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A (possible) solution to Covid-19 (tillett.info)
716 points by danieltillett 50 days ago | hide | past | web | favorite | 575 comments



I'm not qualified to assess the risk, but if the there's indeed ADE (antibody dependent enhancement),[1][2] people once infected with a milder strain may suffer from more severe symptom from the deadlier strains, thus killing more people in the end.

I'm wondering how we may rule out this worst case scenario.

[1] Is COVID-19 receiving ADE from other coronaviruses? https://www.sciencedirect.com/science/article/pii/S128645792...

[2] New blood tests for antibodies could show true scale of coronavirus pandemic https://www.sciencemag.org/news/2020/03/new-blood-tests-anti...


ADE is more a problem for the vaccine approaches. It is one reason we may never have a vaccine for this disease.

Hard to rule out worst case scenarios, we just have to work with what we have and make hard choices.


>ADE is more a problem for the vaccine approaches. It is one reason we may never have a vaccine for this disease.

This is at least partly why there are no SARS/MERS vaccines. There's a paper I'll try to dig up where 4-8 (can't remember) modified vaccine candidates were tested in multiple animal species, and in each case except one, immunity was conferred but exposure to the virus lead to a dangerous autoimmune response which destroyed lung tissue.


That's not ADE as I understand it. ADE is where the virus gets grabbed more easily by cells thanks to the antibodies on it proving handles.


Well yes, because of ADE the normal antibodies released by the immune response immediately increase the replication rate so you have a far more severe reaction upon infection than you would otherwise.

That's why I'm waiting for confirmation of immunity. So far I've only seen increasing numbers of reports of reinfection but that may just be faulty testing.


My understanding is that we had SARS vaccine candidates ready for human testing, but funding died off once SARS disappeared.


Maybe in this context, making a "hard choice" is accepting that something like 0.3% of the world population dies? Historically we saw worse and recovered, while trying to engineer something with no guarantee it won't be massively worse, using an unprecedented and more or less unstoppable strategy, might not be the most prudent thing to do. Looks like a good movie plot though.


We don't have that option, unfortunately. In real life we're dealing with hospitals permanently jammed and new covid patients keep dying every 6 months, plus the huge economic costs from keeping hospitals _at_ capacity as opposed to 10x over capacity.


If the total cost is under $6 trillion, I think the Fed can swing it.


What about Dengue?


Dengue is a different virus. All viruses behave differently.


Wow. What an answer. All flaviviruses cause ADE. Only few attenuated vaccines worked as a strategy. And no they don't shed.


Article [1] is dated Feb 12, and contains the sentence:

"Instead, it [SARS-CoV-2] appears to be no more concerning than the influenza virus." The citation for this claim is an article in Canada's National Post.


I posted and deleted a few comments. I don't know what to make of this and it's getting controversial. If it could be helpful, I'd love to improve it. I just don't know where it fits in ongoing discussions by prominent researchers on analysis of strains and types.

Three things that jump out at me:

a) You'll get more credibility from having a thorough lit review than from listing credentials. Linking to magazine articles from journalists on genetic variations, when there's academic research to cite, is a little bewildering.

b) You don't identify something harmless by just testing asymptomatics. This is counterintuitive, but a great example of the Wason selection task:

https://en.wikipedia.org/wiki/Wason_selection_task

You would probably want to survey the rate of variants in asymptomatics in a certain community, then compare that with the rate of variants in fatal cases in the same community to look for significant differences (and be fully prepared not to find any significant differences beyond chance, a real and likely possibility).

c) I'm still not sure what the author is specifically recommending we do next. Researchers are looking for functional variants, we don't have one to distribute yet, so we should do more sequencing. Ok, great. From what populations? How many geographic areas? Where do we get the samples? There are bottlenecks in sample collection, how do we overcome those? Given (b), how can we get more samples from fatal cases, to compare virulence to those in the general population? Task overloaded hospitals to send us additional samples from dying patients? Is there another way we can get this info?

I don't want to dismiss this out of hand, this might be a good area for additional focused research. I do think there are some key unanswered questions though, and currently a worrying disconnect with the current state of research on variants.

EDIT: Daniel, I know you're going through the comments here, and some of them have gotten pretty harsh, sorry for that. I genuinely hope you're on to something, and are able to continue to refine the post into a more robust and specific proposal using all this feedback, despite the tenor of some of the comments. That's really the best case for all of us, so good luck.


Just woke up (I am in Australia). I expect some harsh comments as the idea is controversial. To your specific points.

a) The post was intended for a lay audience, not other scientists directly. The reason I didn’t write a scientific paper on this is it would sink without a trace as most scientists and doctors are too conservative. It is quite a radical idea and while scientifically sound, it will take mavericks outside of science to see this done. For better or worse it will take the efforts of someone like on of the tech billionaires to push this forward.

b) If I had to choose one aspect that gets most commonly confused by people who read the idea it would be the reason for searching only mild/asymptomatic cases. This is purely an efficiency issue. In an ideal world we would sequence the strains in all cases, look to see if we can find mutants with deletions, and then see what was the clinical outcome of those infected with that strain. If we find that all cases of a particular mutant are mild/asymptomatic then we would have our candidate.

Because we live in a constrained world where it is not possible to sequence all cases, where should we first look? Since we are looking for a mutant that only causes mild/asymptomatic cases we can exclude patients with serious symptoms as a first pass. Once we find a candidate strain that has the right sort of mutation we can then sequence all cases in the local area, both serious and mild to get the full clinical picture. This will make the search much more efficient.

c) I am recommending that we put b) into action and get on with specifically looking for an attenuated (only causes mild disease) strain ASAP. If we find one then we can discuss what to do next, but the first step is to get started.

The good news is this can be done quickly and relatively cheaply provide we have the will and the support of someone with the clout to make it happen. It won’t be easy, but it can be done.


Tech billionaire for publicity, maybe. But just getting a guide ready might help more - everybody with a moderate amount of cash and access to the medical system somewhere can start doing this in his back yard.


> b) You don't identify something harmless by just testing asymptomatics.

True, but I think you are missing part of Daniel's proposal. You don't "just" check for unique variations of the virus in asymptomatic carriers, you also check the sequence for major deletions: We would ideally be looking for a virus strain with a large(ish) deletion in an essential viral gene. This sort of mutation is easy to spot in the SARS-CoV-2 genome data, and because the genetic information has been removed, it makes the virus very unlikely to be able to mutate back into a dangerous strain. Ideally, the strain identified will have infected a number of other people in the local area too so we can know it is safe.

So while you do want to verify that the sequence is not also present in "serious" cases, you are prescreening by a factor that theoretically should correlate to severity. Whether you "need" to do additional testing depends on your assessment of base risk. If you assume that almost everyone is going to be infected with a powerful strain if you do nothing, doing your testing in live cases with a strain you suspect is mild might still be justified. Ideally (as quoted from Daniel) this "testing" might be mostly satisfied by just monitoring those already infected by the original carrier(s) with the same mild strain.


Do you know what the commonly guessed incorrect solution to that card problem supposed to be?


8 and red. Most people don't invert the logic and realize that there is no claim that an odd number can't have a red back. I think confirmation bias accounts for missing the brown.


Do you mean 8 and brown?


> most commonly guessed incorrect solution


My bad, I guess I was the one who misread.


How does the Iceland data suggest the hypotheses that 1) an attenuated strain exists in the wild and 2) it provides immunity to the worse strain? It's asserted in the post, but I don't see it. It seems likely to me their experience isn't any different from any other country's, and they're just testing more.

The idea in the post is obviously a good one if it can be done, it's just that it seems like a generic idea that should be considered for any viral pandemic, which makes me wonder why it's not already an approach people are working on.


It doesn’t which is why I never claimed it did???

As for why people aren’t working on this idea I don’t know. Maybe someone is and they will send me an email and I can update my post. I would certainly be extremely happy with this outcome.


I was responding to this from your blog post:

> This data suggests a simple and testable hypothesis – there are natural strains of SARS-CoV-2 in the world that have mutated to be non-pathogenic (asymptomatic), but are still infective and will provide immunity to the more pathogenic (deadly) strains.

From the structure of the post it sounded like "this data" referred to Iceland plus the Wuhan study.

If you only meant the Wuhan study then apologies for misunderstanding.


Yes both. The Icelandic data suggests there is genetic diversity in SARS-CoV-2 and the Wuhan data suggests there are strains that are less pathogenic.

There is also a Singapore study that has identified strains with large gene deletions, but I haven’t yet updated the post to include it [0].

0. https://www.biorxiv.org/content/10.1101/2020.03.11.987222v1....


Here’s a post from late February that enumerates 42 known strains of 2019-nCoV as a phylogenetic tree: https://nextstrain.org/narratives/ncov/sit-rep/2020-01-30?n=...

I’m a lay person here, but it seems a foregone conclusion that viruses experience frequent mutation, and that a novel virus infecting a new host species for the first time is going to see a relative explosion in mutations due to the extreme increase in the number of opportunities for it to occur.


This seems risky but worth consideration.

Can you provide peer / concept review from virologists?

A few items of feedback:

- You could use a title that includes a distinct word to identify your proposed solution: "Using accentuated COVID-19 strains as a (possible) solution". This helps people to communicate and refer to the idea concisely.

- The top three paragraphs may be known to your target audience; consider allowing the reader to get straight to your point.

- It took me a while (certainly to the Q&A section) to grasp that attenuated virus strains are different from dangerous ones. Explaining this (perhaps in a brief sentence, then repeated and elaborated in a more detailed paragraph) near the top may also help.

- Further references (especially peer review from respected authors) may help gain traction. Decision makers can be -- sensibly -- risk averse in global crises like these.

Good luck!


I am a virologist - well I have published many papers in this area. I have a PhD in molecular microbiology and have been a tenured professor (I now work in the biotech sector). This is not intended to be a scientific paper, but a layman’s summary of the idea so non-technical people can understand the idea.

It is not risky to go looking for a naturally attenuated virus. This is the first step that needs to happen.


Thank you. I certainly get the sense from the article and your comments that you are well-informed.

My suggestion is really one around building trust - it'd help to have others in the same scientific field confirm and/or question the approach.


This is exactly what I want to do. I want to collaborate with those in the position to go looking for one of these attenuated viruses.


It looks like you need to find someone who can help make your post feel more professional - perhaps Ask HN for help or just directly email one of the clued up people here that are open to cold emails (patio11?).

I almost didn’t read it because the title sounds too generically woowoo, and the domain you are using seemed unprofessional. Then on reading the article, you didn’t give your background, an irrelevant picture of a painting opens the article, and the sidebar of your article topics are all over the shop. Sorry for being so negative: it is much easier to find reasons why something doesn’t feel right, and I’m not a fantastic marketer so I can’t offer you fixes I could predict would help.

It seems like a really good idea (are there others that have suggested it?), but I suspect it needs to be more convincing with a bit of repackaging if you want to push it.

Maybe add comments to those 2 papers with an “elevator pitch” or a request for other relevant info, and link to an improved post, and it should bubble up and find the right people to evaluate it.

Edit: also perhaps get your idea onto the various Covid daily link sites: good ideas should bubble up. Use Twitter to relevant people. Pass the idea to this guy who writes fantastically and has audience: https://medium.com/@tomaspueyo/coronavirus-act-today-or-peop...

Good luck, we need some!


> It looks like you need to find someone who can help make your post feel more professional - perhaps Ask HN for help or just directly email one of the clued up people here that are open to cold emails (patio11?).

It would probably have the opposite effect. This way it looks like a probably serious scientist wrote an idea that is probably worth considering on his personal website / blog.

If you give the site the "Hacker News treatment", I suspect that it will immediately look like "somebody with funding is trying to sell me on an idea for some reason". This stuff might work for naive consumers, but naive consumers don't matter here. I am sure that this post is already being shared among experts, and they are the ones who need to decide if this idea has merit or not. Throwing marketing bs at them will probably just hurt the cause.


The site is my personal blog. I thought about writing a more technical level paper, but what I wanted to accomplish is to get this idea in front of a non-scientific audience who can think outside the box (like many of those on HN).

A standard scientific paper will sink without a trace -scientists are just too conservative to take something like this seriously. I hate to say it, but the people who will make something like this a reality are the tech billionaires of this world.


The tech billionaires of this world will not fund anything based on a layman's explanation. They want to fund ideas based on reliable research. The Gates Foundation is staffed with tons of specialists for this reason.


I think that if you really believe your idea has some merit, you should still write a paper. After that you can blog about it for any audience out there and maybe write a follow-up. You're a professional, you know how it works.


I most likely will write such a paper, but the first thing is to get those that can make this happen interested. They are not going to be reading a scientific paper.


This seems like a pretty good idea (good enough that certainly there must already be people working on it) so it seems like if you could find and contact them, maybe you could contribute to their efforts?

It just seems more practical than hail-mary posting on HN https://news.ycombinator.com/item?id=22810639


Well I hope other are working on it, but I haven’t found much evidence of this so far. HN has a pretty diverse audience including a lot of scientists like me.


Wouldn't an attenuated strain vaccine still require years of paperwork and clinical trials too?


Yes. This is why I am suggesting an alternative. It is all in the blog post.


This is an attenuated live vaccine, though. So the risks are similar or worse than just doing a real, engineered vaccine.

If it's mere paperwork, we can solve that with a regular vaccine just as fast. And the regular vaccine would be more likely to be safe, even at an early stage. (Note: I'm a rando, not a medical or biological professional.)


if bureacracy held up the spread of a live coronavirus, we wouldn't be in this mess


The proposal is to intentionally apply a live virus to people, so absolutely there are bureaucratic barriers to this (and for good reason). There is no a priori reason why this should have less red tape than a dead virus.

If we're just going to ignore any regulations and bureaucracy for a live virus (like this proposes), we can do the same for a dead virus.


The reason why this should be able to advance faster than a normal vaccine approach is that we will have epidemiological data that it is safe in humans. Sure it would be nice to have double blinded placebo controlled data, but good epidemiology data is still data on which a regulatory decision could be made. In the current circumstances I think this will satisfy the regulators.


It would only be logical to require a "vaccine-strain" that has the capability for uncontrolled spread to go through much more stringent trials and paperwork than one that is limited by distribution.

The whole argument about attenuated strains being a possible shortcut seems to be a variation of the "natural medicine" fallacy.


Except the experiment has been done for us already by nature. We are not doing the experiment, just observing what has already happened. Sure you would not be able to make a strain of unknown attenuation in the lab and spread it around (this would be very dangerous), but you can use the data that nature has provided us. I am proposing we go and collect that data.


It would probably be helpful to mention that at the start or end of the post. Clear, non-inflated credentials/background with links. (I sometimes see this in italics at the top)


It is not really my style to boast about myself, but yes I should at least provide a link to the about me page.


Sort of a weird ask, but as a real, no shit, virologist, what do you think about changing your messaging to make content more accessible to lazy readers?

I have some half baked ideas about tradeoffs in infection rate and fatality, but I'm worse than a layman, I'm a layman with an opinion.

I'd sorta thought a virus could be real lethal(like ebola) ore real infectious(like a cold) but it's kinda hard to be both at the same time.

it _seems_ like there's a mapping between getting read (infection rate) and convincing people (fatality).

to be super explicit, is messaging a virus? is there a tradeoff in how the message spreads vs how convincing it is?

You've probably got other things to do, but it seems like there's a parallel there, even if imperfect, that's worth looking at. If you got a minute, I'd love to read your thoughts.


Viruses don’t really care about thing like death rate, they just care about how effectively they are spread from person to person (viruses don’t really care about anything, but I am describing how they appear to act if they had a mind).

In general the less deadly viruses spread better as dead people are not able to spread the virus around as well as living people. The general trend is for viruses to become less deadly over time, but it can take a long time for this to happen.


Spread rate would also need to stay in a certain range for a virus to stick around. Spread too fast and there won't be a second wave. The herd immunity effect gives this system some self-balancing properties, but there's surely a tipping point where even that won't help a speeding virus to survive.


> is there a tradeoff in how the message spreads vs how convincing it is?

That doesn't make any sense, viruses that are more fatal don't spread well because dead people are not good spreaders. Very sick people are also less capable spreaders than someone walking around with a persistent cough. Someone who's convinced would be MORE likely to spread a message.


I think it would help to include your bio/qualifications in the blogpost.


Done.


Adding to this:

While you do not recommend ZJ01 due to the potential for it to mutate back into the original strain, isn't it also quite dangerous?

That would likely remain a primary concern for many - we musn't cause large scale harm intentionally. And if we don't know what effects a strain has, it makes it ethically difficult to distribute.

From the ZJ01 Medrxiv[1] page you link to:

"We found, in our 788 confirmed COVID-19 patients, the decreased rate of severe/critical type, increased liver/kidney damage and prolonged period of nuclear acid positivity during virus dissemination, when compared with Wuhan."

[1] - https://www.medrxiv.org/content/10.1101/2020.03.10.20033944v...


This just rules our using ZJ01. There are other attenuated strains out there that will have deletion mutations that can’t mutate back. We need to go find them.


Sorry if it's a stupid question, but hypothetically, would we be able to engineer rather than find a harmless strain of coronavirus with the spike protein of SARS-CoV-2?

If I understand correctly, antigens identify the virus by its S proteins. Would we be able to use the same methods <a href='https://www.nature.com/articles/nm.3985'>as in this paper</a> to replace the S protein in a harmless cold-like coronavirus with the S protein of SARS-CoV-2, and would then the resulting immunity defend against SARS-CoV-2?


This is not a stupid question. Yes we could engineer such a strain, the problem would be testing it given we would not be able to predict how dangerous it was.


Having identified a harmless strain, and presuming regulatory agencies are too slow to be useful, then what?

Send people infected with the harmless version around, after lockdown ends in a month or two, to crowded places?

Would greater virulence be a desirable quality in our reduced strain?


Well if the regulatory agencies decided that they weren’t going to act then I suspect there would be a grass roots level spread of the strain anyway. This would be the worst way to use such a strain, but I don’t think it would be possible to stop this happening.

I don’t think we will get to that point. If we collect good data from the natural spread of any attenuated strain then I think the regulatory authorities will allow its use on the basis of this data.


I hear the phrase "peer review" thrown around so much it's reaching semantic satiation. I get that it's the way respected science gets done, but it's also the laziest possible critique because you're literally asking for someone else to think about it for you.


A naturally attenuated strain would still be regulated. In the US, 21 USC §321(g):

> (1) The term "drug" means… (B) articles intended for use in the diagnosis, cure, mitigation, treatment, or prevention of disease in man or other animals;

CBER would be the responsible center for the FDA. Other countries have analogous regulations.

Could you come to market with a naturally attenuated strain? Yes. Would it take less time? Not really, because you don’t get to do an “end run around the regulations” as you put it in another comment. The logistics of making sure it works and then setting up the supply chain and quality systems are what take the most time. There are no shortcuts in medicine.


There are plenty of shortcuts in medicine. Think how you would stop this strain from being spread by individuals once it was identified. This strain will spread no matter what the FDA says.

Personally I think the regulatory authorities would rapid approve it based on the epidemiology data collected in the process of finding the strain. The FDA has already shown that it can move faster than its usual glacial pace given sufficient motivation.

The much more important question is when are we going to start seriously looking for such a strain?


I don’t see that any regulatory authority would approve something that is capable of spreading, regardless of the possible benefits: it would violate medical ethics. Reread the Belmont Report.

There are many teams all over the world that are looking for less deadly (and more deadly!) strains to guide development of therapies. They’re too busy right now to post on message boards or speak to reporters. It’s however extremely unlikely that a less deadly strain will become the therapy, although it could be the basis of a therapy (but I think this too is unlikely).


All the attenuated live viral vaccines spread. This is one of the reasons they are so effective since they keep herd immunity up. For example, every kid that gets the live polio vaccine spreads it around to their peers and parents.


> All the attenuated live viral vaccines spread.

Can you point me to sources supporting that claim? I searched myself, and what I found says that our knowledge is limited to the polio vaccine:

"Little attention has been given to vaccine transmission, possibly because transmission is rarely measured and largely unknown in humans except for the oral polio vaccine. Whether transmission is indeed rare for other live vaccines, or has merely gone unnoticed, is not clear – polio vaccine transmission is accompanied by evolution to high virulence, creating problems that draw attention to transmission."

From "Transmissible Viral Vaccines", James J. Bull et al., Trends in Microbiology, January 2018. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5777272/


This is a difficult topic to research these days due to the anti-vax/anti-anti-vax noise. :(

It doesn’t appear that horizontal transfer is absurd, and while I’m not immediately seeing a large body of evidence that it happens all the time, it does seem to be generally accepted that it occurs.

Here’s what I believe to be an informative article on the topic: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3667938/


That’s a bug, not a feature: the OPV went to bivalent a few years ago to reduce the odds of vaccine-related cases.


Well your bug is a feature.

The polio vaccine actually went to the inactive form to reduce the risk of polio from one of the vaccine strains reverting to wild type and infecting others. It is still less effective at achieving herd immunity than the live version because of the lack of viral spread.


[flagged]



I am sure all the kids that got polio from someone else vaccine are glad to know this.


It hurts your case if you respond defensively or sarcastically.


Yes :(


Don't be hard on yourself; it happens. It's hard to withstand hours of engagement with internet commenters. The worst comments make a much deeper impression than everything else, just as getting stung by a bee is more memorable than seeing a butterfly.


Serious question: are we not? People are sequencing these things like crazy (c.f. the nextstrain.org data). Epidemiologists are working like mad to come up with data on severity in regions all over the globe. Virologists everywhere are dropping what they're doing otherwise to work on covid.

It sorta strains reason to argue that none of these people thought of looking for an attenuated strain.

Isn't the simpler truth just that finding one takes a lot of ground work that's already being done, but hasn't born fruit yet?


The sequencing is not the important thing here, but the search for strains with gene deletions and contact tracing everyone in the area to find more cases to prove the strain is attenuated. As far as I know nobody is doing this.


You’re fairly hard to get in contact with directly. Would you mind sending me an email? I don’t think I’ll be a your “middle hop”, but I’ll try. My email is lyndsy@<my_HN_username>.com

My username here is my real name, and I should be easy to find. It’s also my username on Twitter, Keybase, and most other popular platforms.


From the update section of the original post:

> If you think you might be that first hop person then please get in contact with me at daniel.tillett@gmail.com


Thank you. I don’t know if that just wasn’t there when I posted, or if I just missed it, but I appreciate it.


It was there, but I put it right at the bottom so at least only people who read the entire post would find it. I am at least a lot easier to get in contact with than anyone with the political clout to make this happen.


they re probably not sequencing asymptomatic people's virus, it would require some specific expedition. it doesn't even sound hard or expensive

reply to @ajross:

how would they know someone is asymptomatic? afaik they are mostly testing people who have symptoms , and their contacts (who will have contracted the same , symptomatic strain)

I think in germany they did antibody testing, or PCR of swabs of people who mostly no longer had a live virus infection to sequence. also, it seems the idea has merit; and i havent read about any team looking for this specific method (identify gene deletions and tracing). It certainly doesn't hurt (and doesnt cost much) to try

btw sweden is doing a survey of live infections in stockholm, however i don't think that they sequence the viruses

to @danieltillet:

maybe post about it in reddit on r/covid19, some epidemiologists hang out there for the latest news


It is not hard to do the sequencing to find candidate attenuated strains (you are just looking for strains with deletions in key genes). The more difficult part is all the contact tracing in the area around where the strain is first found to check if the strain really is attenuated.

The ideal outcome is you find a strain with a deletion and you then test everyone in the area and you find 10,000 more people infected with the strain that have only a mild case and none of these people are in the hospitals. This strain would be very valuable to have.


Are they not? That seems like a pretty obvious experiment to do.

For reference: I have a family member in virology. He reports that everyone he knows is now working on covid, mostly because if they don't they can't come to work on anything. The biggest problem is finding subjects that will produce a paper of any kind. I really don't think research bandwidth is the issue here.

I guess I have to repeat the question as its converse: is there any evidence that this is not happening? If it isn't, let's figure out the right people to pressure and not just discuss it on HN. And if it is, maybe we should let the experts do their work without pretending to have had their ideas for them?


If you know anyone working on my idea please let me know as I will update my blog post. Nothing would please me more than to learn that someone is already doing this on a serious level.


> how would they know someone is asymptomatic? afaik they are mostly testing people who have symptoms

There was literally a paper published yesterday (or the day before) on a blanket screen done on a population in germany to get some data on the undercount of asymptomatic cases. It was front page news on all the mainstream news sites...

I gotta be honest. This whole discussion has an "amateur hour" vibe. I have a hard time believing that professional academics in a long-established and very competetive field really failed to remember how the measles vaccine worked.

It's not that I think this is a bad idea, just that (1) it's almost certainly someone else's idea already, (2) is therefore probably harder to do than presented and (3) is thus not the magic bullet people are looking for.

To wit: stay the fuck home. Maybe someone will save us. They probably won't. We beat this with isolation or we wait for a vaccine.


I think what you are missing here is what is the novel part of my idea and what is the conventional. It is not novel to think of an attenuated vaccine, what is novel is to look for an attenuated strain in a pandemic using genome sequencing. I hope someone else has thought of this, but so far I haven’t seen any evidence of this.

Waiting for vaccine is not a good option. This is a situation with only hard choices.


Why else are hundreds of different labs around the world genome sequencing?


To assess the diversity and spread of the virus it appears. To the best of my knowledge nobody is systematically looking for a natural attenuated strain by genome sequencing. If you are then please get in contact with me.


"Waiting for a vaccine" is mostly a strawman. We're being asked to wait 2-3 months for the outbreaks to reach a size where they can be contained by testing, tracing and quarantine. But that only works if people take this seriously and honor the lockdowns.


Even if this would work in rich countries, this is not a realistic option for people in poor countries. They do not have the money to wait in isolation for the next 3 months.


We’re also likely to see convalescent sera available shortly, and neutralizing antibodies available in several months. Those, along with more widely available testing, will help us tread water until we develop a good drug or vaccine.


Robin Hanson has been covering variolation: http://www.overcomingbias.com/2020/04/variolation-test-desig... and part of the issue is that the FDA is poorly equipped and set up to respond to a pandemic. One obvious solution is to cut through the bureaucracy and make emergency exceptions, but no one with political power in the US seems to know this, or understand it.


Ultimately a decision to use or not use any attenuated strain found will be a political decision.


There's a lot of differences in risk appetite (and actual risk) from state to state.

Maybe the feds could allow states to get a waiver from FDA regulations if they want to try things like variolation.

This would still require someone at the federal level to stick their neck out a little, but (I think) a lot less than if they were to propose something like this as a federal policy.

We've got a federal system, let's make some use of it.


i doubt that , if this magical strain does exist, any regulation is going to stop people from just getting themselves infected


I doubt the regulators would even try to stop it. They can move fast when they want.

The process of finding any useful strain is going generate good data that it is safe anyway.


Alternatively, if this approach actually works, all the countries in the world that can appropriately adapt their regulations will survive, and the ones that choose not to won't.

Natural selection versus bureaucracy!


It's the "figure out if it actually works" part that is going to take most of the time for any potential prophylactic option for COVID-19. The bureaucratic overhead in this particular case is not going to be the inner loop.


Virus can be asymptomatic for a number of reasons. Host factors, such as age, (speculation) history of the previous coronavirus but not covid-19 infections, etc.

Going after covid-19 genomes in a group of asymptomatic and symptomatic 70+ years old with sampling from different regions/countries may give us better data.

Finding a mutated strain which never gives symptoms in old people from diverse locations, diet, health status etc. is the holy grail of this approach.


Yes. What we really want is a strain that has infected a whole lot of people and all of them have had a mild case.


>What we really want is a strain that has infected a whole lot of people and all of them have had a mild case

How about 10 to 50 million ?

I live in Nigeria. Between December and late February, many people in Nigeria and Ghana report experiencing symptoms similar to those that could be caused moderate COVID-19 infection. These included, fever, diarhoea, cough, sore throat, malaise.

Many physicians and scientists I know think it we may have had a mild outbreak of the disease. If so, was this reduced severity due to a mild strain of the virus or to other factors ? It warrants investigation. Your proposal and the theory underlying it make a lot of sense.

I would really like to be able to dig deeper into this.


That is also the symptoms of the ordinary flu which is the more likely candidate.


Lassa fever also occurs often in Nigeria


What's the relationship between Lassa fever and covid-19 ?


People get a fever, and think it is covid, but it is actually lassa


Look up the symptoms of lassa fever. It could not possibly be confused for anything else. Besides, it occurs in specific locales.


>In 80% of those who are infected little or no symptoms occur. These mild symptoms may include fever, tiredness, weakness, and headache.

Those are also covid symptoms


The median age in Nigeria is 18.4 years, while in Italy it's 45.5 years.

Nigeria might have more immunocompromised people due to AIDS. But is there any reliable accounting of deaths, much less the reason?

In any case, I wouldn't be surprised if age and lack of accounting is why you don't see a problem in Nigeria.

Source: https://en.m.wikipedia.org/wiki/List_of_countries_by_median_...


1. Age is not the main factor at play here. While the median age is lower than Italy's there are still a lot of elderly people in Nigeria. On an age and population adjusted basis, Nigeria has nowhere near the number of cases and deaths as Italy.

2. The demographic profile and phylogenetic makeup of Nigeria is similar to Cameroon which has experienced more cases and deaths than Nigeria in both absolute numbers and on a pro-rata basis. This makes some of us believe we are dealing with two different circulating strains in both countries.

3. It definitely is the case that testing is not adequate but a highly susceptible affected population would soon be revealed by the number of symptomatic cases and, (more to the point), deaths. Both indices have remained relatively low


If you are part of a cluster of a viral infection and you suspect Covid, then look for Anosmia as a symptom.

Anosmia is reported in 30%+ of Covid cases. Flu/cold viruses can cause Anosmia but it obviously isn’t common since you don’t hear about it and it isn’t given in lists expected symptoms.

Within a sample of 10 people that have Covid, you have an expected number of people that would have Anosmia.

https://www1.racgp.org.au/newsgp/clinical/push-to-include-an...

Beware of false information https://www.nationalgeographic.com/science/2020/04/lost-your... because AFAIK the journalist has incorrect thinking: “flus and colds are a common cause of Anosmia” DOESN’T mean that “Anosmia is a common symptom” (the abstract they reference is poorly written, still poor journalism IMHO).

I would appreciate any references to data showing how uncommon Anosmia is in cold/flu patients (I did look, but didn’t look hard).


You probably won't find that... You might find a strain where 99.9% of people get a mild case.

Who is going to be the person to recommend deliberately spreading that strain to the world population, knowing that 0.1% of the world, 7 million people, will end up in a hospital and die?

Sure, overall, fewer people might die, but the reality is whichever world leader makes that call has effectively just signed a death warrant for 7 million people. That isn't the way to get re-elected.


I think we can do better than 0.1% death rate. In principle there is no reason we can’t find a strain that is no more dangerous than the coronaviruses that cause the common cold.

One thing is certain and that is unless we go out and look we won’t find anything.


@danieltillett

I could quickly put together a team focused on southern Nigeria and Ghana to find through word of mouth, medical records, contact tracing lists and social media, people who have experienced covid-19 symptoms and are likely to have had the disease. My team would also collect samples from people in the worst affected areas who are asymptomatic. In this way, we could collect data and enough samples to isolate a(?the) virus if any.

Do you know any organisations that could provide funding and support for this ?


It is probably best to contact me offline. My email details are on my website.


0.1% would be great. That's the mortality of the regular flu and we have ramped up the hospitals to cope already so the 0.1% severe cases would be better handled. That would be much better than we manage the flu. It would also make it actually possible to take risk groups and isolate only those for a longer time without crashing the economy. It would be the opposite of the flu where vaccination is focused on risk groups.


You would infect on purpose the 80% of the less vulnerable population for herd immunity


Agreed. But for the heard immunity one does not have to go and vaccinate/expose to an attenuated strain of virus the whole population. Even getting a majority of say under 50yo immunized should have a big effect.

These are special times. In reality it does not matter if this 0.1% +70yo will die after vaccination since the mortality rates in this age group infected with the wild type are bigger by about two orders of magnitude. But out of concern to human rights it will make sense not only to exclude any immunocompromised people but also make it voluntary to the groups where mortality rates are at certain level.


I have posted this again as dang asked me to put it up again.

Happy to answer questions about the idea, but I am most interested in find collaborators to make it happen ASAP.


I just sent your article to my contacts at the White House, Department of Defense, DARPA and a couple of other acronym agencies. I sent this to Director level people (or just under) at those agencies.

No guarantees (they are all swamped). I hope they respond and put you in touch with the right people.


Thanks. This is the problem I have run into which is all the right people are so busy at the moment that they don’t have time to look at something like this from someone like me.


Yes.

I can confirm that your information got to one of my contacts at the White House. He replied saying he would distribute it to the right people. Your guess is as good as mine as to what happens from there. Even people within the White House have trouble penetrating through various layers due to just how busy everyone is (as well as security, etc.).


Thanks once again.


Honestly at this point if you could get FOX News to pick up the story, the White House will know about it immediately.


I am sure you are right, but I don’t happen to know anyone from FOX News. If you do get in contact with me.


I just forwarded your information and article to the producers for the top shows at Fox News. Let's see if they move on it and get in touch.

I've also done the same for CNN producers.

It'll be interesting to see who responds, if any. My standard advice still holds: Don't hold your breath. Sadly. All of these people are far more interested in ratings than things that matter.


A typo correction: In two places you have "overtime" instead of "over time".


Thanks - I will look for these.


Have you posted it here?

https://crowdfightcovid19.org/


I totally missed it from the article but how is he going to tell the deadly strain from the less deadly one? I mean I understand how they can tell the difference between the two strains. But how to tell that some particular strain is less deadly? To the best of my understanding the only way to get there is to sequence the virus from statistically significant number (~10^5 ??) of carriers including the significant proportion of those with asymptomatic cases. Not realistic IMHO.


Not to mention relying on each person's account of the severity of the symptoms, and coding that into a dataset that corresponds to the sequencing results. You need a LOT of asymptomatic people with the strain in order to draw any strong conclusions.

The upside is, you may draw other very interesting conclusions while collecting data for this mission, and be able to "pivot" if you will.


This is all described in the post. I have updated it to make it a little clearer (based on feedback). If you missed it the first time around you might get it now.


You make this statement: "The most important thing to note is that such a virus would not be a vaccine from a regulatory perspective."

Can you provide any evidence to back up this statement? If you were to start intentionally infecting people with a (naturally) attenuated strain claiming that it will confer immunity I suspect authorities would request you get regulatory approval.

If you're approach does require regulatory approval. What advantage does your approach have over those currently in developement? Some of them are just bits of the virus (mRNA that codes for the spike protein) packaged with a delivery mechanism [1].

It's a plausible approach, that has been tested in animal studies. There are a number of other, similarly plausible vaccines entering human trials.

It is however deemed to be too high risk to just start giving the vaccine to large numbers of people. So the vaccine will have to go through (an accelerated) trial process. It will then likely be given to at risk groups (health care professionals), before becoming widely available. Most experts expect this to take at least 16 months (which would be a world record).

Your approach would have the same issues as are present with any other vaccine.

If regulatory authorities are willing to skip trials for your approach, then the same should apply to other vaccines under development.

[1] https://www.modernatx.com/modernas-work-potential-vaccine-ag...


You are looking at this from the wrong perspective. If people start spreading this attenuated strain around on their own what are the regulatory agencies going to do?

Even if you wanted to go down the regulatory pathway for some reason it still has a number of advantages over other approaches.

1. We would know it is safe in humans before we began.

2. We would know what mutations make the virus less pathogenic.

3. Once used it would drive the pathogenic strains to extinction.

4. It will be work in poor countries that can’t afford or distribute a conventional vaccine.

5. It will infect and protect those that are not deliberately infected through contact with others.


> What are regulatory agencies going to to do?

If you were to start doing this without regulatory approval, the most likely outcomes seems that you’d be arrested [1]. Do you have anything that suggests otherwise?

> 1. We would know it is safe in humans before we began.

The regulatory requirements for “knowing it is safe in humans” are currently quite high. As things stand, I would expect trials to be required. Can you provide any evidence to suggest trials wouldn’t be required?

You want to know how the vaccine effects individuals with pre-existing conditions etc. etc. And, as there’s always some risk, you want to be sure that the vaccine is effective.

> 2. We would know what mutations make the virus less pathogenic.

Large scale sequencing of the virus, in individuals and populations will be interesting. Being able to link this patient outcomes is also interesting. And might help in vaccine development. It would be interesting to have a large dataset of viral sequences from asymptomatic individuals. Can we see clear differences between asymptomatic and symptomatic individuals? This would be an interesting dataset, but I’m not sure that the results would be as clear as “look this deletion exists in a sub-population of asymptomatic individuals”. Would be a cool dataset and an interesting project though. There seems to be a lot of NGS data [2] available. This might be a suitable starting point for such a project.

> 4. It will be work in poor countries that can’t afford or distribute a conventional vaccine.

If a vaccine is available, then I suspect there will be sufficient international support to make it widely available. Having an active outbreak anywhere in the world would likely be deemed an unacceptable risk, given the potential for further mutation.

[1] https://www.theverge.com/2020/3/26/21195236/fbi-doj-arrest-f...

[2] https://www.ncbi.nlm.nih.gov/genbank/sars-cov-2-seqs/


I am not going to be spreading the virus around so why would I be arrested? Actually once a “safe” strain was identified and could be tested for it would be impossible to stop it being spread by individuals on their own to those they know.

As we have seen with the whole HCQ fiasco regulations have a habit of getting lowered once there is data, even poor data. If we contact trace everyone who has been infected with the attenuated strain we will get some good data on the safety of the strain. It might not be 100% safe, and we might have some questions, but that is a discussion we can have once we find the strain.

We need to make some hard choices here between certainty and action. Waiting for certainty is a choice that carries a very high cost.


Perhaps I’ve missed something in your argument then. I’d need to understand exactly how you are planning to promote the spread of the attenuated form. If you’re talking about a “sequencing driven” Pox party [1] then I suspect you will run into issues. Particularly if you were to say that the Pox party will infect you with an attenuated form of the virus and vaccinate.

Both the diagnostic (sequencing or otherwise) and claim that you are vaccinating individuals would seem like they’d require regulatory approval. But I’d be interested in evidence that suggests this is not the case in a modern context.

Overall, it seems like the idea is as dangerous as deploying an untested mRNA vaccine. Because of this, I’d suspect that regulatory or other authorities would get involved.

[1] https://en.m.wikipedia.org/wiki/Pox_party


I am not planning on doing anything other than trying to look for the attenuated strain. How it is used is for others - what I am suggesting is once such a strain is found is it will be impossible to stop people spreading it around on their own.


But you do seem to be suggesting that "people spreading it around on their own" is a "solution to Covid-19"?

Otherwise, what is your plan for this attenuated strain? Don't get me wrong, I think large scale sequencing or COVID19 is interesting. But think that attempting to spread a attenuated strain without regulatory approval is probably a very bad idea.


Unregulated spread by individuals is a solution, just not the one I think would be implemented if such a strain were found.

I think it much more likely that the regulatory agency would quickly approve the use of the strain on the basis of the epidemiological data gathered in the process of finding it.


> I think it much more likely that the regulatory agency would quickly approve the use of the strain on the basis of the epidemiological data gathered in the process of finding it.

Have you had experience with dealing with said regulatory agencies?


Unfortunately yes and they normally move at a glacial pace and demand 100% certainty about everything. I do have faith that they are capable of moving faster when the need is as urgent as the need right now.


Daniel, can you please elaborate on this: "Unregulated spread by individuals is a solution" ? How do you envision it ? Virus is not an open source software, you cannot just "make your own copy" without a physical contact. :)


It is ‘a’ solution, but in my opinion not a good one. There are a number of ways this could happen, the easiest is just to send people to the area where it was first found and look for people infected. It is technically very easy to test any sample to make sure it is the right strain.

Even if you can’t get the strain it would not be technically very complex to recreate the virus from scratch once you know what deletion you need.


How could individuals be sure that they're carrying the correct strain, without access to sequencing technology?


A modification of the standard RT-PCR tests can be used to identify if someone has the correct strain. This really is just a matter of making a different set of primers.


So is every coronavirus party going to come with its own set of RT-PCR kits?


I like your idea a lot. It seems that a 12 nucleotide insertion mutation is responsible for a lot of the Covid-19 virulence. If such a large mutation is possible, how would we prevent your loss of function asymptomatic strain from reverting its mutation in the wild? How big of a mutation are you envisioning? Is it impossible for it to be reverted in the wild or just unlikely?

https://www.nature.com/articles/s41591-020-0820-9


I think 12 nucleotides is too small, I would be happier with something north of 30. There have already been strains identified with a deletion of 382 bases [0].

0. https://www.biorxiv.org/content/10.1101/2020.03.11.987222v1....


> More than 50% of the people infected with SARS-CoV-19 are asymptomatic (i.e. they have no illness).

Note: asymptomatic at the time of testing. They may still develop symptoms over time.

https://www.icelandreview.com/sci-tech/is-icelands-coronavir...

https://twitter.com/cmyeaton/status/1246196001775460358


Yes this is true. For the purpose of my idea it doesn’t matter if the person is asymptomatic or they just have a mild case. What is important is the strain identified doesn’t put people in hospital.


The key here is that the vulnerable population needs to tolerate it, too.


Technically they don’t provided we can get the herd immunity up to a decent level in the rest of the population.

While it would be a good idea if the mutated strain was no more dangerous than a common cold coronavirus, we could drive the dangerous strains to extinction without having to infect the vulnerable.


Very difficult to get herd immunity up to a decent enough level without putting the vulnerable portion of the population in great danger though. Most countries are approaching something like 0.1% or 0.2% of the population having been infected. Herd immunity requires 70% - 80% immunity. About 350x - 800x more than what's happened already.

Also the whole thing presumes that immunity is lasting. Some of the data is showing that may not be the case.


The level of herd immunity needed is related to the R0 which is a function of behaviour. This is a really complex topic to discuss, but it is only one we can have once an attenuated strain is found.

Of course the other factor is who is a vulnerable person is a factor of the pathogenicity of the viral strain.


Well this is what many countries and scientists are already doing. It’s just not working as virus is unpredictable and it might infect some but not others.

The best way to find a solution is still try to understand how it acts on different types of people and if they have underlying previous conditions what changes it does, this takes time and I believe that’s the reason there isn’t any cure except by chance in a short time.


Are they already doing that? Is there somewhere I can find the statistics broken out by strain? Or even a list of identifiers of the known strains?

From what I've seen, it's been published in some news articles and such that there "might be" different strains. Haven't seen anything particularly solid yet.


Covid-19 is not mutating like other viruses, but it acts differently on different people, and very problematic for people with pre-existing conditions. Also in some cases again not proven it also infected heart muscles, now it’s not clear yet that it’s due to pneumonia or covid-19. In China they tried plasma from recovered patients and that also didn’t yield very good results. Also in some studies they find a correlation between BCG vaccine and low mortality (again not proven).

The issue with covid-19 is that it’s proving to be much harder to understand than other viruses in spite of not mutating like flu virus. Hopefully by more studies we can increase the chances of developing some cure or may be with so many efforts someone discover cure by chance.


Huh? The key premise of the article is that the SARS-CoV-2 virus is mutating.


Well it’s not mutating the virus they found in initial cases is still the same as the one at present in Patients in Europe and USA.

The premise of article is actually not novel, it’s the way vaccines are made. Smallpox way of developing vaccine in crude way without scientific understanding was done in the early years, now we have come very far.

This virus is really novel that’s the reason novel corona virus (covid-19). Scientists and research community are frantically searching for a vaccine or treatment plan to manage it. So far there is a very limited understanding. Hope can find some way to treat it, otherwise only solution left is relying on herd immunity.


The premise of using an attenuated virus as a vaccine is not novel, but the idea of using genome sequencing to find an attenuated strain and showing through epidemiology that it is safe does seem to be novel.

Even if it doesn’t pan out I think it is worth trying.



Are they tracking that statistic? How many people who test positive later develop the symptoms?

Apparently 80% of those tested later get symptoms: https://twitter.com/TonyBurnetti/status/1246258723774963713


Yes it appears that most people infected eventually get some symptoms. What matters is if they end up in hospital in the ICU or not.

If we can find a strain that just makes you feel like you have a cold that you get over in a week or so then that is what we want.


*will settle for


I don't know if all [corona]viruses move this way but it seems covid illness evolution goes in waves. high symptoms, 2 days ok, high symptoms, 2 days ok, ... repeat a few cycles

It's pretty confusing when symptoms are below a critical threshold and you don't have a test yet.


Doing this stuff will take time, you can later remove sequences where the person later developed symptoms


The results of a study in austria with 1500 randomly selected citizens have just been published, just 5 have been found to be currently infected with SARS-CoV2.

The conclusion is that the prevalence of asymptomatic cases is about 0,32%, CL95 is 0,12-0,76%.

Link (in german): https://www.sora.at/nc/news-presse/news/news-einzelansicht/n...


This goes contrary to what other studies have found. In the Stockholm metropolitan area they found that 2.5% percent of the population was infected [1]. In in a community in Germany, which was the epicenter of the outbreak for a time, they found that 15% of the population tested positive for antibodies [2]. In Iceland they found that 88-93% of the infections are undetected [3].

[1] https://www.folkhalsomyndigheten.se/nyheter-och-press/nyhets...

[2] https://www.land.nrw/sites/default/files/asset/document/zwis...

[3] http://www.igmchicago.org/wp-content/uploads/2020/04/Covid_I...


I don't think it is actually contrary to those other studies. The austrian study randomly selected among the whole population whereas the german study used a cluster connected to a hot-spot. IMO it is measures like social distancing in place for more than 3 weeks at the time of sample-taking in austria that reflect in the data.


It does. The german study was conducted in a town that was relatively heavily tested during its outbreak, and only recorded 2.5% official infections in the population of that town, so the german study showed the actual number to be 7 times as high. This Austrian study found this number to be only ~2.5 times as high. Germany and Austria overall seem to test fairly similarly.


The austrian number says currently active cases are probably 2.5 times as much as official numbers.

German study says in a community linked to an outbreak, there are 14% immune and 2% to be shedding viral DNA.

Austrian study didn't include antibody test (yet).


Is my translation incomplete, or did that German study use a test with unreported sensitivity (but >99% specificity)? 15% could be closer to a lower bound, if so.

On top of that, other research indicates some folks might be recovering without developing antibodies at all (they could be clearing the infection with only their innate immune systems). In that case we couldn't be totally sure about the upper bound anytime soon:

https://www.medrxiv.org/content/10.1101/2020.03.30.20047365v...

https://en.wikipedia.org/wiki/Innate_immune_system


We are really more interested in mild cases, not asymptomatic cases. The evidence seems to be that most asymptomatic infections go on to show some symptoms at a later date.


They didn't really say asymptomatic or mild case, but presumably people with (strong) symptoms would have gotten a test and already be in the official statistics.

The next study that is currently being prepared will include antibody-tests, but it seems logistics and which test to use is not a trivial matter.


Stupid question: if you only search people with mild or even asymptomatic cases, how does that even tell you something about the virus? Should you not also search in (many) severe cases for the candidate, to exclude it from the list of dangerous virii?


There are no stupid questions, just stupid politicians.

We are looking for an attenuated strain and that will be found in people with a mild case. We could sequence all cases, but we would exclude any strain that puts someone in hospital so it is a waste of resources to sequence viruses from people in hospital. From a practical perspective it is better to concentrate on people with only mild cases.


But honestly, if you only look into people with mild cases, how do you know the virus causes these mildness?

If I pick 1k people with mild cases at random, I will find pretty much any strain that currently is in circulation. How do I know which strain is harmless?


You don’t, but what you are looking for is a virus with a largish deletion in an essential gene. You then go and look for anyone in contact with this person and check them and then expand out to the whole local area. If everyone infected with this strain has a mild illness they you have hit the jackpot.

I do describe this in my blog post.


I think GP's point was that if you have a candidate it would also make sense to use sequences from the hospitalised to try and confirm your strain didn't put them there.

Aka this being one mechanism by which you confirm it is only producing mild illness. There's a limited amount you can find out by asking because nobody knows what strain they had.


You really want to find every single person who has been infected with the mutant strain and find out how sick they got. If you find a mutant that infected 10,000 people and didn’t cause any serious illness then you have a pretty good idea it safe.


I think the point is that you have to sequence people in the hospital as well, otherwise you won't know if that particular strain is safe or not.

If it is a rare strain, how will you know if it's safe? Seems like it would have to be a rare strain with thousands of cases and hospitalizations in that population are extremely rare.

Sampling bias and other confounding factors would be a real problem in this search, at least from a statistical point of view, imo.

I also think finding everyone who has been infected with a strain isn't feasible, at best you are sampling from the population.


You actually want to screen all people in the local area for the strain that may have it. If all the people have had a mild case and none of them are in hospital then you have something special.


Ah, so you first check for a candidate and then check a (somewhat random) group of people infected with that candidate for severity. That sounds sensible. Thanks for updating a stranger from the internet!


> There are no stupid questions, just stupid politicians.

politicians aren't stupid, they just play a different game and it looks really dumb from the outside. for them, their moves make sense, they're pros at it.

anyway, you've done very well to find yourself on the top 30 of HN. the smarter press reads this directly. the less smart press reads it a few days later after it spreads through the net via reddits, facebooks, etc. hopefully it's a matter of time a good headline will find its way to pair of eyes in the right place at the right time.


Well I have met quite a few politicians is real life (low level) so I am not sure I would agree with that assessment ;)

Yes hopefully this thread gets some attention from others.


I see two problems with this approach, both political / social:

- No one will want to be the one "deploying" the attenuated strain in a human and then be responsible for some unforeseen death (even if it's just 1 in a billion). Utilitarianism is not widespread nor socially accepted. Even less so in politicians, who are quite risk averse.

- There is no lobby supporting it. There's no $$ to be made and the "vaccine" is basically free.


No one will want to be the one "deploying" the attenuated strain in a human and then be responsible for some unforeseen death (even if it's just 1 in a billion). Utilitarianism is not widespread nor socially accepted. Even less so in politicians, who are quite risk averse.

I would give them more credit, especially in a situation where the status quo includes so many deaths. I was impressed with how readily most states licensed self-driving vehicles, knowing that there would certainly be deaths. Their rationality here likely came from seeing tens of thousands of people dying on the roads each year.


Lets solve this issues once we find the right attenuated strain. Personally I think these sort of social problems will be overcome once we compare with the alternative of sitting around waiting for a vaccine.


The flu vaccine (and others) kills more than 1 in a billion yet we still use it.

And it would not be free, you still need to collect this strain, replicate it at massive scale and then distribute it.


I am not an expert, so I apologize if these are a dumb questions, but here goes:

1) Wouldn't natural selection result in a milder strain crowding out a more deadly strain? After shelter in place lifts, people with a mild strain will be more likely to go out and spread the virus whereas people with the deadly strain will be more likely to stay home sick.

2) Is there any consensus on whether we become immune to COVID after getting it (e.g. if we get a mild strain will we really be immune to a deadly one)? I've heard different opinions and I'm wondering what the leading hypothesis is at the moment.

Thanks!


That sounds correct, but "scientifically" we have to spend million of dollars and months of time to say for sure.


This reminds me of a story 20 years ago when Pittsburgh Steelers (American football) announcer Myron Cope ran into head coach Bill Cowher...

Myron said, "I see that Lee Flowers is playing today after a high ankle sprain 2 weeks ago. But I thought that high ankle sprains took 4 weeks to heal. What gives?"

Coach Cowher replied, "4 weeks is true, Myron, for the first high ankle sprain. But if you recall, Lee had a high ankle sprain on the same foot last year. And since subsequent high ankle sprains only take 2 weeks to heal, he's ready to play."

Myron paused and asked, "Then why don't you just take the whole team out in February and sprain all their ankles?"

(We laughed 20 years ago. Nobody's laughing today.)


This reminds me of the old joke that, because the possibility of there being two bombs on a plane is infinitesimally small, you should always bring your own bomb with you.


I understand the metaphor you’re using, but for the sake of clarity I feel compelled to explain that there is a big difference: ankle-spraining significantly increases in likelihood with each subsequent instance. So “spraining ‘em all” even once would literally result in long-term degradation and increased frequency of injury. They would take less to heal, but would also get injured so often that the aggregated result would be worse than before.

Sadly joints tend to work a bit differently from the immune system (with some exceptions).


Another strain that might be less deadly: https://www.biorxiv.org/content/10.1101/2020.03.11.987222v1....

Also it is a paper from Singapore which should avoid the China negative bias.


This is exactly the sort of strain we want to be looking for all though we want a strain that doesn’t come from hospitalised patients. This deletion is still too pathogenic for our needs, but it does prove these deletion strains are out there. If we look we will find.


How would you allow the harmless strain to spread without also spreading the deadly strain? If you relax or reverse social distancing, wouldn't the deadly strain also have a chance to spread widely again? It seems like you'd need to manually administer this strain to millions of people, or have very carefully administered 'contagion parties' where everyone is pre-screened for the deadly strain, while everyone else keeps social distancing.


> you'd need to manually administer this strain to millions of people

Yes. And how would that compare to the various trillions in stimulus to keep a choking world economy afloat, never mind the deaths that could be avoided?

I don't understand posts like this, they say "if we had a good solution, how could we possibly use it?"


I think you’re reading too much into my post, I was just wondering how to safely carry out this idea.

One reason I was wondering is that manually administering the virus to people seems more akin to a vaccine in nature.


Only if you consider hanging out with someone a vaccine.

As I mentioned in my reply to you it will be impossible to stop this strain from being deliberately spread by people on their own.


Wouldn't the same social distancing measures that keep the dangerous strain at bay keep the "good" one from spreading? And vice versa.


Yes they would, but if people know their friends have the mild version they might choose to break the social distancing rules and go and visit them for a tea and nice close chat.


There are dozens of ways the attenuated strain could be spread. You could do anything from going door to door sticking an infected swab up people’s noses to one of your contagion parties (they would be fun).

Actually once a safe strain was identified it would be impossible to stop people spreading it on their own. People would test to make sure they had the safe strain and then invite everyone they knew around for tea and scones.


Everyone they knew would need screening for the asymptomatic deadly strain first, or there would be a risk of everyone at the party catching the wrong strain.


Depends on how large the party is :)

People will do this on their own once the strain is identified and there is a test for it.


> It seems like you'd need to manually administer this strain to millions of people.

Yes, but this doesn't seem too hard. Just have some infected people spit in a cup, and mix it into large vats of raspberry jam and people can then just spread it on their toast on one morning.


> Currently, there is no evidence to support transmission of COVID-19 by food.

https://www.fda.gov/food/food-safety-during-emergencies/food...


What does food that regulated by the FDA have to do with this?


I don't think the mutations are the reason for asymptomatic cases. Coronaviruses mutate very slowly.

More likely, viral load, immune system strength, overall age and the genetics of the person infected are what determines if the infection is fought off before any symptoms are shown


I address this exact point in my post. This has nothing to do with the proposal.


For my own understanding: where can I read about how coronaviruses mutate slowly?


It is deemed to have an RNA repair mechanism. This is suggested by analogy with other coronaviruses [1,2] and the length of its RNA of ~30k nucleotides while the upper limit for RNA without repair mechanism seems to be 10k [3]. The german wikipedia cites [4] which I found nicer to read.

[1] https://en.wikipedia.org/wiki/Coronavirus#Replication [2] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4984655/ [3] https://de.wikipedia.org/wiki/Coronaviridae#Genom [4] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3127101/


And anyways, the harsh lockdowns currently implemented are basically forcing the virus to evolve into being asymptomatic. Currently, anyone with even mild flu-like symptoms stays home


pardon my ignorance, but is that a good thing or a bad thing? (the first part)


What is viral load, and doesn't it eventually become the same for everyone infected after some time during which the virus multiplies?


My understanding (not an expert) is that there is a difference depending how much of an initial dose of the virus you get. If it is very small then your immune system has more time to respond before the virus replicates to dangerously large numbers, whereas if your initial dose is large then you are starting with a large number of virus particles that replicate too fast for your immune system to respond.


Yeah I think it makes a lot of difference. See doctors at hospitals... even youngs pass out. (I think in a higher rate than usual.)


Yes, that is the discussion I have heard, that healthcare workers without proper PPE get larger doses than those with the right gear and are more likely to fall ill. Same effect applies to the average person in public when exposed to an infected person who may not be showing systems - even imperfect PPE reduces their initial dose and increases their odds of having a less severe infection.


There are several pre-clinical studies with live attenuated viral vectors and replicating viral vectors going on against SARS-CoV-2. https://www.who.int/blueprint/priority-diseases/key-action/l...

Developing attenuated-virus vaccines is by screening serially propagated SARS-CoV-2 for reduced pathogenity has also been suggested already.

1. The outbreak of SARS-CoV-2 pneumonia calls for viral vaccines https://www.nature.com/articles/s41541-020-0170-0

2. Regla-Nava, J. A. et al. Severe acute respiratory syndrome coronaviruses with mutations in the E protein are attenuated and promising vaccine candidates. J. Virol. 89, 3870–3887 (2015). https://www.ncbi.nlm.nih.gov/pubmed/25609816/

Authors idea of spreading the attenuated virus is based on the idea that if the immediate COVID-19 disease can be avoided, increasing viral load in population is smaller risk. I think that's the weak point. If the vaccine is developed and the virus establishes itself in the population, the number of people getting infected will be lower overall and less people will get severe disease due to natural immunity + vaccine.

ps.

> appears to be killing between 1% to 3.5% of the people it infects

Author is confusing case fatality rate (CFR) with infection fatality rate (IFR). Infection fatality ratio seems to be something like 0.6% according to recent estimates. IFR estimates seem to go down over time.


I think you mean infection fatality rate. You gave me a heart attack for a second as I wiki’d it.


This is not a proposal for a live attenuated vaccine.

These numbers on the death rate are not mine, but what has been reported in the scientific literature. Probably the best numbers come from South Korea where they have done a pretty good job of tracking down everyone infected. There the fatality rate is around 1.8%.

Even if the true death rate is 0.6% that still means the deaths of nearly 50 million people worldwide.


Even the sources you cite give case fatality rate not infection fatality rate. You are confusing the two.


The true infection rate is irrelevant. Nobody knows what it is right now and by the time we do it will be too late.


We are talking infection fatality rate not infection rate.

Infection fatality rate is number of people who die after they are infected. That's one of the most important numbers and it can be estimated. It's different from case fatality rate. Number of people diagnosed with COVID-19 who die.

You started your argument trying to argue based on your understanding of what the infection fatality rate is.


Nobody knows the true infection fatality rate. Probably the best estimate we can make is from South Korea where they have done a pretty good job of testing everyone infected. There the infection fatality rate is 1.8% and rising as the cases age out and people in the ICUs die.


> Nobody known the true infection fatality rate.

It can be estimated with increasing accuracy.

> There the infection fatality rate is 1.8% and rising as the cases age out and people in the ICUs die.

You continue citing case fatality rate (CFR) numbers and call them infection fatality rate numbers (IFR). Can you please go back to your sources and read what they say. I bet they are case fatality rates. In South Korea one IFR estimates put the number around 0.4 and 0.7%.

Here are some IFR estimates:

1. Estimating the infection fatality rate of COVID 19 in South Korea by using time series correlations https://figshare.com/articles/Estimating_the_infection_fatal...

2. Estimating the infection and case fatality ratio for coronavirus disease (COVID-19) using age-adjusted data from the outbreak on the Diamond Princess cruise ship, February 2020 https://www.eurosurveillance.org/content/10.2807/1560-7917.E...

3. Using early data to estimate the actual infection fatality ratio from COVID-19 in France https://www.medrxiv.org/content/10.1101/2020.03.22.20040915v...

4. Robust Estimation of Infection Fatality Rates during the Early Phase of a Pandemic https://www.medrxiv.org/content/10.1101/2020.04.08.20057729v...


These lower estimates are all estimates.

Really it is not important from the perspective of doing something about this pandemic as a huge number of people will die at all estimated levels.


Maybe you can now correct the "killing between 1% to 3.5% of the people it infects" part. It's horribly misleading.

IFR < CFR and IFR estimates go always down over time and never up due to the skewed nature of the data. Antibody tests are coming in already and based on them you get very accurate numbers.


I am going to update the post this morning - lots of good feedback from people here on which sections are confusing. I will update this section :)


I want to argue that the flaw in this is with the ability to find any strain that consistently causes only minor symptoms. If you infect a whole group of people with Covid-19 then we would see a distribution of severity from no symptoms to lethal. This broad spectrum is really just it's statistical variance (whatever the underlying distribution really looks like).

It is worth comparing this to things like SARS. The distribution of SARS symptoms would be pretty narrow - everyone gets really sick. So the variance for SARS is small compared to Covid-19. The same could be observed for influenza or rhinoviruses.

The problem with a "milder" Covid-19 is that it might still have the same massive variance in symtpom severity. It might kill less people, but it would still be morally bankrupt to let it spread. In fact, it might be preferable to not reduce the mean severity, but just decrease the variance so it never gets nasty enough to kill without being immuno-compromised.


This paper argues on the basis of symptoms that there might be a milder strain that has dominated some countries vs others

https://www.medrxiv.org/content/10.1101/2020.03.28.20036715v...


There may be other explanations such as past use of vaccines for other diseases, that varies country to country.


Yes. Or just variations in our immune systems. Immune systems are incredibly complex systems. It is difficult to overstate just how complex and varied they are. And they differ between individuals to an amazing extent.

If immunity is important to symptom severity, it may manifest as some weird correlation you might find in a cross-sectional study. Maybe gluten intolerance or a history of acid reflux will be a marker that lets you know what your risk of severe disease are.


In one of the article comments there is an interesting suggestion on reviving the research on DRACO[1]:

> In cell culture, DRACO was reported to have broad-spectrum efficacy against many infectious viruses, including dengue flavivirus, Amapari, and Tacaribe arenavirus, Guama bunyavirus, H1N1 influenza, and rhinovirus, and was additionally found effective against influenza in vivo in weanling mice. It was reported to induce rapid apoptosis selectively in virus-infected mammalian cells while leaving uninfected cells unharmed.

They even had a crowdfunding campaign on Indiegogo[2] but as usual, nobody cares about infectious diseases until the pandemic...

Now the crowdfunding seems moved to another page[3]

[1] https://en.wikipedia.org/wiki/DRACO

[2] https://www.indiegogo.com/projects/1641241

[3] https://riderinstitute.org/discovery/


> nobody cares about infectious diseases until the pandemic...

Bill Gates would like a word.


Why did they choose indiegogo over traditional medical research funding?


The source that wikipedia cites says the following:

"However, research on DRACOs has entered the well-known “Valley of Death” in which a lack of funding prevents DRACOs, and many other promising new drugs, from being developed and advancing toward human medical trials. To progress DRACOs research it needs to be demonstrated against clinically relevant viruses (i.e; HSV). To that end an IndieGoGo campaign (http://igg.me/at/EndTheVirus) was started on October 13, 2015."

They don't seem to elaborate on what the hell they mean by the valley of death.

http://www.prweb.com/releases/2015/10/prweb13018147.htm


Basically there is funding for early research, and for drugs that are really close to release, but the years in between (the drudgery) aren't very interesting to investors so capital is hard to come by to keep projects alive.

An acquaintance is $600m into a new type of Malaria testing and his funding is slowing, but is frustrated because he feels he is closer then ever. Frankly im amazed he got this far, thats a lot of burn.

Basically funding for drug research is all screwy!


Good question. I am even surprised why not Kickstarter - it's more suitable for the larger goals.


Flexible funding allows one to keep the proceeds even if the goal is not met in the allotted time. Kickstarter offers only an all-or-nothing payout for projects (unless something changed the last time I checked).


Apparently China has at least one hospital full of asymptomatics.

https://www.straitstimes.com/asia/east-asia/mystery-of-long-...


> it would be much better to just post a sample of the virus to everyone for example

If COVID-19 is human malware, then this is a human software update.


At what probability of bricking during update would you stay on the old vulnerable version?


How do we know that a less deadly strain actually provides some immunity to a more deadly strain? That seems like an assumption here.


You'd have to sample many thousands of people who either have no symptoms or got sick. If the strain only exists in people with no symptoms then there's a good chance it's not deadly or at least less deadly than the other strains.

Of course you might find the best strain you can find exists in 100% of asymptomatics and 20% of the dead. That would indicate your strain has some non-zero death rate.


His assumption is based on live-attenuated vaccines. The measles vaccine being one of those. All the early vaccines where like that. The process only requires heat inactivation. So you end up with a dead or almost dead virus, which can't replicate anymore. Your immune system recognizes it as a foreign agent, makes antibodies to tag it for removal.

Today we prefer to immunize with a part of the virus structure, which end up doing the same thing.


Still seems like an assumption until its tested/proven. I'd prefer a more evidence based approach, evidence from this virus.


You can only get evidence if you go out and collect the evidence. I am proposing a way we can actually collect this evidence. Saying something won’t work because there is no evidence when you haven’t look for any evidence is not very logical.


Just questioning assumptions, in a healthy skepticism kind of way. I have no expertise here. There is a lot of speculation and general fud surrounding covid-19, seems right to question potential 'solutions' when we are light on facts. To be clear, I never said it wouldn't work, I'm saying that it looks like you assume it will work.


I most certainly have not assumed it will work, in fact I say there is a pretty good chance it won’t. What I do think it could work and that the cost in minor compared to the payoff if it does work.


In which case, we need to think about Medical Ethics. Do we start experimenting with you and your loved ones?


Nobody is being experimented on or proposed to be experimented on. The proposal is to go and look for an attenuated strain and then decide what to do with it if we find one.



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