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].
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.
SARS burnt out fairly readily with mitigation measures, MERS turns out to be quite difficult to catch at all, and the cold's mortality is low enough it's not an enormous priority (especially when coronaviruses only cause 10-15% of those cases).
The effort spent making a vaccine is going to tend to be proportional to the disease's impact. There's no much point continuing development on a SARS vaccine when it hasn't had a new case in fifteen years, after all.
Not exactly true. Moderna, and several others who are leading the vaccine race right now are out front because they had viable SARS and MERS vaccines but no where to test it other than in animal models.
Coronaviruses are easy to vaccinate against. They mutate very slowly. There’s just not a viable business model for them when the symptoms are so mild and treatments are available cheaply over-the-counter.
SARS-CoV-2 genome size is ~30 kb [1], influenza A genome size is ~14 kb [2]. A protein encoded in the SARS-CoV-2 genome is predicted to have exonuclease proofreading activity, which would result in a lower mutation rate [3].
Most think it is worthwhile trying to create a vaccine rather than just giving up and not even trying.
Nobody who knows anything about Coronavirus vaccines thinks it will be easy, but just because something is hard should not be a reason for not trying, especially when the reward for success is huge. All I can say is I am glad Salk and all the other Polio vaccine researchers didn’t just give up without trying because it was difficult.
I think the grandparent post is wondering why everyone is so confident we'll _succeed_.
There are people who think we should lock down everything for 12 months because a vaccine will be done by then. Really. There are. That point of view just completely boggles my mind.
We may not need a vaccine. This was about gene deletions as opposed to mutations. A while back there was an analysis of what each gene coded for. A number of them seemed to suppress natural responses to infection, so it seemed obvious that a less deadly version was just a few deletions away.
If infectiosness could be maintained while reducing death rate (a big if) then you'd have a naturally spreading vaccine. Theoretically we only need to quarantine the severe cases and let it evolve to a cold.
IIRC by the time a SARS vaccine came out, human transmission had already been stopped through other measures. There was no ethical way to do human clinical trials.
Assuming that one located a naturally mild strain of virus (which I personally remain bearish on), for it to produce useful (in the regulatory sense) information a challenge trial, you would need to establish that the response of individuals to the mild strain (which by definition differs from the more lethal strain) is representative of the response to the more lethal strain of virus.
Yes, but that is where you use epidemiology. If you track down each person in the local area infected with the mutant strain and follow their clinical course you can work this out. You can also do serology to make sure the immune response is similar, etc.
There will always be the possibility that the attenuated strain varies is some major but subtle way from the non-attenuated strains, but this is not something ever seen before with other viruses. If you demand to know everything and the answers to all possible risks up front medical science doesn’t advance.
I demand to know enough information to be able to give proper informed consent to study volunteers.
I think your ideas are possible, but the likelihood of success is quite low and the effort required to do the proper studies is far greater than you estimate. Our resources are better spent on much more developed programs with better defined odds of success.
My helpful closing suggestion is to speak with some epidemiologists and clinical researchers to see if you can get some budgetary efforts for what you propose, or failing that, try to locate a review article or two. Good luck.
A bit off subject, but I'm curious if you've ever run across any information that indicates certain length genomic sequences (say 8 nucleotides in a row or so) follow some sort of "order" in their numbering in the entire sequence?
> While it might be possible to use a natural attenuated strain as a vaccine directly, the real value of having such a strain may be in using it as a safer test strain in a human challenge trial of a conventional vaccine. This could shave many months off us getting an effective vaccine for COVID-19 [1].
Could you explain this further as to why this allows us to shave many months off?
My current extremely naive understanding of testing would be, at least one group would be unexposed, unvaccinated trial: 1, vaccine, 2 inject, 3 expose to virus 4, measure
If Step 3 is expose, how does a safer strain speed this up?
The reason it would be faster is at the moment it is not considered ethical to deliberately expose people to the virus after giving them a vaccine. Because we can’t do the exposing we have to use the large field trial approach and wait for people to get ill on their own (or not). These take a long time. If we had a safe strain of the virus then we could do the exposing.
I explain this much more in a previous post on my blog [0].
In practise they would probably be testing on heavily-exposed people (doctors and nurses etc). But it would speed things up some to be able to do controlled exposure.
There are those that argue even without a safer strain it is ethical under certain circumstances to still perform that sort of "challenge trial" though, where people are deliberately exposed. A number of conditions would have to be met, such as all volunteer participation of course, very clear explanation and demonstration of understanding, no financial incentive, etc. But a faster vaccine could save many more lives than would be risked in the trial, and the risk itself could be very low, given the trial participants would be monitored closely and would get excellent medical care. Also obviously it would be restricted to young, healthy people without pre-existing conditions.
To me it seems like a solid argument that given all those conditions (and possibly others I haven't thought of or mentioned), such a trial should be allowed. My understanding is that there are many people preemptively volunteering to participate.
Even if it is ethical to use a strain we know is dangerous, we would still be amiss to use such a strain just because we were too lazy to look for a safer strain. We should only use a dangerous strain if we try hard and fail to find a safer strain. We haven’t even tried yet.
Not the OP, but allow me to jump in. Two years ago, I ate something perhaps and I had a severe allergic reaction. I went from a perfectly healthy individual to a familiar face in the ER in a matter of days (4 times there in a span of a month). I took prednisone for 6 months. All tests came fine. In the eyes of modern medicine, I was still a perfectly healthy individual. My doctor told me that that is the case with 95% of the people with chronic allergies - we simply don't know what's the root cause of their problem. In other words, the immune system is extraordinarily complex, and if you could avoid messing up with it, you should probably do that.
Now, a vaccine does exactly that. It plays some games with the immune system. Sometimes the outcome of the game is weird, just take a look at [1]. Here's a random snippet:
"Encephalitis (severe brain reaction), which can lead to permanent brain damage (as many as 1 per 83,000)."
Variolation as opposed to vaccination, has the advantage that the only side effect is that you can get the disease itself, but no weird interactions with the immune system. All right, in the case of Covid19, the disease can have such weird interactions, so it's difficult to say it's an obviously better alternative, but still, that's the main idea.
> Variolation as opposed to vaccination, has the advantage that the only side effect is that you can get the disease itself, but no weird interactions with the immune system.
This seems to me to be a bit of a false distinction: all the symptoms are ultimately "weird interactions with the immune system"; and this is especially true for the more deadly responses to the virus, AFAICT.
That said, after nearly 3 million confirmed cases, we should have a reasonable sample of how the genes in this virus interact with the immune system; it certainly seems to be introducing fewer variables to delete some of these genes than to try adding something else into the mix.
Isn't there still a big question over how long immunity will last? (can you get a feel for this from the structure of the proposed attenuated strain?).
I'm not sure about the idea of using any particular strain as the basis for a vaccine. But the severity data for various strains might well be helpful in vaccine development.
I'm guessing that this is a riff on using cowpox as a vaccine for smallpox. However, modern vaccines often use inactive virus, separated viral components, unrelated viruses for delivery, etc. And now, I've read, mRNA to drive host synthesis of antigenic viral components.
Edit: OK, I see that you propose using less dangerous strains for testing vaccine effectiveness. Good idea!
The idea in this post is not to use any safer strain as a vaccine, but to use it as a tool to speed up the development of other vaccines. If we can find a safer strain then we may be able to use it in a challenge trial which we can’t do with the normal dangerous strain for ethical reasons.
This is explored in more detail in my [1] reference above.
Hi Daniel,
When you first put up the idea, it seemed like your emphasis was on using the attenuated strain directly as a vaccine (and benefiting from its ability to propagate itself). This post suggests more to help test a conventional vaccine.
Could you comment on reasons for the change of approach?
Yes that is right. While the idea of using such a strain as a vaccine directly was the focus of my first post, this was controversial.
Even if you think it is too risky to use a natural attenuated strain as a vaccine, such as strain would be very useful as a tool to accelerate other vaccines. As I said in my first post how to use any such strain is not up to me, but if it can be used to get us to a vaccine sooner it is worth looking into.
If we are going consider doing a challenge trial we should at first make the effort to see if we can find a safer strain to use.
Possibly, but if its anything like the current virus then the mortality might still rise by orders of magnitude for older people, and people with reduced resistance to the disease could still die.
Which, if it's even less likely to cause symptoms is almost sure to happen if the virus is spread among the population.
Maybe, but the idea here is not to use any strain found as a vaccine directly, but as a tool to test other vaccines.
Instead of running a large Phase III field trial where we wait for people to get infected, we could use the safer strain to do a challenge trial where we deliberately try to infect the volunteers with the attenuated strain. This will give us an answer much sooner and avoid exposing many people to a vaccine that maybe doesn’t work.
The problem I think is that the step where people are infected with a (supposedly!) less harmful virus is just like testing a vaccine. It’s another substance to be tested on healthy individuals.
You can’t know the long term effects on the attenuated virus in a large group so the same caution and slow pace would have to be used to test that. First! All you did was go from testing one thing to testing two things (an attenuated virus and the vaccine).
If the attenuated virus could somehow (quickly) be deemed harmless in humans then I agree it could be a shortcut, but is that really possible?
Yes. The whole idea of looking for a natural attenuated strain is we can use the natural spread of this strain to prove it is safe. This is explored in a lot more detail in the other recent posts on my blog.
Yes it is possible, but the only way we will know is if we look. I am arguing we should look.
There are a number of issues with the approaches suggested by the author. In particular they’ve suggested an attenuated strain be spread by something similar to Pox Parties. Many might find these suggestions misguided and dangerous...
I have not suggested that "pox party" spread would be a good idea, just that it would be hard to stop if a natural attenuated strain was found and that this would influence the way the regulatory agencies viewed its licensing.
This is not really relevant to the idea of using an attenuated strain to accelerate the development of other vaccines. This would be done under controlled conditions where the attenuated strain would not spread.
Yes, the input I'd provide is that the writer doesn't have a particularly good grasp of virology, but people in this community are upvoting as if this is authoritative. People who write authoritative blog posts without expertise right now should consider themselves part of the disinfo problem.
I'll be concrete: the expected correlation between the cited deletions and pathogencity should be considered to approach zero. No evidence supports the hypothesis that single codon or single nucleotide deletions correlate with attenuation of strains. Furthermore, a basic understanding of molecular biology is all that's needed to dismiss the notion of a generalized correlation between observing deletions (or even insertions! or any general mutation!) and the pathologic outcome of infection with a virus. Biology doesn't support general claims of this nature. This is not a well-informed line of reasoning.
Even the title of the post is wrong! These are not "gene deletions." These are single codon deletions or deletions of a few nucleotides. No genes have been deleted!!
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I have been a tenured academic (Senior Lecturer) within the School of Pharmacy and Applied Science at La Trobe University, Australia teaching and researching in the areas of phage therapy (bacterial virology), pharmacy, environmental microbiology, bioinformatics and cancer.
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Since that seems easy enough to look up and call him out on if he were lying, I am inclined to believe that it's true.
I am inclined to believe his take on things over yours, given that the only info I can see immediately about you is your info blurb stating, "Damn kids, get off my lawn."
That said, I don't think anyone is treating what he says as gospel. But it's an interesting perspective.
At the risk of starting a flame war, lvs is mostly correct.
These are NOT whole gene deletions, they are nucleotide deletions. Genes are usually longer than 33 nucleotides, by my count the largest deletion he sees. For reference, that’s 11 amino acids, rule of thumb for an average protein length is about 200 amino acids.
The author highlights that many of these deletions are not codon aligned, which means that if you make this mutation, the resulting protein is highly unlikely to be translated properly. This is true, however devoid of context.
Most of the mutations are very rare. The highest frequency one occurs 400 or so out of at minimum 10,000 examples. Next one is 36/10,000. It’s possible these matter, it’s also possible these viral sequences are just low quality and the mutations are an artifact. It’s also possible that these mutations don’t actually matter to viral function for whatever reason. For example, if the mutation is at the end of a protein, it could screw up everything downstream but the protein before the mutation works just fine, i.e. mutation doesn’t matter. It’s just hard to tell with the data in this article.
The concept that maybe there are attenuated strains isn’t completely bogus, there is some thought a Singapore strain (with a massive deletion of 380 nucleotides, or 10x what we see here [1]) might be less infective. This is speculation and we don’t know yet, but that sounds maybe possible to me as a PhD Biochemist (if we’re gonna get all credential-spreading here).
However saying “The really interesting deletion mutations are those in the non-structural accessory genes. These are the genes that are likely to play an important role in pathogenicity and it would be expected that some of these mutations may make the virus less dangerous (attenuated).” Is really pushing it. I don’t know of any science to believe this one way or another, viruses are pathogenic for a variety of reasons, both accessory and core (whatever that means) proteins matter.
In short, given the uncertainty, we can hope there’s a less infectious strain out there, but this article provides precious little evidence to that effect.
Lvs is mostly wrong. I am not claiming any of these mutant strains are attenuated, I am saying that deletion mutants exists and we should investigate them to see if they are attenuated.
I am not providing evidence that an attenuated strain exists, just evidence that it could exist because the right type of mutations are found in SARS-CoV-2. The only way we are going to find out if there are attenuated strains is to look for them which as far as I know nobody is trying.
So let's remember how evolution works, shall we? Evolution selects for strains that reproduce the most and selects against ones with attenuated reproduction rates. That's the whole basis of biology. If you've observed a wild strain sequenced in a database, that should be considered direct evidence that it reproduces well enough to have been sampled as a representative isolate.
> as far as I know nobody is trying
Of course we are. We are deeply engaged in studying the key residues that mediate all aspects of viral infection, reproduction, and clinical pathology. That's another way of saying that an incredible number of researchers have dropped everything to study the genetic and molecular determinants of pathogenicity. Don't worry -- we are on it.
> we can hope there’s a less infectious strain out there
But how? We are able to surveil only a tiny fraction of genomes, relative to strains circulating. How would a "less infectious strain" ever emerge to the extent we'd have a high probability of sampling it? Darwin argues against this version of the idea.
Nevertheless, the OP is also wrong that it's faster to produce a live attenuated vaccine by finding one in the wild than it is to use tried-and-true viral vectors that are easy to reengineer, have previously received regulatory approval, and indeed are already in active trials (e.g. Oxford's adenoviral trial). It's also easier to trial heat-killed virus -- and indeed, that too is being trialed.
We can actually sample quite a large percentage of the strains out there if we actually try. COG-UK has already sampled 10,000 out of the few 100,000s in the UK without really trying.
Can you please stop saying I am arguing for things I am not arguing for? More time spent reading and less posting would improve your argument.
Yes, there are about 13k genomes deposited in the databses right now, but they are from all over the world -- not just the UK.
But yes, given infinite capacity it would be excellent to sequence from every single patient. It would be a dream, but sadly we're barely able to get enough cotton swabs and RNA isolation kits right now to run a basic qPCR for 10% of the population, let alone get all those viral genome sequences. It would be fascinating to have that many, of course.
You do realise that there are over a million positive samples sitting in freezers in the USA alone. You do know that a single modern DNA sequencing instruments can sequence more than 500,000 viral genomes in one 48 hour run?
It’s my understanding that viruses have a complex fitness function. If you think about it, the ideal virus spreads like crazy but doesn’t make anyone sick. If you make someone sick, you reduce the time they spend in the world so you spread less. Killing the host is definitely a no-no from the viral perspective, now you spread dramatically less. So viruses actually tend to evolve toward less intense disease. It’s why novel viruses kill so much more than viruses that have been around in the human population for a long time.
Forced evolution to lower infectivity is also a common way to make vaccines, so I’m quite certain one of the 100 or so vaccine efforts is trying this.
However, it’s not clear that the deletions in the OP are attenuating. If we end up with attenuated virus, it will likely come from a directed evolution experiment, not just getting lucky with a natural strain. Even such a natural strain would likely need to go through a fair bit of directed evolution to attenuated it to the point of harmlessness.
We don’t know if the deletions already seen in the current genome data set are attenuated or not as nobody has checked. I am suggesting that we check.
The bigger point I was making is that there are many deletion mutants out there. We should be looking for more and checking if they are attenuated or not. We might be very unlucky and find there are none, but that seems rather defeatist given we haven’t even tried.
I don’t know. It is a novel idea as it wasn’t possible more than 10 years ago to search. My personal experience is new ideas struggle to get any support until they are shown to be correct and then everyone says it was always obvious.
I don't know enough about any of it to consider arguments.
I apologize for the probably overly snarky comment. I woke up in the middle of the night and was having a hard time falling back to sleep.
I really wouldn't be surprised if the two of you are in more agreement than either of you realize. "Violent agreement" as I've sometimes heard it called.
Also for the record, I didn't downvote you. Just provided my response of why I was inclined to believe the author over you.
The citation does not refute or pertain to my statement. Yes, very specific mutations/indels can attenuate strains -- welcome to biology -- but the broad claim that the general observation of mutations/indels is somehow indicative of attenuated strains circulating in the wild is entirely unsupported and facially ridiculous.
I am not claiming any of this. I am saying that the right type of mutations exist in the SARS-CoV-2 genomes that attenuated strains COULD exist.
If they do I am arguing we should look for them rather than sitting in our armchairs coming up with possible reasons they don’t and so not even bothering.
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.
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...