SARS-CoV-2 escape in vitro from highly neutralizing Covid-19 convalescent plasma (2020)
biorxiv.org
biorxiv.org
They expected 'co-incubation' might produce a variant that escapes prior immunity, as represented by convalescent plasma containing antibodies. They performed this co-incubation for "more than 90 days". They confirmed what they were looking for – what they were essentially trying to create: a virus with a novel collection of mutations that escaped immunity.
It was thus plausibly gain-of-function research, aka "Enhanced Potential Pandemic Pathogen research", on a virus whose danger level was far beyond "Potential Pandemic Pathogen". This research enhanced an actual pandemic pathogen.
Did it pass gain-of-function review? How secure was the lab it occurred in?
Note that some theorize the Omicron variant, now causing panic & fresh travel bans around the world, originated from a long-lived infection in an immunocompromised patient – where it had time, like in this experiment, to incrementally add many mutations over many generations. Omicron was perhaps even under the selective pressure of a similar external-antibodies treatment.
But aren’t we already used to this? From what I understand the flu vaccine is constantly updated and with multiple strains combined every single year. There’s a committee that already does this for influenza, it doesnt seem like to big deal to add one for covid?
I think science should be limited to scientists, and this is a good example. I am not a researcher but I know enough to know what I do not know. People saying that this "virus mutates quickly" is not only wrong but makes it scarier than it is.
Every virus mutates when it is in a new host. A variant is created when that mutation confers some survival benefit.
But COVID actually mutates MUCH SLOWER than influenza!!!!
https://pubmed.ncbi.nlm.nih.gov/33064680/
"Both viruses depend on a viral RNA polymerase to express their proteins, but only SARS-CoV-2 has a proofreading mechanism, which results in a low mutation rate compared to influenza."
https://www.astrazeneca.com/what-science-can-do/topics/disea...
"The average mutation rate of SARS-CoV-2 remains low and steady, and is much slower than other RNA viruses such as influenza viruses. Unlike coronaviruses, influenza viruses (which cause the flu) are prone to changes through processes called antigenic drift and antigenic shift.3,4"
The only thing that makes SARS2 a bigger problem that the flu is the R value, or how fast it spreads. Flu is between R1 and R2, while Delta was between R5 and R7.
So the issue is not one of mutations, but of spread. Vaccines do not stop the spread and that is a problem. Even when vaccinates you have no symptoms but you will catch the virus and create mutations.
A total worldwide lockdown, IMO, would have stopped this dead because of the low mutation rate. But unfortunately governments favored the economy over lives. And I also blame Fauci and Trump for not making enough N95 masks and Fauci actually discouraging their use in the beginning.
At this point it is with us forever since wildlife will continue to spread it. Eventually it will settle to a place where it kills X amount of people and we will be OK with it as we have become OK with the flu killing 30,000 to 70,000 people a year.
The GP asked a question, obviously out of a place of wanting to learn.
How else are new scientists produced if we don’t let non-scientists engage in science?
> because it seems like the virus mutates quickly
The problem is that there is too much misinformation floating around, some to claim the virus is fake or innocuous, some to claim that it's more scary than it is.
Anyway, I agree that it's good that non scientist participate in the discussion. It would be nice if the experts here can fix the error (preferably with links to the sources).
I'm not an expert in biology/medicine, so I can help very little here, but in other topics I can do more. [Nobody is posting about the Em-Drive recently, so I can't post my usual rant against it :( .]
Now, late 2021, it appears we are seeing more covid mutations than flu mutations.
How can this be? For one, we have massively more SARS-Cov-2 cases than flu cases. You could have the fastest mutating virus in the world but if it could only transmit to one host per year it would mutate slower than a virus which mutated 100x slower but had over a billion infections per year.
I believe you’ve committed the very error you warned against.
With flu vaccines we could do an annual vaccine production schedule as there was one big season in most countries. But with SARS-Cov-2 there is a wave cycle and the problem space gets trickier. Seems to be about four waves a year.
You cannot just say things like this without citing evidence. It is so frustrating. The flu virus IN VIRTO at any time will mutate faster because it does not have a mechanism to correct mutations like SARS2 does.
The second statement I posted was straight from Astra Zenica in 2021 so why did you pick the one you wanted and refute it just because it was old? Because you are lazy and just want to be right.
This is from OCTOBER 19, 2021, all you need to do was search. But I am just done with the internet, everyone is everything but no one is nothing. I am going to be nothing.
https://www.npr.org/sections/goatsandsoda/2021/10/29/1050465... "Six months into the pandemic, the virus seemed to be following the predicted course. "To date, there have been very few mutations observed," molecular biologist Peter Thielen at Johns Hopkins University told NPR in June 2020 for a story with the headline: "This Coronavirus Doesn't Change Quickly, And That's Good News For Vaccine Makers.""
“ Last month, Kistler and her colleagues at the University of Washington published a new metric to measure how quickly SARS-CoV-2 is evolving as it adapts to living inside humans. When Kistler first saw the value, she was shocked. "SARS-CoV-2's rate of adaptation is remarkably high right now," she says, "like roughly four times higher for SARS-CoV-2 than it is for seasonal flu."
But please, continue attacking people.
You perhaps missed this because you ignored my central point, which is that production of mutations is a result of mutability multiplied by transmission. SARS-Cov-2 transmission numbers dwarf typical flu caseloads.
The paper you cited only looks at mutability. The AstraZeneca article is an explainer with no new research. And it’s from February, pre-Delta.
(I'm guessing USA stats here?) I suspect Seasonal Flu had been involved in killing far more people per year; Flu tests were never administered to such a large % of people, esp in Summer.
I was in NYC through the first couple waves and in the beginning, we were arguing over droplet size and transmissibility. People were wiping everything down to avoid contagion. There was no real respiratory concern outside of being right up in someone’s face.
I honestly don’t think anybody knew, let alone a conspiracy, to convey bad information to the public. They just flat out didn’t know.
It wasn’t until further experimentation over the summer of 2020 that the primary means of transmission is through very fine respiratory action.
> The variant has a large number of mutations, of which some are concerning.[8] 32 mutations affect the spike protein, the main antigenic target of antibodies generated by infections and of many vaccines widely administered. Many of those mutations had not been observed in other strains.[9][10]
> The variant is characterised by 30 amino acid changes, three small deletions and one small insertion in the spike protein compared with the original virus, of which 15 are located in the receptor binding domain (residues 319-541). It also carries a number of changes and deletions in other genomic regions. Of note, the variant has three mutations at the furin cleavage site.[11] The furin cleavage site increases SARS-CoV-2 infectivity.[12]
See https://en.wikipedia.org/wiki/SARS-CoV-2_Omicron_variant
The "receptor binding domain" is the portion of the spike protein that actually binds to the ACE2 receptor the virus uses to get into our cells.
In contrast, Delta has 3 mutations in the RBD (https://asm.org/Articles/2021/July/How-Dangerous-is-the-Delt...) and it has 10 mutations affecting the spike protein (https://gvn.org/covid-19/delta-b-1-617-2/)
The problem with that is with a lot of the vulnerable population. This isn't "the flu".
The overall evolutionary path for the virus is most likely to be in the direction of higher infectivity and lower deadliness. Viruses don't tend to replicate in dead hosts, so, a virus that doesn't kill people is fitter evolutionarily than one which does. This means that, while the virus is certainly not going away, the risk eventually will.
This may take a long time, though. It may take decades.
Here is an article from New Scientist that says essentially the same thing, but in more detail: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7825868/
Edit: Fixed typos
o DNA is really complex to work with; designing proteins is harder when you don't have the luxury of being Nature itself and trying it out in vivo.
o You will have a PR problem of hilarious proportions. Virus genetic engineering research labs are a few points short of popular support at the moment.
Both are safe, but in the oral one the virus can go to another person and cause no problems, and then to another and cause no problems, and after like a year jumping hosts it can mutate and become dangerous. Now most of the the polio cases are caused by virus that mutated from the version of the vaccine. https://en.wikipedia.org/wiki/Polio_vaccine#Vaccine-induced_...
The number is much smaller that the number of cases before the vaccine, but it's concerning anyway. So they are trying to discontinue the use of the vaccine with the inactivated virus, but the other one is better when most of the population is not vaccinated. https://en.wikipedia.org/wiki/Polio_vaccine#Schedule
So ... probably the authorization and test necessaries to use a new vaccine with and attenuated virus are more difficult than a vaccine with an inactivated virus (or a vector virus, of mRNA, that also can't spread).
* So they are trying to discontinue the use of the vaccine with the weakened virus, but the it's better when most of the population is not vaccinated.
This make me feel that spreading it is better than not spreading it at this point. Luckily it is much more infectious.
Any lung infection will have a lasting effect (in survivors).
In lucky cases, pneumonia is caused by bacteria sensitive to antibiotics. If it's viral (flu, SARS/MERS/SARS-Cov-2 or anything else) or antibiotic resistant hospital bactery, that's basically it.
At the same time, COVID is also significantly more dangerous than Influenza for the older age groups. The two diseases are very different, but we still need to compare them to get an understanding of the actual dangers. We've always lived with the danger of communicable diseases. It's never going away. If we constantly bombard people with the risks of this particular disease, it will cause a lot of stress and anxiety, which is significantly associated with all-cause mortality.
[1] https://freopp.org/comparing-the-risk-of-death-from-covid-19...
The article you link does not claim that long term impairment is frequent. From the article:
> A UK study estimates that between 7% and 18% of people who had COVID-19 went on to develop some symptoms of long COVID that lingered for at least 5 weeks.
However, this study does not consider severity of symptoms. Someone with a persistent cough for 5 weeks after infection is considered to have “long COVID,” just as someone with massive loss of pulmonary function is considered to have “long COVID.” It also does not control for long COVID symptoms that are merely correlatory, e.g. insomnia. I had intermittent insomnia for the first few months of the pandemic, because I was afraid for the state of the world. Yet if I had contracted COVID in those months, I too could be considered a long COVID sufferer.
I have yet to see a study that estimates the prevalence of severe long-term symptoms causally stemming from COVID infections. My guess is that it’s vanishingly small; given the sheer number of COVID infections, it would be obvious to everyone if a sizable portion of them actually went on to develop severe long-term symptoms. If 7-18% of COVID infections actually resulted in the severe long COVID symptoms described in the article (e.g. “extreme fatigue, breathlessness, [or] difficulty concentrating”), it would be extremely evident on a societal level.
You do not have relevant acquaintances to confirm that anecdotally - numbers aside, as a real risk?
> it would be extremely evident on a societal level
For the cognitive aspect, I am not sure it could become so evident, given the already suboptimal situation. (If you live in a place where "all are bright", please let me know what that encouraging utopia is: I will relocate within the month.) This is not sarcasm or even irony: I believe that cognitive issues are ignored in many societies, and/hence a further decline will hardly be visible. Again, a few in my circle have noted that, but they just go on working as before. This friend of mine had an accident years ago, and started losing his "laser-like precision": he mentioned his concern with the director, who replied «You are simply getting older». I believe that the consideration of relative cognitive falls is very normally relegated to either passing episodes or normal ageing as revealed in natural jerks.
That seems like a weak counter-argument. If this was the case we'd be hearing, and reading, about it everywhere.
The poster was referring to post infection "long covid", and stated suspect that the number of actual cases of "infection caused consequences" could be small. Before, in priority, challenging that idea, the poster was asked whether he actually met acquaintances who were "normal" before infection, and claiming being dramatically hit many months after. This is to pose a preliminary point about the existence of the problem, before considering the magnitude - one black swan entails black swans exist. That was the scope. So, not really an argument (to the poster's full point).
> If this was the case we'd be hearing, and reading, about it everywhere
Hearing, it depends who you hear; reading, I think mention of long covid can be found with reasonable frequency. I submitted one of the divulgative articles in mid October ( https://news.ycombinator.com/item?id=28854321 ). Progress in the development of information leaves could "always" be faster and better.
>The mean (SD) age of survivors was 54.4 (8.9) years, 140 196 (56%) were male, and 197 777 (79%) were hospitalized during acute COVID-19
I would expect the prevalence of severe long-term symptoms to be much higher in a population that was predominantly hospitalized for acute COVID than in the general population. I could not find any stratification by age/risk group/vaccination status from a cursory look at the study, although maybe it’s buried somewhere.
I still have yet to see a study that assesses, given full vaccination, the risk of developing severe long-term symptoms for different risk groups (e.g. ages/comorbidities). This is the most relevant metric for easing restrictions, since acute symptoms for vaccinated individuals have already been shown to be on par with a flu. If chronic symptoms are nonexistent, then there’s no reason to not totally ease restrictions amongst highly vaccinated populations.
https://www.newscientist.com/article/mg25033403-400-long-cov...
The fact that most VOCs popped in areas with little to no vaccination coverage quite aligns with that.
For omicron the main hypothesis is it actually evolved in a severely immunocompromised HIV patient.
Edit:
This isn't exactly new[0] and it's also been witnessed for SARS-CoV-2[1]:
> These compilations of case reports indicate the need to identify whether certain forms of immunosuppression are associated with an increased risk of such multimutational escape patterns — for instance, specific cancers or specific therapies, such as the development of B-cell aplasia related to CAR T-cell or anti-CD20 therapy, prolonged use of glucocorticoids, long-term chemotherapy, or radiotherapy. Similarly, organ transplant recipients and those with untreated or poorly controlled human immunodeficiency virus infection may also have prolonged SARS-CoV-2 infection and could constitute a reservoir of divergent escape variants that can spread in the general community. Prolonged viral replication in the context of an inadequate immune response facilitates the emergence of immune-pressure escape mutations.[0]
I'd appreciate an actual counter argument, other than a poorly understood Marek disease analogy.
* Hiding this fact is a serious problem of the 'never name a mutation by a place' new WHO policy.
Considering that even the most highly vaccinated places on earth are shattering records of infection rates, it seems implausible that vaccinating the rest of the world would somehow fix this issue. The "most unvaccinated" places on earth are also some of the most populous, therefore a variant is most likely to arise there out of pure chance.
In this case, due to the large number of mutations, the prime suspect is an untreated HIV patient with a lingering infection, which is most likely to happen in the southern parts of Africa. It's not clear whether vaccines prevent lingering infection in such a case.
OP was suggesting intentionally limiting vaccination. If 'natural' immunity can also allow for antibody-evading mutations, than we get nothing from limiting vaccinations - my point exactly.
>Considering that even the most highly vaccinated places on earth are shattering records of infection rates, it seems implausible that vaccinating the rest of the world would somehow fix this issue.
We cannot make mutation never happen, but we can limit the damage by vaccinating more. This will help us gain time to get more effective medications.
No, that doesn't follow. Vaccines target a spike protein specifically, hence selecting for a variant that defeats that particular kind of immunity, making vaccines obsolete for those that need them the most. This is a hypothetical vaccine-escape variant, not this Omicron variant. We know nothing about its actual capability for vaccine-escape.
Natural immunity targets the whole virus, so whatever immune-escape such a virus evolves, it would have to be far more comprehensive to have a significant effect. We may or may not have that in this particular variant and we're still at the very beginning of that wave:
https://pbs.twimg.com/media/FFGNLl3XMAsNQXE?format=jpg&name=...
A virus avoiding spike antibodies would have an advantage whether these antibodies were 'natural' or not, so it's far from clear natural immunity wouldn't lead to the same mutations - all the VOCs hail from mostly unvaxed countries, which leads to the suspicion that it does.
Sure, the 'naturally immune' sick people having extra N-targeting antibodies would be in an advantage vs the virus, but the cost of that is having a real corona infection earlier on, with all the risk simply being frontloaded.
* EDIT: the Chinese vaccines are inactivated virus vaccines. One wonders whether they fare better or worse vs this variant. Then again, maybe this variant will fail to transmit effectively and will just kill itself off like Beta did.
> Sure, the 'naturally immune' sick people having extra N-targeting antibodies would be in an advantage vs the virus, but the cost of that is having a real corona infection earlier on, with all the risk simply being frontloaded.
It's not a binary, when people get vaccinated and then infected (or vice versa), they do develop broader immunity. Frontloading the risk of infection versus vaccination may well be justified in the young and healthy population, but that opinion has been ostracized from the mainstream.
> the Chinese vaccines are inactivated virus vaccines. One wonders whether they fare better or worse vs this variant.
Not all of them are, but CoronaVac is. This[1] suggests that while efficacy of CoronVac against wild-type infection was modest (51%), the reduction when confronted with Gamma was very small (49.6%).
> Then again, maybe this variant will fail to transmit effectively and will just kill itself off like Beta did.
Beta didn't "kill itself off", it led to wave that rivaled Delta/Gamma in some cases. It ended up being outcompeted by Delta/Gamma.
[1] https://www.who.int/news-room/feature-stories/detail/the-sin...
There isn't. We have to theorize on the move, so to speak.
>Frontloading the risk of infection versus vaccination may well be justified in the young and healthy population, but that opinion has been ostracized from the mainstream.
The problem is that people took the wrong assumptions when calculating the risk of disease. All our calculations of risk are based on hospital treatment being available: providing Oxygen, Dexamethasone and ECMO treatment to critically ill patients, and no extra deaths due to healthcare overload.
No scenario when we 'let it rip' involves being able to give Oxygen to all young people who need it, and there will be extra deaths due to overload. The clever people suggesting intentional infection assumed risk factors dependent on current policies without understanding that under their policies risk would shoot up.
>Beta didn't "kill itself off", it led to wave that rivaled Delta/Gamma in some cases. It ended up being outcompeted by Delta/Gamma.
That's functionally equivalent to 'killing itself off', or at least being much less of a threat. I recall Beta's transmission factor was lower than Alpha? Was it because it missed some key mutations, or because mutating to avoid immunity came with a cost?
This is highly speculative. Considering the exposure and infection rates among the younger population, particularly those of school age, can't we say we did let it rip? Infection seroprevalence in blood-donors was at 20% by July[1]. How much worse could it possibly be?
https://jamanetwork.com/journals/jama/fullarticle/2784013?al...
(Ominous music)
>Infection seroprevalence in blood-donors was at 20% by July[1]
Seriously though, two points:
A) I have doubts about this measurement - that level (83.3% with antibodies!) should have been enough for herd immunity in May 2021, yet we don't see it in the US, cases being broadly static in the last month*.
Perhaps American blood donors are highly nonrepresentative even after demographic adjustments? Or they're catching people with very low levels of antibodies but without true immunity? The paper is thorough regarding geographic and demographic factors, but isn't very clear on the technical details of the measurement itself beyond 'we did it, here are the results'.
Or we could argue the US had herd immunity in May yet lost it two months after, that's not very encouraging, not even for 'natural' immunity.
B) Assuming the researchers are correct, that's 20% for over a year. That's very different from having it way quicker.
>can't we say we did let it rip?
School closures, remote learning, masks even at that age. Obviously there have been (arguably way overzealous) efforts at controlling COVID even at the youngest ages.
* There's a very recent fall, it's probably reporting lag - or it's really down, but per the research that should have already happened long ago.
The 83% includes immunity from vaccination which, as we know now, is not sufficient for herd immunity. Natural immunity may not be sufficient either.
> School closures, remote learning, masks even at that age. Obviously there have been (arguably way overzealous) efforts at controlling COVID even at the youngest ages.
In many cases, schools didn't get closed during much of the Delta wave and incidence in the young population was particularly high. As for masks: They have a modest effect at best (20% risk reduction).
I never thought about it that way. That would mean, if the virus evolves a more efficient ACE-2 binding domain that the mRNA vaccines fail to recognize, the vaccinated population would be more at risk than the unvaccinated population who has been previously exposed.
"Geneticists and infectious disease specialists there have uncovered potentially dangerous coronavirus mutations in a 36-year-old woman with uncontrolled HIV who was unable to shake the SARS-CoV-2 virus for close to eight months."
That was reported back in June:
https://www.latimes.com/science/story/2021-06-03/why-reachin...
[2] https://www.ft.com/content/06334a7b-30cc-40bf-942b-e3bcd2efb...
[0] https://www.theguardian.com/world/2021/nov/26/vaccine-resist... [EDIT]
SARS2 mutates much more slowly than Influenza so, IMO, we actually NEED to get people more infected. I would not be saying this if we locked every country down in the beginning but this is where we are.
In fact, the 4 other endemic coronaviruses in the human population with zoonotic origin can be traced via mutational drift to their leap to humans; the most recent I believe came from cattle in the 1800s.
These other coronaviruses are mostly a problem only for immunocompromised individuals such as transplant recipients.
The real issue IMO is whether SARS-CoV-2 was artificially engineered (ok, even if it weren’t it is more like SARS and MERS) and whether it will remain potently virulent even for healthy individuals who are exposed as children (as we all were to the endemic coronaviruses).
What is “the polyclonal antibody response of a highly neutralizing COVID-19 convalescent plasma” in less technical terms?
It's been used in Ebola outbreaks as a "hail mary" to cure people - it's also one of the more absurdly easy things to do - pretty much just take a blood sample, spin out the platelets and inject the plasma left behind (clinically you can be a lot more careful, but its one of the weirdest effective "primitive" treatments you can do).
Highly neutralizing -> very effective at murdering COVID virus
Polyclonal antibody response -> the person's immune system produced different antibodies to fight COVID which probably attack different parts of the virus
Basically, you take the blood plasma of someone recently recovered from COVID-19 with high antibody counts and filter antibodies out of it, that are then administered to critically ill patients. Same procedure is used in manufacturing snake venom antidotes (with horses as host bodies, since they are able to resist snake bites). More about this can be read e.g. here: https://www.mayoclinic.org/tests-procedures/convalescent-pla...
As for the different type of antibody - tl;dr of https://www.ptglab.com/news/blog/polyclonal-vs-monoclonal-an... is "monoclonal antibodies are all of the same configuration and target one specific molecule, whereas polyclonal antibodies have a higher amount of variance in matching".
As for "what exactly did they do" - they took samples of the specific virus and exposed it to such a blood plasma sample, and noticed escape, aka surviving infectious viruses. Which in turn is bad news as it means that this specific strain of virus at least has the potential capability to evade the body's immune system protection that has been built up by infection or immunization.
As this is an "in vitro" test though, this means that it may also be possible that an "in vivo" test (=exposing a live human instead of a blood sample) would fail.
Is anyone making and testing new vaccines that address the new variants? One would expect the variants just have a few key protein changes, which could be vaccinated against.
And more importantly, do we see any hope of accelerated timelines for nearly identical vaccines that target slightly different proteins?
I wonder if maybe the manufacturing data required for approval could be expedited in these sort of minor vaccine version updates?
https://investors.modernatx.com/news-releases/news-release-d...
Also the Novavax producers.
RSS feeds hours ago were full of "ready in 100 days" expressions; as I am making posts-vetting checks on search engines I am seeing one «would have the shot ready for testing and manufacturing in the next few weeks» (https://www.straitstimes.com/world/united-states/novavax-tes...).
But there’s plenty of supply chain and manufacturing aspects of the approval that seem like wouldn’t need any more stringency than the ongoing monitoring for the currently approved vaccines, from my lay persons perspective anyway
Headlines be like “[last year’s] vaccine less effective against [this year’s] variant” but omitting everything in the brackets when this is an obvious standard used for every seasonal pathogen…..
I’m also curious about who is doing what
This article argues we will not only need a booster but effective a whole new vaccine against this new Corona variant.