Build new vaccine production facilities.
It seems clear that focusing on the vaccine pipeline will become critical in the coming months, and we need to get ahead of it ASAP. Currently, the plan is to wait for safety approvals, then start manufacturing. That will obviously change - when we have moderate confidence that a vaccine is effective, we will want to start manufacturing, but there are several candidates, and too little productive capacity to make large quantities of several different vaccines. In fact, there is too little productive capacity to make any one vaccine in global quantities without stopping manufacture of other vaccines.
Vaccine manufacturing is very complex, and needs specialized facilities with clean rooms, sterilization facilities, very specific types of HVAC, etc. Building these is capital intensive, and there has been too little capacity for quite a while, leading to occasional vaccine shortages. I think we should be pushing large companies and governments to figure out how to create greater production capacity for vaccines. This is a global public good anyways. There are a few economic concerns for companies doing this, but right now is the perfect time to get government subsidies for such capital intensive projects.
How specific are vaccine production facilities to individual vaccines? To what extend can we build them before knowing which of our vaccines will succeed in the clinical trials?
From what I understand, we use eggs to incubate and clean-rooms to produce the final product for all of them, and I understood that vaccine producers can switch between which ones they make, with a couple month delay for incubation and switching over.
FWIW, eggs are actually specific to influenza vaccine manufacturing. Page 3 of this book chapter ( https://reader.elsevier.com/reader/sd/pii/B9780128021743000059?token=F492A74B3C4545B108379536769CF93D7F1DB89321DADE859256496F5D85CB6259372D34376809219BBBE2FFFDEF25FB ) has a really nice table showing the production process of a number of different vaccines - they are all very different from one another. This is why we need new vaccine platform technologies - i.e., tech that can be used to produce multiple different vaccines. mRNA vaccines would fall into this category and is a reason why Moderna's mRNA vaccine candidate for COVID-19 would be so exciting if it works.
Whoah, lipid-coated mRNA vaccines, not as an intermediate step but as the actual delivery method? That's actually new to me! Sounds like it's mRNAs coding for some subset of the viral proteins, which probably get assembled into proteins in your cells and then get used as something for antibodies to respond against. mRNAs should then just degrade themselves with time.
I have no idea what the most efficient method for producing those is; I am very used to vaccines being protein-based. This probably is in the realm where it's simple enough that modifying PCR-protocols to produce RNA instead might actually work reasonably well, although RNA is generally more fragile and error-prone and that could be a problem.
You'd be using nucleotides, not amino acids, but mRNA from DNA is a short-enough assembly line that you might not need cells to do it.
(Protein production has a lot of dependencies. mRNA transcription should basically just require your DNA of interest, nucleotides (x4), and a transcriptase protein. Maybe add a transcription factor or two.)
HeLa definitely is a human cell line (although that was for Ebola, they may end up using a different cell line). That's good, that probably scales up easily.
The peer-reviewed literature has several papers talking about GI symptoms of COVID19, and there are several GI cells that are ACE2+ that are plausible targets. What I am wondering is the following a potential vaccine strategy?
innoculate with live strain in GI tract to avoid respiratory infection
If the same type of facility works for almost every kind of vaccine, do we think there would be interest in constructing the facilities as a speculative venture? Consider:
1. The economy is in chaos and may remain so, which I expect to produce unusually affordable access to design firms, construction crews, raw materials, and land.
2. There will be a strong incentive for regulators/inspectors to move with best speed, and the current administration at least in the US has a track record of being friendly to shortcuts.
3. If the facilities are already built, thi...
Contact Tracing at Scale!
One thing we need, that the Less Wrong community could likely help with, is contact tracing capability at scale. I know of one such project in the US - https://www.covid-watch.org/ The Covid Watch project, based out of Stanford.
I think the major tech companies need to set up and throw a ton of engineering and design resources at contact tracing efforts. They currently control the software supply chain to most mobile devices on earth, and thus are ideally placed to help track the spread of infections.
The more testing we have, the more effective contact tracing will be, so this needs to be paired with an increase in testing world-wide, as previously mentioned in the thread.
There might be benefits to having an privacy sensitive open-source solution like the one proposed in Covid-Watch over a Google/Facebook solution.
https://www.lesswrong.com/posts/fxfsc4SWKfpnDHY97/landfish-lab?commentId=4ftZGNxtNRiwgXTbf
My collection of links to the projects I know about in this space and some news coverage of them.
I would strongly encourage people to try brainstorming some questions. Even if you don't come up with anything directly useful you might jog someone else's creativity. Remember to go for quantity over quality on your first pass.
Epidemiology questions that, while we probably can't do much about, would be useful to try to ad hoc model given how bad official info has been so far:
Are estimates of doubling time off from bad modeling of rapid test ramping making it seem faster than it is?
What is actual hospital elasticity? Is there an existing gathering of data on this from previous disasters?
How long do human trials need to be before they are rolled out to the majority of the population? Just to the extremely vulnerable? What is the gears level model here?
What granularity of travel restriction makes the most sense? In general, how can cities and counties act knowing that federal response may (will continue to be) be too slow?
Which physical objects have longer supply chains and thus can be expected to be less robust to disruption?
What mental health problems can we expect to spike hard in the next 1-6 months given people feeling shut in and helpless?
What are the most predictable second order disasters?
Does moral hazard show up anywhere here?
What's most likely to be ignored during this? Civil liberties? Already seen discussion of that. What's even more ignored?
I've seen people from a Stanford lab asking on facebook about being put in touch with someone from an MIT lab. How can lab cross talk increase?
If UV 210nm turns out to be effective, how can you build your own flashlight/lightsaber (from the virus' perspective) out of off the shelf parts?
Which continuing failures of the FDA are highly predictable? What can be done to mitigate that expectation at the hospital and lab level?
How can models take into account reference classes. e.g. Many models are averaging naively which means essentially all the data points are from the least controlled regions with the widest error bars.
I would strongly encourage people to try brainstorming some questions. Even if you don't come up with anything directly useful you might jog someone else's creativity. Remember to go for quantity over quality on your first pass.
Thanks Romeo.
Setting a 5 minute timer:
Pushing to get to a total of 10 items:
The requirements on multiplying ventilator use through sharing is
1. Equal tube lengths.
2. Equal lung capacity.
3. Equal lung resistance.
4. Same patient weight (approx)
the question is can any of these requirements be broken though clever use of 3d printed valves or other JIT solutions?
What is actual hospital elasticity? Is there an existing gathering of data on this from previous disasters?
No answer here but a subquestion might be what are the essentials for an effective "hospital bed" for a COVID-19 patient? What are the binding/constraining elements? We know ventilators for critical cases are one. Others? What about those for serious versus critical -- if we can treat serious cases well but in some makeshift hospital room (say an empty hotel) does that help us limit the demand for ICU space?
Second thought here. You have in...
Scaling up testing seems to be critical. With easy, fast and ubiquitous testing, huge numbers of individuals could be tested as a matter of routine, and infected people could begin self-isolating before showing symptoms. With truly adequate testing policies, the goal of true "containment" could potentially be achieved, without the need to resort to complete economic lockdown, which causes its own devastating consequences in the long term.
Cheap, fast, free testing, possibly with an incentive to get tested regularly even if you don't feel sick, could move us beyond flattening the curve and into actual containment.
Even a test with relatively poor accuracy helps, in terms of flattening the curve, provided it is widely distributed.
So I might phrase this as a set of questions:
Relevant thread: https://www.lesswrong.com/posts/pjLgE2efAozz82JmR/sars-cov-2-pool-testing-algorithm-puzzle
I'd love to work on this if someone can put me in contact with a medical professional who understands how these tests work.
Why doesn't Japan have a huge outbreak already? (924 reported cases today, according to the Johns Hopkins tracker): https://www.bloomberg.com/news/articles/2020-03-19/a-coronavirus-explosion-was-expected-in-japan-where-is-it
Why does India have so few cases? (160 reported cases today): https://www.weforum.org/agenda/2020/03/quarantine-india-covid-19-coronavirus/
For each country – what proportion of newly reported cases comes from ramping up testing, and what proportion comes from newly infected people?
Will the economic impact of coronavirus be inflationary or deflationary on net? (for USD)
It would be great to have a list with the current teams that are working on a COVID-19 vaccine. Is such a list out there or otherwise, does someone want to create one?
Why haven't we ever created a vaccine for a coronavirus before?
Is coronavirus vaccine development more limited by need for technological innovation or economic incentive?
There was a twitter thread I didn't save that said:
1. we have vaccines for cat and dog CVs
2. Human CVs are unrewarding to vaccinate against because they only cause 30% of colds, so you can only advertise a reduction, not total prevention, of colds.
Does hydroxychloroquine + azithromycin effectively treat COVID-19?
See Gautret et al. 2020, a small trial of this (not randomized) that found a big effect.
I looked into this a bit with a friend who's an MD, and it turns out that this paper isn't very good.
Study not randomized, groups not balanced by disease severity, several treatment-group patients excluded from the data after trial started because they got worse (some went to ICU; one died).
From p. 10 of the paper:
We enrolled 36 out of 42 patients meeting the inclusion criteria in this study that had at least six days of follow-up at the time of the present analysis. A total of 26 patients received hydroxychloroquine and 16 were control patients....
To Address the Problem: “How do I convince others to act?”
By now it seems clear that social distancing and shelter-in-place protocols are the most effective for reducing the spread of infection. I don’t know about other regions, but compliance in the US is unfortunately low. If increasing compliance is desirable, even when balanced against economic concerns, how do we encourage it?
Part of the problem is that people have to seek out information to become informed. Time and energy have to be invested for a person to figure out how important it is to stay home, and what sources of information are reliable.
Proposed Solution: Hospitals and medical groups should write letters to their entire mailing list pleading with people to stay home if possible. A message from your doctor’s office is far more persuasive than a general government announcement or news report. It’s local, personal, and credible. Everyone opens an email from their doctor.
Medical providers can explain the staff and resource shortages they face. They can explain that if everyone stays off the road as much as possible, this reduces accidents and frees up first-responders and scarce emergency room capacity (how significant would this be?). They can encourage a moratorium on other risky activities like extreme sports, even though those don’t violate social distancing rules (how significant would this be?).
This proposal is virtually costless, near effortless, can be implemented immediately, and would hopefully be effective.
Is it worthwhile to focus on getting medical providers to do this? If so, how do we reach out to them and maximize the number who do it ASAP?
What sources are governments using for decision-making?
The biggest impacts seem to me to be via influencing government. The UK government, for instance, is still very reticent to enforce widespread testing or mandatory quarantine. Their 'quarantine guidance' for households with symptoms looks like this, which seems patently foolish for a number of reasons.
Influencing governments' decision making is high-impact and potentially tractable via getting modelling and trial data to them. The UK Government publish their 'scientific basis for decision making' but it appears to be weeks out of date and unreferenced.
With that in mind, how do we get better decision-making information into government? What theory of change can we find for influencing policy makers? I believe this should be primarily targeted towards larger organisations and researchers who can have more direct influence, but may be useful for individuals as well.
Sir Patrick Vallance seems to be the key figure behind the UK policy. The guy was a professor of medicine in the past and who heads the Government Office for Science. Their policy is likely much more driven by modeling then the policy of other countries where the policies are decided by politicians instead of people with that kind of credentials.
To the extend that they have data on that page that's weeks out of date it's likely because the page has little to do with their actual decision making processes.
Vallance might still be wrong, but I think it's wrong to model him as being simply misinformed.
Hey everyone who is following this closely- I've been sprinting madly for the last six weeks and hit my limit. You can expect a retrospective post and perhaps a phase 2 agenda in the next few weeks, but for now I am resting.
Welp, I did not make that deadline. Unfortunately the conditions that led me and the LW team to miss that deadline- high opportunity costs- are not likely to change soon, so instead of holding out for perfection I'm just going to share a couple of thoughts.
I was brought on to lead covid research efforts at LW as an experiment. The hope was that there was significant untapped research capacity, which could be unlocked by providing some structure (hence the research agenda). The structure was not only supposed to give people a sense of what would be useful to research, but reassurance that their research would actually be used, and social reinforcement. This mostly did not pan out- I think I did useful research during the time in question, I think other people produced useful research during that time, but questions I asked tended to be answered by only me.
The experiment was well worth running, and the team got a lot of information on infrastructure useful to support coordinated research (most notably it led to some reworks of Questions). But after 6 weeks it was not achieving its stated goal and had not found something clearly high value to pivot to, so I called it.
I'm currently working with Kyle Scott and Anna Salamon on an estimate of deaths due to hospital overflow (lack of access to oxygen, mechanical ventilation, ICU beds), which we'll hopefully post in the next few days. The post will review evidence about basic epidemiological parameters.
Update: We decided not to finish this post, since the points we wished to convey have now mostly been covered well elsewhere; Kyle may still write up his notes about the epidemiological parameters at some point.
Alas. Could you briefly link to the other places that have conveyed the ideas sufficiently well for your tastes?
I wouldn't describe any posts I've seen as conveying the idea sufficiently well for my taste, but would describe some—like this NY Times piece—as adequately conveying the most decision-relevant points.
When I started writing, there was almost no discussion online (aside from Wei Dai's comment here, and the posts it links to) about what factors might prove limiting for the provision of hospital care, or about the degree to which those limits might be exceeded. By the time I called off the project, the US President and ~every major newspaper were talking about it. I think this is great—I much prefer a world where this knowledge is widespread. But given how fast COVID-related discourse was evolving, I think I erred in trying to make loads of points in a single huge post, rather than publishing it in pieces as they became ready.
There is one potentially decision-relevant point that I hoped to make, that I still haven't seen discussed elsewhere: there may be two relevant hospital overflow thresholds. The ICU bed threshold and the ventilator threshold are fairly low; given our current expected supply in a crisis, we'll exceed them if more than about 70k people require them at once. But I think (not confident in this yet) that our capacity for distributing oxygen is something like 10x higher. And if that threshold gets exceeded, the infection fatality rate may rise by something like 10%. So on this model, while it would obviously be ideal to push the curve below both thresholds, it's imperative to at least flatten the curve beneath the oxygen threshold. Which is easier, since it's higher.
I'm not sure this model is accurate, and I haven't yet decided whether to write it up. I feel hesitant, after having wasted 10 days underestimating the efficiency of the covid-modeling market, but it seems useful to propagate if true. If someone else is interested in looking into it, I'd be happy to discuss.
I'm looking for opinions on this video, by a virology professor. which so far is my favorite explanation of basic coronavirus science. It covers basic things others didn't (that there are literally no enzymes in a coronavirus capsule, it's just mRNA), and some more specific things that I really wanted to know (like where in the lifecycle chloroquine and azithromycin appear to be disruptive). Before I crown it king, I'd like to get feedback on how easy-to-understand and useful this is for other people.
Caveats: spends a fair amount of time on things I found interesting but not on a straight path to usefulness, like swine flu.
Other contenders are
This post was edited on 3/22 to add answers
This post was edited on 3/23 to add new questions to the agenda and swap out the spotlight questions. (Thanks to elityre and romeostevensit for suggestions)
This post was edited on 3/30 to add two answers to "What are the basic epidemiological parameters of C19?"
This post was edited on 4/6 to:
What is the basic science of coronavirus? E.g. this guide is trying, but requires more background knowledge than ideal and leaves a lot out.
It's very unclear to me how you can simultaneously overcome both "requires more background knowledge than ideal" and "leaves a lot out", at least without just giving someone a stack of textbooks to read.
I'm like ~2/3 of the way through writing a post on coronavirus structure, which might turn into a series of posts on coronavirus biology if I have time, and this is actually pretty hard. The amount of background knowledge required to really understand what's going on is huge; I have a biology PhD and I'm only skimming it.
So any post that attempts to attack this has a high chance of being at least two of incomprehensible, useless, very long, and dull. I'm doing my best to overcome this, but it's tricky.
I ended up being pretty happy with both of the following, although neither was complete.
Okay, but those are textbook chapters. If you're looking for those I recommend Chapter 28 of Fields Virology, 6th edition (similar information to Fehr & Perlman, better presentation, somewhat more comprehensive).
But do you really think LessWrong should be going for something more comprehensive than that? I don't really see the value in that, as opposed to getting a smart-person's-summary that links to more comprehensive resources.
But do you really think LessWrong should be going for something more comprehensive than that
...no, for the reasons you state. And I'm not sure why you think I do. Having found those I wasn't planning on actively searching for a better answer (although I'm looking forward to checking out both the chapter you recommend and the posts you are writing).
Sorry, I think these comments came across as more aggressive than I was intending. I think there's mutual confusion/talking at cross-purposes here. I'm not sure it's worth digging into too much since I'm not sure there's actually any decision-relevant disagreement, so feel free to disregard the following (uh, even more than usual) if you don't fancy digging into this further. :-)
I'm not sure why you think I do.
From my perspective, my confusion arises from the following:
Based on this conversation I think I'm probably misinterpreting what inclusion on the agenda implies you'd like to see LessWrongers do.
I’ve gone through a lot of introductions to this post but maybe this is the most honest one:
I am scared. Quite scared, actually. My chances of catching COVID-19 are actually quite low, and my chances of surviving it if I do are quite high, and I’m still scared. What if I get into a car accident and have to go to the ER? Will they have a bed for me? Will I leave with coronavirus? What are my pregnant friends going to do? What is anyone over 70 going to do?
My goal, and the goal of everyone on the LW staff, and I assume most everyone who’s participated in all the coronavirus threads, has been to figure out what is happening and what we can do about it. We’ve already done a lot. Posts like Seeing the Smoke got coronavirus on people’s radar faster than it otherwise would have been, aided by the numerous modeling threads backing it up. The Quarantine Preparations thread gave people a starting place to act from. The Justified Practical Advice (summary) thread let us share our expertise, in ways that led to concrete behavioral changes. More recently we examined asymptomatic transmission. I’ve had a legit, reasonably high ranking government official say they look at us to see where everyone else will be in weeks.
This is currently the LessWrong team’s top priority, and they’ve done a number of things over the recent weeks to facilitate research and action on coronavirus, including hiring me to be a point person on it. To facilitate as much progress as possible over the coming weeks, habryka and I have compiled a list of what we consider the most important questions in fighting COVID, and are asking anyone with the skill to help us answer them.
That list is at the end of this post. But first, what is the overall plan here?
Who are we trying to help?
We have three broad categories of potential beneficiaries in mind:
How Are We Doing That?
I am managing a Coronavirus Agenda, composed of what myself and habryka think are the most important coronavirus-related questions to answer (think we missed some? Please comment). But the full agenda is kind of overwhelming, and there are benefits to coordinating multiple people around the same question, so every so often I’ll pull out Spotlight Questions to generate a critical mass of attention around the most critical questions. I want to say “every so often” will be once a week, but I feel like those kinds of commitments are for situations where I know within an order of magnitude how many people are going to die in that week. I will spotlight as often as seems merited by the situation at the time.
If your eye is caught by a question on the agenda that’s not currently spotlighted, of course pursue your interest. That’s the point of sharing the whole agenda. And if you think the agenda is missing something important, of course pursue that, and add a comment explaining it if you have time so I can add it.
Without further adieu, the spotlight questions...
Spotlight Questions
What is the impact of varying initial viral load of COVID-19?
The hypothesis that lower initial viral load leads to better outcomes, and might be worth pursuing deliberately, is a central assumption is Zvi’s post Taking Initial Viral Load Seriously. Is it true?
Economics Questions
The Full Agenda
These are the questions about coronavirus I and habryka (and in the future, commenters on this post) most want answered. We’ll be nudging LessWrong to pursue them over the coming weeks, but for clarity wanted to share the whole thing as a package.
Some of these someone has already answered, or attempted to answer, in which case I’ve linked to the (attempted) answers. I’ll continue to update as more answers come in: