This is a follow up post to a previous post on mine on how we might look for a natural attenuated (mild) strain of SARS-CoV-2 by genome sequencing [0]. While the COG-UK has not been looking directly for such a strain, their data does show that strains with the right type of mutations do exists.
While it might be possible to use a natural attenuated strain as a vaccine directly, the real value of having such a strain may be in using it as a safer test strain in a human challenge trial of a conventional vaccine. This could shave many months off us getting an effective vaccine for COVID-19 [1].
There are a number of issues with the approaches suggested by the author. In particular they’ve suggested an attenuated strain be spread by something similar to Pox Parties. Many might find these suggestions misguided and dangerous...
I have not suggested that "pox party" spread would be a good idea, just that it would be hard to stop if a natural attenuated strain was found and that this would influence the way the regulatory agencies viewed its licensing.
This is not really relevant to the idea of using an attenuated strain to accelerate the development of other vaccines. This would be done under controlled conditions where the attenuated strain would not spread.
Yes, the input I'd provide is that the writer doesn't have a particularly good grasp of virology, but people in this community are upvoting as if this is authoritative. People who write authoritative blog posts without expertise right now should consider themselves part of the disinfo problem.
I'll be concrete: the expected correlation between the cited deletions and pathogencity should be considered to approach zero. No evidence supports the hypothesis that single codon or single nucleotide deletions correlate with attenuation of strains. Furthermore, a basic understanding of molecular biology is all that's needed to dismiss the notion of a generalized correlation between observing deletions (or even insertions! or any general mutation!) and the pathologic outcome of infection with a virus. Biology doesn't support general claims of this nature. This is not a well-informed line of reasoning.
Even the title of the post is wrong! These are not "gene deletions." These are single codon deletions or deletions of a few nucleotides. No genes have been deleted!!
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I have been a tenured academic (Senior Lecturer) within the School of Pharmacy and Applied Science at La Trobe University, Australia teaching and researching in the areas of phage therapy (bacterial virology), pharmacy, environmental microbiology, bioinformatics and cancer.
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Since that seems easy enough to look up and call him out on if he were lying, I am inclined to believe that it's true.
I am inclined to believe his take on things over yours, given that the only info I can see immediately about you is your info blurb stating, "Damn kids, get off my lawn."
That said, I don't think anyone is treating what he says as gospel. But it's an interesting perspective.
At the risk of starting a flame war, lvs is mostly correct.
These are NOT whole gene deletions, they are nucleotide deletions. Genes are usually longer than 33 nucleotides, by my count the largest deletion he sees. For reference, that’s 11 amino acids, rule of thumb for an average protein length is about 200 amino acids.
The author highlights that many of these deletions are not codon aligned, which means that if you make this mutation, the resulting protein is highly unlikely to be translated properly. This is true, however devoid of context.
Most of the mutations are very rare. The highest frequency one occurs 400 or so out of at minimum 10,000 examples. Next one is 36/10,000. It’s possible these matter, it’s also possible these viral sequences are just low quality and the mutations are an artifact. It’s also possible that these mutations don’t actually matter to viral function for whatever reason. For example, if the mutation is at the end of a protein, it could screw up everything downstream but the protein before the mutation works just fine, i.e. mutation doesn’t matter. It’s just hard to tell with the data in this article.
The concept that maybe there are attenuated strains isn’t completely bogus, there is some thought a Singapore strain (with a massive deletion of 380 nucleotides, or 10x what we see here [1]) might be less infective. This is speculation and we don’t know yet, but that sounds maybe possible to me as a PhD Biochemist (if we’re gonna get all credential-spreading here).
However saying “The really interesting deletion mutations are those in the non-structural accessory genes. These are the genes that are likely to play an important role in pathogenicity and it would be expected that some of these mutations may make the virus less dangerous (attenuated).” Is really pushing it. I don’t know of any science to believe this one way or another, viruses are pathogenic for a variety of reasons, both accessory and core (whatever that means) proteins matter.
In short, given the uncertainty, we can hope there’s a less infectious strain out there, but this article provides precious little evidence to that effect.
Lvs is mostly wrong. I am not claiming any of these mutant strains are attenuated, I am saying that deletion mutants exists and we should investigate them to see if they are attenuated.
I am not providing evidence that an attenuated strain exists, just evidence that it could exist because the right type of mutations are found in SARS-CoV-2. The only way we are going to find out if there are attenuated strains is to look for them which as far as I know nobody is trying.
So let's remember how evolution works, shall we? Evolution selects for strains that reproduce the most and selects against ones with attenuated reproduction rates. That's the whole basis of biology. If you've observed a wild strain sequenced in a database, that should be considered direct evidence that it reproduces well enough to have been sampled as a representative isolate.
> as far as I know nobody is trying
Of course we are. We are deeply engaged in studying the key residues that mediate all aspects of viral infection, reproduction, and clinical pathology. That's another way of saying that an incredible number of researchers have dropped everything to study the genetic and molecular determinants of pathogenicity. Don't worry -- we are on it.
> we can hope there’s a less infectious strain out there
But how? We are able to surveil only a tiny fraction of genomes, relative to strains circulating. How would a "less infectious strain" ever emerge to the extent we'd have a high probability of sampling it? Darwin argues against this version of the idea.
Nevertheless, the OP is also wrong that it's faster to produce a live attenuated vaccine by finding one in the wild than it is to use tried-and-true viral vectors that are easy to reengineer, have previously received regulatory approval, and indeed are already in active trials (e.g. Oxford's adenoviral trial). It's also easier to trial heat-killed virus -- and indeed, that too is being trialed.
We can actually sample quite a large percentage of the strains out there if we actually try. COG-UK has already sampled 10,000 out of the few 100,000s in the UK without really trying.
Can you please stop saying I am arguing for things I am not arguing for? More time spent reading and less posting would improve your argument.
Yes, there are about 13k genomes deposited in the databses right now, but they are from all over the world -- not just the UK.
But yes, given infinite capacity it would be excellent to sequence from every single patient. It would be a dream, but sadly we're barely able to get enough cotton swabs and RNA isolation kits right now to run a basic qPCR for 10% of the population, let alone get all those viral genome sequences. It would be fascinating to have that many, of course.
You do realise that there are over a million positive samples sitting in freezers in the USA alone. You do know that a single modern DNA sequencing instruments can sequence more than 500,000 viral genomes in one 48 hour run?
It’s my understanding that viruses have a complex fitness function. If you think about it, the ideal virus spreads like crazy but doesn’t make anyone sick. If you make someone sick, you reduce the time they spend in the world so you spread less. Killing the host is definitely a no-no from the viral perspective, now you spread dramatically less. So viruses actually tend to evolve toward less intense disease. It’s why novel viruses kill so much more than viruses that have been around in the human population for a long time.
Forced evolution to lower infectivity is also a common way to make vaccines, so I’m quite certain one of the 100 or so vaccine efforts is trying this.
However, it’s not clear that the deletions in the OP are attenuating. If we end up with attenuated virus, it will likely come from a directed evolution experiment, not just getting lucky with a natural strain. Even such a natural strain would likely need to go through a fair bit of directed evolution to attenuated it to the point of harmlessness.
We don’t know if the deletions already seen in the current genome data set are attenuated or not as nobody has checked. I am suggesting that we check.
The bigger point I was making is that there are many deletion mutants out there. We should be looking for more and checking if they are attenuated or not. We might be very unlucky and find there are none, but that seems rather defeatist given we haven’t even tried.
I don’t know. It is a novel idea as it wasn’t possible more than 10 years ago to search. My personal experience is new ideas struggle to get any support until they are shown to be correct and then everyone says it was always obvious.
I don't know enough about any of it to consider arguments.
I apologize for the probably overly snarky comment. I woke up in the middle of the night and was having a hard time falling back to sleep.
I really wouldn't be surprised if the two of you are in more agreement than either of you realize. "Violent agreement" as I've sometimes heard it called.
Also for the record, I didn't downvote you. Just provided my response of why I was inclined to believe the author over you.
The citation does not refute or pertain to my statement. Yes, very specific mutations/indels can attenuate strains -- welcome to biology -- but the broad claim that the general observation of mutations/indels is somehow indicative of attenuated strains circulating in the wild is entirely unsupported and facially ridiculous.
I am not claiming any of this. I am saying that the right type of mutations exist in the SARS-CoV-2 genomes that attenuated strains COULD exist.
If they do I am arguing we should look for them rather than sitting in our armchairs coming up with possible reasons they don’t and so not even bothering.
Maybe, but the idea here is not to use any strain found as a vaccine directly, but as a tool to test other vaccines.
Instead of running a large Phase III field trial where we wait for people to get infected, we could use the safer strain to do a challenge trial where we deliberately try to infect the volunteers with the attenuated strain. This will give us an answer much sooner and avoid exposing many people to a vaccine that maybe doesn’t work.
The problem I think is that the step where people are infected with a (supposedly!) less harmful virus is just like testing a vaccine. It’s another substance to be tested on healthy individuals.
You can’t know the long term effects on the attenuated virus in a large group so the same caution and slow pace would have to be used to test that. First! All you did was go from testing one thing to testing two things (an attenuated virus and the vaccine).
If the attenuated virus could somehow (quickly) be deemed harmless in humans then I agree it could be a shortcut, but is that really possible?
Yes. The whole idea of looking for a natural attenuated strain is we can use the natural spread of this strain to prove it is safe. This is explored in a lot more detail in the other recent posts on my blog.
Yes it is possible, but the only way we will know is if we look. I am arguing we should look.
Possibly, but if its anything like the current virus then the mortality might still rise by orders of magnitude for older people, and people with reduced resistance to the disease could still die.
Which, if it's even less likely to cause symptoms is almost sure to happen if the virus is spread among the population.
> While it might be possible to use a natural attenuated strain as a vaccine directly, the real value of having such a strain may be in using it as a safer test strain in a human challenge trial of a conventional vaccine. This could shave many months off us getting an effective vaccine for COVID-19 [1].
Could you explain this further as to why this allows us to shave many months off?
My current extremely naive understanding of testing would be, at least one group would be unexposed, unvaccinated trial: 1, vaccine, 2 inject, 3 expose to virus 4, measure
If Step 3 is expose, how does a safer strain speed this up?
The reason it would be faster is at the moment it is not considered ethical to deliberately expose people to the virus after giving them a vaccine. Because we can’t do the exposing we have to use the large field trial approach and wait for people to get ill on their own (or not). These take a long time. If we had a safe strain of the virus then we could do the exposing.
I explain this much more in a previous post on my blog [0].
There are those that argue even without a safer strain it is ethical under certain circumstances to still perform that sort of "challenge trial" though, where people are deliberately exposed. A number of conditions would have to be met, such as all volunteer participation of course, very clear explanation and demonstration of understanding, no financial incentive, etc. But a faster vaccine could save many more lives than would be risked in the trial, and the risk itself could be very low, given the trial participants would be monitored closely and would get excellent medical care. Also obviously it would be restricted to young, healthy people without pre-existing conditions.
To me it seems like a solid argument that given all those conditions (and possibly others I haven't thought of or mentioned), such a trial should be allowed. My understanding is that there are many people preemptively volunteering to participate.
Even if it is ethical to use a strain we know is dangerous, we would still be amiss to use such a strain just because we were too lazy to look for a safer strain. We should only use a dangerous strain if we try hard and fail to find a safer strain. We haven’t even tried yet.
In practise they would probably be testing on heavily-exposed people (doctors and nurses etc). But it would speed things up some to be able to do controlled exposure.
Not the OP, but allow me to jump in. Two years ago, I ate something perhaps and I had a severe allergic reaction. I went from a perfectly healthy individual to a familiar face in the ER in a matter of days (4 times there in a span of a month). I took prednisone for 6 months. All tests came fine. In the eyes of modern medicine, I was still a perfectly healthy individual. My doctor told me that that is the case with 95% of the people with chronic allergies - we simply don't know what's the root cause of their problem. In other words, the immune system is extraordinarily complex, and if you could avoid messing up with it, you should probably do that.
Now, a vaccine does exactly that. It plays some games with the immune system. Sometimes the outcome of the game is weird, just take a look at [1]. Here's a random snippet:
"Encephalitis (severe brain reaction), which can lead to permanent brain damage (as many as 1 per 83,000)."
Variolation as opposed to vaccination, has the advantage that the only side effect is that you can get the disease itself, but no weird interactions with the immune system. All right, in the case of Covid19, the disease can have such weird interactions, so it's difficult to say it's an obviously better alternative, but still, that's the main idea.
> Variolation as opposed to vaccination, has the advantage that the only side effect is that you can get the disease itself, but no weird interactions with the immune system.
This seems to me to be a bit of a false distinction: all the symptoms are ultimately "weird interactions with the immune system"; and this is especially true for the more deadly responses to the virus, AFAICT.
That said, after nearly 3 million confirmed cases, we should have a reasonable sample of how the genes in this virus interact with the immune system; it certainly seems to be introducing fewer variables to delete some of these genes than to try adding something else into the mix.
I'm not sure about the idea of using any particular strain as the basis for a vaccine. But the severity data for various strains might well be helpful in vaccine development.
I'm guessing that this is a riff on using cowpox as a vaccine for smallpox. However, modern vaccines often use inactive virus, separated viral components, unrelated viruses for delivery, etc. And now, I've read, mRNA to drive host synthesis of antigenic viral components.
Edit: OK, I see that you propose using less dangerous strains for testing vaccine effectiveness. Good idea!
The idea in this post is not to use any safer strain as a vaccine, but to use it as a tool to speed up the development of other vaccines. If we can find a safer strain then we may be able to use it in a challenge trial which we can’t do with the normal dangerous strain for ethical reasons.
This is explored in more detail in my [1] reference above.
Hi Daniel,
When you first put up the idea, it seemed like your emphasis was on using the attenuated strain directly as a vaccine (and benefiting from its ability to propagate itself). This post suggests more to help test a conventional vaccine.
Could you comment on reasons for the change of approach?
Yes that is right. While the idea of using such a strain as a vaccine directly was the focus of my first post, this was controversial.
Even if you think it is too risky to use a natural attenuated strain as a vaccine, such as strain would be very useful as a tool to accelerate other vaccines. As I said in my first post how to use any such strain is not up to me, but if it can be used to get us to a vaccine sooner it is worth looking into.
If we are going consider doing a challenge trial we should at first make the effort to see if we can find a safer strain to use.
Isn't there still a big question over how long immunity will last? (can you get a feel for this from the structure of the proposed attenuated strain?).
I suspect if that is done it’ll be just one more argument for infinite delays, because well we tested it with this inactive virus but how can we be sure it works the same with the real one? Let’s just test a bit more for a few months.
I wonder why everyone believes so strongly we will create a viable vaccine.
The FDA has never approved a vaccine for humans that is effective against any member of the coronavirus family, which includes SARS, MERS, and several that cause the common cold.
If political pressure/regulatory relaxation allows a vaccine to enter the market I would be suspicious of its efficacy.
Not exactly true. Moderna, and several others who are leading the vaccine race right now are out front because they had viable SARS and MERS vaccines but no where to test it other than in animal models.
Coronaviruses are easy to vaccinate against. They mutate very slowly. There’s just not a viable business model for them when the symptoms are so mild and treatments are available cheaply over-the-counter.
SARS-CoV-2 genome size is ~30 kb [1], influenza A genome size is ~14 kb [2]. A protein encoded in the SARS-CoV-2 genome is predicted to have exonuclease proofreading activity, which would result in a lower mutation rate [3].
We may not need a vaccine. This was about gene deletions as opposed to mutations. A while back there was an analysis of what each gene coded for. A number of them seemed to suppress natural responses to infection, so it seemed obvious that a less deadly version was just a few deletions away.
If infectiosness could be maintained while reducing death rate (a big if) then you'd have a naturally spreading vaccine. Theoretically we only need to quarantine the severe cases and let it evolve to a cold.
SARS burnt out fairly readily with mitigation measures, MERS turns out to be quite difficult to catch at all, and the cold's mortality is low enough it's not an enormous priority (especially when coronaviruses only cause 10-15% of those cases).
The effort spent making a vaccine is going to tend to be proportional to the disease's impact. There's no much point continuing development on a SARS vaccine when it hasn't had a new case in fifteen years, after all.
IIRC by the time a SARS vaccine came out, human transmission had already been stopped through other measures. There was no ethical way to do human clinical trials.
Most think it is worthwhile trying to create a vaccine rather than just giving up and not even trying.
Nobody who knows anything about Coronavirus vaccines thinks it will be easy, but just because something is hard should not be a reason for not trying, especially when the reward for success is huge. All I can say is I am glad Salk and all the other Polio vaccine researchers didn’t just give up without trying because it was difficult.
I think the grandparent post is wondering why everyone is so confident we'll _succeed_.
There are people who think we should lock down everything for 12 months because a vaccine will be done by then. Really. There are. That point of view just completely boggles my mind.
Assuming that one located a naturally mild strain of virus (which I personally remain bearish on), for it to produce useful (in the regulatory sense) information a challenge trial, you would need to establish that the response of individuals to the mild strain (which by definition differs from the more lethal strain) is representative of the response to the more lethal strain of virus.
Yes, but that is where you use epidemiology. If you track down each person in the local area infected with the mutant strain and follow their clinical course you can work this out. You can also do serology to make sure the immune response is similar, etc.
There will always be the possibility that the attenuated strain varies is some major but subtle way from the non-attenuated strains, but this is not something ever seen before with other viruses. If you demand to know everything and the answers to all possible risks up front medical science doesn’t advance.
I demand to know enough information to be able to give proper informed consent to study volunteers.
I think your ideas are possible, but the likelihood of success is quite low and the effort required to do the proper studies is far greater than you estimate. Our resources are better spent on much more developed programs with better defined odds of success.
My helpful closing suggestion is to speak with some epidemiologists and clinical researchers to see if you can get some budgetary efforts for what you propose, or failing that, try to locate a review article or two. Good luck.
A bit off subject, but I'm curious if you've ever run across any information that indicates certain length genomic sequences (say 8 nucleotides in a row or so) follow some sort of "order" in their numbering in the entire sequence?
> If we find that everyone who was infected with a particular deletion strain only had a mild case of COVID-19, then we have our candidate attenuated strain which could be used to accelerate vaccine development in a challenge trial.
Heavy emphasis on "candidate". How can you tell if people had a mild case because the virus had deletions or because they mounted an appropriate immune response? It's not clear that the vaccine will be protective.
I have addressed this many times before, but yes almost everyone with a mild case just has an immune system that is good at controlling the virus. This is irrelevant to finding an attenuated strain.
The real value of finding an attenuated strain (one that causes mild illness in everyone) is that it would be ethical to use it in a challenge trial of a conventional vaccine. The Oxford vaccine group for example are planning a large field trial because they don’t think it is ethical to expose people to the normal dangerous strains. If we found an attenuated strain we could speed things up massively.
You showed as greyed out, which can only mean people downvoted you which I simply cannot understand: you said valid things, which I cannot believe were downvoted. What happened?
There are almost certainly significant "Reopen All The Things" brigades running active on social media and nuking anything that might go against their agenda. HN is no exception.
You can see this in early and Layer 1/2 posts that go negative while later and Layer 3/4 thread posts that get high amounts of positive upvotes after the initial wave has moved on.
I'm only guessing, but I don't think this is likely. To the contrary, I think you are being downvoted by people who think you aren't taking the virus seriously enough. They fear that your approach will be used by people who want open up the economy before it's safe, feel you are being presumptuous in thinking you as an individual can change the outcome of the disease, and believe the best we can do is to trust the official experts. I think it's political. I think you are essentially being hit by "friendly fire" by people who think you are aiding the enemy. But this is only a guess, assuming the downvotes correspond to the negative comments. It would be nice to know what people are actually thinking.
I understand the concept of an attenuated strain. I don't see why the deletion mutants have to be found in the wild - it's easy enough to delete or modify genes in the lab to create an attenuated strain. For example, some groups have replaced VSV's glycoprotein with the coronavirus spike protein.
And as I said, you can't know if the people who had mild infections did so because the virus was deficient or whether their immune response was good. It's not enough to have the antigen, you also need the right adjuvant to mount a response. The last thing you want is to have antibodies that recognize the virus, but do not activate the immune system.
The fact that the live attenuated approach worked with polio doesn't mean that it'll work with coronavirus, and if we're not careful we could accidentally worsen the situation.
I agree that this is worthwhile area of pursuit, but one that will take a long time to bear fruit. Maybe you think that studying the variants in the wild will allow us to skip over some animal studies with the live attenuated virus, but I doubt they can be skipped.
I have no background in this whatsoever, so feel free to ignore my comment, but my guess is that finding them in the wild along with a large-enough (and representative-enough) infected population without severe symptoms basically saves the work of trying 5k different possible variant in animals — just skip the the promising candidate directly, no?
I like the idea of pairing clinical data with virus sequence information from infected patients. That seems like medicine of the future.
However, the PCR-based diagnostic tests that are current being used rely on amplifying only a small part of the virus genome so we are actually blind to how the rest of the virus is changing in the larger population (at least in routine diagnostic tests).
That is right. We don’t know what mutations might make the virus attenuated (mild), but we can use what Nature has done to tell us. We also get human data on safety thrown in for free. This makes a huge difference in how quickly we can use a new strain in people even under controlled conditions.
Ignorant question: is it possible to have something resembling a human immune system without a full body? One level would be just a container of liquid with live white and red blood cells, possibly connected to an oxygenation machine; you would insert some infected cells, then sample it or otherwise observe it periodically. If you need lung tissue or other non-blood cells for the virus to infect, then having disembodied blobs of flesh with blood vessels, being fed nutrients and oxygen, would be the next level.
Of course, if this testing infrastructure doesn't already exist, I imagine creating it would be too slow to help with this particular plague.
I know you prefaced your ignorant question with "Ignorant question:", and I don't think it's wrong to ask questions of experts on HN. (That's one of the best things about this site!) However, I'm downvoting you anyway because, despite that preface, you seem to be falling into the trap of a smart geek in one field vastly (vastly!) oversimplifying the complexities of another field, and acting as if all we needed to solve this problem was for someone like yourself to come up with this fantastic idea.
No, you can't approximate a human immune system with red and white blood cells in a container of liquid. No, adding some other cells in there won't help. If that were effective, we'd be doing it already. You are either overestimating your own ingenuity or underestimating the ingenuity of tens of thousands of scientists, doctors, and engineers.
Alternatively, OP could be answered by someone saying that this is already being done. And apparently it is in some form, according to a sibling comment of yours. Maybe that’s incorrect, but you chose the least charitable interpretation instead of “Hey, here’s an idea. Why doesn’t it work like I think it would, and does it have any uses in any form?”
The question was, "is it possible to have something resembling a human immune system without a full body?"
The answer is no, for somewhat obvious reasons. The human immune system involves many organs and tissues and cells working together in very complex ways.
And I think your charitable interpretation is quite a bit too charitable. OP did not say anything like "why doesn't it work like I think it would".
My last sentence shows that I don't think my comment is going to save us from (or even help with) this pandemic. I also chose to ask it in a thread towards the bottom where the OP is answering not-new concerns. I think you have pattern-matched me (well, you say as much) and have read some intentions into my comment.
For the record, my main intention was to get an expert to say something that would gratify my curiosity and that of other readers. I hadn't heard of it before, so I assumed it was likely impractical at the moment, but guessed that technology would eventually get there.
Also, are you an expert in this field? Your sibling comment seems to be saying "yes they are working on it, no it's not practical yet except for HIV" (I presume because HIV infects white blood cells), which is at odds with your second paragraph. (Edit: Though, to be very precise, the examples from the sibling comment are about measuring infectivity and—I guess—the impact of drugs, not immune response.) It would be ironic if a non-expert gave an ignorant dismissal of a question for being ignorant.
this is sort of how HIV production works in the lab, as it was explained to me. CD8+ cells (iirc) in solution with some other cell types/buffer medium are infected with some population of HIV particles, and the infection spreads to the other cells. this helps researchers see whether certain strains are replication-competent etc. you don't really need the red blood cells or oxygenation machine.
there's other approaches to make "organs on a chip" for drug trial screening, since lab models with only one type of cells don't capture the effects of other types, but it's really not fully baked yet.
No. The immune system is incompletely understood and staggeringly complex. It’s not a single performer or a band: it’s a symphony. You can examine individual parts to your heart’s desire, but the true nature of the immune system arises in the emergent properties of the system.
Your “first level” is something we already do with primary and immortalized cells and it can be a useful model. Your next level would be called co-culture and it also is something we already do. These can be static cultures or connected to flow systems or bioreactors or whatever. These are imperfect models, but they can help to yield useful answers for questions in the model’s scope. The closest fidelity to human immune systems would be animal models, and the closest of these would be Rhesus macaques, and indeed these are used for vaccine development.
This is so far the most exciting news I have seen since January. Would it help achieve herd immunity without having any vaccine? In other words, let the "vaccine" spread as fast as possible so more lives can be saved.
There's no feasible way to "let" a virus spread faster than another. Some spread faster than others naturally, and some mitigation tactics (c.f. masks vs. gloves vs. hand washing vs. social isolation) work differently against different viruses. But there's no way to pick a specific strain and say "we want everyone to get that one".
Now, you might culture it in a lab and then inject it into people deliberately so they develop antibodies that then work against the "true" virus. This technique is called "vaccination".
This is a report on some progress on one particular vaccine type. But it's minor progress. What we need is an attenuated strain. What this shows is just that there are some spreading strains with gene deletions (which is the kind of mutation which tends to produce attenuated strains). There's a lot of work to get from there to a vaccine.
>There's no feasible way to "let" a virus spread faster than another.
You can certainly "let" a virus spread faster than another.
Society chooses to let the flu spread more easily than ebola despite them having similar R0.
In this case, you could vary school closure criteria, tracing effort, or quarantine duration by strain.
The linked website (https://www.cogconsortium.uk/data/) has hidden links which you need to hover over to know it's a link. if you visited the site and haven't found anything to look at, try hovering your mouse around.
Could one theoretically sequence their genome before and after infection and use contemporary gene editing techniques to restore any changes made? Could we version-control our DNA?
I have to say, I cannot understand why the idea of doing a challenge trial is controversial. If you are using healthy, young, volunteers who are observed and have good access to medical care, how could it be unethical?
We allow people to donate a kidney to another person, and that carries a significant amount of risk, and only one person benefits.
We allow assisted suicide in many places.
We allow people to assume great risks in auto racing, professional football, and boxing, and that's just for entertainment.
We allow doctors to treat COVID patients, sometimes without even proper PPE, knowing that a significant number will catch it. Many doctors are also not young, not in good health, and have preexisting conditions.
So all of this is allowed, but when the potential result is a vaccine that could save millions of lives, somehow this is unethical?
I have to agree if there is full consent and extensive risk analysis. You wouldn’t step into a formula one car if you knew the wheels would fall off. You’d have to be convinced the team did everything to make the car the safest it could be.
That's what makes it a good analogy. It's gotten safer in recent decades, but for most of its history the fatality rate of a career in Formula 1 was around 20%. It probably is on the order of 1% today (not every time you get in the car, but over a career).
As a former medical researcher the underlying issue is that regulations only ratchet one way. There’s numerous ethics and oversight committees to please and rules put in place because of negligence or misconduct. There’s a line between human experimentation and research and they try to keep you far away from anything that could be interpreted as straddling it.
> I have to say, I cannot understand why the idea of doing a challenge trial is controversial. If you are using healthy, young, volunteers who are observed and have good access to medical care, how could it be unethical?
I think the most prelevant is COVID-19, at full strength, still kills seemingly healthy young people. The author mentions this in another article:
> The important question we have to consider is if it is ethical to deliberately expose even the young and healthy to the dangerous SARS-CoV-2 virus when we know it could seriously injure or kill them.[0]
In this article, we potentially have a weaker strains on our hands that could qualify as a fully ethical challenge trial that could accelerate the development.
At the end of the day, challenge trials are Phase trials with less restrictions in hopes of trading accuracy/rigor for speed.
Is it worth it? I don't know. I'm not knowledgeable enough to say one way or another.
If you can use a weaker strain and presumably get the same results, of course, pick the safer option. However, if you can't, and people of sound mind are volunteering for noble reasons, why wouldn't we do that?
Is it worth it? We've lost about 200,000 people worldwide just in the past month from this disease. It's the leading cause of death in many countries. In healthy young people (20s, no preexisting conditions), the fatality rate is well under 0.1%.
If the vaccine doesn't work at all, which is unlikely, you'd expect 0-1 deaths from the trial. To save perhaps a single life of a willing, altruistic volunteer subject while hundreds of thousands die every month, and the world is confined to its homes is to me, utter insanity.
Do we tell firefighters to not go into a burning building to save lives, even if there is considerable risk?
If this is the state of medical ethics, the field should be torn down and rebuilt. To deny approval for a challenge trial with volunteers is mass murder.
Yes; but the explanation is unfortunately modern medical ethics is misnamed. The focus isn't on ethics, but on protecting the ethics board from accusations that they directly allowed someone to die or suffer.
The process is similar for most forms of regulation. The equilibrium is where no accident can be pinned on the regulators rather than on any sort of system-wide optimum. It can be very frustrating to deal with.
I've just learned in my thread above with the article author that there is no concept of exposing people post vaccination Phase II or III to see if it was effective. We normally wait a long time to see if people get sick. If it's effective them we go to mass rollout.
That's where the huge time savings is.
My previous statement of "it's a Phase trial with less restrictions" isn't true. It's making the feedback loop tighter.
With this new knowledge, I'm relatively convinced we should be doing a challenge trial to speed up the roll out.
This is a great point. In order to get statistical significance, you need to subject the same number of people to the virus. In a non-challenge trial, we feel better about ourselves because the challenge is "natural", the subjects would have been exposed to it anyhow. In a challenge trial, you deliberately expose them. Either way, roughly the same number of people will be exposed to the virus.
Meanwhile, maybe 1,000,000 people a day are catching COVID. The bottleneck that stops that from continuing every single day involves some risk (if the vaccine doesn't work), of a few hundred people, who are in the most favorable position if they catch it, who volunteered.
"Better 1,000,000 people die from COVID than one person die that tried to stop it."
Me either, but it is considered so. Challenge trials can be considered ethical, but only when the risk to the volunteer is minimal.
Even if we (society) did decide that doing a challenge trial is worth the risk, we would be amiss to not look for a safer strain to use first. Only if we can’t find one after making a serious effort should we even think about using a dangerous strain.
I'm not sure why you're being downvoted; this seems like a legitimate question to me. Pasting a comment I made in another thread here:
> There are those that argue even without a safer strain it is ethical under certain circumstances to still perform that sort of "challenge trial" though, where people are deliberately exposed. A number of conditions would have to be met, such as all volunteer participation of course, very clear explanation and demonstration of understanding, no financial incentive, etc. But a faster vaccine could save many more lives than would be risked in the trial, and the risk itself could be very low, given the trial participants would be monitored closely and would get excellent medical care. Also obviously it would be restricted to young, healthy people without pre-existing conditions.
To me it seems like a solid argument that given all those conditions (and possibly others I haven't thought of or mentioned), such a trial should be allowed. My understanding is that there are many people preemptively volunteering to participate.
I'm not an ethicist, but I would be wary of the people "preemptively volunteering".
While the majority might have purely altruistic reasons, others could be dealing with mental illnesses that lead them to inappropriate action.
In the same way that there are older people saying things like "I'm willing to take my chances so that young people's jobs/lives/economy aren't destroyed" there are highly likely to be people offering to be guinea pigs for reasons that should ethically exclude them.
By lowering the risk to the absolute maximum level possible, as suggested by the OP, it could be possible to have a challenge trial within ethical boundaries.
This is more than "oh regulation is about CYA and that's what's holding us up", this is about "we don't kill or injure people in medical research, even if others might be saved."
Certainly it would be necessary to ensure people are of sound mind and understand the risk they're taking. That said, if we're talking about young, healthy people volunteering, and given they will be monitored throughout the trial, I would guess their risk of death would be on the order of 1/1000, if not better. (Based on recent estimates of overall CFR on the order of 0.5% out of NYC and such.)
That's not a risk I personally would want to take, but it's on the order of the risk people take when donating a kidney. (And of course for most people the process will be much less arduous than a kidney donation.) We consider that acceptable to save a single life, whereas a faster vaccine would save many. So my prior would be that most people volunteering for something like this are simply altruistic, similar to a kidney donor, rather than mentally ill.
This is very cool. Pardon my ignorance about this, my bio education is limited. If I understand it correctly, would it be possible to purposely infect willing volunteers in order to find a potentially attenuated strain for a vaccine?
Sort of. The basic idea is that we use an attenuated strain to safely test one of the more conventional vaccines being developed by deliberately trying to infect those people vaccinated (i.e. a challenge trial).
Of course an attenuated strain may be able to be used as a vaccine directly, but this is somewhat controversial.
Not sure this helps us much. The problem is augmentation. A vaccine could take a healthy young person who would have had an asymptomatic infection, and change that into severe disease. Infecting them with an attenuated strain doesn't give enough certainty about the risk of augmentation with the real thing.
It is also a large effort to produce a medical grade attenuated strain that you could infect people with in a trial.
I think you are referring to ADE (antibody dependent enhancement). This is a function of the vaccine, not the virus. The idea here it to use a strain you know is safer than one you know is more dangerous.
For a challenge trial you only need enough virus for a few thousand people at most. It is not difficult to produce this amount of virus in cell culture.
Yes although antibodies aren’t the only mechanism. I’m not worried about post-vaccine enhancement with the attenuated strain, I’m worried that you can’t reliably demonstrate the vaccine doesn’t cause enhancement after the real infection.
This problem exists with or without finding an attenuated strain. A better way to think about this is let’s say we had two strains of the virus isolated - one that killed 10% of people infected and the other that killed less than 0.0001%. Which one should we use in a challenge trial?
I’m not sure what your point is. Ultimately you need to demonstrate a vaccine is safe and efficacious for the real disease. An attenuated strain isn’t the real disease.
No you don’t if you choose the right attenuated strain, but even if you decided for some insane reason that you had to test the vaccine with a pathogenic strain you do this after you have shown that the vaccine protected the vaccinated person from the attenuated strain.
FTR, at least the preprint written by SinoVac about their inactivated vaccine (which is in Phase 1, and Phase 2 beginning shortly IIRC), claims that they observed no ADE in rhesus macaques.
The world actually is a giant field test at the moment. Many people get infected by potentially different strains of COVID. There is no need to infect voluntaries as thousands already get infected by the choose of the virus every day.
This data should be used: E.g. are there extreme examples, like many inhabitants of an elderly home getting infected but noone dies?!
One should look out for this and use this to boost the development of treatments and vaccines.
Gene deletions are expected to some extent as a result of natural mutations.
The author is hypothesising that there should already exist natural virus particles ("in the wild") with key genes deleted that render it harmless to humans, and that these harmless strains may also be spreading in the population. We could possibly identify harmless virus particles with wide-ranging testing of asymptomatic people, and statistically identify what genes (or what parts of the genome) are important for disease.
The author's concept is that this would have potential as a vaccine. It's similar in concept to the polio vaccine, or giving cowpox to prevent smallpox infection.
In my opinion, the author is making several hypothetical leaps of logic that don't make this feel like a workable plan.
The author proposes to test 50,000 people and use this to identify safer strains: in my opinion that wildly underestimates what would be needed for this to have a chance of working.
Since the virus looks to be harmless in the vast majority of people it infects, it will be difficult and dangerous to distinguish strains that are genuinely harmless.
Fifth the same, but as a counter argument sequencing 10,000 strains has found 69 candidate attenuation strains and that was without even trying.
Sixth no. It is actually quite easy to distinguish a harmless strain from a normal pathogenic strain as we can use the high morbidity rate as a proxy for danger.
You've identified 69 strains (assuming no errors or false positives)
Saying they are candidate attenuation strains is like saying sugar is a candidate treatment.
[Edited after reconsidering, because it's worse than that:]
Saying they are candidate attenuation strains is like saying drinking bleach is a candidate treatment. They are highly likely to still be extremely harmful.
If, hypothetically, you have identified a strain that has had no severe outcomes even in a large cohort of people with known risk factors, then that strain is most likely harmless.
Of course we don't have this kind of data (yet), but the principle is valid.
This is why it is a good idea to read the entire post before commenting. The process of checking each candidate strain requires going into the local community where the index case was found and looking for more cases.
Oh so brave to be using a throwaway account to attack someone. Do you understand what the word candidate means? These 69 strains COULD be attenuated, but until we actually check into this we don’t know. The only way to find out is to actually investigate.
How could it possible be harmful to check the clinical history of the patient that was infected with these deletion strains?
Gene deletions are actually very common for virus. At their reproductive cycle, the genes have to be kind of "collected" into their shells; a deletion means only that one of the genes wasn't there at the right time.
SARS-CoV-2 is a single-segmented, double-stranded RNA virus. There are no genes being "collected", just two complementary RNA strands that are replicated directly from source RNA and wound into a packed structure by helicases. Gene deletions are extraordinarily uncommon for most viruses, because viruses don't generally carry around entire non-essential genes. SNPs and small indels are indeed common, and because the genome is well-annotated, many of them can be characterized into synonymous, non-synonymous structurally significant/insignificant, frameshift, or non-coding mutations. In the case where a mutation appears to disrupt a gene through a frameshift or structurally significant mutation, further evidence is needed (like multiple independent isolates) that the mutation is not a sequencing artifact.
In the case of the link that OP posted (http://cov-glue.cvr.gla.ac.uk/#/deletion), only non-frameshifting deletions in coding regions are listed. Most deletions listed are one- or two- codon deletions observed in multiple isolates, which is good evidence. Aside from the terminology issues, OP's claim that some of these deletions may result in an attenuated virus is plausible, subject to further analysis of the structural effect of these mutations (which can be modeled in silico). I don't think it would be useful to "go and visit the people who were infected with each of the different deletion strains and investigate what was their clinical outcome" as OP suggests, since that would be confounded by many factors.
Trying to isolate live attenuated virus from the human population in this way carries a lot of risks and potential ethical issues, and amounts to a very low-throughput, difficult screen. The far higher throughput, better researched method that labs are prepared to do is to infect an animal (possibly genetically engineered to be more human-like in its molecular machinery) and wait for the virus to evolve to target that animal, which will make it less virulent in human. However, for SARS-CoV-2 this is especially tricky because of how explosively fast its replication cycle is. Most vaccine trials for coronavirus are working on presenting the human immune system with pieces of the virus instead of live attenuated virus.
I would encourage everyone in this thread to read the scientific literature on this, which is abundant and freely available, for example this review: https://www.nature.com/articles/nrd.2015.37.pdf
Could you explain what risks there are in trying to isolate attenuated viruses from the human population? What are the ethical issues? Not the use of such an attenuated strain, just the isolation.
Just a small correction on the 69 deletion strains - they are all in gene coding reasons, but they are both frameshift and non-frameshift mutants.
Looking for a naturally occurring attenuated strain is a waste of time. The problem isn't a lack of vaccine candidates, it's a matter of testing latency. Any attenuated strain is just a live virus vaccine and this doesn't skip you to the head of the regulatory line. Finally, synonymous recoding with CpG enrichment is a more robust way to attenuate than relying on natural attenuation.
I don't know. My lab work was primarily with site directed mutagenesis in DNA viruses (PhiX 174). Production seems like it would be the trickiest part -- How do you produce the capsid in sufficient quantity without the machinery it needs for replication? Maybe you just transfect it into cells. Perhaps you clone some viral genes into the host genome and remove them from the virus? I don't know what this would do with regards to packing the remanent genome into the capsid.
Ah the “give up before we even try” approach. Did you actually read the post before commenting?
Sure you can develop a putative attenuated strain in the lab, but how are you going to collect human data on it quickly? The spread of a natural attenuated strain gives us something that no lab-generated strain can - human data right now.
“This Week in Virology” podcast addressed this mutation issue just last week. Basically 20 out of 30,000+ genes have mutated. This is one of the slowest viral mutations, 5x slower than seasonal influenza. While most viruses tend to become milder as mutations and transmission happens, SARS-CoV-2 mutates so slow that the mortality will be high for quite some time. The good news is that a vaccine should provide long-lasting protection more like the measles shot rather than an annual flu vaccine that is hit or miss.
This Week in Virology has debunked the claims that there multiple strains of the virus that are either more transmissible, or more or less severe, or that your immune system would react differently to.
Here is what they had to say in episode 590[1]:
Vincent Racaniello: There are a series of articles here, where there have been some claims about different circulating lineages and what that means. Are you on this, Cathy?
Cathy Spindler: Right. So, there was an article that I first saw in the LA Times "Chinese Scientists Say Second Coronavirus Strain Is More Dangerous"[2]. But in that there's a link to virological.org, which we talked about another article posted there a couple of weeks ago[3], and they really debunk this and think even that this Chinese article about a second Coronavirus should be retracted. Two of the key claims that are reached by misunderstanding and overinterpreation of data and an additional analysis suffers from methodological limitations. So this long thing on virological.org goes in to the reasons why there's no real evidence for two different strains, a more severe strain and a less severe strain.
Rich Condit: It also provides a nice summary of this sort of variation in sequence that's being observed in the virus over time, which is good.
Vincent: Yeah, it's a good article. We'll put a link. It's worth reading, but as everyone should know, when these [indistinct] viruses, every replication cycle they sustain mutations in their genomes and the lethal ones are gone, the viruses don't reproduce, but some of them stay and if they're neutral they remain. So they can be characteristic. So the virus introduced in to the Washington area is a single introduction and then it's spread and you can tell that because it has a unique set of mutations compared to say, the Chinese isolate, but it doesn't mean anything biologically. It's just markers.
Rich: And the markers are really interesting because they give you insight in to, I mean the insight that I got from observing what came out of the Washington cases is that from looking at the sequence of the virus they concluded that in fact it had been circulating for some time, and they could even get a very very rough estimate of how many cases might be out there based on the variation in sequence and the time at which the disease first showed up in a person.
Vincent: I think there are some emails later about this. People are concerned that, and people suggest in these papers, at least the one here, that we're being critical of that it could be evolved to be more virulent or more transmissible. There's no evidence for that whatsoever.
Rich: This is the kind of thing that... it just won't go away!
Vincent: Oh, it doesn't go away... new outbreak and it comes back.
Rich: Yeah, and there's no evidence. People have looked at this. We've gone over this for several.. Zika, Ebola, where's there's been variation and people point to a particular variation and they say, "This is going to make it more virulent" or something, and then the experiments ultimately get done and no. It hasn't made a difference.
Vincent: And also the issue of increased transmissibility, I think this virus is already very transmissible as it is, and I think the mutations that made it effectively transmissible among humans, which happened very early on, I don't know, either in animals or in humans early on, before we knew about it, they're done, and it's going to be hard to know what they were. MERS coronavirus has never acquired those high transmissibility changes and it keeps fizzling out and then you have another reintroduction from camels but this particular SARS-Cov-2 sustained them probably early on and it's a very good transmitter. It doesn't need to get better, at least from my anthropocentric view. We never really know what viruses are selected by, but I...
While this is true, this has absolutely nothing to do with my post. You seem motivated enough to understand this topic in some depth so I think you would benefit from reading through all my posts on this topic and thing carefully about what I am arguing.
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[ 0.22 ms ] story [ 223 ms ] threadWhile it might be possible to use a natural attenuated strain as a vaccine directly, the real value of having such a strain may be in using it as a safer test strain in a human challenge trial of a conventional vaccine. This could shave many months off us getting an effective vaccine for COVID-19 [1].
0. https://www.tillett.info/2020/04/05/a-solution-to-covid-19/
1. https://www.tillett.info/2020/04/24/it-is-unethical-to-not-s...
It seems contradictory article author is in front page, but at the same time author's comments are downvoted.
https://news.ycombinator.com/item?id=22830320
There are a number of issues with the approaches suggested by the author. In particular they’ve suggested an attenuated strain be spread by something similar to Pox Parties. Many might find these suggestions misguided and dangerous...
This is not really relevant to the idea of using an attenuated strain to accelerate the development of other vaccines. This would be done under controlled conditions where the attenuated strain would not spread.
I'll be concrete: the expected correlation between the cited deletions and pathogencity should be considered to approach zero. No evidence supports the hypothesis that single codon or single nucleotide deletions correlate with attenuation of strains. Furthermore, a basic understanding of molecular biology is all that's needed to dismiss the notion of a generalized correlation between observing deletions (or even insertions! or any general mutation!) and the pathologic outcome of infection with a virus. Biology doesn't support general claims of this nature. This is not a well-informed line of reasoning.
Even the title of the post is wrong! These are not "gene deletions." These are single codon deletions or deletions of a few nucleotides. No genes have been deleted!!
""" I have been a tenured academic (Senior Lecturer) within the School of Pharmacy and Applied Science at La Trobe University, Australia teaching and researching in the areas of phage therapy (bacterial virology), pharmacy, environmental microbiology, bioinformatics and cancer. """
Since that seems easy enough to look up and call him out on if he were lying, I am inclined to believe that it's true.
I am inclined to believe his take on things over yours, given that the only info I can see immediately about you is your info blurb stating, "Damn kids, get off my lawn."
That said, I don't think anyone is treating what he says as gospel. But it's an interesting perspective.
These are NOT whole gene deletions, they are nucleotide deletions. Genes are usually longer than 33 nucleotides, by my count the largest deletion he sees. For reference, that’s 11 amino acids, rule of thumb for an average protein length is about 200 amino acids.
The author highlights that many of these deletions are not codon aligned, which means that if you make this mutation, the resulting protein is highly unlikely to be translated properly. This is true, however devoid of context.
Most of the mutations are very rare. The highest frequency one occurs 400 or so out of at minimum 10,000 examples. Next one is 36/10,000. It’s possible these matter, it’s also possible these viral sequences are just low quality and the mutations are an artifact. It’s also possible that these mutations don’t actually matter to viral function for whatever reason. For example, if the mutation is at the end of a protein, it could screw up everything downstream but the protein before the mutation works just fine, i.e. mutation doesn’t matter. It’s just hard to tell with the data in this article.
The concept that maybe there are attenuated strains isn’t completely bogus, there is some thought a Singapore strain (with a massive deletion of 380 nucleotides, or 10x what we see here [1]) might be less infective. This is speculation and we don’t know yet, but that sounds maybe possible to me as a PhD Biochemist (if we’re gonna get all credential-spreading here).
However saying “The really interesting deletion mutations are those in the non-structural accessory genes. These are the genes that are likely to play an important role in pathogenicity and it would be expected that some of these mutations may make the virus less dangerous (attenuated).” Is really pushing it. I don’t know of any science to believe this one way or another, viruses are pathogenic for a variety of reasons, both accessory and core (whatever that means) proteins matter.
In short, given the uncertainty, we can hope there’s a less infectious strain out there, but this article provides precious little evidence to that effect.
1.) https://www.biorxiv.org/content/10.1101/2020.03.11.987222v1....
I am not providing evidence that an attenuated strain exists, just evidence that it could exist because the right type of mutations are found in SARS-CoV-2. The only way we are going to find out if there are attenuated strains is to look for them which as far as I know nobody is trying.
> as far as I know nobody is trying
Of course we are. We are deeply engaged in studying the key residues that mediate all aspects of viral infection, reproduction, and clinical pathology. That's another way of saying that an incredible number of researchers have dropped everything to study the genetic and molecular determinants of pathogenicity. Don't worry -- we are on it.
But how? We are able to surveil only a tiny fraction of genomes, relative to strains circulating. How would a "less infectious strain" ever emerge to the extent we'd have a high probability of sampling it? Darwin argues against this version of the idea.
Nevertheless, the OP is also wrong that it's faster to produce a live attenuated vaccine by finding one in the wild than it is to use tried-and-true viral vectors that are easy to reengineer, have previously received regulatory approval, and indeed are already in active trials (e.g. Oxford's adenoviral trial). It's also easier to trial heat-killed virus -- and indeed, that too is being trialed.
Can you please stop saying I am arguing for things I am not arguing for? More time spent reading and less posting would improve your argument.
But yes, given infinite capacity it would be excellent to sequence from every single patient. It would be a dream, but sadly we're barely able to get enough cotton swabs and RNA isolation kits right now to run a basic qPCR for 10% of the population, let alone get all those viral genome sequences. It would be fascinating to have that many, of course.
Forced evolution to lower infectivity is also a common way to make vaccines, so I’m quite certain one of the 100 or so vaccine efforts is trying this.
However, it’s not clear that the deletions in the OP are attenuating. If we end up with attenuated virus, it will likely come from a directed evolution experiment, not just getting lucky with a natural strain. Even such a natural strain would likely need to go through a fair bit of directed evolution to attenuated it to the point of harmlessness.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC136581/#idm1399...
The bigger point I was making is that there are many deletion mutants out there. We should be looking for more and checking if they are attenuated or not. We might be very unlucky and find there are none, but that seems rather defeatist given we haven’t even tried.
https://blogs.sciencemag.org/pipeline/archives/2020/04/23/a-...
I apologize for the probably overly snarky comment. I woke up in the middle of the night and was having a hard time falling back to sleep.
I really wouldn't be surprised if the two of you are in more agreement than either of you realize. "Violent agreement" as I've sometimes heard it called.
Also for the record, I didn't downvote you. Just provided my response of why I was inclined to believe the author over you.
https://www.mdpi.com/1999-4915/11/11/1016
If they do I am arguing we should look for them rather than sitting in our armchairs coming up with possible reasons they don’t and so not even bothering.
Instead of running a large Phase III field trial where we wait for people to get infected, we could use the safer strain to do a challenge trial where we deliberately try to infect the volunteers with the attenuated strain. This will give us an answer much sooner and avoid exposing many people to a vaccine that maybe doesn’t work.
You can’t know the long term effects on the attenuated virus in a large group so the same caution and slow pace would have to be used to test that. First! All you did was go from testing one thing to testing two things (an attenuated virus and the vaccine).
If the attenuated virus could somehow (quickly) be deemed harmless in humans then I agree it could be a shortcut, but is that really possible?
Yes it is possible, but the only way we will know is if we look. I am arguing we should look.
Which, if it's even less likely to cause symptoms is almost sure to happen if the virus is spread among the population.
Could you explain this further as to why this allows us to shave many months off?
My current extremely naive understanding of testing would be, at least one group would be unexposed, unvaccinated trial: 1, vaccine, 2 inject, 3 expose to virus 4, measure
If Step 3 is expose, how does a safer strain speed this up?
I explain this much more in a previous post on my blog [0].
0. https://www.tillett.info/2020/04/24/it-is-unethical-to-not-s...
Thanks for this explanation and the series of blog posts.
To me it seems like a solid argument that given all those conditions (and possibly others I haven't thought of or mentioned), such a trial should be allowed. My understanding is that there are many people preemptively volunteering to participate.
Now, a vaccine does exactly that. It plays some games with the immune system. Sometimes the outcome of the game is weird, just take a look at [1]. Here's a random snippet:
"Encephalitis (severe brain reaction), which can lead to permanent brain damage (as many as 1 per 83,000)."
Variolation as opposed to vaccination, has the advantage that the only side effect is that you can get the disease itself, but no weird interactions with the immune system. All right, in the case of Covid19, the disease can have such weird interactions, so it's difficult to say it's an obviously better alternative, but still, that's the main idea.
[1] https://www.historyofvaccines.org/content/articles/vaccine-s...
This seems to me to be a bit of a false distinction: all the symptoms are ultimately "weird interactions with the immune system"; and this is especially true for the more deadly responses to the virus, AFAICT.
That said, after nearly 3 million confirmed cases, we should have a reasonable sample of how the genes in this virus interact with the immune system; it certainly seems to be introducing fewer variables to delete some of these genes than to try adding something else into the mix.
I'm not sure about the idea of using any particular strain as the basis for a vaccine. But the severity data for various strains might well be helpful in vaccine development.
I'm guessing that this is a riff on using cowpox as a vaccine for smallpox. However, modern vaccines often use inactive virus, separated viral components, unrelated viruses for delivery, etc. And now, I've read, mRNA to drive host synthesis of antigenic viral components.
Edit: OK, I see that you propose using less dangerous strains for testing vaccine effectiveness. Good idea!
This is explored in more detail in my [1] reference above.
Even if you think it is too risky to use a natural attenuated strain as a vaccine, such as strain would be very useful as a tool to accelerate other vaccines. As I said in my first post how to use any such strain is not up to me, but if it can be used to get us to a vaccine sooner it is worth looking into.
If we are going consider doing a challenge trial we should at first make the effort to see if we can find a safer strain to use.
The FDA has never approved a vaccine for humans that is effective against any member of the coronavirus family, which includes SARS, MERS, and several that cause the common cold.
If political pressure/regulatory relaxation allows a vaccine to enter the market I would be suspicious of its efficacy.
Coronaviruses are easy to vaccinate against. They mutate very slowly. There’s just not a viable business model for them when the symptoms are so mild and treatments are available cheaply over-the-counter.
From what I've read, creating a sufficiently safe vaccine has been quite a challenge.
Wait can you expand on that? I thought RNA viruses mutate very quickly?
[1] https://mra.asm.org/content/9/11/e00169-20
[2] https://en.m.wikipedia.org/wiki/Influenza_A_virus#Structure_...
[3] https://translational-medicine.biomedcentral.com/articles/10...
If infectiosness could be maintained while reducing death rate (a big if) then you'd have a naturally spreading vaccine. Theoretically we only need to quarantine the severe cases and let it evolve to a cold.
and/or its safety.
The effort spent making a vaccine is going to tend to be proportional to the disease's impact. There's no much point continuing development on a SARS vaccine when it hasn't had a new case in fifteen years, after all.
Nobody who knows anything about Coronavirus vaccines thinks it will be easy, but just because something is hard should not be a reason for not trying, especially when the reward for success is huge. All I can say is I am glad Salk and all the other Polio vaccine researchers didn’t just give up without trying because it was difficult.
I think the grandparent post is wondering why everyone is so confident we'll _succeed_.
There are people who think we should lock down everything for 12 months because a vaccine will be done by then. Really. There are. That point of view just completely boggles my mind.
But we still have to try.
There will always be the possibility that the attenuated strain varies is some major but subtle way from the non-attenuated strains, but this is not something ever seen before with other viruses. If you demand to know everything and the answers to all possible risks up front medical science doesn’t advance.
I think your ideas are possible, but the likelihood of success is quite low and the effort required to do the proper studies is far greater than you estimate. Our resources are better spent on much more developed programs with better defined odds of success.
My helpful closing suggestion is to speak with some epidemiologists and clinical researchers to see if you can get some budgetary efforts for what you propose, or failing that, try to locate a review article or two. Good luck.
With the economic cost to the USA alone running at $500 billion a month are we really constrained by resources?
I have spoken to many scientists and clinicians about this. There is a great deal of activity going on to put this into action.
https://github.com/kordless/covid19_viz/blob/master/README.m...
Heavy emphasis on "candidate". How can you tell if people had a mild case because the virus had deletions or because they mounted an appropriate immune response? It's not clear that the vaccine will be protective.
The real value of finding an attenuated strain (one that causes mild illness in everyone) is that it would be ethical to use it in a challenge trial of a conventional vaccine. The Oxford vaccine group for example are planning a large field trial because they don’t think it is ethical to expose people to the normal dangerous strains. If we found an attenuated strain we could speed things up massively.
You can see this in early and Layer 1/2 posts that go negative while later and Layer 3/4 thread posts that get high amounts of positive upvotes after the initial wave has moved on.
https://www.ncbi.nlm.nih.gov/pubmed/16043204 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7103385/
And as I said, you can't know if the people who had mild infections did so because the virus was deficient or whether their immune response was good. It's not enough to have the antigen, you also need the right adjuvant to mount a response. The last thing you want is to have antibodies that recognize the virus, but do not activate the immune system.
https://en.wikipedia.org/wiki/Antibody-dependent_enhancement...
https://jvi.asm.org/content/94/5/e02015-19
https://www.researchgate.net/publication/340005309_Potential...
The fact that the live attenuated approach worked with polio doesn't mean that it'll work with coronavirus, and if we're not careful we could accidentally worsen the situation.
I agree that this is worthwhile area of pursuit, but one that will take a long time to bear fruit. Maybe you think that studying the variants in the wild will allow us to skip over some animal studies with the live attenuated virus, but I doubt they can be skipped.
I have no background in this whatsoever, so feel free to ignore my comment, but my guess is that finding them in the wild along with a large-enough (and representative-enough) infected population without severe symptoms basically saves the work of trying 5k different possible variant in animals — just skip the the promising candidate directly, no?
However, the PCR-based diagnostic tests that are current being used rely on amplifying only a small part of the virus genome so we are actually blind to how the rest of the virus is changing in the larger population (at least in routine diagnostic tests).
Of course, if this testing infrastructure doesn't already exist, I imagine creating it would be too slow to help with this particular plague.
No, you can't approximate a human immune system with red and white blood cells in a container of liquid. No, adding some other cells in there won't help. If that were effective, we'd be doing it already. You are either overestimating your own ingenuity or underestimating the ingenuity of tens of thousands of scientists, doctors, and engineers.
The answer is no, for somewhat obvious reasons. The human immune system involves many organs and tissues and cells working together in very complex ways.
And I think your charitable interpretation is quite a bit too charitable. OP did not say anything like "why doesn't it work like I think it would".
For the record, my main intention was to get an expert to say something that would gratify my curiosity and that of other readers. I hadn't heard of it before, so I assumed it was likely impractical at the moment, but guessed that technology would eventually get there.
Also, are you an expert in this field? Your sibling comment seems to be saying "yes they are working on it, no it's not practical yet except for HIV" (I presume because HIV infects white blood cells), which is at odds with your second paragraph. (Edit: Though, to be very precise, the examples from the sibling comment are about measuring infectivity and—I guess—the impact of drugs, not immune response.) It would be ironic if a non-expert gave an ignorant dismissal of a question for being ignorant.
there's other approaches to make "organs on a chip" for drug trial screening, since lab models with only one type of cells don't capture the effects of other types, but it's really not fully baked yet.
Your “first level” is something we already do with primary and immortalized cells and it can be a useful model. Your next level would be called co-culture and it also is something we already do. These can be static cultures or connected to flow systems or bioreactors or whatever. These are imperfect models, but they can help to yield useful answers for questions in the model’s scope. The closest fidelity to human immune systems would be animal models, and the closest of these would be Rhesus macaques, and indeed these are used for vaccine development.
Now, you might culture it in a lab and then inject it into people deliberately so they develop antibodies that then work against the "true" virus. This technique is called "vaccination".
This is a report on some progress on one particular vaccine type. But it's minor progress. What we need is an attenuated strain. What this shows is just that there are some spreading strains with gene deletions (which is the kind of mutation which tends to produce attenuated strains). There's a lot of work to get from there to a vaccine.
You can certainly "let" a virus spread faster than another. Society chooses to let the flu spread more easily than ebola despite them having similar R0.
In this case, you could vary school closure criteria, tracing effort, or quarantine duration by strain.
We allow people to donate a kidney to another person, and that carries a significant amount of risk, and only one person benefits.
We allow assisted suicide in many places.
We allow people to assume great risks in auto racing, professional football, and boxing, and that's just for entertainment.
We allow doctors to treat COVID patients, sometimes without even proper PPE, knowing that a significant number will catch it. Many doctors are also not young, not in good health, and have preexisting conditions.
So all of this is allowed, but when the potential result is a vaccine that could save millions of lives, somehow this is unethical?
I think the most prelevant is COVID-19, at full strength, still kills seemingly healthy young people. The author mentions this in another article:
> The important question we have to consider is if it is ethical to deliberately expose even the young and healthy to the dangerous SARS-CoV-2 virus when we know it could seriously injure or kill them.[0]
In this article, we potentially have a weaker strains on our hands that could qualify as a fully ethical challenge trial that could accelerate the development.
At the end of the day, challenge trials are Phase trials with less restrictions in hopes of trading accuracy/rigor for speed.
Is it worth it? I don't know. I'm not knowledgeable enough to say one way or another.
[0] https://www.tillett.info/2020/04/24/it-is-unethical-to-not-s...
Is it worth it? We've lost about 200,000 people worldwide just in the past month from this disease. It's the leading cause of death in many countries. In healthy young people (20s, no preexisting conditions), the fatality rate is well under 0.1%.
If the vaccine doesn't work at all, which is unlikely, you'd expect 0-1 deaths from the trial. To save perhaps a single life of a willing, altruistic volunteer subject while hundreds of thousands die every month, and the world is confined to its homes is to me, utter insanity.
Do we tell firefighters to not go into a burning building to save lives, even if there is considerable risk?
If this is the state of medical ethics, the field should be torn down and rebuilt. To deny approval for a challenge trial with volunteers is mass murder.
The process is similar for most forms of regulation. The equilibrium is where no accident can be pinned on the regulators rather than on any sort of system-wide optimum. It can be very frustrating to deal with.
That's where the huge time savings is.
My previous statement of "it's a Phase trial with less restrictions" isn't true. It's making the feedback loop tighter.
With this new knowledge, I'm relatively convinced we should be doing a challenge trial to speed up the roll out.
Challenge trial are used in trials on things like the common cold. SARS-CoV-2 is considered too dangerous to use in a challenge trial.
Meanwhile, maybe 1,000,000 people a day are catching COVID. The bottleneck that stops that from continuing every single day involves some risk (if the vaccine doesn't work), of a few hundred people, who are in the most favorable position if they catch it, who volunteered.
"Better 1,000,000 people die from COVID than one person die that tried to stop it."
Even if we (society) did decide that doing a challenge trial is worth the risk, we would be amiss to not look for a safer strain to use first. Only if we can’t find one after making a serious effort should we even think about using a dangerous strain.
> There are those that argue even without a safer strain it is ethical under certain circumstances to still perform that sort of "challenge trial" though, where people are deliberately exposed. A number of conditions would have to be met, such as all volunteer participation of course, very clear explanation and demonstration of understanding, no financial incentive, etc. But a faster vaccine could save many more lives than would be risked in the trial, and the risk itself could be very low, given the trial participants would be monitored closely and would get excellent medical care. Also obviously it would be restricted to young, healthy people without pre-existing conditions.
To me it seems like a solid argument that given all those conditions (and possibly others I haven't thought of or mentioned), such a trial should be allowed. My understanding is that there are many people preemptively volunteering to participate.
While the majority might have purely altruistic reasons, others could be dealing with mental illnesses that lead them to inappropriate action.
In the same way that there are older people saying things like "I'm willing to take my chances so that young people's jobs/lives/economy aren't destroyed" there are highly likely to be people offering to be guinea pigs for reasons that should ethically exclude them.
By lowering the risk to the absolute maximum level possible, as suggested by the OP, it could be possible to have a challenge trial within ethical boundaries.
This is more than "oh regulation is about CYA and that's what's holding us up", this is about "we don't kill or injure people in medical research, even if others might be saved."
That's not a risk I personally would want to take, but it's on the order of the risk people take when donating a kidney. (And of course for most people the process will be much less arduous than a kidney donation.) We consider that acceptable to save a single life, whereas a faster vaccine would save many. So my prior would be that most people volunteering for something like this are simply altruistic, similar to a kidney donor, rather than mentally ill.
Of course an attenuated strain may be able to be used as a vaccine directly, but this is somewhat controversial.
It is also a large effort to produce a medical grade attenuated strain that you could infect people with in a trial.
For a challenge trial you only need enough virus for a few thousand people at most. It is not difficult to produce this amount of virus in cell culture.
This data should be used: E.g. are there extreme examples, like many inhabitants of an elderly home getting infected but noone dies?!
One should look out for this and use this to boost the development of treatments and vaccines.
Gene deletions are expected to some extent as a result of natural mutations.
The author is hypothesising that there should already exist natural virus particles ("in the wild") with key genes deleted that render it harmless to humans, and that these harmless strains may also be spreading in the population. We could possibly identify harmless virus particles with wide-ranging testing of asymptomatic people, and statistically identify what genes (or what parts of the genome) are important for disease.
The author's concept is that this would have potential as a vaccine. It's similar in concept to the polio vaccine, or giving cowpox to prevent smallpox infection.
In my opinion, the author is making several hypothetical leaps of logic that don't make this feel like a workable plan.
The author proposes to test 50,000 people and use this to identify safer strains: in my opinion that wildly underestimates what would be needed for this to have a chance of working.
Since the virus looks to be harmless in the vast majority of people it infects, it will be difficult and dangerous to distinguish strains that are genuinely harmless.
Third no. I am not arguing this at all.
Fourth is pure opinion.
Fifth the same, but as a counter argument sequencing 10,000 strains has found 69 candidate attenuation strains and that was without even trying.
Sixth no. It is actually quite easy to distinguish a harmless strain from a normal pathogenic strain as we can use the high morbidity rate as a proxy for danger.
Saying they are candidate attenuation strains is like saying sugar is a candidate treatment.
[Edited after reconsidering, because it's worse than that:] Saying they are candidate attenuation strains is like saying drinking bleach is a candidate treatment. They are highly likely to still be extremely harmful.
If, hypothetically, you have identified a strain that has had no severe outcomes even in a large cohort of people with known risk factors, then that strain is most likely harmless.
Of course we don't have this kind of data (yet), but the principle is valid.
Right now, we're not looking, but we should be. That's the point.
How could it possible be harmful to check the clinical history of the patient that was infected with these deletion strains?
Gene deletions are actually very common for virus. At their reproductive cycle, the genes have to be kind of "collected" into their shells; a deletion means only that one of the genes wasn't there at the right time.
In the case of the link that OP posted (http://cov-glue.cvr.gla.ac.uk/#/deletion), only non-frameshifting deletions in coding regions are listed. Most deletions listed are one- or two- codon deletions observed in multiple isolates, which is good evidence. Aside from the terminology issues, OP's claim that some of these deletions may result in an attenuated virus is plausible, subject to further analysis of the structural effect of these mutations (which can be modeled in silico). I don't think it would be useful to "go and visit the people who were infected with each of the different deletion strains and investigate what was their clinical outcome" as OP suggests, since that would be confounded by many factors.
Trying to isolate live attenuated virus from the human population in this way carries a lot of risks and potential ethical issues, and amounts to a very low-throughput, difficult screen. The far higher throughput, better researched method that labs are prepared to do is to infect an animal (possibly genetically engineered to be more human-like in its molecular machinery) and wait for the virus to evolve to target that animal, which will make it less virulent in human. However, for SARS-CoV-2 this is especially tricky because of how explosively fast its replication cycle is. Most vaccine trials for coronavirus are working on presenting the human immune system with pieces of the virus instead of live attenuated virus.
I would encourage everyone in this thread to read the scientific literature on this, which is abundant and freely available, for example this review: https://www.nature.com/articles/nrd.2015.37.pdf
Just a small correction on the 69 deletion strains - they are all in gene coding reasons, but they are both frameshift and non-frameshift mutants.
Sure you can develop a putative attenuated strain in the lab, but how are you going to collect human data on it quickly? The spread of a natural attenuated strain gives us something that no lab-generated strain can - human data right now.
Here is what they had to say in episode 590[1]:
Vincent Racaniello: There are a series of articles here, where there have been some claims about different circulating lineages and what that means. Are you on this, Cathy?
Cathy Spindler: Right. So, there was an article that I first saw in the LA Times "Chinese Scientists Say Second Coronavirus Strain Is More Dangerous"[2]. But in that there's a link to virological.org, which we talked about another article posted there a couple of weeks ago[3], and they really debunk this and think even that this Chinese article about a second Coronavirus should be retracted. Two of the key claims that are reached by misunderstanding and overinterpreation of data and an additional analysis suffers from methodological limitations. So this long thing on virological.org goes in to the reasons why there's no real evidence for two different strains, a more severe strain and a less severe strain.
Rich Condit: It also provides a nice summary of this sort of variation in sequence that's being observed in the virus over time, which is good.
Vincent: Yeah, it's a good article. We'll put a link. It's worth reading, but as everyone should know, when these [indistinct] viruses, every replication cycle they sustain mutations in their genomes and the lethal ones are gone, the viruses don't reproduce, but some of them stay and if they're neutral they remain. So they can be characteristic. So the virus introduced in to the Washington area is a single introduction and then it's spread and you can tell that because it has a unique set of mutations compared to say, the Chinese isolate, but it doesn't mean anything biologically. It's just markers.
Rich: And the markers are really interesting because they give you insight in to, I mean the insight that I got from observing what came out of the Washington cases is that from looking at the sequence of the virus they concluded that in fact it had been circulating for some time, and they could even get a very very rough estimate of how many cases might be out there based on the variation in sequence and the time at which the disease first showed up in a person.
Vincent: I think there are some emails later about this. People are concerned that, and people suggest in these papers, at least the one here, that we're being critical of that it could be evolved to be more virulent or more transmissible. There's no evidence for that whatsoever.
Rich: This is the kind of thing that... it just won't go away!
Vincent: Oh, it doesn't go away... new outbreak and it comes back.
Rich: Yeah, and there's no evidence. People have looked at this. We've gone over this for several.. Zika, Ebola, where's there's been variation and people point to a particular variation and they say, "This is going to make it more virulent" or something, and then the experiments ultimately get done and no. It hasn't made a difference.
Vincent: And also the issue of increased transmissibility, I think this virus is already very transmissible as it is, and I think the mutations that made it effectively transmissible among humans, which happened very early on, I don't know, either in animals or in humans early on, before we knew about it, they're done, and it's going to be hard to know what they were. MERS coronavirus has never acquired those high transmissibility changes and it keeps fizzling out and then you have another reintroduction from camels but this particular SARS-Cov-2 sustained them probably early on and it's a very good transmitter. It doesn't need to get better, at least from my anthropocentric view. We never really know what viruses are selected by, but I...