This is well written, and passes the "not a crank" test that many will surely apply. Mathematicians get inundated with unsolicited false proofs of famous theorems, and the cranks always give themselves away by various "poker tells" that they are too delusional to control. This is not that; it is a serious proposal, and it escapes being wrongly classified as otherwise.

I am reminded of a famous computer scientist I know, who dropped everything for years because he had an idea about the CD4-CD8 ratio in Aids patients. Aids patients have fewer CD4 cells. Perhaps the body was only sensing the total, and could be triggered to make replacements for the lost CD4 cells if one medically removed CD8 cells. Remind anyone of rebalancing a portfolio during a market crash? I can find no trace of this effort online, so it's not my place to name the researcher. Science does a poor job of recording its failures.

In any case, it didn't work; medicine is very hard. Be prepared for this idea to be wrong, too, despite best intentions.

You might want to summarize this in the submitted post itself to reduce friction for the readers (and thereby maybe increasing the odds of success).

The post is pretty much just a summary, but I will post it here too.

Edit. HN is not letting me reply to people with questions (shaking small fist). If would like me to answer anything then post a question on my blog.

It will in a while. There is a delay (dead time) until a reply link appears which increases the deeper a comment is in a thread. This is to prevent particularily heated discussions where people just fire responses without thinking too much.

HN has a rate limiter for some posters (like me) that will not allow you to post at all after a certain number of posts/day

Why Bill Gates? Or why start with him?

Get a grant from anywhere reputable. You need to work your way up the ladder through a ton of hard work. I don't mean that's how the system should work, but each rung of the ladder will be a signal to the next rung that your idea is worth the opportunity cost of not considering a competing idea.

Waiting for Gates or another almost god-like figure can be an excuse to avoid hard work or the pain of failure. I don't think it matters that this is "in the public interest" instead of purely for personal gain.

If you're right about these strains being out there, I don't think you'd have to do a worldwide search. A local search in any metro area should be successful. Unless I misunderstand your proposal.

Have you looked into my background? I know all about how the how the system works. I am not looking to avoid hard work.

As for why Bill Gates I specifically said I am looking for people with the clout to make this happens - while I am sure Bill would understand my proposal so would lots of other smart people.

I don’t wish to be snarky, but yes you have misunderstood my proposal.

Sorry, no I didn't look at your background at all. My comment was basically reflexive because people are constantly trying to skip the middle steps of getting the attention of super high profile people when I see those incremental steps as the only reason the system can continue to function. But there also has to be ways of escaping the system when very good or novel ideas come around. Like maybe yours.

Wish you the best in your efforts and please don't let comments like mine dissuade you from any possible route to helping get us out of this mess.

> people with the clout to make this happen

You said you are in Australia? The Australian government has the clout to make this happen.

But we don’t have the cases. I am not the Australian government, but if you happen to have the direct line to our PM I will be most happy for you to make a call and set up a meeting.

So you're saying we need to check all the mild cases for that 0.1% chance that they have the attenuated strain. You say that even the mild cases have the dangerous form of the virus most of the time.

Do you think we could find the attenuated case more easily of we tested immune compromised people that have mild to no symptoms? Because if they did have the dangerous form of the virus, the symptoms wouldn't be mild. So we know that if you have the virus and are immunocompromised and have mild symptoms, it's probably not your immune system that is strong but the fact that the virus strain you have is attenuated?

Or does that not work because the amount of people you can test that have those conditions is just too low to find any?

Yes for this to work you are going to have to screen a lot of people with mild cases to find the very rare mutant that is attenuated. The chance this rare mutating just happens to infect an immune compromised person is low. Just looking through the entire population of mild cases will be much quicker as the limiting factor is not the genome sequencing of the viral strains.

A decent percentage of people are also asymptomatic with most influenza strains. You probably know friends/acquaintance who says they never get the flu in winter, even though it's highly likely they have gotten the virus before, it's just their inflammation response for whatever reason (likely genetic variation) doesn't produce symptoms.

Source: https://www.nhs.uk/news/medical-practice/three-quarters-of-p...

Yes this is true, but it has nothing to do with finding an attenuated strain. I addressed this in my post and yes many people who have a mild symptoms are infected with a dangerous strain, but an attenuated strain will only cause mild symptoms. If you want to find an attenuated strain you have to look in people with mild symptoms.

> If you want to find an attenuated strain you have to look in people with mild symptoms

Shouldn't we be looking at people with no symptoms? I know this is not ideal as we're likely only testing symptomatic people.

Yes we want to test asymptomatic people too. Some countries like Germany and South Korea are doing are better job of testing widely and so they have many more mild/asymptomatic samples that can be screened.

> test asymptomatic people for COVID-19 and then genome sequence the SARS-CoV-2 strain that has infected them with the aim of identifying a virus with mutation(s) in an essential viral gene(s)

But without these essential genes the virus would not multiply / infect people anyway, right? Also, how is it different from inactivated vaccines that are currently being developed ? Also, why cant someone engineer such a virus with appropriate deletions?

https://www.cell.com/immunity/fulltext/S1074-7613(20)30120-5...

1. You are looking for partial deletions of essential genes, not full. Many of these deletions are going to weaken the virus, but not cause the virus to not be able to replicate.

2. An inactivated vaccine will have to be given again and again. A live attenuated vaccine can drive the dangerous strains to extinction. Also attenuated vaccines protect those not vaccinated.

3. In theory you could engineer a virus with deletions, but nobody knows what deletions will work. By using natural deletions you know are mild you get around this problem. It also solves the regulatory issue as you are not going to be able to quickly test a lab made strain.

and how would we know that the harmless-virus infection protects against the dangerous strain?

are there already databases of sequenced strains?

and how would the regulatory aspect work? if the harmless individual is no longer infectious, how would people be infected

1. You would check the person’s immune response. With luck they have infect a pool of people in the local area which should give you more data.

2. Yes there are, but we need to look for a quite rare mutant.

3. We would be genome sequencing clinical samples - these would be kept in storage until the data comes back.

It is a good idea, but just like the other dozens of possible vaccines it still needs to go through all trial phases, so it's not quicker than the other vaccines which could 'potentially be deployed today' (RNA etc)

No it doesn’t which is the reason why the idea is more than an idea for another vaccine. Even if it did it, it would be a ecological solution that would mean we could stop vaccinating in the future - a bit like how we were able to stop vaccinating for smallpox once the attenuated viral vaccine drove it to extinction in the wild.

Why would it need less trials than a vaccine? Are there special regulations?

Because it is natural. You don’t need permission from the FDA to catch a natural virus.

Aren’t a lot of vaccines just weakened versions of natural viruses?

Insulin is natural, would not they require testing before it could be used to treat a new disease?

Yes many (most) viral vaccines are weakened versions of natural viruses, but the weakened versions were created in the lab.

Yes insulin is natural, but it needs to be processed and purified via a lab process (if from pigs) or grown up in a vat of cells for the human form.

Wow that’s a huge loophole then. If true you might be on to something. That’s pretty cool.

It’s also sad we have to go to these Herculean lengths to bypass the slowness of the FDA.

Yep. I do think there will be some major changes out of this experience that will change how the FDA and the whole medical system works. Things that were “impossible” before like telemedicine were suddenly able to be implemented.

Well that is interesting, for a SW developer point of view :)

Do you have reasons to think biotech's are not currently putting the same methodology into place for their upcoming vaccine?

No idea. Someone has to be the first person to have thought of any idea and maybe it is me (unlikely). I personally don’t care about this, I just want to see the idea acted upon.

Here is the post for those who don’t want to follow the link.

Like nearly everyone on the planet I am worried about COVID-19. SARS-CoV-2 (the virus that causes COVID-19) appears to be killing between 1% to 3.5% of the people it infects and has a R0 (i.e. how many new people each person infected goes onto infect) of between 2.5 to 3.9. Left to run wild, the virus will likely kill tens of millions of people worldwide.

The governments of the world have implemented strict population isolation protocols to try and limit the spread of the virus, but the economic cost of this is extremely high. A vaccine for COVID-19 is 12 to 18 months away (at best).

We are stuck in a diabolic situation where the only way to prevent the economy sliding into a slump deeper than the Great Depression is to consign many tens of millions of people to an early grave. Is there a way out?

SARS-Cov-2 Viral Diversity

SARS-CoV-2 like all viruses mutates (changes) overtime. Many of these genetic changes are small (single nucleotides) that are not important to the replications or transmission of the virus from person to person, but they can be used to identify the origin of the virus. DeCODE genetics has been testing Icelanders for COVID-19 and genome sequencing the SARS-CoV-2 strains isolated. They have found two very important pieces of information:

1. More than 50% of the people infected with SARS-CoV-19 are asymptomatic (i.e. they have no illness). 2. They can identify the geographical origin of the strains by the genetic differences (mutations) between the different strains.

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.

If we can find one of these non-pathogenic viral strains out in the wild we could give it to everyone in the world and solve our diabolic problem. This non-pathogenic strain would act much like the live attenuated (oral) polio vaccine.

How do we find the attenuated SARS-CoV-2 strains?

This hypothesis is worthless if we have no way of finding any of these non-pathogenic SARS-CoV-2 viral strains. Luckily there is a quick and cheap way to find these strains if they exist – test asymptomatic people for COVID-19 and then genome sequence the SARS-CoV-2 strain that has infected them with the aim of identifying a virus with mutation(s) in an essential viral gene(s). This approach is cheap (a couple of hundreds of dollars a virus strain) and quick (a week or less). With almost no effort or cost we could sequence a few thousand viral strains from asymptomatic people until we find a virus strain with the right mutations to make it harmless and which is in effect an attenuated vaccine. We would know that this strain can still reproduce in people and lead to immunity, but not make people seriously ill.

What viral mutations are we looking for in a good non-pathogenic viral strain?

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.

Has this ever been done before?

Yes. The polio, measles, rubella, mumps, and chicken pox vaccines are all live attenuated viruses. Even something as dangerous as smallpox was controlled in the 18th century using a variation of this idea called Variolation. The idea was the doctor would deliberately infect you with a less harmful strain of smallpox to make you immune to the more deadly strains of smallpox. Of course, they didn’t know how this approach worked in the 18th century, but it was still very effective and millions of people were saved from dying from smallpox by it.

What are the risks?

The major risk is the virus we think is safe is not 100% safe. While we can use community spread of the identified strain to estimate how safe it will be (i.e. if it has infected 1000 people and none have got seriously ill then we should have a pretty good idea that it is safe), but our knowledge will be incomplete. We can of course spend the next few years testing and trialling, but if we do this by the time any strain is shown to be 99.999% safe (not even the polio vaccine is 100% safe) we will have all got COVID-19 and the world’s economy will be a smoking ruin.

We have a choice of taking some small risk now, or face the certainty of a much worse problem later. Time to accept some risk and do something.

Q & A

I have been getting a few questions on this post so I thought I would address them here.

How do you know there is an attenuated viral strain out there?

I don’t. I am hypothesising that there is one (or more) based on the known mutation rate of coronaviruses and the number of cases. Coronaviruses mutate continuously (this is why companies like deCODE can tell the geographical origin of different strains) as the molecular machinery for replicating their RNA genome is not very accurate. When you combine this with the millions of mild cases out in the world, the odds are on our side that there is at least one person infected with a strain that has a mutation that makes the virus less dangerous (attenuated). We just need to look for this strain – luckily the tools we need to use (genome sequencing) are now cheap and quick. What would have been impossible 20 years ago can now be done in a week.

Aren’t most people who have mild/asymptomatic cases infected with the dangerous strain?

Yes. Almost all (>99.9%) of people who are infected (and have a mild case) are infected with a dangerous strain of the virus, they just happen to have an immune system that can control the virus well. With COVID-19 a mild case does not mean you are infected with an attenuated strain – for most people with a mild case if they happen to infect a person with preexisting conditions or who is old, that person will be at a high risk of dying. A mild case does not equal a harmless strain.

My argument is coming from the other direction. While almost all mild cases of COVID-19 are caused by a dangerous strain of SARS-CoV-2, an attenuated strain of SARS-CoV-2 will only cause mild disease. If you want to find an attenuated strain you need to look at mild cases even though >99.9% of the people you check will be infected with a dangerous strain. What we want to find is one of the rare natural viral mutants that is attenuated. Where you will find such a mutant is in people with a mild form of the disease.

Can’t we just wait for the vaccine?

No. Apart from the time it will take to develop, trial, and mass produce a vaccine (12-18 months), it is unlikely that any vaccine will be practicable. The reason why is immunity to respiratory viruses (like corona) doesn’t last long – 6 months to 2 years. We would have to keep vaccinating everyone in the world every year (or maybe every 6 months if we are unlucky). This just isn’t going to work in the real world (especially poor countries) and is one of the reasons we don’t have a vaccine for the coronavirus strains that cause the common cold. Unless we can drive the current dangerous SARS-CoV-2 strains to extinction we are going to have a problem with this disease indefinitely.

Isn’t social distancing and quarantining solving the problem?

Yes and no. Yes countries like South Korea and Australia have shown that through mass screening and social distancing you can keep a lid on the disease, but this leaves the population susceptible to a new outbreak. Singapore and Japan have recently seen this in action where they eased restrictions and found the disease came back and they had to reintroduce restrictions. I don’t think many people want to live for years with cycles of restrictions, easings and further outbreaks.

Wouldn’t the use of such an attenuated strain just be a vaccine?

Yes in one way, but it is a little more subtle. Assuming we can find an attenuated strain, then how to best use it a separate question. Giving it deliberately to lots of people would change the ecosystem for the dangerous strains of the virus. The dangerous strains would find it dificult to spread through the community as many (most) people would have already been infected (and hence immune) with the attenuated strain. Overtime the dangerous strains would become rarer, and the attenuated strains more common, until eventually the dangerous strains would go extinct and we would just be left with the mild version. While we would not be able to get rid of this mild strain, it would just be another of the hundreds of viruses out there causing common colds. The idea is at its base is really to replace the dangerous strains with a less dangerous strain that we can live with.

Nice idea, but it would likely have problems with regulators. I am not a doctor, but these are my thoughts.

Yes, there are "non-pathogenic" strains. I'm pretty sure that my mild symptoms that encouraged me to self-isolate a week earlier than the government lockdown were the result of one of those strains.

However, SARS-1 had long-term consequences for those who were infected in the past [1]. I think that the risks of these sequelae are the reason why prevention is recommended instead of herd immunity. It's possible that the mild strains of COVID-19 will be so prevalent in the environment that I won't be able to avoid them completely, but pursuing eradication is possible (e.g. smallpox, rinderpest) and will probably be the focus of much public health attention in the decades to come.

Edit: You're right that a live attenuated vaccine like polio can mutate back into a dangerous form, and this has been a problem for eradication efforts. Therefore vaccinated people should self-isolate for 2 weeks to find out whether it will mutate.

Also, as you say, "immunity" might not last for life. Perhaps as little as a few months. Isolate for 2 weeks every 3 months, and risk the vaccine mutating to a more dangerous form? I don't think that's a practical solution. I do agree that the non-pathogenic strains should be researched heavily, as a source of clues for developing a vaccine, it just won't be as simple as infecting people on purpose with a different strain.

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

> The major risk is the virus we think is safe is not 100% safe.

IANAD, but IMHO you cannot just sequence the virus in asymptomatic people - you have to sequence a randomized, sizable % of the whole positive population, including mild or severe cases, and the dead too. Only then you'll be able to "paint a picture" of the different strains' effects on humans and slap some confidence data to each identified strain. Your idea definitely looks promising though.

That was my thought as well - basically, how do you know if the strain doesn't kill if you don't check for severe and lethal cases linked to the same strain? I understand the part about looking for specific mutations, and assuming they would indicate the "usual" complications with the deadlier strains would not be present, but mutations are not exactly predictable, right? If they don't cause the sympthoms of the current deadly strain - they may be causing something else completely, which could be as deadly a little bit later down the line - isn't this a reasonble concern, @danieltillett?

I'm no expert in this field, hence my dumb question: lets assume we find such an attenuated strain and "infect" people with it such that they could all build the anti-bodies for it. Couldn't the dangerous strain still mutate itself over time in a way where the anti-bodies for the attenuated strain wouldn't help anymore or is this rather considered unlikley (since the virus then would have to become fundamentally different)? In other words, would we then end up with the possibility of similar mutations as with the seasonal flue where this "vaccine" with an attenuated strain would have to be renewed periodically? In any case, thanks for working on this!

There are no dumb questions with this problem. What I think you are asking is if the dangerous strains could mutate enough that an immune response to the selected attenuated strain no longer work. The answer is yes this could happen, but if it does we just repeat the process of finding a new attenuated strain.