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There are many SARS-CoV-2 strains with gene deletions

183 points by danieltillett 6y ago

danieltillett 6y ago
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]. 0. https://www.tillett.info/2020/04/05/a-solution-to-covid-19/ 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-search-for-an-attenuated-sars-cov-2-strain/ https://www.tillett.info/2020/04/24/it-is-unethical-to-not-s...
- cocoa19 6y ago
  Can downvoters provide some input? It seems contradictory article author is in front page, but at the same time author's comments are downvoted.
  - new299 6y ago
    I recommend reading the previous thread to understand some of the issues: https://news.ycombinator.com/item?id=22830320 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...
    - danieltillett 6y ago
      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.
  - lvs 6y ago
    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!!
    - war1025 6y ago
      His "About me" page states: """ 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.
      - entee 6y ago
        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. 1.) https://www.biorxiv.org/content/10.1101/2020.03.11.987222v1.full.pdf https://www.biorxiv.org/content/10.1101/2020.03.11.987222v1....
- dehrmann 6y ago
  If you find a safe enough strain, it might as well be a vaccine.
  - alkonaut 6y ago
    And to test it and establish that it’s that mild safe will take as long as making any other vaccine. That’s the catch.
    - danieltillett 6y ago
      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.
      - alkonaut 6y ago
        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?
        danieltillett 6y ago
        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.
- irjustin 6y ago
  > 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?
  - danieltillett 6y ago
    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]. 0. https://www.tillett.info/2020/04/24/it-is-unethical-to-not-search-for-an-attenuated-sars-cov-2-strain/ https://www.tillett.info/2020/04/24/it-is-unethical-to-not-s...
    - irjustin 6y ago
      Got it, my assumption for Step 3 existing is wrong. It simply doesn't! Thanks for this explanation and the series of blog posts.
    - tempestn 6y ago
      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.
- mirimir 6y ago
  Thanks for pointing to the data. 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!
  - danieltillett 6y ago
    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.
- musiciangames 6y ago
  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?
  - danieltillett 6y ago
    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.
- hazeii 6y ago
  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?).
  - GTP 6y ago
    He talks about this here: https://www.tillett.info/2020/04/05/a-solution-to-covid-19/ https://www.tillett.info/2020/04/05/a-solution-to-covid-19/
- tinus_hn 6y ago
  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.
- dstroot 6y ago
  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.
  - CyanLite4 6y ago
    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.
    - gridlockd 6y ago
      > Coronaviruses are easy to vaccinate against. From what I've read, creating a sufficiently safe vaccine has been quite a challenge.
    - aledalgrande 6y ago
      > Coronaviruses are easy to vaccinate against. They mutate very slowly. Wait can you expand on that? I thought RNA viruses mutate very quickly?
      - totony 6y ago
        From what I understand, covid is a relatively small rna strand vs e.g. the flu which makes significant mutation way more rare
        rotexo 6y ago
        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]. [1] https://mra.asm.org/content/9/11/e00169-20 https://mra.asm.org/content/9/11/e00169-20 [2] https://en.m.wikipedia.org/wiki/Influenza_A_virus#Structure_and_genetics https://en.m.wikipedia.org/wiki/Influenza_A_virus#Structure_... [3] https://translational-medicine.biomedcentral.com/articles/10.1186/s12967-020-02344-6 https://translational-medicine.biomedcentral.com/articles/10...
- IdoRA 6y ago
  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.
  - danieltillett 6y ago
    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.
    - IdoRA 6y ago
      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.
      - danieltillett 6y ago
        How have you determined the likelihood of success and the effort required? 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.
pazimzadeh 6y ago
> 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.
- danieltillett 6y ago
  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.
  - ggm 6y ago
    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?
    - autokad 6y ago
      hn down-voted the author for voicing and clarifying his positions on the article shared on hn.
    - bsder 6y ago
      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.
wuxb 6y ago
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.
- newacct583 6y ago
  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.
  - SubiculumCode 6y ago
    Sure you could, via intentional infection by cultivated strains.
    - deleted 6y ago
      [deleted]
  - s1artibartfast 6y ago
    >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.
noway421 6y ago
The linked website (https://www.cogconsortium.uk/data/ 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.
- danieltillett 6y ago
  It seems to be a work in progress. It might be worth sending them a bug report.
test6554 6y ago
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?
- 01100011 6y ago
  Covid-19 isn't a retrovirus. It does not directly change the host's DNA. The article is talking about deletions in the genes of the virus.
- deleted 6y ago
  [deleted]
cameldrv 6y ago
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?
- prox 6y ago
  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.
  - s1artibartfast 6y ago
    And what if it is still a deathtrap that will kill 1% of people that step into it?
    - tempestn 6y ago
      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).
- mjthrowaway1 6y ago
  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.
SubiculumCode 6y ago
Off topic, I wish HN downvoting cost something, maybe a bit of karma. Downvoting is too common.
- mirimir 6y ago
  Indeed. I believe that a downvote ought to cost perhaps 0.2 karma.
- thinkingemote 6y ago
  It does. Users need to be over a certain age and/or have themselves enough karma to downvote.
  - dang 6y ago
    Age doesn't affect it. You just need > 500 karma.
voz_ 6y ago
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?
- danieltillett 6y ago
  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.
Gatsky 6y ago
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.
- danieltillett 6y ago
  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.
  - Gatsky 6y ago
    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.
    - danieltillett 6y ago
      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?
      - Gatsky 6y ago
        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.
FHermisch 6y ago
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.
laurensr 6y ago
Luckily enough we can detect gene deletions using our Office suite's spellcheck: https://xkcd.com/2298/ https://xkcd.com/2298/
deleted 6y ago
[deleted]
pmoriarty 6y ago
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 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/ http://www.microbe.tv/twiv/twiv-590/ at about 13 minutes in [2] - https://www.latimes.com/science/story/2020-03-05/chinese-scientists-say-second-coronavirus-strain-more-dangerous https://www.latimes.com/science/story/2020-03-05/chinese-sci... [3] - http://virological.org/t/response-to-on-the-origin-and-continuing-evolution-of-sars-cov-2/418 http://virological.org/t/response-to-on-the-origin-and-conti... [4] - http://www.microbe.tv/twiv/twiv-592/ http://www.microbe.tv/twiv/twiv-592/ at about 1 hour and 41 minutes in [5] - https://www.microbe.tv/twiv/twiv-596/ https://www.microbe.tv/twiv/twiv-596/ at about 39 minutes in
rv-de 6y ago
Can somebody ELI16 why gene deletions are expected and what is the significance of this happening?
- marcosdumay 6y ago
  > why gene deletions are expected 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.
  - ak217 6y ago
    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 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 https://www.nature.com/articles/nrd.2015.37.pdf
bhickey 6y ago
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.
- rrmm 6y ago
  Would having just the virus envelope (with surface protiens) without the RNA payload be effective to provoke an immune response?
  - bhickey 6y ago
    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.
- danieltillett 6y ago
  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.
CyanLite4 6y ago
“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.

183 points by danieltillett 6y ago

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]. 0. https://www.tillett.info/2020/04/05/a-solution-to-covid-19/ 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-search-for-an-attenuated-sars-cov-2-strain/ https://www.tillett.info/2020/04/24/it-is-unethical-to-not-s...

cocoa19 6y ago
Can downvoters provide some input? It seems contradictory article author is in front page, but at the same time author's comments are downvoted.
- new299 6y ago
  I recommend reading the previous thread to understand some of the issues: https://news.ycombinator.com/item?id=22830320 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...
  - danieltillett 6y ago
    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.
- lvs 6y ago
  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!!
  - war1025 6y ago
    His "About me" page states: """ 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.
    - entee 6y ago
      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. 1.) https://www.biorxiv.org/content/10.1101/2020.03.11.987222v1.full.pdf https://www.biorxiv.org/content/10.1101/2020.03.11.987222v1....
dehrmann 6y ago
If you find a safe enough strain, it might as well be a vaccine.
- alkonaut 6y ago
  And to test it and establish that it’s that mild safe will take as long as making any other vaccine. That’s the catch.
  - danieltillett 6y ago
    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.
    - alkonaut 6y ago
      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?
      - danieltillett 6y ago
        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.
irjustin 6y ago
> 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?
- danieltillett 6y ago
  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]. 0. https://www.tillett.info/2020/04/24/it-is-unethical-to-not-search-for-an-attenuated-sars-cov-2-strain/ https://www.tillett.info/2020/04/24/it-is-unethical-to-not-s...
  - irjustin 6y ago
    Got it, my assumption for Step 3 existing is wrong. It simply doesn't! Thanks for this explanation and the series of blog posts.
  - tempestn 6y ago
    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.
mirimir 6y ago
Thanks for pointing to the data. 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!
- danieltillett 6y ago
  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.
musiciangames 6y ago
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?
- danieltillett 6y ago
  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.
hazeii 6y ago
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?).
- GTP 6y ago
  He talks about this here: https://www.tillett.info/2020/04/05/a-solution-to-covid-19/ https://www.tillett.info/2020/04/05/a-solution-to-covid-19/
tinus_hn 6y ago
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.
dstroot 6y ago
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.
- CyanLite4 6y ago
  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.
  - gridlockd 6y ago
    > Coronaviruses are easy to vaccinate against. From what I've read, creating a sufficiently safe vaccine has been quite a challenge.
  - aledalgrande 6y ago
    > Coronaviruses are easy to vaccinate against. They mutate very slowly. Wait can you expand on that? I thought RNA viruses mutate very quickly?
    - totony 6y ago
      From what I understand, covid is a relatively small rna strand vs e.g. the flu which makes significant mutation way more rare
      - rotexo 6y ago
        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]. [1] https://mra.asm.org/content/9/11/e00169-20 https://mra.asm.org/content/9/11/e00169-20 [2] https://en.m.wikipedia.org/wiki/Influenza_A_virus#Structure_and_genetics https://en.m.wikipedia.org/wiki/Influenza_A_virus#Structure_... [3] https://translational-medicine.biomedcentral.com/articles/10.1186/s12967-020-02344-6 https://translational-medicine.biomedcentral.com/articles/10...
IdoRA 6y ago
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.
- danieltillett 6y ago
  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.
  - IdoRA 6y ago
    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.
    - danieltillett 6y ago
      How have you determined the likelihood of success and the effort required? 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.

pazimzadeh 6y ago

> 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.

danieltillett 6y ago
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.
- ggm 6y ago
  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?
  - autokad 6y ago
    hn down-voted the author for voicing and clarifying his positions on the article shared on hn.
  - bsder 6y ago
    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.

wuxb 6y ago

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.

newacct583 6y ago
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.
- SubiculumCode 6y ago
  Sure you could, via intentional infection by cultivated strains.
  - deleted 6y ago
    [deleted]
- s1artibartfast 6y ago
  >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.

noway421 6y ago

The linked website (https://www.cogconsortium.uk/data/ 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.

danieltillett 6y ago
It seems to be a work in progress. It might be worth sending them a bug report.

test6554 6y ago

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?

01100011 6y ago
Covid-19 isn't a retrovirus. It does not directly change the host's DNA. The article is talking about deletions in the genes of the virus.
deleted 6y ago
[deleted]

cameldrv 6y ago

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?

prox 6y ago
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.
- s1artibartfast 6y ago
  And what if it is still a deathtrap that will kill 1% of people that step into it?
  - tempestn 6y ago
    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).
mjthrowaway1 6y ago
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.

SubiculumCode 6y ago

Off topic, I wish HN downvoting cost something, maybe a bit of karma. Downvoting is too common.

mirimir 6y ago
Indeed. I believe that a downvote ought to cost perhaps 0.2 karma.
thinkingemote 6y ago
It does. Users need to be over a certain age and/or have themselves enough karma to downvote.
- dang 6y ago
  Age doesn't affect it. You just need > 500 karma.

voz_ 6y ago

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?

danieltillett 6y ago
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.

Gatsky 6y ago

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.

danieltillett 6y ago
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.
- Gatsky 6y ago
  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.
  - danieltillett 6y ago
    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?
    - Gatsky 6y ago
      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.

FHermisch 6y ago

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.

laurensr 6y ago

Luckily enough we can detect gene deletions using our Office suite's spellcheck: https://xkcd.com/2298/ https://xkcd.com/2298/

deleted 6y ago

[deleted]

pmoriarty 6y ago

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 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/ http://www.microbe.tv/twiv/twiv-590/ at about 13 minutes in [2] - https://www.latimes.com/science/story/2020-03-05/chinese-scientists-say-second-coronavirus-strain-more-dangerous https://www.latimes.com/science/story/2020-03-05/chinese-sci... [3] - http://virological.org/t/response-to-on-the-origin-and-continuing-evolution-of-sars-cov-2/418 http://virological.org/t/response-to-on-the-origin-and-conti... [4] - http://www.microbe.tv/twiv/twiv-592/ http://www.microbe.tv/twiv/twiv-592/ at about 1 hour and 41 minutes in [5] - https://www.microbe.tv/twiv/twiv-596/ https://www.microbe.tv/twiv/twiv-596/ at about 39 minutes in

rv-de 6y ago

Can somebody ELI16 why gene deletions are expected and what is the significance of this happening?

marcosdumay 6y ago
> why gene deletions are expected 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.
- ak217 6y ago
  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 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 https://www.nature.com/articles/nrd.2015.37.pdf

bhickey 6y ago

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.

rrmm 6y ago
Would having just the virus envelope (with surface protiens) without the RNA payload be effective to provoke an immune response?
- bhickey 6y ago
  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.
danieltillett 6y ago
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.

CyanLite4 6y ago

“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.