Coronavirus

[AlanSubie4Life]

Moderna says its vaccine is less effective against one coronavirus variant

Coronavirus Disease 2019 (COVID-19)

Actually this is still good news (it has been extremely poorly reported in the press - though the NY Times updated their extremely poorly written "take" from this morning). It's definitely prudent for Moderna to start the process of creating a booster that provides a more strongly neutralizing response to a virus with a more optimal RBD (receptor binding domain), but overall it is still good news:

mRNA-1273 vaccine induces neutralizing antibodies against spike mutants from global SARS-CoV-2 variants

B.1.351 is the South African variant which is of the most concern:

"Importantly, the VSV PsVN GMT of these human sera to the full B.1.351 spike variant was still 1/290, with all evaluated sera able to fully neutralize."

So, the vaccine is still effective enough against this variant - though the level of reduction in neutralizing activity is nearly sufficient to initiate a change in the vaccine.

The question is: How much more optimal can the changes to the receptor binding domain get? That's the change that's occurring in this virus, which allows it to latch on more securely - the N501Y mutation. (Inside the B.1.1.7 Coronavirus Variant ) It may be at this point that further changes have dramatically lower competitive advantage over this initial mutation (and there appears to be convergent evolution occurring resulting in this similar mutation in several different strains - including one in California, which implies it may be close to optimal). That would mean there may not be much more evolutionary drive to create further changes which would result in an even lower neutralization GMT (geometric mean titer). That's what I'm hoping!

If the antibodies generated by the vaccine are still numerous enough and a close enough match to latch onto the spike protein and prevent binding to cells, and that appears to be the case, that is good news, for now. At least that's my layman's impression.

The bigger danger is once vaccination becomes more widespread, there's going to be a competitive advantage to variants that manage to directly escape this immune response. We haven't really seen that evolutionary driving force become widespread, yet (we do see it to some extent if people are getting reinfected, probably, but those cases seem rare). (Though there is some thought that some of these variants have been driven rapidly by exactly that - rapid evolution of the virus in a compromised individual who cannot clear the infection - so the virus continues to optimize against any immune response that may be present - this theory (and it's just a theory) is supported by analysis of the genome, which shows up as a branch in the tree with MANY mutations that built up rapidly, which isn't something that typically occurs).

All the more reason to get as many people vaccinated as possible, and also to continue to apply strong suppression techniques to drive infections to zero. We still need to cut off transmission! Otherwise we are opening ourselves up to variants which escape the vaccine. The more transmission, the higher the risk of this happening. N95s for all!!!

I was finally able to order medical-grade 3M N95s on eBay, for my parents, FWIW. So that's good. It's about f'ing time! I don't think medical grade is necessary, really; the standard N95 should be fine (it's about a factor of 2 difference in price), but I got the medical grade because the straps seemed more robust (elastic plus fabric) rather than the straight elastic bands on the non-medical grade N95. Hopefully they're legit (but I'm optimistic they are).

 

[TEG]

I still haven't gotten an answer if there is a natural process that uses these spike proteins that would be helpful, but COVID vaccine would cause us to block it. Is it only bad viruses using that spike protein to gain entry to our cells?

Also, we are in a new frontier where we may block some "natural" cycle of mutation and evolution that would have otherwise steered our future generations, but now we are taking control and not letting these viruses control us that way.

(Another way to put it is that we want everyone to be on the vaccines to protect those who's natural immunities would not have done so well. )

Natural evolution might have resulted in future generates being more COVID resistant, but we are trying to handle that with vaccine technology instead.

 

[AlanSubie4Life]

I still haven't gotten an answer if there is a natural process that uses these spike proteins that would be helpful, but COVID vaccine would cause us to block it. Is it only bad viruses using that spike protein to gain entry to our cells?

I already tried to answer this. But remember, the antibodies bind to the VIRUS spike. Not the receptor on our cells (ACE2 receptor). It's not clear to me whether there would be anything floating around in the body which these antibodies would also bind to. My understanding is when the antibodies bind to the protein, even if it's not right at the receptor, it changes the conformation of the protein - twisting it and deforming it, so that the RBD is no longer good - even if it's not bound right at the RBD. There are lots and lots of different antibodies generated that attach all over the spike protein, in any case.

There are hormones which bind to the ACE2 receptor (From Wikipedia: "ACE2, in turn, cleaves the carboxyl-terminal amino acid phenylalanine from angiotensin II (Asp-Arg-Val-Tyr-Ile-His-Pro-Phe) and hydrolyses it into the vasodilator angiotensin"). I don't know what stops antibodies from binding to these hormones. It may just not work very well since they're not as big as the spike protein and the antibodies may therefore not be a good match for it at all (the strength of binding of the antibody to the spike I think is kind of determined by the complicated interaction of the antibody and the protein, and that might be very dissimilar or non-existent for a very small signalling molecule). Angiotensin II is a very small molecule, relative to the spike protein, just 8 amino acids long, so seems unlikely that an antibody would bind to it: Angiotensin II (medication) - Wikipedia

(Compare to the spike protein, which is 3x 1273 amino acids in length.)

Also, we are in a new frontier where we may block some "natural" cycle of mutation and evolution that would have otherwise steered our future generations, but now we are taking control and not letting these viruses control us that way.

Not 100% sure of what you're saying.

The immunity is not heritable (it's not incorporated into the DNA).

As far as keeping people alive who happen to have poor immune responses...it seems like it's mostly driven by age, not any particular genetic issue which results in weakness and susceptibility to COVID.

There's no evidence that natural evolution would lead to people more resistant to COVID. And even if it did, in a matter of years there is just going to be some other pandemic virus that arises. One possible endpoint for COVID is that it becomes endemic, and all children end up with vaccine-induced or natural immunity which lasts for life, so it just becomes another virus floating around out there that never causes major problems. Or, it may be eradicated.

 

[TEG]

Yeah, thanks. What I was alluding to would be a subtle long term process. And not even necessarily in our best interests. It isn't totally clear to me how much we should let nature decide vs us trying to control our own future destiny.


I also have to be careful here to make sure it doesn't get turned into some anti-vax sort of thought. I am "pro-mask" and "pro-vaccine", but try to ponder the longer term benefits and consequences of what we do.
( How will humanity be different in 1000 years if we are all taking a cocktail of MRNA vaccines... )

 

[uujjj2]

Sounds like the vaccines will work against the South Africa variant, but they won't be 95% effective like they are against the main variants.

 

[uujjj2]

California's case and hospitalization rates have been dropping, and Newsom has moved California back to a lower tier of restrictions. Mrs. Uujjj would have preferred doing it two weeks from now.

Interestingly, back in April/May during the first wave Mrs. Uujjj thought we had kept the stay-home orders in effect too long.

 

[AlanSubie4Life]

Sounds like the vaccines will work against the South Africa variant, but they won't be 95% effective like they are against the main variants.

Certainly they are less likely to be 95% effective.

However, it seems like it depends on what the cause of the 5% non-effective is. Is it because no neutralizing antibodies are generated in those cases? That wouldn't change with a change to the virus. And if that's the dominant cause, then the overall effectiveness would be about the same. Presumably there is a distribution of types (how effective) and numbers (concentration) of antibodies generated in response to a vaccine challenge.

My understanding is that there's a "threshold" effect. My understanding is that you only need the antibodies to be good enough and numerous enough to fully neutralize the virus. (And perhaps that concentration also depends on the initial dose of virus?)

But the neutralization curves could be such that a 6-fold reduction in neutralization capability (on average) only results in a 1% decrease in efficacy. It all depends how far the original neutralization response was above the threshold required to be effective. It if was 100 times higher than needed, but is now only 15 times higher than needed, it may not have much effect on the overall effectiveness. (There's for sure going to be a distribution of antibody responses, so one reason why there would be more failures is because that tail of reduced responses results in more responses that are below the threshold. Part of that tail is due to ineffective antibody response, part of it is due to general reduced antibody numbers & the rest is due to an antibody response that is not optimized to the new virus sequence and thus less effective.)

Maybe an immunologist could comment.

Another way to look at this: Both vaccines (after eliminating the 14-day initial interval) show about 92% effectiveness after the first dose (low N). The second dose increases antibody response by about 10-100x, from what I understand (it's in some of the published papers from Pfizer/Moderna).

So, 10-100x increase in antibody count increases effectiveness by 3%. If you then reduce the effectiveness by a factor of 6 (like for the South African strain), you'd expect effectiveness between 92% and 95%. (In actuality, it looks to me like the rate of cases doesn't change much before and after the second dose - so that implies to me that even the 10x-100x lower antibody concentration after the first dose is more than enough to be neutralizing. So it may be that lowering the effectiveness of antibodies by 6x doesn't change things at all, at these extremely high levels after the second dose.)

Also worth nothing that that 95% number in both cases includes the cases in the first 14 days after vaccination. So overall effectiveness if you dump (ignore) those cases is even higher than 95%. As I understand it. You can look at the curves above to eyeball it. There are definitely cases after the second dose, but it's just a very small handful. Most of the jump in cases in the vaccinated group occurs in the first 14 days after the first shot. Looks to me like about 2/3 of the cases. (It actually looks like the Pfizer vaccine may be more effective than Moderna, when eliminating those initial cases from the picture, though they're pretty similar, and the N is so small it's very hard to say.)

So if you eliminate/ignore those and attribute them to carelessness before a proper immune response is generated, the current vaccines are actually about 98% effective. And maybe they'd be 96% effective with 10x fewer antibodies (maybe).

 

[TheTalkingMule]

Carlos Slim and the President of Mexico both have tested positive. Carlos is old as hell, but he can write a check big enough to save an unhealthy 81 year old. Viva La Social Distancing!

 

[AlanSubie4Life]

Also worth nothing that that 95% number in both cases includes the cases in the first 14 days after vaccination.

So if you eliminate/ignore those and attribute them to carelessness before a proper immune response is generated, the current vaccines are actually about 98% effective.

I'll just rescind this part of my comment; these are false statements. The 95% numbers are just calculated 7 days after the second dose. You have to read the report from Pfizer/Moderna to see the details:

first primary efficacy endpoint, vaccine efficacy (VE) for BNT162b2 against confirmed COVID-19 was evaluated in participants without evidence of prior SARS-CoV-2 infection prior to 7 days after Dose 2.

https://www.fda.gov/media/144416/download

Here's the key chart (I added some missing data that isn't explicit but is in the actual plot earlier in the document - this is where the 92% effectiveness of dose 1 comes from, when measured > 14 days after dose 1 but before dose 2):

In any case my speculative comments above, about the threshold, still stand; please just exclude the false statements about efficacy I made above.

 

[AlanSubie4Life]

https://twitter.com/SCOTTeHENSLEY/status/1353820335087493122?s=20

Apropos:

Neutralizing activity drops from super awesome to awesome, in the presence of variants, according to this immunologist.

Probably going to be fine, with what we know about now. But variants will continue to proliferate rapidly with these high disease levels, so we're definitely playing with fire (even if the evolution tends to be convergent). Everyone should wear an N95 respirator and follow the guidance.

Also, the FDA is thinking about the process for updating the mRNA vaccine, apparently. (I should hope so!) And it sounds like it would not follow the full process of the original approval and would be something similar to flu vaccine updates (though the details are unclear and it would be good to have specifics on any timeline and how it would be administered (as a supplemental booster, I assume?) ):

https://twitter.com/DrWoodcockFDA/status/1353857669979897857?s=20


Back to Pfizer effectiveness after one dose, I found a table where someone did the calculations based on the numbers in the above post, complete with confidence intervals:

https://twitter.com/Jamal___James/status/1353897903777931264?s=20

 

[TEG]

'New weapon' to kill COVID? UCSF-led team finds drug that could be far more effective than remdesivir

Plitidepsin has potent preclinical efficacy against SARS-CoV-2 by targeting the host protein eEF1A | Science

 

[wdolson]

Yeah, thanks. What I was alluding to would be a subtle long term process. And not even necessarily in our best interests. It isn't totally clear to me how much we should let nature decide vs us trying to control our own future destiny.


I also have to be careful here to make sure it doesn't get turned into some anti-vax sort of thought. I am "pro-mask" and "pro-vaccine", but try to ponder the longer term benefits and consequences of what we do.
( How will humanity be different in 1000 years if we are all taking a cocktail of MRNA vaccines... )

I've pondered this for years. With modern medicine we save a lot of people who would have died young and not reproduced in previous generations. Those people grow up and pass on genes that may have a weakness for some condition that would be fatal without medical intervention.

On the one hand it's a good thing human lives are saved, but is it good for the human genome in general?

BTW, glad to hear your wife is out of the hospital.

Did you get tested for the antibodies? Maybe you had it a while ago and had an asymptomatic case?

 

[bkp_duke]

I've pondered this for years. With modern medicine we save a lot of people who would have died young and not reproduced in previous generations. Those people grow up and pass on genes that may have a weakness for some condition that would be fatal without medical intervention.

On the one hand it's a good thing human lives are saved, but is it good for the human genome in general?

BTW, glad to hear your wife is out of the hospital.

Did you get tested for the antibodies? Maybe you had it a while ago and had an asymptomatic case?

Most of those "young deaths" had little to nothing to do with their genetic fitness.

This is a eugenics argument, and as a die-hard Star Trek fan, I don't like where eugenics arguments go in general.

 

[JRP3]

It seems reasonable to assume that interfering with natural selection could have consequences. It does in other organisms.

 

[TespaceX]

To those mentioning natural selection....so, we should maybe rethink vaccinations for the usual things as well?

 

[TEG]

I've pondered this for years. With modern medicine we save a lot of people who would have died young and not reproduced in previous generations. Those people grow up and pass on genes that may have a weakness for some condition that would be fatal without medical intervention.
On the one hand it's a good thing human lives are saved, but is it good for the human genome in general?

Exactly...

BTW, glad to hear your wife is out of the hospital.
Did you get tested for the antibodies? Maybe you had it a while ago and had an asymptomatic case?

No... I don't think my doctor would order that for me, and it would be hospital blood test. Thinking it is not worth it to ask because:
#1: Going to hospital for a blood test is COVID risk if I didn't really have it.
#2: I am under quarantine now anyways, so can't go anywhere for a while.
#3: Hospitals are super busy so don't need a healthy person using their resources to satisfy their curiosity.

I would really like to know if I have antibodies since my wife thinks I must have brought it home asymptomatically as she can't figure out any other possible exposure vector.
Could I have caught it in my gut from something I ate? (I did occasionally order some curbside pick-up lunch when heading over to the pharmacy. Only possible symptoms I can recall was a day of indigestion...)

I guess when I finally get the vaccine if I have a very strong reaction to the first dose, then I would be able to guess I probably already had it.

 

[bkp_duke]

To those mentioning natural selection....so, we should maybe rethink vaccinations for the usual things as well?

No, we should not. This anti-vaxxer argument is so myopic and so beguiles their minimal understanding of biology that it really does showcase the general ignorance of the anti-vaxxer movement.

1) Viruses mutate and "evolve" at a rate 1bil times what humans do (at minimum). This in and of itself means that any necessary "evolution" or natural selection for humans to out-compete a virus by natural immunity is just never going to happen. Virus generations are measured in hours, ours are in years.

2) Humans have ALREADY evolved this WONDERFUL defense mechanism . . . called our brains. Our ability to reason and manipulate our surroundings (in this case develop vaccines to improve survivability) is the EXACT reason we evolved higher intelligence. Sadly, it looks like this process is still ongoing, as the higher-reasoning ability of the anti-vaxxer appears to be behind the curve of most of the rest of the population (someone has to bring up the rear, right?)

3) Along the lines of #2 above, we already have a well-evolved immune system, but like all things it is not perfect. Vaccines are simply a way to utilize that immune system and bypass the bulk of disease.


The only reason the anti-vaxxer arguments even get any traction is because they are the beneficiaries of the 2-3 generations before them being vaccinated and they have not had the unfortunate experience to see loved ones die from preventable diseases. Ever seen a kid die from measles encephalitis? I have, it's not pretty. Ever see a young boy get the mumps, and then 15 years later find out he cannot father children because he is sterile? I have. All completely preventable, but their parents were so arrogant that they thought they were smarter than those people trained to know better.

 

[madodel]

But isn't science our mutation for preserving the entire human race? Many of the extinctions occurring now apparently are manmade because of our ignoring science.

 

[TEG]

But isn't science our mutation for preserving the entire human race? Many of the extinctions occurring now apparently are manmade because of our ignoring science.

There is also the dilemma if we are using the science right.. We have invented some very powerful tools, but are still learning the best way to use them. How bad are the learning curve mistakes along the way?

 

[TEG]

...Viruses mutate and "evolve" at a rate 1bil times what humans do (at minimum)....
...Humans have ALREADY evolved this WONDERFUL defense mechanism . . . called our brains. Our ability to reason and manipulate our surroundings (in this case develop vaccines to improve survivability) is the EXACT reason we evolved higher intelligence...

So assuming we have a future with drug companies watching natural virus evolution and trying to rush to market the latest new MRNA vaccines to slow/stop the spread, it makes me ponder the idea of going to the "source" to limit the virus evolution.
For instance, should we (eventually) make MNRA vaccines for animals like bats and pangolins and send teams into nature to inoculate them in the hope that we could someday wipe out whole classes of viruses instead of eternally trying to slow them once they jump to humans?
We hope to inoculate the whole human race in record time... What about other life forms that can spread and mutate the viruses? Does this idea seem absurd?