There are many SARS-CoV-2 strains with gene deletions
tillett.info
tillett.info
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].
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.
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...
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.
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.
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.
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.
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.
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.
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.
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 don't think there's any evidence, and it's very hard to get that evidence. That paper tells you what you need to prove that mutations are doing something phenotypically. It's very hard to get that.
Rich: It has occurred to me that people who don't think about this stuff every day might be a little confused by this discussion relative to the discussion that goes on all the time about variation in influenza virus strains, and new strains coming up and having to change the vaccine and stuff. But that's different. That's variation in the influenza virus that makes it evade the existing immunity, and those sorts of variations arise so you get circulation of viruses that you don't have as good an immune response to, but that's different than a virus making mutations that make it more virulent. It's a different story.
Then they talk about it again in episode 592[4]:
Alan Dove: David sends a link to a paper on possibly being two strains of SARS-CoV-2. This says, "I've seen this pop up."
Vincent Racaniello: These are just basically single nucleotide polymorphisms.
Dove: Oh those, yeah.
Rich Condit: This is the paper where they were talking about an S-type and an L-type and one maybe being more pathogenic than another and blah blah blah blah. Basically, yes, there's variation in the virus. It doesn't necessarily mean anything.
Racaniello: No. They have no evidence that's it's functionally of any importance at all. No. But he does say "this virus has now conducted many human-to-human transmissions. Have we discovered mutations that enhance transmission? Welcome to evolution." Well, the problem is you need to have the virus before it started transmitting efficiently among people. Right? And we don't have that and I'm not sure we ever will. But then maybe you could look at it and see what changes occur. And I'm not sure you could ever do anything about it because you can't infect people and we don't have a good animal model for transmission so, no. Unfortunately we won't be able to know about that.
And in episode 596[5]:
Rich Condit: So the second question is the doctor asking.. It's basically, can the virus mutate so you wouldn't be immune to it? And our understanding, my understanding with SARS-CoV-2 now is that there's no evidence that it's going to undergo what we call antigenic drift, right, that it will be SARS-CoV-2 for the foreseable future, and once you mount an immune response to that you'll be immune to it and there won't be, as far as we know, new strains coming up to which you will not be immune. These things, the human coronaviruses seem to be pretty stable over time. Yes, they can accumulate mutations but they are of essentially no consequence.
Alan Dove: And as viruses go, these coronaviruses, because of the proofreading are actually more stable than a lot of other viruses. Probably what the doctor is thinking of is that this is analogous to flu, where you do see antigenic drift and antigenic shift, and where yeah, you get different strains circulating all the time. But there's no evidence, as Rich said, that SARS-CoV-2 is doing any of that.
[1] - http://www.microbe.tv/twiv/twiv-590/ at about 13 minutes in
[2] - https://www.latimes.com/science/story/2020-03-05/chinese-sci...
[3] - http://virological.org/t/response-to-on-the-origin-and-conti...
[4] - http://www.microbe.tv/twiv/twiv-592/ at about 1 hour and 41 minutes in
[5] - https://www.microbe.tv/twiv/twiv-596/ at about 39 minutes in