
There are many SARS-CoV-2 strains with gene deletions - danieltillett
https://www.tillett.info/2020/04/28/there-are-many-sars-cov-2-strains-with-gene-deletions/
======
danieltillett
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-s...](https://www.tillett.info/2020/04/24/it-is-unethical-to-not-search-
for-an-attenuated-sars-cov-2-strain/)

~~~
dstroot
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
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.

~~~
aledalgrande
> Coronaviruses are easy to vaccinate against. They mutate very slowly.

Wait can you expand on that? I thought RNA viruses mutate very quickly?

~~~
totony
From what I understand, covid is a relatively small rna strand vs e.g. the flu
which makes significant mutation way more rare

~~~
rotexo
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_...](https://en.m.wikipedia.org/wiki/Influenza_A_virus#Structure_and_genetics)

[3] [https://translational-
medicine.biomedcentral.com/articles/10...](https://translational-
medicine.biomedcentral.com/articles/10.1186/s12967-020-02344-6)

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

~~~
learnstats2
From what I understand:

Gene deletions are expected to some extent as a result of natural mutations.

The author is hypothesising that there should already exist natural virus
particles ("in the wild") with key genes deleted that render it harmless to
humans, and that these harmless strains may also be spreading in the
population. We could possibly identify harmless virus particles with wide-
ranging testing of asymptomatic people, and statistically identify what genes
(or what parts of the genome) are important for disease.

The author's concept is that this would have potential as a vaccine. It's
similar in concept to the polio vaccine, or giving cowpox to prevent smallpox
infection.

In my opinion, the author is making several hypothetical leaps of logic that
don't make this feel like a workable plan.

The author proposes to test 50,000 people and use this to identify safer
strains: in my opinion that wildly underestimates what would be needed for
this to have a chance of working.

Since the virus looks to be harmless in the vast majority of people it
infects, it will be difficult and dangerous to distinguish strains that are
genuinely harmless.

~~~
danieltillett
First two paragraphs I have no issue with.

Third no. I am not arguing this at all.

Fourth is pure opinion.

Fifth the same, but as a counter argument sequencing 10,000 strains has found
69 candidate attenuation strains and that was without even trying.

Sixth no. It is actually quite easy to distinguish a harmless strain from a
normal pathogenic strain as we can use the high morbidity rate as a proxy for
danger.

~~~
throwaway2245
You've identified 69 _strains_ (assuming no errors or false positives)

Saying they are candidate attenuation strains is like saying sugar is a
candidate treatment.

[Edited after reconsidering, because it's worse than that:] Saying they are
candidate attenuation strains is like saying drinking bleach is a candidate
treatment. They are highly likely to still be extremely harmful.

~~~
danieltillett
Oh so brave to be using a throwaway account to attack someone. Do you
understand what the word candidate means? These 69 strains COULD be
attenuated, but until we actually check into this we don’t know. The only way
to find out is to actually investigate.

How could it possible be harmful to check the clinical history of the patient
that was infected with these deletion strains?

~~~
throwaway2245
So you're agreeing that my interpretation was correct.

~~~
danieltillett
No

------
noway421
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
It seems to be a work in progress. It might be worth sending them a bug
report.

------
cameldrv
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?

~~~
irjustin
> I have to say, I cannot understand why the idea of doing a challenge trial
> is controversial. If you are using healthy, young, volunteers who are
> observed and have good access to medical care, how could it be unethical?

I think the most prelevant is COVID-19, at full strength, still kills
seemingly healthy young people. The author mentions this in another article:

> The important question we have to consider is if it is ethical to
> deliberately expose even the young and healthy to the dangerous SARS-CoV-2
> virus when we know it could seriously injure or kill them.[0]

In this article, we potentially have a weaker strains on our hands that could
qualify as a fully ethical challenge trial that could accelerate the
development.

At the end of the day, challenge trials are Phase trials with less
restrictions in hopes of trading accuracy/rigor for speed.

Is it worth it? I don't know. I'm not knowledgeable enough to say one way or
another.

[0] [https://www.tillett.info/2020/04/24/it-is-unethical-to-
not-s...](https://www.tillett.info/2020/04/24/it-is-unethical-to-not-search-
for-an-attenuated-sars-cov-2-strain/)

~~~
cameldrv
If you can use a weaker strain and presumably get the same results, of course,
pick the safer option. However, if you can't, and people of sound mind are
volunteering for noble reasons, why wouldn't we do that?

Is it worth it? We've lost about 200,000 people worldwide just in the past
month from this disease. It's the leading cause of death in many countries. In
healthy young people (20s, no preexisting conditions), the fatality rate is
well under 0.1%.

If the vaccine doesn't work at all, which is unlikely, you'd expect 0-1 deaths
from the trial. To save perhaps a single life of a willing, altruistic
volunteer subject while hundreds of thousands die every month, and the world
is confined to its homes is to me, utter insanity.

Do we tell firefighters to not go into a burning building to save lives, even
if there is considerable risk?

If this is the state of medical ethics, the field should be torn down and
rebuilt. To deny approval for a challenge trial with volunteers is mass
murder.

~~~
irjustin
I've just learned in my thread above with the article author that there is no
concept of exposing people post vaccination Phase II or III to see if it was
effective. We normally wait a long time to see if people get sick. If it's
effective them we go to mass rollout.

That's where the huge time savings is.

My previous statement of "it's a Phase trial with less restrictions" isn't
true. It's making the feedback loop tighter.

With this new knowledge, I'm relatively convinced we should be doing a
challenge trial to speed up the roll out.

~~~
danieltillett
There is a concept of using a challenge trial, only it can only be used when
the risk to the volunteer is very low.

Challenge trial are used in trials on things like the common cold. SARS-CoV-2
is considered too dangerous to use in a challenge trial.

------
CyanLite4
“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.

------
pazimzadeh
> 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
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.

~~~
waterhouse
Ignorant question: is it possible to have something resembling a human immune
system without a full body? One level would be just a container of liquid with
live white and red blood cells, possibly connected to an oxygenation machine;
you would insert some infected cells, then sample it or otherwise observe it
periodically. If you need lung tissue or other non-blood cells for the virus
to infect, then having disembodied blobs of flesh with blood vessels, being
fed nutrients and oxygen, would be the next level.

Of course, if this testing infrastructure doesn't already exist, I imagine
creating it would be too slow to help with this particular plague.

~~~
nardi
I know you prefaced your ignorant question with "Ignorant question:", and I
don't think it's wrong to ask questions of experts on HN. (That's one of the
best things about this site!) However, I'm downvoting you anyway because,
despite that preface, you seem to be falling into the trap of a smart geek in
one field vastly (vastly!) oversimplifying the complexities of another field,
and acting as if all we needed to solve this problem was for someone like
yourself to come up with this fantastic idea.

No, you can't approximate a human immune system with red and white blood cells
in a container of liquid. No, adding some other cells in there won't help. If
that were effective, we'd be doing it already. You are either overestimating
your own ingenuity or underestimating the ingenuity of tens of thousands of
scientists, doctors, and engineers.

~~~
gbear605
Alternatively, OP could be answered by someone saying that this is already
being done. And apparently it is in some form, according to a sibling comment
of yours. Maybe that’s incorrect, but you chose the least charitable
interpretation instead of “Hey, here’s an idea. Why doesn’t it work like I
think it would, and does it have any uses in any form?”

~~~
nardi
The question was, "is it possible to have something resembling a human immune
system without a full body?"

The answer is no, for somewhat obvious reasons. The human immune system
involves many organs and tissues and cells working together in very complex
ways.

And I think your charitable interpretation is quite a bit too charitable. OP
did not say anything like "why doesn't it work like I think it would".

------
FHermisch
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.

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

~~~
bhickey
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.

------
voz_
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
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.

------
laurensr
Luckily enough we can detect gene deletions using our Office suite's
spellcheck: [https://xkcd.com/2298/](https://xkcd.com/2298/)

------
Gatsky
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
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
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
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
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.

~~~
danieltillett
No you don’t if you choose the right attenuated strain, but even if you
decided for some insane reason that you had to test the vaccine with a
pathogenic strain you do this after you have shown that the vaccine protected
the vaccinated person from the attenuated strain.

~~~
Gatsky
How do you know you’ve chosen the right attenuated strain?

------
wuxb
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
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
Sure you could, via intentional infection by cultivated strains.

------
pmoriarty
_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-
sci...](https://www.latimes.com/science/story/2020-03-05/chinese-scientists-
say-second-coronavirus-strain-more-dangerous)

[3] - [http://virological.org/t/response-to-on-the-origin-and-
conti...](http://virological.org/t/response-to-on-the-origin-and-continuing-
evolution-of-sars-cov-2/418)

[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

~~~
danieltillett
While this is true, this has absolutely nothing to do with my post. You seem
motivated enough to understand this topic in some depth so I think you would
benefit from reading through all my posts on this topic and thing carefully
about what I am arguing.

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

~~~
thinkingemote
It does. Users need to be over a certain age and/or have themselves enough
karma to downvote.

~~~
dang
Age doesn't affect it. You just need > 500 karma.

------
test6554
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
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.

