Infection Dynamics
    Epidemiologists suggest that respiratory infections are deadlier lower in the lungs but more infectious higher in the system. Is this a fundamental tradeoff? Would a "both-and" virus be possible? What evolutionary advantages might viruses have in infecting the lower lungs?
  11. Government Stockpiles and Interventions
    What stockpiles of H5N1 vaccines exist? What options are available for increasing testing and vaccination of livestock? How are governments incentivizing medication, vaccine, and PPE production?
  12. Political Considerations
    Should we examine how a Trump presidency or similar political scenarios might influence the interaction between local and federal health agencies?
  13. Species-to-Species Spread
    The rapid spread of H5N1 to multiple bird and mammal species raises the question of whether humans will inevitably be affected. Is this worth exploring in-depth?
  14. Mortality and Long-term Effects
    What demographics do other flu strains tend to affect most? Are there long-term side effects comparable to "long COVID"?
  15. Mutation and Vaccine Efficacy
    How quickly do flu strains, especially H5N1, tend to mutate? What implications does this have for vaccine efficacy and cross-reactivity? How much asymptomatic spread occurs with flu, and how long does it remain airborne?
  16. No Deaths Yet
    How should we update based on the fact that, contrary to past occurrences of H5N1 that had a ~50% CFR, none of the 58 confirmed cases have died?

Finally, I’d be interested to hear which of these questions or areas you find most compelling. Are there other questions or directions you’d like to explore? This will help me prioritize my efforts.


Epidemic Scares That Did Not Pan Out

  • 1976 - Legionnaires' Disease: Initially alarming but identified as a bacterial infection treatable with antibiotics. (Not relevant: bacterial)
  • 2001 - Anthrax Attacks: Bioterrorism-related bacterial outbreak causing fear but limited deaths. (Not relevant: bacterial)
  • 2005 - Avian Flu (H5N1): No confirmed US human cases despite global fears. (Relevant)
  • 2014 - Ebola: Strict public health measures limited US cases to three. (Relevant)
  • 2016 - Zika Virus: Local transmission limited to parts of Florida and Texas. (Not relevant: mosquito vector)

I love this detailed list. I've responded in-line to every one, but feel free to ask more questions, here or over email. 

 

  1. Livestock vs. Wild Birds
    The distinction between livestock and wild birds is significant. Livestock are in much closer contact with humans and are biologically closer as well. How granular of an analysis are you interested in here?

I care about wild birds to the extent they're spreading disease to livestock or serve as reservoirs.

I've also heard a wide number of mammals have been infected. I care about this to the extent it affects humans and livestock. E.g. does this suggest it's airborne after all, or say something about the mutation rate?

 

  1. US-specific H5N1 Trends
    It's peculiar that H5N1 seems so prevalent in the US. Could this be due to measurement bias, or does the US simply have more factory farming? How interested are you in exploring the reasons behind this trend?

I'm interested in quantifying the quality of US surveillance, but otherwise deprioritize this.  

  1. Citations and Depth
    While most points aren’t cited (which is fine), it might be valuable to compile both a list of key aspects and resources for further reading. Are you looking for a more polished, thoroughly cited document?

Citations are important to the extent they let people check and build on your work. But if it's a widely known consensus such that it's easy to look up but complicated to cite, it's not important to add a citation. E.g. my fact about RNA segments is very easy to check but would have been annoying to find a citation for because I learned it 20 years ago. 

Overall citations for the current state of things (e.g. how many human infections of unknown providence) are more important than citations for basic science.

  1. Biological Factors of Severity
    Binding to human receptors is just one factor controlling the severity and infectiousness of a virus. Would you like a deeper dive into the biology of respiratory infections and what makes them dangerous?

Low priority. Pass on resources if you find them but don't bother with synthesis. 

  1. Tamiflu and Xofluza
    Wikipedia notes that Tamiflu has limited evidence of being worth the side effects. Are you interested in a detailed evaluation of its effectiveness? Similarly, how interested are you in assessing the likelihood of shortages and efficacy of Tamiflu/Xofluza during an H5N1 pandemic?

I'm very interested in tamiflu's efficacy. Some specific important questions: 

  • is tamiflu more effective when taken very early? when did the people in the studies that found low efficacy take tamiflu? My understanding is it is effective for prophylactic use, which suggests earlier is better.
  • how does the math change if the flu is more dangerous or virulent?

Not interested in assessing likelihood of shortages.

  1. Over-the-counter Tests
    Is the issue a lack of over-the-counter tests specifically for H5N1, or for flu in general? General flu PCR testing is likely available—should we investigate this?

My assumption is the European OTC tests will catch H5N1, but if that's wrong I'd like to know. 

I don't care much about non-home tests, except I am interested in the national flu surveillance program and how much we can trust it. 

 

  1. Trajectory of Illness
    For past H5N1 cases, is there a treatable "window of opportunity" before the infection becomes severe? How critical is it to determine whether mild cases might escalate and require aggressive intervention?

Very interested in this. 

 

  1. Historical Epidemics
    I could pull together a list of relevant modern epidemics (human-to-human airborne transmission without an animal vector). Are there any specific criteria you'd like to prioritize?

The reference class is "things that got at least as far as H5N1 did this year"- widespread in livestock and with some humans infected.

 

  1. Cross Immunity
    While cross immunity seems important, determining decision-relevant information may be challenging. Would you like a summary of existing knowledge or only actionable insights?

Medium priority for a summary of existing knowledge, bonus points for a quantitative model even if it's low confidence.

 

  1. Respiratory Infection Dynamics
    Epidemiologists suggest that respiratory infections are deadlier lower in the lungs but more infectious higher in the system. Is this a fundamental tradeoff? Would a "both-and" virus be possible? What evolutionary advantages might viruses have in infecting the lower lungs?

If you happen to stumble on relevant information I'd like to hear it, but I don't want synthesis.

  1. Government Stockpiles and Interventions
    What stockpiles of H5N1 vaccines exist? What options are available for increasing testing and vaccination of livestock? How are governments incentivizing medication, vaccine, and PPE production?

Yes to stockpiles, yes to shallow investigation of options for livestock.

  1. Political Considerations
    Should we examine how a Trump presidency or similar political scenarios might influence the interaction between local and federal health agencies?

No.

  1. Species-to-Species Spread
    The rapid spread of H5N1 to multiple bird and mammal species raises the question of whether humans will inevitably be affected. Is this worth exploring in-depth?

Yes.

  1. Mortality and Long-term Effects
    What demographics do other flu strains tend to affect most? Are there long-term side effects comparable to "long COVID"?

We know who normally gets hit hardest by diseases, I'm only interested in deviation from that.

No to "long flu", because I am already convinced it exists but the data on it is bad.

  1. Mutation and Vaccine Efficacy
    How quickly do flu strains, especially H5N1, tend to mutate? What implications does this have for vaccine efficacy and cross-reactivity? How much asymptomatic spread occurs with flu, and how long does it remain airborne?

Yes to mutation rate, especially if you can quantify what's needed to allow human-to-human transfer.

Yes to general flu knowledge like asymptomatic period and time airborne.

  1. No Deaths Yet
    How should we update based on the fact that, contrary to past occurrences of H5N1 that had a ~50% CFR, none of the 58 confirmed cases have died?


 

This paper says there has been one death from the current clade. I'm very interested in knowing if that's correct. It also says tamiflu was found to reduce mortality in earlier, more deadly forms of H5N1.

 

That's a lot, so here are my top three priorities: vaccine efficacy (wide confidence intervals are fine), treatment efficacy, and likelihood of human-to-human transmission.

Great, that's clarifying. I will start with Tamiflu/Xofluza efficacy as it's important, and I think it will be most tractable via a straightforward lit review.

No need to pay me for this. It's just an anecdote. 

I live near a farm where there are chickens and a donkey. The chickens routinely sit on, and poop on, the donkey. I imaging the same happens with cows when they cohabitate with birds. 

I am no biologist but I thought it would be fun to give it a try. Hoping it's not too late to participate.
For the purpose of this experiment, I assumed everything written in sound scientific papers was right, as I had neither the time nor the knowledge to do a proper truth-check.

Here is what I found :  

The fact that we see very few human cases compared to what we could expect for a virus which can become human-compatible with a single point mutation could be partially explained by the heterogeneity of the mutation rate over the genome:

  •  in this paper, a 1 to 100 ratio of mutation rate inside the human genome is mentioned : https://pubmed.ncbi.nlm.nih.gov/35218359/
       There are known factors which hints at a low / large mutation rate for a sequence, so one could investigate further whether this would be the case for the "single point mutation" mentioned
    -> you can divide the probability by 100 in the best case

A paper where they infect ferret with H5N1 and test how to mutate the genome to make it airborne:

  • https://pmc.ncbi.nlm.nih.gov/articles/PMC4810786/
  • "Four amino acid substitutions in the host receptor-binding protein hemagglutinin, and one in the polymerase complex protein basic polymerase 2, were consistently present in airborne-transmitted viruses."

As an alternative to tamiflu which can also be used in combination with it : favipiravir

  • https://www.sciencedirect.com/science/article/pii/S0163725820300401, a 2020 paper about it
  • licensed as an influenza drug in Japan
  • when used in combination with tamiflu, a 2020 paper (with small sample size = 40) suggests that combining tamiflu with favipiravir improve significantly the efficiency
  • as it has been envisioned as a drug against COVID, it's easy to find meta-analyses on the side-effects of this drug
  • a huge problem with tamiflu is that the influenza viruses develop resistance to it. favipiavir does not seem to have this problem

I'm having trouble parsing but I think the first point is about the mutation rate in humans? I don't expect that to be informative about flu virus except as a floor.

Ah yes, you're right. I don't know why but I made the mental shortcut that the mutation rate was about the DNA of cows / humans and not the flu virus.

The general point still holds : I am wary of the assumption of a constant mutation rate of the flu virus. It really facilitates the computation, but if the computation under this simplifying hypothesis leads to a consequence which contradict reality, I would interrogate this assumption.
It's surprising to have so few human cases considering the large number of cows infected if there is a human-compatible viron per cow. 

Another cause of this discrepancy could also be that due to the large mutation rate, a non-negligible part of the virons are not viable / don't replicate well / ... 

There are papers which show heterogeneity for influenza / RNA viruses but I don't really know if it's between the virus population (of the same kind of virus) or within the genome. And they are like a factor 4 or so in the papers I have seen. So maybe less relevant than expected.

Regarding the details, my lack of deep knowledge of the domain is limiting. But as a mathematician who had to modelize real phenomenon and adapt the model to handle the discrepancy between the model's conclusion and reality, that's the train of thought which comes naturally to mind. 

What percent of cows in infected dairy herds were actually sick?

According to AVMA, less than 10%: link. It looks like that's only the symptomatic animals though, so your answer might depend on how you define "actually sick."

How did H5N1 spread from bird to cow if it requires fluids?

Cows occasionally eat birds. That might do it.

What does it need to get airborne?

I'm not sure this is the right question: as I understand it, the flu generally spread on fluids (mainly saliva), and if the droplets are small enough (< 5μm diameter), they get classified as aerosols and called airborne.

How sure are you that flu is generally spread through fluids? It seems like the medical system is ~prejudiced against the concept of airborne transmission. 

Qn: Could you clarify the intended audience and final use case for this research? It would help to choose between technical depth/accessibility/level of supporting info.

The use case is a lesswrong post people use to make decisions (which could be written by me, or you, but it's looking like @DirectedEvolution).

For a treatment besides Tamiflu: https://en.wikipedia.org/wiki/2009_swine_flu_pandemic cites the who and CDC stating that H1N1 developed resistance to Tamiflu but not Relenza

In December 2012, the World Health Organization (WHO) reported 314 samples of the 2009 pandemic H1N1 flu tested worldwide have shown resistance to oseltamivir (Tamiflu).[172] It is not totally unexpected as 99.6% of the seasonal H1N1 flu strains tested have developed resistance to oseltamivir.[173] No circulating flu has yet shown any resistance to zanamivir (Relenza), the other available anti-viral.[174]

The treatment plan at the time included Tamiflu/Relenza/experimental third thing (FDA approved for flu treatment in adults since 2014)

If oseltamivir (Tamiflu) is unavailable or cannot be used, zanamivir (Relenza) is recommended as a substitute.[50][168] Peramivir is an experimental antiviral drug approved for hospitalised patients in cases where the other available methods of treatment are ineffective or unavailable.[169]

I think 2009 H1N1 is a good example of how things could go, as it happened in the modern day.

Here is some info about antivirals for H5N1, a collation of information that I find relevant, and details from a very recent paper that studied Baloxavir/Favipiravir: https://docs.google.com/document/d/17xa3bdaCgK1Sf3Xpt6WEnzkZbECgGsdFJStBZ67e648/edit?tab=t.0

What this does not include at the moment is information on resistance.

Seems like there was a 2003-2004 H5N1 scare/abortive epidemic in east Asia. Ultimately killed 12 people.

https://pmc.ncbi.nlm.nih.gov/articles/PMC3367332/

Additional major epidemics or scares that didn’t pan out ($50 for first few, $25 for later)

2014-15 HPAI outbreak in the US, which didn't ultimately make it to humans

This is outside the reference class I intended (needed at least one human case), but since I didn't specify that I'll award a token $10. Please let me know what your paypal is.

“Xofluza is more effective than Tamiflu but I can’t find anywhere to buy it online”

  • Both drugs are prescription-only medications so you would need a valid prescription to access it. Telehealth would suffice for prescription and online pharmacies can home deliver. 

If I get more time later today I will update this comment.