SARS-CoV-2 501Y.V2 escapes neutralization by South African COVID-19 donor plasma

Looks like this was posted again, so I'll post my response here as well:

This is correct, but just want to add that many may interpret this as a positive sign, it is not necessarily. In many cases, binding antibodies increase cell infectivity. Also, there is some research that indicates the presence of non-neutralizing antibodies without the corresponding neutralizing antibodies and humoral response may be a factor in the development of antibody dependent enhancement. As far as we know, it is the neutralization potency that strongly correlates with disease severity.

I agree, the headline is definetly not what the research shows. See my other comment on non-neutralizing antibodies. Please change the title to the original one.

Yep. It's an irresponsible headline, like so many others, renewing panic even amongst the crowd here.

I hope your comment and others like it are not lost amongst all the others so quick to call for a doubling-down of imposed quarantines and lock downs without regard for collateral damage, based on their partial knowledge of the immune system and lack of perspective.

The paper you cited actually states that existing vaccines are less effective: “However, neutralization by 14 of the 17 most potent mAbs tested was reduced or abolished by either K417N, or E484K, or N501Y mutations.”

You should continue to wear a mask. You should continue to social distance. You should continue to avoid congregating indoors with strangers.

Please note, that neutralization by antibodies is only one of the many possible ways how our immune system can take action. Antibody recognition is still possible with the found mutant:

"To determine whether 501Y.V2 is still recognized by non-neutralizing antibodies, the binding of polyclonal sera (from Fig.2a) to a recombinant 501Y.V2 RBD+SBD1 protein and an RBD+SBD1 from the original lineage was assessed by ELISA (Fig.2b). These data revealed that binding of polyclonal plasma to 501Y.V2 RBD+SBD1 was only substantially affected in a minority of cases (14 of 44 with ≥five-fold reduction, 32%). Most of the convalescent plasma/serum suffered less than four-fold reductions in total binding activity (as measured by area under the curve), suggesting a considerable non-neutralizing antibody component are still able to bind the 501Y.V2 spike antigen"

re: E484K

1) it's in the spike protein. I think it's in the area that typically elicits antigen response. That's super bad news. If you look carefully, it's near the cleft of a representative antibody (fig 1a), and the buried surface area is high across the board on (clinically?) sampled antibodies (fig 1e), suggesting its importance.

2) it's a mutation that changes the charge state of one of the amino acid residues. E->K, changes a negative charge to a positive charge, potentially very bad if typically antibodies have a positive surface charge to interact with it, now they will be repelled. Since individual humans make random antibodies, even if there is no charge interaction, K amino acid is bigger than E, and so there is likely a shape interaction that could get disrupted by the "new bump" in the spike.

Is it a serious cause for concern? Yeah, almost certainly. The current round of vaccinations will probably be rendered inactive.

IMO the fastest way around this is to quickly approve a reformulation of the moderna/pfizer vaccines that encode for the new amino acid, or better yet, a cocktail of both.

For the more traditional protein-based vaccines, it could be more challenging, because the gut feeling is that an amino acid change like this could pose more of a risk to the effectiveness of the formulation for delivery of the vaccine (mrna is more "neutral" information medium that typically exerts less of a chemical change to the delivered product when altered).

In any case this emergent phenomenon will be certainly challenging to the regulatory landscape around vaccination.

disclaimer: I own MRNA stock.

I found this on Wikipedia.

"On 7 January 2021 it was reported that Pfizer researchers had found the Pfizer and BioNTech COVID-19 vaccine in tests involving 20 blood assays to be capable of affording protection against one of the 501.V2 variant mutations (N501Y, shared with variant B1.1.7). Further investigation was to be undertaken to ascertain the level of protection involved."

https://en.wikipedia.org/wiki/501.V2_variant

Which came from this article.

https://www.theguardian.com/world/2021/jan/08/pfizer-vaccine...

But I can't find the original or subsequent studies.

From the article:

"These data highlight the prospect of reinfection with antigenically distinct variants and may foreshadow reduced efficacy of current spike-based vaccines."

So it suggests that only spike-based vaccines may have reduced efficacy against it. I suppose the inactivated-virus vaccines should be fine. Which would put China and India at huge advantage (https://www.nytimes.com/interactive/2020/science/coronavirus...).

Do you have a link, or some sort of corroborating evidence to support this statement

Worth noting that peer review is also a bit (or a lot slow) and not perfect, and that all peer-reviewed studies have in the past been not peer reviewed.

Link?

Edit: If you're talking about this press release, I believe this is referencing a different variant.

https://www.pfizer.com/news/press-release/press-release-deta...

I mean, if flu vaccines are any indication, what is more likely is we never cure it, but we end up with yearly covid shots to gain immunity to each year's strain(s)

The issue with the flu isn't that it rapidly mutates but that we can't quite predict which mutations will happen each season. Developing a vaccine for a new strain of the flu is pretty mechanical at this point but each seasonal flu vaccine is really a combination of three different strains that World Health Organization scientists predict will be the dominant strains causing the most damage (it gets reevaluated twice a year). The way that most people take the vaccine (a live but weakened version of the virus) it's impractical, even dangerous, to give them all of the strains at once so an educated guess of three strains is our chosen sweet spot.

The common cold is an even more extreme version of that process but we haven't figured out an economic way of developing rapid vaccine candidates for rhino/coronavirus strains like we have for the flu. Moderna's RNA method might be a game changer here but it'll take a while for their method to be approved as a platform instead of a single drug candidate.

The common cold isn't just one virus. Many different viruses cause cold symptoms, including several coronaviruses. In particular HCoV-OC43 is quite similar to SARS-CoV-2. If you're exposed to one of those common cold viruses then it generally won't give you immunity to any of the others.

This is one of the first variants that avoids our current plan of defense: antibody plasma.

At a minimum, it means that treating COVDID19 may require further tests to see if we have COVID19, or... what probably will be called COVID20 or COVID21 (for 2020 or 2021, depending on when we want to pin the "origin date" of this virus variant). I'm assuming COVID20 in my ignorance...

If COVID19 treatment doesn't work, doctors will then have to try COVID20 treatment.

--------------

It really depends on how much COVID20 has mutated compared to COVID19, as well as how effective Pfizer, Moderna, AstraZenica, and Johnson & Johnson's vaccines are against COVID20.

They've only been tested against COVID19 (the 2019 variant). We'll have to run tests to see if our defenses are good enough for COVID20, or if we have to start the vaccine race all over again.

This one is spreading more widely in South Africa and has also been found in other countries already. It has an advantage in populations that have prior immunity from natural infection.

> . In South Africa, genomic data highlighted that the 501Y.V2 variant rapidly displaced other lineages circulating, and preliminary studies suggest the variant is associated with a higher viral load, which may suggest potential for increased transmissibility; however, this, as well as other factors that influence transmissibility, are subject of further investigation.

> As of 30 December, the 501Y.V2 variant from South Africa has been reported from four other countries to date.

https://www.who.int/csr/don/31-december-2020-sars-cov2-varia...

> is there some reason to believe this variant is more easily spread and will become common?

Yes, there are two reasons: increasing natural immunity and vaccinations.

I think in general not causing death in the target host is a naturally selected trait in viruses. The least lethal viruses are the ones that spread the most.

This has been observed in herpes, which has evolved to infect nervous system cells but explicitly not nerve cells in the brain (which would cause death).

So considering that, perhaps future strains of COVID will reduce their lethality while increasing their ability to infect.

The primary benefit of the vaccine over 'natural' immunity (other than avoiding actual exposure) is the emphasis on neutralizing antibody formation.

This is an interesting take for sure that I hadn't heard before. Do you have more information on how they could have accelerated things?

If feels like the risk of shipping a vaccine that later is found to have adverse side effects would be so dangerous to the trust of the FDA that it would be really dangerous. Think of the shattered trust on both the FDA side and on vaccines in general, feels like maybe that would be too big a risk to take.

The FDA is slow? Compared to what? They approved the first vaccine 3 days after the NHS.

If your window of success vs. failure is very small, you simply have to test before you push to prod. Especially when using a technique with a long history of failed attempts.

On the flip side, you have a sizable portion of the population that feels even the Emergency Use Authorization (EUA) by the FDA was rushed (To be clear, I'm playing the Devil's Advocate here - I personally don't disagree with the FDA's decisions, and got my own shot weeks ago)

Genuine Q: which steps of the process do you see as superfluous? Pfizer announced the end of the phase 3 trials on November 18th, they submitted an application to the FDA for EUA on the 20th of November (or sometime shortly after), and the EUA was granted on the 11th of December.

It didn't take 11 months for the FDA to give the OK. It took 11 months to design a vaccine from scratch, conduct phase I safety trials, phase 2 human safety and dosage trials, and a phase 3 trial to determine efficacy. This includes actual production of the mRNA & its vector in quantities sufficient for the trial, subject recruitment, shipping logistics worldwide to participants, administration of the test doses, data collection, analyses, and compiling results. Honestly, 11 months from start to finish seems like an amazingly short time to achieve so much.

Given that most of the vaccines were produced "at risk" (i.e. before the trials showed that they were effective), I doubt that if the FDA had approved these vaccines on the day they were designed, we would have significantly more doses in people's arms today.

You seem to be arguing that if FDA had begun widespread inoculation earlier with the current vaccines, variant COVID strains would not have arisen.

But that's wrong on several levels. Even if we had started producing vaccine en-masse in March, it would still take many more months (several years) to inoculate everyone on the planet. These novel strains would still have arisen within that time frame.

We would also have introduced additional problems that undertested therapies often suffer from and that the Chinese vaccine appears to have -- low efficacy. If quickly approved vaccines were no more than 50% efficacious on large fraction of the planet's peoples, herd immunity would take longer to accumulate and novel strains would still emerge.

Of course, toxicity is another likelier outcome from undertesting a new vaccine. Others can assess that risk better than I. In short, when it comes to combating pestilence, there's no free lunch.

Probably not. The second dose of the vaccine is more about ensuring that you are covered for a long time. So long as everyone gets the second dose in a few months we are fine. If we wipe out COVID there is no reason to give second doses at all.

It would seem that the horse is already out of the barn. Flights would have needed to be curtailed much earlier. In addition, we're seeing similar mutations popping up independently in geographical areas - seems to be evolutionary pressure in these directions.

If you COORDINATE lockdowns and everyone works in harmony they can be very short.

You could even schedule them in advance.

My guess is we will need to FDA approve the mRNA vaccine development platform so we can develop a cocktail of spike mRNA vaccines and you will take 1 or more of them. We will need some kind of rapid clinical trial procedure to get updated mRNAs tested.. I am not sure what they do with the yearly flu vaccine in this regard but a similar approach is necessary. Then we will need a rapid surveillance program as well.

We will also need to update / create more antibody treatments like Regeneron's.

But that's a lot of technology to solve the wear a mask and social distance problem.

We need to keep the fire from spreading because it will just come back and burn down the things it missed the first time.

I suspect we will be dealing with rolling covid lockdowns for the next 10+ years.

Yeah, this is not great news. I hope the vaccine makers are looking at adding coverage for these variants to the existing vaccines. That should be relatively easy to do for the mRNA vaccines, but possibly harder for the adenovirus based vaccines like the Oxford/AZ and the J&J. The question is whether they would have to go through a full phase 3 trial for this kind of addition or would this be more like how we add coverage to different flu viruses to the annual flu vaccines?

> The callouts there are "complete escape [from] convalescent plasma" (prior exposure won't help you)

Whether prior exposure helps also depends on T-cell response. At this point it's well established that immunity lasts for some unknown period of time past when most antibodies have left the bloodstream.

exiting discussion

Sure hope we're not globally in the process of inducing maladaptive immunity to emerging strains that turn out to get extensive spread...

https://en.wikipedia.org/wiki/Original_antigenic_sin

> How often do you know someone die of cancer?

That depends on how many smokers and ex-smokers you know. It makes it all the sadder because the death was preventable. Which puts it into a similar headspace with Covid.

Death rate will surely go up if there are multiple strains of this going around that are different enough you could catch 'em all, over time.

It is important to note that the current mortality rate is the mortality rate with treatment, and with varying degrees of spread mitigation measures. If hospitalization rates exceed the available beds, the mortality rate will rise.

What about "long covid"?

It looks like 1 in 10 people infected experience symptomps for more than 12 weeks. [1]

Just because you aren't likely to die doesn't mean you'd be fine.

[1] https://www.ons.gov.uk/news/statementsandletters/theprevalen...