High genetic barrier to SARS-CoV-2 polyclonal neutralizing antibody escape
nature.com
nature.com
> 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)?
Why would someone get vaccinated post infection?
(To catch it once is unfortunate...)
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.
PCR tested positive both times, double jabbed in-between. You might not like the fact that it's possible, but that doesn't make it impossible.
1) You seem to be the one projecting a world view based off an anecdote. Chill.
2) Law of large numbers. A small percentage of a very large number is still a large number.
3) Here you go again with made up "facts" that aren't even anecdata.
> Cases of reinfection with COVID-19 have been reported
Seems pretty conclusive. They're referred to as "breakthrough cases", and not as rare as you seem to believe. What's more important is that the risk of hospitalization and death in breakthrough cases is considerably reduced.
> I would encourage you to do no further research
I would encourage you to do more. Making up "facts" to make a point does nothing to strengthen your position (whatever that may be – seems more like you just wanted to rant).
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).
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.
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.
> 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.
> 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?
Mutant ABC is the target. First Mutant A becomes the predominant strain. There might be some Mutant AB or AC in the population, but the controlling factor is currently Mutant A.
Eventually, Mutant A therapies/vaccines are introduced and Mutant A starts to lose its hold. Mutant AB isn't treated by the new treatments (or they're less effective, or Mutant AB goes undetected longer, etc.). Mutant AB becomes king of the hill. Repeat with Mutant ABC.
All this would assume that there's no Mutant B or Mutant BC or Mutant AC that increases in prevalence. All the mutations would have to build up over time or occur simultaneously by coincidence (or you could get a combination).
It's just basic evolution - organism follows the niche. We have a hard time recognizing it because generation turnover is so rapid. Instead of taking ~30 years for 2.5 offspring, it's a few days for millions of offspring.
I don't think mode of reproduction matters much when we're talking at this scale. While the virus creates stable clones across generations, I would think they're more susceptible to mutations and any viable mutation is quickly amplified exponentially. Just like the old high school bio experiment to demonstrate antibiotic resistance, only your respiratory mucus membranes are the medium. Those bacteria reproduced asexually.
If the cell is infected by multiple viruses, sometimes there's crossover where the instructions for one get mixed with the instructions for another. So, yes, multiple mutations can end up being combined of they infect a single individual.
It actually doesn't even have to be the same virus. This is how many zoonotic diseases develop -- take a piece of a virus that can attack humans and combine it with a different virus that doesn't attack humans.
Natural immunity targets far more locations than just the spike. Whereas the Pfizer vaccine only targets that spike.
So it presents a scenario with crippled natural immunity vs the full capabilities of the mRNA vaccine.
Which means in this "super mutant" scenario, the mRNA will always need natural immunity be effective, but natural immunity will only need vaccination if both the spike is mutated as described, and if non-spike targets are also mutated to be resistant.
Which is far more unlikely than the already unlikely "super mutant" spike.
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.
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.
Or they stand a very high risk of creating and releasing the doomsday variant they are worried about in the first place...
(For the record, if spike proteins were themselves in any way harmful to life on their own, Moderna and Pfizer wouldn't be the primary vaccine vendors for the US right now.)
I think it's fairly well accepted that they can cause myocarditis [1], which has killed some [2]. Better than getting the virus, but they appear to be capable of harm. I've naively wondered if the young men are getting jabbed in veins, rather than muscle tissue.
1. https://www.cdc.gov/coronavirus/2019-ncov/vaccines/safety/my...
Approval doesn't mean absolute safety, since that's absolutely impossible to achieve. This is considered acceptable (as shown by the CDC page listing it as a risk), since an actual infection is worse, for most.
> 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.
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?
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.
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.
The human adaptive immune response is massively parallel, and you can liken it to multiple progressive selection rounds for antibody candidates. As such, it is intuitive that this process would create a set of antibodies that targets not just a single antigen in multiple ways, but multiple antigens in multiple ways, resulting in more robust response (see polyclonal b-cell response)
As for the latter, the issue, as already stated, is in understanding the side effects and efficacy profiles of said vaccine. Clinical trials are long and expensive processes.
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.
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.
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://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...
> 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
https://www.nytimes.com/interactive/2021/08/10/us/covid-brea...
Minor live infections to build immunity is called variolation, it's a tactic that was used effectively historically against smallpox, but effectively got obsoleted by vaccination, which doesn't kill as many people.
Despite that, let's concede the vaccine does kill people: I'm not sure that's unethical though if more people end up dead because the population didn't quickly achieve immunity and stop the spread of the virus. There are a lot of ethical frameworks out there and in the US we are actually a majority rule so as a society we should generally be protecting the interests of the majority of people except in cases where it leads to sever oppression or breach of civil liberties. We are okay with the draft (forced risk of death) during times of war yet somehow when the enemy is unfamiliar in the form of a virus we aren't?
To confirm efficacy they gave the vaccine to half of a population likely to develop the disease naturally. Then they compared how many people for sick in each group. That's why testing took a year instead of 2 months, they have to wait for enrollees to get sick naturally.
If we ignore ethics, I guess we could get more nuanced efficacy information out of a small sacrificial population. But that is just not done. Not even during a pandemic.
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.
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.
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?
https://en.wikipedia.org/wiki/Antibody-dependent_enhancement