8 ms·

Sadly, note that the study talked about here [1] is investigating the effect of the N501Y mutation, not the more worrying E484K mutation found in the South Afri

Sadly, note that the study talked about here [1] is investigating the effect of the N501Y mutation, not the more worrying E484K mutation found in the South African 501.v2 strain that likely does escape antibody drugs and reduces neutralization by convalescent sera from past infections. [2] [1]: https://www.biorxiv.org/content/10.1101/2021.01.07.425740v1 https://www.biorxiv.org/content/10.1101/2021.01.07.425740v1 [2]: https://www.biorxiv.org/content/10.1101/2020.12.31.425021v1 https://www.biorxiv.org/content/10.1101/2020.12.31.425021v1

pageandrew 6y ago
Does the 501.v2 strain resist vaccine antibodies as well, or only things like the antibody cocktail / convalescent plasma therapy?
- whoisburbansky 6y ago
  The first paper describes the effect of mRNA based vaccine derived serum on both variants, showing that both variants are affected about equally by the vaccine, if I’m not horribly mistaken?
  - alevskaya 6y ago
    The first study is only studying the effect of the N501Y mutation as found in several emergent strains, not the E484K mutation.
    - whoisburbansky 6y ago
      Yes, sorry, I phrased that badly. I meant N501 and Y501 when I said both variants here.
- alevskaya 6y ago
  What I meant by sera above was general adaptive immunity. It's likely to partially resist past immunity from both vaccines (esp. from the spike-only vaccines: moderna, pfizer, etc) and natural infections from older strains. We'll probably know a lot more about it soon, but we may need to update our vaccines to include this mutant class.
whoisburbansky 6y ago
Am I reading the second paper correctly when I say this was conducted on a sample size of 11, and they found that the E484K mutation had saw no reduction in neutralization in some of those subjects? I’m trying to get a better sense of the numbers involved to figure out how much credence to lend to the dangers posed by the second mutation.
- alevskaya 6y ago
  It's unlikely to _completely_ escape immunity - humans will raise antibodies against different regions of the spike protein, but it does seem to confer a pretty significant average resistance to patient sera. There's another study looking specifically at several different monoclonal antibodies against this mutation at: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7723407/ https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7723407/
  - whoisburbansky 6y ago
    When you say average here, is that in the sense of average resistance over time for a given patient or average resistance across a population? The paper seemed to imply a great deal of heterogeneity in individual responses to the variant, so significant average would just be something like part of the population affected very badly, another part not at all, vs everyone affected mildly?
    - alevskaya 6y ago
      Averaged over a population - some people will have resistant sera and others not depending on the parts of sars-cov-2 targeted by their polyvalent antibody response. Note that this is only looking at antibodies, not T-cell responses... so the clinical consequences are harder to predict, but it's certainly a bit concerning.
      - whoisburbansky 6y ago
        Ah, I see. Thanks, that clears things up quite a bit. It’s potentially mildly bad news but not the end of the world, is what it sounds like then.
f430 6y ago
> does escape antibody drugs and reduces neutralization by convalescent sera from past infections what does this mean in plain words? this SA variant has a totally new evasion system? what exactly are we dealing with here? what causes it to rapidly mutate like this?
- esyir 6y ago
  It's a virus. Mutation to avoid detection is par the course. Essentially, each replication means mutation, and over time, variants emerge. Think of why you need a seasonal flu vaccine and not one flu vaccine.
- dnautics 6y ago
  Viruses are typically rapidly mutating so you should consider them to be a fuzzy statistical ensemble around the "official" sequence, even in one patient. Therefore these viruses can facilely jump over hills in the gradient descent of optimization; but keep in mind optimization is not just a one-factor thing. If you are interested in this the keyword is "viral metagenome" An E to K mutation converts a surface negative charge to a surface positive charge. So if your antibodies were expecting a negative charge and therefore putting positive charges near that place when they attach to the virus, the polarity on the mutant has now shifted and the antibodies will be repelled from the mutant virus.
  - Erlich_Bachman 6y ago
    > Therefore these viruses can facilely jump over hills in the gradient descent of optimization It warms to see that the similarities of some aspects of biological life to the current AI/ML terms has entered the lexicon, well at least on HN crowd. The fact that it makes a lot of sense to use those terms hints that we might indeed be on the right track to building AGI and understnding the life itself in general.
    - quonn 6y ago
      How is there gradient descent or even a gradient in biological mutations? If anything there could be an analogy to undirected trial & error as in genetic algorithms.
dnautics 6y ago
An N to Y mutation is associated with tighter specificity in binding protein protein interfaces. An E to K mutation is changing the surface charge from negative to positive so it shouldn't be surprising that it reduces antibody's ability to recognize, assuming it's in the most recognized pocket. Hopefully this will be a relatively easy cut and paste into the existing vaccine cassette if it turns out to spread really widely.
- JamesBarney 6y ago
  I'm far more worried about the FDA and logistics than technical limitations. Even if you could make this fix in a day, it'll take months to get FDA approval, and then you still have to manufacture and distribute it. And by that time the populous will have gotten immunity the old fashion way.
  - dnautics 6y ago
    Indeed. And the likelihood of escape are worse the greater the infected population x time to new vaccine. I'm increasingly worried that covid-19 is the slow loris of viruses. Too slow and mild to warrant panic-mode measures (I don't mean lockdowns), just gonna be an annual millimation of the population.
    - howlgarnish 6y ago
      Aren't we in panic mode measures already? I'm not sure there's much more most countries can realistically implement even if there's a 10x more lethal variant.
      - meddlepal 6y ago
        I think Parents point was that eventually we will have to give up on panic mode and accept deaths from this each year.
      - the8472 6y ago
        During initial containment china welded apartments shut and organized essentials deliveries by dedicated couriers for each city block. And then there's the option of military-enforced cordons. There are multiple levels of panic left untapped.
jb1991 6y ago
I wonder why it says: > works against a key mutation in the highly transmissible new variants of the coronavirus discovered in Britain and South Africa
- dmix 6y ago
  Both the South African and UK variant seem to be under the name 501Y.V2 but the South African version has a mutation not seen in the UK strain: > The variant in South Africa carries two other mutations in the spike protein (E484K and K417N, among others) which are not present in the U.K. strain This three day old article also anticipated this study results: > While scientists believe the U.K. variant is not likely to affect the efficacy of the vaccines currently being rolled out in the West, there is more uncertainty regarding the other strain. https://www.cnbc.com/2021/01/06/south-africa-covid-strain-a-guide-to-what-you-need-to-know.html https://www.cnbc.com/2021/01/06/south-africa-covid-strain-a-... I’m guessing they are both of the same “strain” but of different “variant”. But I don’t know enough about how virus taxonomy works to validate that. Sounds like two levels of mutation...
mvanaltvorst 6y ago
Say that Pfizer were able to simulate 50 possible mutations and put all of them into a single vaccine, would there be any risk that the antibodies could interact with each other in some way that makes the vaccines less effective? Also another scenario: say that we get yearly Covid shots that contain the latest strains, would these accumulate over the years and start interacting with each other?
- Retric 6y ago
  As I understand it, the second isn’t an issue so 50 vaccines over 50 years would be fine, that’s how seasonal flu vaccines are done. The first is mostly a question of how similar they are. Best case original vaccine covers all strains without modification, worst case you need 50 different vaccines. But the most likely combination is a mix where you might need say 5 vaccines, each of which over an overlapping subset of the 50 strains to various degrees of effectiveness.
  - danarmak 6y ago
    The immune system presumably has a limited capacity of circulating antibodies. By introducing new antibodies, do we reduce the amount of previous antibodies, and does this reduce their immune response? Is there a concept or metric of "antibody dilution"?
    - Retric 6y ago
      Antibody production ramps up and down rapidly, it’s memory cells that get altered by vaccines. https://en.wikipedia.org/wiki/Immunological_memory https://en.wikipedia.org/wiki/Immunological_memory That said the immune system is extremely complex, but here is a simplified version, which gives a reasonable overview: https://microbenotes.com/cells-of-the-immune-system/ https://microbenotes.com/cells-of-the-immune-system/
    - dannyw 6y ago
      While correlation is not causation, I find it interesting that the human immune system only remembers the common cold and seasonal influenza for several months, but diseases like the polio for much longer. https://biology.stackexchange.com/a/21802 https://biology.stackexchange.com/a/21802
TheRealSteel 6y ago
Does this mean there's now a variant that is immune to all the vaccines, and we're basically back at square one with the pandemic?!?! :( or am I misunderstanding? Is it still protected against from mRNA vaccines, but just not prevented by immunity from past infections? I have no knowledge of biology whatsoever.
- mckirk 6y ago
  From what I've gathered, it's more like: It's likely that the vaccine will have reduced efficacy (seen over the whole population) against this new strain. That's because your immune system essentially learns to recognize a random part of the virus, and if it ends up "training" itself using that part of the spike protein that's changed in this strain, it won't detect the virus.
- graeme 6y ago
  Not square one. It’s unlikely there would be 0% efficacy. But it could be less. But also not square one because it takes literally a day to redesign mrna vaccines for new variants. Then hopefully they can be approved faster the second go and manufactured/distributed more quickly. But I’d say all northern hemisphere countries should do their best to focus on local elimination in summer 2021. Most of europe had it in reach summer 2020 but decided to reopen early and keep the virus at a low level. That was an abject failure. It probably only would have taken another month of heavy restrictions to eliminate. The mutations we’re seeing in the winter of high case volumes caution against doing another cycle like this.
  - FuckButtons 6y ago
    That was very much the opinion of the immunologists I have been reading the opinions of recently. Giving this virus opportunity to mutate through allowing circulation is playing with fire next to a dynamite factory.
  - TheRealSteel 6y ago
    Great, thanks for the info. mRNA tech really is amazing!! I agree. Everywhere should've pursued elimination strategy like Australia and New Zealand, and even at this late stage would be the best option.
partingshots 6y ago
For the vaccine to lose effectiveness, the mutation would have to drastically alter the spike protein of the virus. This is effectively impossible as the virus is dependent on a functioning spike protein in order to infect cells, and the machinery involved with the mechanics of the spike are extremely delicate. Errant mutations that would cause compositional changes to the shape of the protein are almost guaranteed to cause functional failure. Using terminology, this is what we call a highly conserved area. In both cases for the South African or UK strain, if you take a look at the areas where mutations have occurred, you’ll see that the code responsible for generating the spike protein is basically completely unaffected. This will generally hold true for any successive future strains.
- enchiridion 6y ago
  While that may be true, I think that scale plays a role here. The ancestors of this virus were bouncing around between a relatively small set of humans and animals for a while before becoming SARS-CoV-2. Now with a significant portion of the world infected, it does not seem unreasonable that it would mutate. Although at that point it probably would not be considered the same virus anymore.
- deleted 6y ago
  [deleted]
- hn_throwaway_99 6y ago
  This doesn't make much sense to me, given that coronaviruses, with spike proteins, have existed for eons, and humans have had lots of time to build up immunity to previous coronaviruses (ones that cause colds, for example). So there was something about the Covid-19 coronavirus spike proteins that was different enough where it didn't look like "familiar" coronaviruses, so I see no reason why it couldn't evolve further to evade whatever antibodies humans are able to build up to the vaccines.
  - sudosysgen 6y ago
    You can make multiple spike proteins that target the same receptor. This generally happens when a virus from another animal (and thus with a slightly different version of the receptor) adapts to humans. Basically, a gradient descent from a very different starting point ending up in a different local minima. The question is, is the spike protein at a local minima (very probably quite close to it), and could it jump to another local minima then? Most likely not. It's possible it will evolve to make our antibodies slightly less effective, likely as a trade off for infectiousness, but incredibly unlikely the spike protein would evolve to be unrecognizable to our immune systems. Historically, this doesn't happen all that often, except for viruses with chronic infections over years that can do a deeper search over the gradient, but even then it generally takes years to decades.
ksk 6y ago
The pfizer vaccine also elicits T Cell response/cell mediated immunity. I'm guessing there are a few more studies in the pipeline..
zebrafish 6y ago
Discussion of [2] on /r/covid19: https://www.reddit.com/r/COVID19/comments/kqz7y5/comprehensive_mapping_of_mutations_to_the/ https://www.reddit.com/r/COVID19/comments/kqz7y5/comprehensi...

pageandrew 6y ago

Does the 501.v2 strain resist vaccine antibodies as well, or only things like the antibody cocktail / convalescent plasma therapy?

whoisburbansky 6y ago
The first paper describes the effect of mRNA based vaccine derived serum on both variants, showing that both variants are affected about equally by the vaccine, if I’m not horribly mistaken?
- alevskaya 6y ago
  The first study is only studying the effect of the N501Y mutation as found in several emergent strains, not the E484K mutation.
  - whoisburbansky 6y ago
    Yes, sorry, I phrased that badly. I meant N501 and Y501 when I said both variants here.
alevskaya 6y ago
What I meant by sera above was general adaptive immunity. It's likely to partially resist past immunity from both vaccines (esp. from the spike-only vaccines: moderna, pfizer, etc) and natural infections from older strains. We'll probably know a lot more about it soon, but we may need to update our vaccines to include this mutant class.

whoisburbansky 6y ago

Am I reading the second paper correctly when I say this was conducted on a sample size of 11, and they found that the E484K mutation had saw no reduction in neutralization in some of those subjects? I’m trying to get a better sense of the numbers involved to figure out how much credence to lend to the dangers posed by the second mutation.

alevskaya 6y ago
It's unlikely to _completely_ escape immunity - humans will raise antibodies against different regions of the spike protein, but it does seem to confer a pretty significant average resistance to patient sera. There's another study looking specifically at several different monoclonal antibodies against this mutation at: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7723407/ https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7723407/
- whoisburbansky 6y ago
  When you say average here, is that in the sense of average resistance over time for a given patient or average resistance across a population? The paper seemed to imply a great deal of heterogeneity in individual responses to the variant, so significant average would just be something like part of the population affected very badly, another part not at all, vs everyone affected mildly?
  - alevskaya 6y ago
    Averaged over a population - some people will have resistant sera and others not depending on the parts of sars-cov-2 targeted by their polyvalent antibody response. Note that this is only looking at antibodies, not T-cell responses... so the clinical consequences are harder to predict, but it's certainly a bit concerning.
    - whoisburbansky 6y ago
      Ah, I see. Thanks, that clears things up quite a bit. It’s potentially mildly bad news but not the end of the world, is what it sounds like then.

f430 6y ago

> does escape antibody drugs and reduces neutralization by convalescent sera from past infections what does this mean in plain words? this SA variant has a totally new evasion system? what exactly are we dealing with here? what causes it to rapidly mutate like this?

esyir 6y ago
It's a virus. Mutation to avoid detection is par the course. Essentially, each replication means mutation, and over time, variants emerge. Think of why you need a seasonal flu vaccine and not one flu vaccine.
dnautics 6y ago
Viruses are typically rapidly mutating so you should consider them to be a fuzzy statistical ensemble around the "official" sequence, even in one patient. Therefore these viruses can facilely jump over hills in the gradient descent of optimization; but keep in mind optimization is not just a one-factor thing. If you are interested in this the keyword is "viral metagenome" An E to K mutation converts a surface negative charge to a surface positive charge. So if your antibodies were expecting a negative charge and therefore putting positive charges near that place when they attach to the virus, the polarity on the mutant has now shifted and the antibodies will be repelled from the mutant virus.
- Erlich_Bachman 6y ago
  > Therefore these viruses can facilely jump over hills in the gradient descent of optimization It warms to see that the similarities of some aspects of biological life to the current AI/ML terms has entered the lexicon, well at least on HN crowd. The fact that it makes a lot of sense to use those terms hints that we might indeed be on the right track to building AGI and understnding the life itself in general.
  - quonn 6y ago
    How is there gradient descent or even a gradient in biological mutations? If anything there could be an analogy to undirected trial & error as in genetic algorithms.

dnautics 6y ago

An N to Y mutation is associated with tighter specificity in binding protein protein interfaces. An E to K mutation is changing the surface charge from negative to positive so it shouldn't be surprising that it reduces antibody's ability to recognize, assuming it's in the most recognized pocket. Hopefully this will be a relatively easy cut and paste into the existing vaccine cassette if it turns out to spread really widely.

JamesBarney 6y ago
I'm far more worried about the FDA and logistics than technical limitations. Even if you could make this fix in a day, it'll take months to get FDA approval, and then you still have to manufacture and distribute it. And by that time the populous will have gotten immunity the old fashion way.
- dnautics 6y ago
  Indeed. And the likelihood of escape are worse the greater the infected population x time to new vaccine. I'm increasingly worried that covid-19 is the slow loris of viruses. Too slow and mild to warrant panic-mode measures (I don't mean lockdowns), just gonna be an annual millimation of the population.
  - howlgarnish 6y ago
    Aren't we in panic mode measures already? I'm not sure there's much more most countries can realistically implement even if there's a 10x more lethal variant.
    - meddlepal 6y ago
      I think Parents point was that eventually we will have to give up on panic mode and accept deaths from this each year.
    - the8472 6y ago
      During initial containment china welded apartments shut and organized essentials deliveries by dedicated couriers for each city block. And then there's the option of military-enforced cordons. There are multiple levels of panic left untapped.

jb1991 6y ago

I wonder why it says: > works against a key mutation in the highly transmissible new variants of the coronavirus discovered in Britain and South Africa

dmix 6y ago
Both the South African and UK variant seem to be under the name 501Y.V2 but the South African version has a mutation not seen in the UK strain: > The variant in South Africa carries two other mutations in the spike protein (E484K and K417N, among others) which are not present in the U.K. strain This three day old article also anticipated this study results: > While scientists believe the U.K. variant is not likely to affect the efficacy of the vaccines currently being rolled out in the West, there is more uncertainty regarding the other strain. https://www.cnbc.com/2021/01/06/south-africa-covid-strain-a-guide-to-what-you-need-to-know.html https://www.cnbc.com/2021/01/06/south-africa-covid-strain-a-... I’m guessing they are both of the same “strain” but of different “variant”. But I don’t know enough about how virus taxonomy works to validate that. Sounds like two levels of mutation...

mvanaltvorst 6y ago

Say that Pfizer were able to simulate 50 possible mutations and put all of them into a single vaccine, would there be any risk that the antibodies could interact with each other in some way that makes the vaccines less effective? Also another scenario: say that we get yearly Covid shots that contain the latest strains, would these accumulate over the years and start interacting with each other?

Retric 6y ago
As I understand it, the second isn’t an issue so 50 vaccines over 50 years would be fine, that’s how seasonal flu vaccines are done. The first is mostly a question of how similar they are. Best case original vaccine covers all strains without modification, worst case you need 50 different vaccines. But the most likely combination is a mix where you might need say 5 vaccines, each of which over an overlapping subset of the 50 strains to various degrees of effectiveness.
- danarmak 6y ago
  The immune system presumably has a limited capacity of circulating antibodies. By introducing new antibodies, do we reduce the amount of previous antibodies, and does this reduce their immune response? Is there a concept or metric of "antibody dilution"?
  - Retric 6y ago
    Antibody production ramps up and down rapidly, it’s memory cells that get altered by vaccines. https://en.wikipedia.org/wiki/Immunological_memory https://en.wikipedia.org/wiki/Immunological_memory That said the immune system is extremely complex, but here is a simplified version, which gives a reasonable overview: https://microbenotes.com/cells-of-the-immune-system/ https://microbenotes.com/cells-of-the-immune-system/
  - dannyw 6y ago
    While correlation is not causation, I find it interesting that the human immune system only remembers the common cold and seasonal influenza for several months, but diseases like the polio for much longer. https://biology.stackexchange.com/a/21802 https://biology.stackexchange.com/a/21802

TheRealSteel 6y ago

Does this mean there's now a variant that is immune to all the vaccines, and we're basically back at square one with the pandemic?!?! :( or am I misunderstanding? Is it still protected against from mRNA vaccines, but just not prevented by immunity from past infections? I have no knowledge of biology whatsoever.

mckirk 6y ago
From what I've gathered, it's more like: It's likely that the vaccine will have reduced efficacy (seen over the whole population) against this new strain. That's because your immune system essentially learns to recognize a random part of the virus, and if it ends up "training" itself using that part of the spike protein that's changed in this strain, it won't detect the virus.
graeme 6y ago
Not square one. It’s unlikely there would be 0% efficacy. But it could be less. But also not square one because it takes literally a day to redesign mrna vaccines for new variants. Then hopefully they can be approved faster the second go and manufactured/distributed more quickly. But I’d say all northern hemisphere countries should do their best to focus on local elimination in summer 2021. Most of europe had it in reach summer 2020 but decided to reopen early and keep the virus at a low level. That was an abject failure. It probably only would have taken another month of heavy restrictions to eliminate. The mutations we’re seeing in the winter of high case volumes caution against doing another cycle like this.
- FuckButtons 6y ago
  That was very much the opinion of the immunologists I have been reading the opinions of recently. Giving this virus opportunity to mutate through allowing circulation is playing with fire next to a dynamite factory.
- TheRealSteel 6y ago
  Great, thanks for the info. mRNA tech really is amazing!! I agree. Everywhere should've pursued elimination strategy like Australia and New Zealand, and even at this late stage would be the best option.

partingshots 6y ago

For the vaccine to lose effectiveness, the mutation would have to drastically alter the spike protein of the virus. This is effectively impossible as the virus is dependent on a functioning spike protein in order to infect cells, and the machinery involved with the mechanics of the spike are extremely delicate. Errant mutations that would cause compositional changes to the shape of the protein are almost guaranteed to cause functional failure. Using terminology, this is what we call a highly conserved area. In both cases for the South African or UK strain, if you take a look at the areas where mutations have occurred, you’ll see that the code responsible for generating the spike protein is basically completely unaffected. This will generally hold true for any successive future strains.

enchiridion 6y ago
While that may be true, I think that scale plays a role here. The ancestors of this virus were bouncing around between a relatively small set of humans and animals for a while before becoming SARS-CoV-2. Now with a significant portion of the world infected, it does not seem unreasonable that it would mutate. Although at that point it probably would not be considered the same virus anymore.
deleted 6y ago
[deleted]
hn_throwaway_99 6y ago
This doesn't make much sense to me, given that coronaviruses, with spike proteins, have existed for eons, and humans have had lots of time to build up immunity to previous coronaviruses (ones that cause colds, for example). So there was something about the Covid-19 coronavirus spike proteins that was different enough where it didn't look like "familiar" coronaviruses, so I see no reason why it couldn't evolve further to evade whatever antibodies humans are able to build up to the vaccines.
- sudosysgen 6y ago
  You can make multiple spike proteins that target the same receptor. This generally happens when a virus from another animal (and thus with a slightly different version of the receptor) adapts to humans. Basically, a gradient descent from a very different starting point ending up in a different local minima. The question is, is the spike protein at a local minima (very probably quite close to it), and could it jump to another local minima then? Most likely not. It's possible it will evolve to make our antibodies slightly less effective, likely as a trade off for infectiousness, but incredibly unlikely the spike protein would evolve to be unrecognizable to our immune systems. Historically, this doesn't happen all that often, except for viruses with chronic infections over years that can do a deeper search over the gradient, but even then it generally takes years to decades.

ksk 6y ago

The pfizer vaccine also elicits T Cell response/cell mediated immunity. I'm guessing there are a few more studies in the pipeline..

zebrafish 6y ago

Discussion of [2] on /r/covid19: https://www.reddit.com/r/COVID19/comments/kqz7y5/comprehensive_mapping_of_mutations_to_the/ https://www.reddit.com/r/COVID19/comments/kqz7y5/comprehensi...