[HN Gopher] High genetic barrier to SARS-CoV-2 polyclonal neutra...
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High genetic barrier to SARS-CoV-2 polyclonal neutralizing antibody
escape
Author : SubiculumCode
Score : 55 points
Date : 2021-09-20 20:02 UTC (2 hours ago)
(HTM) web link (www.nature.com)
(TXT) w3m dump (www.nature.com)
| eganist wrote:
| > Thus, optimally elicited human polyclonal antibodies against
| SARS-CoV-2 should be resilient to substantial future SARS-CoV-2
| variation and may confer protection against potential future
| sarbecovirus pandemics.
|
| So if I'm extrapolating correctly: any vaccine which can
| stimulate production of this or similar polyclonal antibodies
| should prove exceptionally difficult for the virus to overcome
| through evolutionary pressure.
|
| Anyone more intelligent than me on this topic able to help me
| understand how likely this is to come to fruition?
| gatronicus wrote:
| > should prove exceptionally difficult for the virus to
| overcome through evolutionary pressure
|
| Which is why we need gain of function experiments to accelerate
| this process and get ahead of the virus so that we are prepared
| for the eventual successful mutation.
| timr wrote:
| Gain of function experiments are not all the same. If you use
| an artificial selection approach (wherein selective pressure
| is applied to a huge library of random variations), then
| maybe.
|
| If you have labs picking-and-choosing what mutations to make
| (what usually happens), then no. That's just hubris. People
| stumble around in the dark, occasionally find a truffle, and
| pat themselves on the back for having such a great truffle-
| finding method.
|
| Even for good artificial selection systems, mutational space
| is so gigantic that it's hard to cover properly: not just the
| point mutations (i.e. converting one amino acid to another)
| but also insertions, deletions and transpositions. There's no
| artificial selection system I'm aware of that can
| recapitulate mutational space.
| gatronicus wrote:
| Which is why we need "intelligent design" to "help" the
| virus jump over this combinatorial problem.
|
| For example we can try spikes from different related
| viruses, or pick and choose various other tricks, like
| furin cleavage sites, for example like in this rejected
| 2018 EcoHealth coronavirus research DARPA grant proposal:
|
| https://twitter.com/JamieMetzl/status/1439989291858513929
| eightysixfour wrote:
| My, admittedly limited, understanding is that the immuno
| response to a natural infection is "broader" and targets more
| of the viral proteins ("we show that multiple neutralizing
| epitopes, within and outside the receptor binding domain (RBD),
| are variably targeted by human polyclonal antibodies") while
| the vaccine only introduces a single or small number of
| proteins for the immune system to respond to.
|
| If that is the case then we would want vaccines that include
| more mRNA instructions for creating more unique viral proteins
| to expand the number our immune system has been exposed to. I
| have no idea how challenging that is.
| gatronicus wrote:
| > I have no idea how challenging that is.
|
| Technically it's easy, Moderna already has multi target
| vaccines (for other diseases), one with 7 different targets.
| It can be as easy as literally creating 7 different vaccine
| liquids and then mixing them all in a single vial.
|
| The problem is deciding what to put in, what ratio, possible
| side effects, etc... Lots of combinations which can mean lots
| of expensive and slow clinical trials.
| CodeWriter23 wrote:
| I'm not an expert for sure though my read is the most expedient
| way out of this situation is plasma donation / transplantation.
| sarpeedo wrote:
| The issue with plasma donation is that the plasma contains
| antibodies which are temporary (6ish months). What we want is
| to elicit a response which produces memory B cells so the
| vaccinated individual can create their own antibodies. That
| can only happen through vaccination or infection.
| walterbell wrote:
| This Rockefeller University study is about blood/serum
| antibodies. It would be good to compare with the efficacy of
| nasal/mucosal antibodies in individuals who recovered from Covid
| infection, which could stop infection in the upper respiratory
| tract before reaching blood.
| tomrod wrote:
| Do they typically differ?
| walterbell wrote:
| From a recent BBC article on immunity,
| https://www.bbc.com/news/health-58270098
|
| _> There is a whole different suite of antibodies (known as
| immunoglobulin As) in the nose and lungs, compared with those
| (immunoglobulin Gs) that we measure in the blood. The former
| is more important as a barrier to infection. Natural
| infection, because it is in the nose rather than a jab in the
| arm, may be a better route to those antibodies, and nasal
| vaccines are being investigated too._
|
| Existing vaccines prioritize reducing the risk of illness
| after infection, rather than stopping infection in the first
| place. CDC updated their vaccine definition in Sept. 2021, to
| make this distinction clearer.
| polishdude20 wrote:
| Slightly off topic but are there any books one can recommend for
| understanding how this stuff works biologically?
| rolph wrote:
| any human immunology text [e.g.]
|
| https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7872131/
|
| molecular biology specific to coronavirus
| https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7131312/
|
| sars specific literature
| https://www.dovepress.com/understanding-the-molecular-biolog...
|
| https://www.nature.com/articles/s41579-020-00468-6?error=coo...
| walterbell wrote:
| For edutainment, there's a manga/anime called Cells at Work
| (https://mangarock.to/manga/1684/cells-at-work/first-
| chapter#...) whose final (June 2021) installment covers
| Covid-19. Includes a character called Killer T Cell,
| https://cellsatwork.fandom.com/wiki/Killer_T_Cell_(Squad_Lea...
|
| _> Killer T Cell is loud, obnoxious, and quick-tempered,
| resulting in rivalries with many cells. He also despises it
| when a non-white blood cell forms a friendship or relationship
| with one of his kind. As an immature thymocyte he went through
| training at Thymus school, where apprentice cells like himself
| learn to become Mature Thymocytes._
|
| Season 1 is streaming: https://www.netflix.com/title/81028791
| spywaregorilla wrote:
| So... sort of like the inverse of crop monoculture problems?
| elromulous wrote:
| Can someone who's more knowledgeable on the topic comment on the
| following: if natural immunity is more robust (as one would
| expect - the immune system is exposed to many spikes that way, as
| opposed to just the one), why don't we first immunize with the
| vaccine, and then expose people to the alpha variant, so as to
| develop a more robust (i.e. natural) response without the risk.
| Larrikin wrote:
| No vaccine is 100% effective and it is unethical to
| purposefully expose people to disease.
| gfodor wrote:
| Huh? The ethics of therapies that expose people to pathogens
| is complicated - many examples where exposure can be ethical
| as long as patient is aware of the risks. Arguably all
| vaccines fall into this ethical framework, and other
| immunizations which involve exposure.
| dcow wrote:
| Under what ethical framework?
| oskarpearson wrote:
| https://en.m.wikipedia.org/wiki/Human_challenge_study
| disambiguation wrote:
| yet this exactly what the pharma companies did during the
| clinical trials to confirm the vaccines' efficacy.
| sarpeedo wrote:
| Before Chicken Pox vaccination was invented people would hold
| "Pox Parties" to infect and immunize their children at a
| young age when risk of severe infection was low.
|
| https://en.wikipedia.org/wiki/Pox_party
| walterbell wrote:
| You would want the exposure to be nasal, so that would require
| a distribution system for inhalers containing the alpha
| variant.
|
| From the date of the first vaccine, until 2 weeks after the
| second vaccine, the immune system goes through many changes
| enroute to gaining protection from serious illness. It is
| recommended to avoid immune system stress, exposure to any
| pathogens (e.g. visiting hospitals), physical exertion, etc.
| during the 2 week period immediately after the first vaccine.
| If one is infected with anything earlier than 2 weeks after the
| 2nd vaccine, it will be recorded as an unvaccinated infection.
|
| Anyone (vaccinated, partially vaccinated or unvaccinated) who
| gets infected should immediately avail themselves of early
| treatment options, e.g. monoclonal antibodies (free and
| available in some states), upcoming antiviral tablets from
| Pfizer and Merck (in trials) or other therapeutics on the
| global market. Early treatment speeds recovery. Without early
| treatment, the graph of outcomes becomes complex.
| jpxw wrote:
| One reason amongst many others is the risk of a vaccine-
| resistant strain emerging. There'd be a pretty enormous
| evolutionary pressure for that outcome under those
| circumstances.
| sarpeedo wrote:
| I would point out fear of resistance is not a good reason to
| withhold vaccination or withhold care. Resistance will always
| eventually happen through evolution. What's important is that
| care is given when indicated.
| jopsen wrote:
| > the immune system is exposed to many spikes that way...
|
| Why not just develop anther vaccine or two? Wasn't the point
| with the mRNA vaccines that they would easily be tweaked to
| target another spike?
| angelzen wrote:
| While I am a complete neophyte, from what I learned so far
| immunity is non-linear. Antibody dependent enhancement and
| original antigenic sin come to mind. We can't just pile up
| vaccines and expect the effects to always be positive.
|
| https://en.wikipedia.org/wiki/Antibody-dependent_enhancement
|
| https://en.wikipedia.org/wiki/Original_antigenic_sin
| dougmwne wrote:
| I think the best answer is that we are just beginning to
| understand the immune response to infection and our vaccines
| and that the exact pathway to create the best, most protective
| and longest lasting immunity is still an area of active
| research. We just don't know enough at this point.
| sarpeedo wrote:
| Actually this is sort of a thing. For example the polio vaccine
| has a killed vaccine (analogous to spikes) and a live
| attenuated vaccine. The live vaccine has higher risk of side
| effects but provides more robust immunity.
|
| Vaccine schedules can be designed to give the killed version
| first for some immunity followed by live vaccine to provide
| more robust immunity.
|
| None of the COVID vaccines so far are live attenuated vaccines
| as far as I'm aware.
| eightysixfour wrote:
| This is interesting!
|
| > By aggregating VOC-associated and antibody-selected spike
| substitutions into a single polymutant spike protein, we show
| that 20 naturally occurring mutations in SARS-CoV-2 spike are
| sufficient to generate pseudotypes with near-complete resistance
| to the polyclonal neutralizing antibodies generated by
| convalescents or mRNA vaccine recipients
|
| So there are 20 known potential mutations which, when all put
| together, creates a virus that would be nearly completely
| resistant to existing vaccinations.
|
| > however, plasma from individuals who had been infected and
| subsequently received mRNA vaccination, neutralized pseudotypes
| bearing this highly resistant SARS-CoV-2 polymutant spike, or
| diverse sarbecovirus spike proteins.
|
| So, perhaps unsurprisingly, if you've had the virus and then
| received a vaccine, it appears that you have a very high level of
| immunity, including to future potential variants.
|
| I cannot pull the paper itself, did they test people who were
| breakthrough cases following vaccination (instead of infection
| then vaccination)?
| neurobashing wrote:
| I think we need the denominator here to put '20' into context.
| 20 out of 100 million possible mutations is, meh, I'll take
| those odds. 20 out of 100, well, that's something else
| entirely, isn't it.
| eightysixfour wrote:
| Edited because a correction by another user helps to clarify
| - it is not about the 20 mutations (which they created a
| mutant spike will all 20 of them!) though, it is more about
| what was and was not effective in defendening against the
| mutant spike.
| hadlock wrote:
| Coronaviruses are RNA viruses, so there's only a single
| copy of the genetic material, vs DNA with two copies. The
| result of RNA viruses is that they typically mutate at a
| much higher rate than DNA viruses. There are viruses that
| mutate faster than Coronaviruses, though.
| zmmmmm wrote:
| You chopped off a crucial part of the sentence that completely
| changes its meaning. The real sentence is:
|
| > By aggregating VOC-associated and antibody-selected spike
| substitutions into a single polymutant spike protein, we show
| that 20 naturally occurring mutations
|
| _Aggregating_ ... into a _polymutant_ spike. That means they
| put all 20 mutations together, each of them carefully selected
| from variants of concern or antibody attachment sites, into one
| single spike protein. Basically they created the most crazy
| supermutant resistent spike they could. The chance of which
| would be astronomically small in nature. And their conclusion
| is that even then a good dose of vaccine allows the body to
| eliminate it.
| eightysixfour wrote:
| Thanks, you're right and I've updated it to clarify.
|
| > And their conclusion is that even then a good dose of
| vaccine allows the body to eliminate it.
|
| That's not the same thing I got from the conclusion, it
| sounded like you needed to have a previous infection + the
| vaccine to clear it. What am I missing?
| robrenaud wrote:
| Did I misread? This super spike protein defeats merely the
| vaccinated, but not the naturally infected and then
| vaccinated, AFAIU.
| openasocket wrote:
| Additionally, could that even happen naturally? Since viruses
| only reproduce asexually, there's no way for multiple
| strain's mutations to somehow be combined together, right?
| throwawaylinux wrote:
| Polymutant just means it has multiple mutations, right? I'm
| not sure what crazy supermutant resistant is. Does it say
| anywhere that this was the most crazy supermutant resistant
| spike they could possibly create, or just that they combined
| some natural mutations?
| dougmwne wrote:
| No, their engineered mutant completely evaded normal
| immunity, but that was the purpose of the study, to find a
| virus that would, then test it against the super immunity
| discovered in some individuals. This super immunity was able
| to neutralize the virus, helping to support the idea that
| there is a special immunity in certain infected then
| vaccinated people that we should strive to replicate in
| future vaccines.
| twofornone wrote:
| >So, perhaps unsurprisingly, if you've had the virus and then
| received a vaccine, it appears that you have a very high level
| of immunity
|
| Why would someone get vaccinated post infection?
| dougmwne wrote:
| It is currently recommend, and studies, such as this one,
| show that you will be highly protecting yourself from future
| variants you would have otherwise had low immunity against.
| oskarpearson wrote:
| For the same reason most vaccines require two doses. And for
| the same reason some countries are planning or doing booster
| shots.
|
| Antibody levels drop rapidly after an infection, if they
| persist at all.
|
| Getting a vaccination after infection re-triggers the immune
| system and makes antibodies more likely to persist for
| longer.
|
| Reading up on this many months ago it seemed likely that
| natural infection plus a single vaccination would be
| equivalent to two vaccine shots.
|
| There was research about only needing to give one shot of
| vaccines like AstraZeneca to people with previous infection.
| It was considered too complex to manage, and the research as
| to efficacy wasn't finalised, so they stuck with two.
|
| Having had Covid, plus two shots of something like
| AstraZeneca is presumably somewhere in the region of a
| standard two-shot-plus-booster campaign.
|
| I don't really understand much of this paper, but given other
| comments it seems to be a reasonable idea.
| gameswithgo wrote:
| For more robust immunity, many people do this.
| ngvrnd wrote:
| it is in fact recommended.
| scoot wrote:
| But apparently not effective in all cases. A friend of
| mine in their early 20s has Covid a second time, having
| been vaccinated after their first infection.
|
| (To catch it once is unfortunate...)
| bsder wrote:
| A vaccine doesn't prevent you from catching a virus again
| --especially if you get a big bolus.
|
| It _does_ mean that your body is prepared to sweep the
| virus out faster and prevent it from spreading as far in
| your body.
|
| In computer terms, a vaccine reduces the _latency_
| between when your body gets a virus and when it reaches
| critical immune response to get the virus under control.
|
| So, for example, while you may get Covid in your nose,
| being vaccinated means that it doesn't get down into your
| lungs and heart and cause damage down there (the issues
| that cause most people to be hospitalized).
| rednerrus wrote:
| But these are outliers, right?
| amirhirsch wrote:
| I don't know why your comment bothers me so much, but...
|
| No, your friend didn't have COVID a second time after
| being vaccinated after their first infection. Especially
| lacking any clarification that they were in fact tested
| positive both times, you are merely contributing to noise
| on the internet.
|
| 1) "a friend of yours" is not a data point on which
| others should base their worldview (unless their
| testicles got huge and their fiance called it off, why
| even share?)
|
| 2) reinfection is rare
|
| 3) it is likely the first time they think they had covid,
| they weren't tested, and actually had the flu.
|
| Here is the CDC information on reinfection:
| https://www.cdc.gov/coronavirus/2019-ncov/your-
| health/reinfe...
|
| As of August 6, 2021, the CDC has nothing conclusive to
| say on the matter: "Cases of reinfection with COVID-19
| have been reported, but remain rare . "
|
| Anecdotes are noise, and I would encourage you to do no
| further research.
| xtorol wrote:
| Why wouldn't they?
| dnautics wrote:
| there are of course unknown risks associated with putting
| anything into your body. But it's probably still a good
| idea.
| bsder wrote:
| Because your immune system isn't guaranteed to pick up on the
| most relevant part of a pathogen.
|
| While lots of people got diseases like smallpox and measles
| only once, others would get them several times. The
| difference is what part of the virus your antibodies selected
| to attack.
|
| The spike protein seems to be both extremely important to
| SARS-CoV-2 and relatively unchanging.
|
| If your body creates antibodies to it, you will have immunity
| on par with the vaccines.
|
| If your body doesn't create antibodies to it, you have a
| mixed bag of immunity. Getting a vaccine buffs that up.
|
| Immune systems are very buggy learning systems. This is good
| from a _species_ survival perspective, but not always for a
| specific individual.
| dougmwne wrote:
| They only tested the plasma from people who were infected,
| people vaccinated with Pfizer, and people who were infected,
| then vaccinated.
|
| The 20 mutations they mention was a set of 20 mutations to a
| single spike protein that they then attached to a carrier virus
| to test plasma neutralization. It's not the full space of
| possible mutations that could cause immunity escape, but it is
| one that they found with a plausibly low number of mutations
| that it could occur in the wild that would result is almost
| total escape for vaccinated or previously infected.
|
| An interesting result was that the infected then vaccinated
| individuals developed antibodies that targeted a very broad
| range of coronaviruses, including their engineered virus,
| delta, many other variants, and the original SARS.
|
| It's suggested that future vaccines could be engineered to
| produce this broad immunity.
|
| The immune system is almost terrifyingly complex.
| devin wrote:
| > An interesting result was that the infected then vaccinated
| individuals developed antibodies that targeted a very broad
| range of coronaviruses, including their engineered virus,
| delta, many other variants, and the original SARS.
|
| Glad you brought this up, but from what I understand this
| isn't actually all that interesting (read: surprising). mRNA
| vaccines target the spike protein because it's functional and
| well-conserved. Natural infection means your immune system
| sees many more proteins.
| dougmwne wrote:
| Yes, but natural infection did not produce this broad
| immunity in their samples, only infected then vaccinated
| developed this special kind of broad immunity. That is
| supprising in a way, that we could coax the immune system
| into producing a special kind of immunity that wouldn't
| otherwise be likely to occur naturally. It opens an area of
| research into what mRNA sequence or dosing regimen could
| reproduce this immunity for a future super vaccine.
| angelzen wrote:
| Natural infection was one event vs. natural infection +
| vaccine being two events separated by a time interval. It
| may be that we are stumbling upon a natural mechanism
| that makes recurring infections almost impossible past
| 2nd event.
| bpodgursky wrote:
| Given the... _possible_... origins of this virus, I hope they
| are being exceedingly careful about actually synthesizing a
| virus with all of these mutations at once.
|
| Or they stand a very high risk of creating and releasing the
| doomsday variant they are worried about in the first place...
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(page generated 2021-09-20 23:01 UTC)