Coronavirus

[AlanSubie4Life]

Here is some new data and information on Pfizer (paywall etc)...not really surprising of course.

Pfizer-BioNTech Vaccine Is Highly Effective After One Dose and Can Be Stored in Normal Freezers, Data Shows

Don’t need to keep the vaccine as cold, either. Weird. Isn’t this something they could just know based on their knowledge of the components involved?

 

[daniel]

The UK strategy is the correct one, if you are looking to stamp out the pandemic and save lives.

There is controversy about that. More data will tell, but at this point it's not possible to know for sure. In particular, we don't know how long immunity lasts after a single dose, and we don't know if the second dose is as effective when delayed significantly after the standard 2-week waiting period.

We do know that after two weeks after the second dose (when administered according to schedule) the chance of a severe case of the illness or death is practically zero, and the chance of a mild case is very small. We also know that the chance of such a person passing the virus to another is very small. And we know that protection from the variants so far identified is very good.

We know that protection after two doses plus two weeks is excellent. We don't yet know about single-dose response. The UK strategy may be a valid experiment given the shortage of vaccine, but it cannot categorically be said to be the "correct" one.

 

[bkp_duke]

There is controversy about that. More data will tell, but at this point it's not possible to know for sure. In particular, we don't know how long immunity lasts after a single dose, and we don't know if the second dose is as effective when delayed significantly after the standard 2-week waiting period.

We do know that after two weeks after the second dose (when administered according to schedule) the chance of a severe case of the illness or death is practically zero, and the chance of a mild case is very small. We also know that the chance of such a person passing the virus to another is very small. And we know that protection from the variants so far identified is very good.

We know that protection after two doses plus two weeks is excellent. We don't yet know about single-dose response. The UK strategy may be a valid experiment given the shortage of vaccine, but it cannot categorically be said to be the "correct" one.

I can say with 99.9% certainty it is the correct strategy. There is enough data to make an assertion like that. ESPECIALLY with vaccines with this level of effectiveness after a single dose (95% is nearly unheard of in vaccines - we are super happy with 60-70%).

Additionally, your time-frame for the 2nd dose is incorrect. It's not 2 weeks after the first. It's 4 weeks for Moderna, 3 for Pfizer. There is no "magic interval" for boosters. In kids, we usually space them out to a year later so that they simply line up with the annual visit to their PCP, in order to have the highest administration percentage for the booster.

No one conducts a clinical trial checking efficacy of the booster interval for more than at max 2 intervals (and usually just one).


As Elon likes to point out - if you go back to "first principles" you can usually reason through things with a high degree of certainty. First principles of immunity dictates that after the primary immune response has been built up (~14 days), there is no magic interval for administration of the booster. You are simply looking to prime the already created memory B and T cells to further generate a memory response.

 

[daniel]

I can say with 99.9% certainty it is the correct strategy. There is enough data to make an assertion like that. ESPECIALLY with vaccines with this level of effectiveness after a single dose (95% is nearly unheard of in vaccines - we are super happy with 60-70%).

Additionally, your time-frame for the 2nd dose is incorrect. It's not 2 weeks after the first. It's 4 weeks for Moderna, 3 for Pfizer. There is no "magic interval" for boosters. In kids, we usually space them out to a year later so that they simply line up with the annual visit to their PCP, in order to have the highest administration percentage for the booster.

No one conducts a clinical trial checking efficacy of the booster interval for more than at max 2 intervals (and usually just one).


As Elon likes to point out - if you go back to "first principles" you can usually reason through things with a high degree of certainty. First principles of immunity dictates that after the primary immune response has been built up (~14 days), there is no magic interval for administration of the booster. You are simply looking to prime the already created memory B and T cells to further generate a memory response.

You can say it, but that doesn't make it so.

Careless mistake on my part about the 2 weeks. Thanks for the correction.

Laypersons ignoring the experts and reasoning from "first principles" without significant education in the subject matter are bound to come to faulty conclusions.

 

[JRP3]

FYI, the US is also collecting post-vaccine data. I've been filling out a web form sent to me via text every day (for 7 days after the shot) or every week (weeks 2, 3, and 4 after the first or second shot) - a requirement for registering to get the shot. So the US is collecting post-vaccine data at a good clip.

Is that a California requirement? Because I don't think any of the people I know who have gotten the vaccine have been required or even asked to do that.

 

[bkp_duke]

Is that a California requirement? Because I don't think any of the people I know who have gotten the vaccine have been required or even asked to do that.

The site I'm reporting to is run by the CDC:
https://vsafe.cdc.gov

When I got the first shot, everyone at the location I was at had to scan a QR code and register to report post-vaccine symptoms. I don't know if every site is doing this, but I've talked to friends in other states that had to do it as well.

 

[bkp_duke]

You can say it, but that doesn't make it so.

Careless mistake on my part about the 2 weeks. Thanks for the correction.

Laypersons ignoring the experts and reasoning from "first principles" without significant education in the subject matter are bound to come to faulty conclusions.

I'm not a layperson. I have an M.D., and a Ph.D. in molecular biology. I have first hand research experience with viruses.

What are your credentials?

 

[AlanSubie4Life]

I can say with 99.9% certainty it is the correct strategy.

I would certainly bet on the single-dose strategy if I had to bet. I would not be that certain though.

For all the reasons you mention.

However, one of the big concerns with the single-dose was an environment that resulted in more variants that escape a marginal immune response. That risk certainly seems higher with the single-dose strategy. And the Manaus experience makes one wonder.

(The other concern raised was efficacy, which seemed to be pretty clearly a non-issue
from the initial data (should have had definitive data though), and longevity of protection was likely to be decent from “first principles” as you said.)

So that’s the main concern I see with that approach. I still think the single-dose is probably the right call though. I would have suggested vaccinating everyone above ~55 and very vulnerable with single dose first, HCWs with two, and then start circling back.

We’ll never do this in the US though, unless we have data acceptable to the FDA. If the data addressing all concerns are not clear and of the required quality, they’re going to stay the course.

 

[bkp_duke]

I would certainly bet on the single-dose strategy if I had to bet. I would not be that certain though.

For all the reasons you mention.

However, one of the big concerns with the single-dose was an environment that resulted in more variants that escape a marginal immune response. That risk certainly seems higher with the single-dose strategy. And the Manaus experience makes one wonder.

(The other concern raised was efficacy, which seemed to be pretty clearly a non-issue
from the initial data (should have had definitive data though), and longevity of protection was likely to be decent from “first principles” as you said.)

So that’s the main concern I see with that approach. I still think the single-dose is probably the right call though. I would have suggested vaccinating everyone above ~55 and very vulnerable with single dose first, HCWs with two, and then start circling back.

We’ll never do this in the US though, unless we have data acceptable to the FDA.

Viral escape is more population size dependent (i.e. number of infected individuals), and mutational rate dependent, than anything. But with vaccines this effective after a single dose, that's very low risk. You are only gaining a few % with the 2nd dose, and we've done more with less-effective vaccines in the past (smallox comes to mind). And I agree with your "top-down" approach by age.


Think of it this way, when firefighters go to put out a big fire, they don't sit around waiting and watching a small area to make sure the embers are 100% out, they keep fighting the front lines, the big flames, and mop up later. It's not a perfect analogy, but it's darned close.

A first-dose strategy, especially splitting the Moderna dose in half, would accomplish that (by analogy) fastest. The "mop-up" would be the second dose throughout the population.


We are already going to be facing an uphill battle from the anti-vaxxer movement, and then after that the complacent people that "oh, well the pandemic is past, I don't see a reason to get vaccinated now".

 

[AlanSubie4Life]

But with vaccines this effective after a single dose, that's very low risk.

I’m not concerned about B.1.1.7 which is dominant in Israel. It’s the B.1.357 and similar which are associated with much lower neutralizing titers (~6x - of course there is a broad range) with Pfizer/Moderna-induced sera. Not a problem for two doses. But for a single-dose it is less clear. A single dose would appear to put antibody levels below the neutralizing level for those variants. (In other words: we don’t know what the Pfizer efficacy against B.1.357 is after one dose.)

There is currently a paucity of actual clinical data on efficacy of Pfizer/Moderna against these variants (even with two doses). We just have test tube results so far.

But lack of neutralization with a single-dose would be somewhat consistent with reinfection reports with B.1.357 and P.1, P.2, after natural infection. Similar antibody levels after natural infection vs. single-dose (though vaccine level is more consistent it seems). These reinfection reports are really unclear though. Hard to know exactly how common reinfection is with these variants after infection by the original variant.

A first-dose strategy, especially splitting the Moderna dose in half, would accomplish that (by analogy) fastest.

I am definitely on board with that. I wish Moderna had actually done the full trial with this.

Another article similar to above with a more easily escaped paywall:
Covid-19 Live Updates: Pfizer’s Vaccine Works Well With 1 Dose and Can Be Stored More Easily

 

[bkp_duke]

Related note - the single dose effectiveness data for the Moderna and Pfizer vaccines really puts the J&J and AstraZenica vaccines into a distant 3rd place in terms of "single dose effectiveness". That was supposed to be the stand out feature of J&J and AstraZenica, and they are both now eclipsed by the mRNA vaccines.

 

[AlanSubie4Life]

You are only gaining a few % with the 2nd dose,

Follow-up:
This is a bit misleading since it is actually increasing titers by 10x-100x. So that few % won’t necessarily remain that way for all variants. It might be 30-40% more effective (or more - just random guessing here from me - for example, seems conceivable you could have ~30% efficacy after one dose, with ~93% efficacy after 2 doses, depending on how things lined up) with the variants associated with lower neutralizing titers. Once you drop antibody levels below that neutralizing line, it starts to depend heavily on how well these lab tests correlate with clinical results.

It’s all very nonlinear!

 

[bkp_duke]

Follow-up:
This is a bit misleading since it is actually increasing titers by 10x-100x. So that few % won’t necessarily remain that way for all variants. It might be 30-40% more effective (or more - just random guessing here from me - for example, seems conceivable you could have 30% efficacy after one dose, with 93% efficacy after 2 doses, depending on how things lined up) with the variants with lower neutralizing titers. Once you drop antibody levels below that neutralizing line, it starts to depend heavily on how well these lab tests correlate with clinical trial results.

It’s all very nonlinear!

As I've mentioned, Titer levels are NOT what you should be tracking. They are one marker of effectiveness, but all titers wane (you are likely still immune to measles, but have EXTREMELY low titers). What is important is that you have Memory B and T cells.

You need to stop using titers as your effectiveness metric, it is flat out wrong and not what scientists consider the gold standard: disease prevention.


It is the ENTIRE point of why mammals evolved to produce Memory B and T cells - these are fast-acting little factories that divide and crank out antibodies by the trillions once they are exposed to their antigen. It's FAR FAR more effective than maintaining high titer levels of every pathogen we have ever been exposed to.

 

[AlanSubie4Life]

really puts the J&J and AstraZenica vaccines into a distant 3rd place in terms of "single dose effectiveness".

I hope we don’t have to wait months for second dose trial results. Hopefully J&J included these results in their submission to the FDA. My understanding was that they were trying it.

You need to stop using that as your effectiveness metric, it is flat out wrong and not what scientists consider the gold standard: disease prevention.

I’m not using them for that purpose, as I stated in my post!!!! But in the absence of clinical data (and we don’t have clinical data on Pfizer/Moderna single-dose vs B.1.357) we don’t have much else to go on. It is required to use some correlate to guide expectations in the meantime - we have nothing else.

Specifically:

it starts to depend heavily on how well these lab tests correlate with clinical results.

To be clear: all vaccines that have not been abandoned, to one degree or another, have shown efficacy against severe disease against all variants.

But in this context, we were talking about the possibility of immune escape, not disease prevention.

I have made it very clear that I would bet that giving single doses would be best for disease prevention and saving lives, at least in the short term (longer term is complicated by these other considerations, and I don’t know what the likelihood is of those issues, but I still suspect that single dosing is the right call, especially if we keep extremely strong mitigation measures in place, even after disease levels drop to near zero).

 

[jerry33]

Is that a California requirement? Because I don't think any of the people I know who have gotten the vaccine have been required or even asked to do that.

For us it was not a requirement to get the shot, but on the handout given with the first shot it asks you to register.

 

[bkp_duke]

Antibody levels should only be considered "diagnostic and informative" in the context of either acute infection, or immediately post-infection or vaccination. After that, levels are expected to wane.

Also, vaccines are designed for disease prevention. Immune escape is at best considered a secondary criteria (nice to have, but if the disease doesn't kill you or leave you with lasting complications, we consider it a win).

 

[AlanSubie4Life]

After that, levels are expected to wane.

Yep.

Immune escape is at best considered a secondary criteria

In the case of a novel virus like this that has been recently introduced to humans, you’d kind of expect a fairly fast evolutionary shift to a new optimum, which sort of seems to be happening.

So I think the risk of incorrect targeting and ineffectual coverage by a single dose is a bit higher in this case than a “traditional” case for a well-established disease. So weighting these considerations might be a bit different.

But, those boosters would likely work well and probably will have sticking power (further mutation I’d expect to proceed more slowly especially if we can get disease levels down). They can’t come soon enough!

If we knew the timeline on those, we might be able to make better strategic decisions about single-dosing in the near term. B.1.357 is pretty rare still in this country, so we have some time.

FDA is not going to change their tune though, is my guess.

 

[AlanSubie4Life]

It is the ENTIRE point of why mammals evolved to produce Memory B and T cells - these are fast-acting little factories that divide and crank out antibodies by the trillions once they are exposed to their antigen

Question for you: how does maximum titer in the past correlate with the strength of that renewed antibody response (after waning has occurred) upon re-exposure? And how does it correlate with killer T-cell response, if at all?

 

[bkp_duke]

Question for you: how does maximum titer in the past correlate with the strength of that renewed antibody response (after waning has occurred) upon re-exposure? And how does it correlate with killer T-cell response, if at all?

It's not well known, and changes significantly as you age, but you have to remember, and this is the gotcha, the antibody response is just one branch of the immune system. It doesn't dictate everything. T-cell response and innate immunity (i.e. the clean-up crew we call them) are also extremely important. Antibodies are just easy to measure, because they are large molecules with specific binding (so we can create tests for them relatively easily).

 

[Slipstream]

It looks like the UK is going with herd immunity in one dose experiment.

More Than 193 Million Shots Given: Covid-19 Tracker

Scroll to the bottom: 24.6% 1 dose, only 0.9% 2 doses.

Over 193 million shots given in the UK already? That's impressive.