Covid-19 #25: The Prisoner’s Dilemma

[HoodedCrow]

U.S.A.  U.S.A.! More than half the population are on our side, but the rest...

The previous Republican administration in the States actually wanted  people from the major cities to die, so that they could build false narrative about Democratic cities. They did it anyway. You know, the densely populated cities that generated revenue. Their own cities.

Reagan, Bush and T made me a constitutional monarchist.:)

 

[Altherion]

The tide appears to be turning in the US. New cases are down in every state and Biden's administration has announced that vaccine shipments are up:

Quote

 

President Biden's COVID-19 czar Jeff Zients told governors on Tuesday that the weekly vaccine supply going out to states is increasing by more than 20% to 13.5 million doses this week, Jen Psaki, the White House press secretary, announced.

Psaki also said the supply going directly to pharmacies will double to 2 million this week.

 

The grand total number of doses needed is around 420 million because the vaccines are not authorized for children and there are around 210 million adults in the US. Thus far, around 55 million doses have been administered so we need 365 million more. If the rate of 15.5 million per week is not an anomaly and can be sustained, this should only take another 5 months or so.

[Fragile Bird]

57 minutes ago, Altherion said:

The tide appears to be turning in the US. New cases are down in every state and Biden's administration has announced that vaccine shipments are up:

The grand total number of doses needed is around 420 million because the vaccines are not authorized for children and there are around 210 million adults in the US. Thus far, around 55 million doses have been administered so we need 365 million more. If the rate of 15.5 million per week is not an anomaly and can be sustained, this should only take another 5 months or so.

210 M adults in the US out of 328 M? That’s impossible. There are not 118 M people under 18. I think you must have left out a few age categories. 24% of the country is under 18. 76% of the country is 249 M people.

That means at least 498 M doses of a two-dose vaccine, which they all are except J&J. That means 443 M doses still needed. That’s 28.5 weeks, about the first or second week of September to vaccinate everyone, which isn’t going to happen. 80% would mean about 200 M people, 400 M doses, or 345 M more are needed. That’s about 22 weeks or the end of July. Factor in J&J vaccine and it might be the start of July, but I assume vaccinations will slow down quite a bit once you get passed 50% - 60% of the population done.

[The Anti-Targ]

The Govt decided to move AKL to level 2 from last night. Basically this is everything open, but group size limited to 100, and restaurants and cafes must seat people and have single servers per table, and masks are mandatory on all public transport. I'm not really in total agreement with that decision because the source of the outbreak isn't known. But perhaps the people making the recommendations and decisions know enough to be very confident that it has a known border link and it is not an infection brewing away out in the wild. I guess the next 3-5 days will tell. So fingers crossed.

[Mudguard]

8 hours ago, The Anti-Targ said:

I'm not entirely convinced that big pharma needs to be the model for anything in the health sector really. Universities with pharmacological schools given decent research grants and financial returns for making pharma breakthroughs could provide just as good output as the current big pharma model. Money and profits isn't the only motivator in healthcare and science. So yes, big pharma has provided a lot of very useful drugs and vaccines. But we didn't need big pharma for them to be discovered and put to good use. Indeed a different model might have avoided most or potentially all of the well documented and proven bad stuff that big pharma has done.

Academic research labs are good at doing basic research, which often leads to new drugs being discovered, but they are not suited for the manufacture and sale of drugs at a large scale, nor are they generally well funded enough to bankroll and run large clinical trials.  Clinical trials require more than just money, so just handing a university piles of cash isn't going to allow them to run the clinical trials.  For a phase 3 trial, you often enroll thousands of subjects, meaning you need to be able to manufacture thousands of doses for all the subjects.  Universities can't do that.

[Mlle. Zabzie]

18 minutes ago, Mudguard said:

Academic research labs are good at doing basic research, which often leads to new drugs being discovered, but they are not suited for the manufacture and sale of drugs at a large scale, nor are they generally well funded enough to bankroll and run large clinical trials.  Clinical trials require more than just money, so just handing a university piles of cash isn't going to allow them to run the clinical trials.  For a phase 3 trial, you often enroll thousands of subjects, meaning you need to be able to manufacture thousands of doses for all the subjects.  Universities can't do that.

To be perfectly accurate, Big Pharma often contracts out trials.

[The Anti-Targ]

8 minutes ago, Mudguard said:

Academic research labs are good at doing basic research, which often leads to new drugs being discovered, but they are not suited for the manufacture and sale of drugs at a large scale, nor are they generally well funded enough to bankroll and run large clinical trials.  Clinical trials require more than just money, so just handing a university piles of cash isn't going to allow them to run the clinical trials.  For a phase 3 trial, you often enroll thousands of subjects, meaning you need to be able to manufacture thousands of doses for all the subjects.  Universities can't do that.

It's not really about manufacture, it's about IP and patents. large scale cooperative trials conducted by multiple universities can carry out the logistical elements of clinical trials with a global reach. The manufacturing infrastructure in the university system doesn't exist, now, because the system has been geared towards big pharma for several decades. But that does not mean modest scale manufacturing infrastructure couldn't exist in public research / academic institutions that would be sufficient to be fully in control of all clinical trials. There are hundreds, possibly thousands of universities and research institutes around the world that could potentially have thousand dose scale manufacturing facilities. Just because the current system is what it is doesn't make it the best, ideal or most efficient system. It does however make it very profitable for the businesses and very expensive for the patients.

[Mudguard]

9 minutes ago, The Anti-Targ said:

It's not really about manufacture, it's about IP and patents. large scale cooperative trials conducted by multiple universities can carry out the logistical elements of clinical trials with a global reach. The manufacturing infrastructure in the university system doesn't exist, now, because the system has been geared towards big pharma for several decades. But that does not mean modest scale manufacturing infrastructure couldn't exist in public research / academic institutions that would be sufficient to be fully in control of all clinical trials. There are hundreds, possibly thousands of universities and research institutes around the world that could potentially have thousand dose scale manufacturing facilities. Just because the current system is what it is doesn't make it the best, ideal or most efficient system. It does however make it very profitable for the businesses and very expensive for the patients.

The universities hold the patents for their discoveries.  They just have no interest or capability to commercialize their discoveries on their own, so they sell exclusive licenses to their patents to big pharma for royalties.  If they wanted to try and develop the drug on their own, no one is stopping them.  It just doesn't make any sense financially or practically.  It's really expensive to set up drug manufacture operations with appropriate quality controls, and the smaller the operation, the less economy of scale you have.  It make no sense for each university to try and set up a small drug pilot plant on site. 

[Mlle. Zabzie]

15 minutes ago, Mudguard said:

The universities hold the patents for their discoveries.  They just have no interest or capability to commercialize their discoveries on their own, so they sell exclusive licenses to their patents to big pharma for royalties.  If they wanted to try and develop the drug on their own, no one is stopping them.  It just doesn't make any sense financially or practically.  It's really expensive to set up drug manufacture operations with appropriate quality controls, and the smaller the operation, the less economy of scale you have.  It make no sense for each university to try and set up a small drug pilot plant on site. 

On the manufacturing side, a LOT of who you think of as “big pharma” outsource some or all of their production to specialized contract manufacturers.  The big money is in the IP.

[Mudguard]

6 minutes ago, Mlle. Zabzie said:

On the manufacturing side, a LOT of who you think of as “big pharma” outsource some or all of their production to specialized contract manufacturers.  The big money is in the IP.

Both manufacturing and clinical trials, as you mentioned in your other post, can involve many partners.  Even if a big pharma company makes the drug, many, many raw materials are provided by other manufacturers.  But they may outsource the manufacture of a drug for a variety of reasons (i.e., lack of capacity, specialized expertise, local regulations, etc.).  For the coronavirus vaccines, AstraZeneca is partnering with the Serum Institute of India for manufacture of its vaccine for some regions.  And Pfizer is working with a company that specializes in lipid formulations to make the lipid nanoparticles used to deliver the mRNA in their vaccine.  Regulations from other countries also may require that big pharma partner up with a local company, like in China.

Bottom line is that universities aren't really suited at managing this process.  The professors certainly don't have time.  The university would have to try and set up a company to do all this, and most (probably all) universities aren't prolific enough to sustain such operations full time year after year for it to make sense.  There's many reasons why universities just stick with basic research, and then hand off the baton to an industry partner.

[The Anti-Targ]

I wonder if the reason we are starting to see a significant fall off in cases in the USA and other countries is because natural infection-recovery-immunity has reached something close to a herd immunity effect? If, for instance, the IFR for COVID-19 is 0.15%, it means everyone in the USA has now been infected. Given the USA is still seeing 60K+ deaths per day clearly not everyone has been infected, but it is pretty likely 50%+ people have been infected (0.3% IFR), 80% of whom never got tested and hence are not accounted in the confirmed numbers being officially reported. A 1% IFR means only 50 million total infections, but I doubt the testing system has been that good to have found >50% of all infected people.  would mean ~50% is not herd immunity, but this rate definitely provides a measure of protection and makes further massive waves, even without much vacination, unlikely. Unless of course immunity wanes sooner than hope for and 10s of millions of people infected early last year are now susceptible once again.

A research paper sought to estimate age related IFRs and came to the following conclusion:

https://www.medrxiv.org/content/10.1101/2020.07.23.20160895v7

Quote

Our analysis finds a exponential relationship between age and IFR for COVID-19. The estimated age-specific IFR is very low for children and younger adults (e.g., 0.002% at age 10 and 0.01% at age 25) but increases progressively to 0.4% at age 55, 1.4% at age 65, 4.6% at age 75, and 15% at age 85. Moreover, our results indicate that about 90% of the variation in population IFR across geographical locations reflects differences in the age composition of the population and the extent to which relatively vulnerable age groups were exposed to the virus.

If you take those age group IFRs and run them across the age break down of the US population I wonder what kind of infection total infection rate the 500K deaths gives us. Too lazy to do the maths myself.

18 minutes ago, Mudguard said:

The universities hold the patents for their discoveries.  They just have no interest or capability to commercialize their discoveries on their own, so they sell exclusive licenses to their patents to big pharma for royalties.  If they wanted to try and develop the drug on their own, no one is stopping them.  It just doesn't make any sense financially or practically.  It's really expensive to set up drug manufacture operations with appropriate quality controls, and the smaller the operation, the less economy of scale you have.  It make no sense for each university to try and set up a small drug pilot plant on site. 

Small scale manufacturing facilities are economically viable, because there are many small scale pill, potion and capsule companies in the dietary supplement area. They don't operate to the same exacting standards as drug manufacturing, but 95% of operations are identical for reputable dietary supplements. 

But now that 3D bio printing of ribeye steak is now an actual thing, there must be pharma potential with this technology that can make small scale production cheaper than would have been imagined just a few years ago. 

[Altherion]

2 hours ago, Fragile Bird said:

210 M adults in the US out of 328 M? That’s impossible. There are not 118 M people under 18. I think you must have left out a few age categories. 24% of the country is under 18. 76% of the country is 249 M people.

That means at least 498 M doses of a two-dose vaccine, which they all are except J&J. That means 443 M doses still needed. That’s 28.5 weeks, about the first or second week of September to vaccinate everyone, which isn’t going to happen. 80% would mean about 200 M people, 400 M doses, or 345 M more are needed. That’s about 22 weeks or the end of July. Factor in J&J vaccine and it might be the start of July, but I assume vaccinations will slow down quite a bit once you get passed 50% - 60% of the population done.

You are right; I took the first number from searching for it on Google, but that turns out to be from a long time ago. So yes, it's 6.5 months rather than 5 at the current rate for the grand total, but that's still not too bad especially since not everyone will want it.

I do wonder what will happen with the J&J vaccine. On the one hand, it's only a single shot, but on the other, it's clearly inferior to the Pfizer and Moderna ones. Also, the latter two have already been used by tens of millions of people and the effects are more or less known whereas any new one will always be at least a few months behind.

[Mudguard]

4 minutes ago, The Anti-Targ said:

I wonder if the reason we are starting to see a significant fall off in cases in the USA and other countries is because natural infection-recovery-immunity has reached something close to a herd immunity effect? If, for instance, the IFR for COVID-19 is 0.15%, it means everyone in the USA has now been infected. Given the USA is still seeing 60K+ deaths per day clearly not everyone has been infected, but it is pretty likely 50%+ people have been infected (0.3% IFR), 80% of whom never got tested and hence are not accounted in the confirmed numbers being officially reported. A 1% IFR means only 50 million total infections, but I doubt the testing system has been that good to have found >50% of all infected people.  would mean ~50% is not herd immunity, but this rate definitely provides a measure of protection and makes further massive waves, even without much vacination, unlikely. Unless of course immunity wanes sooner than hope for and 10s of millions of people infected early last year are now susceptible once again.

A research paper sought to estimate age related IFRs and came to the following conclusion:

https://www.medrxiv.org/content/10.1101/2020.07.23.20160895v7

If you take those age group IFRs and run them across the age break down of the US population I wonder what kind of infection total infection rate the 500K deaths gives us. Too lazy to do the maths myself.

Small scale manufacturing facilities are economically viable, because there are many small scale pill, potion and capsule companies in the dietary supplement area. They don't operate to the same exacting standards as drug manufacturing, but 95% of operations are identical for reputable dietary supplements. 

But now that 3D bio printing of ribeye steak is now an actual thing, there must be pharma potential with this technology that can make small scale production cheaper than would have been imagined just a few years ago. 

Many of these random dietary supplement companies don't actually make or package the pills themselves.  They contract out with a company, often in China or somewhere else that can do it for cheap, and then they slap their own label on it.

If there is one area in drug development that universities could fill, it would be for drugs used to treat extremely rare diseases.  Big pharma isn't generally interested because there isn't any money to be made, so it normally falls to universities, government labs, or small startups that take advantage of orphan drug grants, to fill the gap.  Progress is normally pretty slow as you can imagine.  

I doubt 50% of the US has been infected, and it's certainly not a good idea to assume that 50% are immune right now because of prior infection.  Earlier in the summer Sweden was claiming that they were nearing herd immunity to explain the reason for their sharp decline in cases, which we now know to be completely wrong.  Many other countries in Europe also saw a sharp decline too in cases during the summer.  People were assuming that countries were only detecting 1 in 10 or 1 in 20 cases, even though the antibody based surveillance testing wasn't showing anything even close.

[Zorral]

Just forget that 'herd immunity' myth, OK?

Though ... this from a staff writer for the magazine, not an epidemiologist.

"COVID-19 Cases Are Dropping Fast. Why?
Four reasons: social distancing, seasonality, seroprevalence, and shots.:

https://www.theatlantic.com/ideas/archive/2021/02/why-covid-19-cases-are-falling-so-fast/618041/

Quote

 

4. Partial immunity: Is the virus running out of bodies?
The coronavirus needs bodies in order to survive and replicate, and it now has access to fewer welcome hosts. Fifteen to 30 percent of American adults have already been infected with COVID-19, according to CDC estimates. Since people recovering from COVID-19 typically develop lasting immunological protection for many months (at least), the number of antibodies swirling around the U.S. population may naturally constrict the original coronavirus’s path forward.

America’s seroprevalence—that is, the number of people with coronavirus antibodies from a previous infection—is not randomly distributed across the country. Instead, immunity is probably concentrated among people who had little opportunity to avoid the disease, such as homeless people, frontline and essential workers, and people living in crowded multigenerational homes. It might also include people who were more likely to encounter the virus because of their lifestyle and values, such as risk-tolerant Americans who have been going to eat at indoor restaurants.

What I’m describing here is not herd immunity. Nothing is herd immunity, really. But it is partial immunity among the very populations that have been most likely to contract the disease, perhaps narrowing the path forward for the original SARS-CoV-2.

The emphasis here is on the word original, because we cannot forget the variants. The virus mutations from South Africa and Brazil in particular may elude the immunological protection among COVID-19 survivors, according to Mokdad. “In studies of seropositive and seronegative people”—that is, people with and without antibodies—“it didn’t seem to make a difference for the South Africa variant; everybody got the new variant equally,” he told me. “So we have to be looking at variants that previous infections are not protecting.”

This fact heightens the importance of accelerating vaccinations before these variants take off in the United States. And, as it happens, vaccinations are the last piece of our explanatory portfolio....

 

 

[Mudguard]

8 minutes ago, Altherion said:

You are right; I took the first number from searching for it on Google, but that turns out to be from a long time ago. So yes, it's 6.5 months rather than 5 at the current rate for the grand total, but that's still not too bad especially since not everyone will want it.

I do wonder what will happen with the J&J vaccine. On the one hand, it's only a single shot, but on the other, it's clearly inferior to the Pfizer and Moderna ones. Also, the latter two have already been used by tens of millions of people and the effects are more or less known whereas any new one will always be at least a few months behind.

For the US, the J&J vaccine probably isn't going to be used that much.  We have the cold storage infrastructure to properly store the mRNA vaccine throughout essentially the entire country, so why use the J&J vaccine if we've secured enough of the mRNA vaccines?  If someone is really against getting two shots, they could opt to use the J&J one.  Maybe it also makes sense to use it on the lower risk population, like the young and healthy, while saving the mRNA vaccines for the people most at risk.

Outside the US, I think the J&J vaccine could prove very useful if it's as good as the Oxford/AstraZeneca vaccine but with a single dose.  I think it also doesn't require difficult cold storage requirements.

[Fragile Bird]

Pfizer has announced tonight that it is much less effective against the South African variant, in laboratory testing. But, it is still above the "threshold" level for a vaccine. The news report I just saw did not explain what percentage the threshold is. Would that be 50%? Shepard Smith was interviewing someone from the White House team.

https://www.bloomberg.com/news/articles/2021-02-17/pfizer-shot-produces-fewer-antibodies-versus-south-africa-strain

eta: Smith was interviewing Andy Slavitt, Senior Covid-19 advisor to the White House.

[The Anti-Targ]

Herd immunity is just lazy shorthand for "partial population immunity that reduces the rate of spread and incidence of the disease". Since that's a 14-word phrase partial herd immunity is a not entirely misleading, briefer approximation of the same concept, that suffices for discussion on a non-scientific forum created to talk about a fantasy book series. But yes, strictly speaking herd immunity is wrong. But I'm lazy so I'll probably still use it, apologies in advance.

I was initially surprised the CDC puts the upper estimate of total infection at 30% and as low as 15%. They will no doubt have a better handle on the age distribution, but when I worked out a very back of the envelope potential age distribution and IFR calculation based on the numbers posted above I came out with 74.5 million total infected, and that's 22% of the population. That is based on 500K of the oldest demographic with a 15% IFR having been infected to date. OTOH if the USA has done a very good job at protecting the two highest age groups from getting infected then the total population infected looks a bit more like 125 million or 38% of the population. So I think with a 15-30% estimated total prevalence that suggests the US has done a poor to middling job at protecting the older demographics from the disease.

[Padraig]

26 minutes ago, Fragile Bird said:

Pfizer has announced tonight that it is much less effective against the South African variant, in laboratory testing. But, it is still above the "threshold" level for a vaccine. The news report I just saw did not explain what percentage the threshold is. Would that be 50%?

Yes.  50%.  See here.  I was reading elsewhere that it will be a lot quicker to get a vaccine variant approved (compared to the origin vaccines).  Not that we are close to having one ready.

1 hour ago, Mudguard said:

Maybe it also makes sense to use it on the lower risk population, like the young and healthy, while saving the mRNA vaccines for the people most at risk.

Effectively, that is what a lot of Europe is doing with AZ.  Leave Pfizer/Moderna for the "at risk" groups and make serious dents in the rest of the population with AZ (or J&J).  Can bring forward the timeline for the latter population by months.  Not that other countries wouldn't love to get the AZ/J&J's of this world, if the US wants to donate them but i'd be really worried if I was in South Africa at the moment.  Its variant seems to be the most resilient to current vaccines.  What do you do!

2 hours ago, Mlle. Zabzie said:

On the manufacturing side, a LOT of who you think of as “big pharma” outsource some or all of their production to specialized contract manufacturers.  The big money is in the IP.

And yes, it seems if anyone wants to shake up the big pharma industry, they have to focus on IP.  Everything else is driven from that.

[The Anti-Targ]

36 minutes ago, Padraig said:

Yes.  50%.  See here.  I was reading elsewhere that it will be a lot quicker to get a vaccine variant approved (compared to the origin vaccines).  Not that we are close to having one ready.

...

And yes, it seems if anyone wants to shake up the big pharma industry, they have to focus on IP.  Everything else is driven from that.

Doing that is effectively the same process, or similar, to getting the annual flu jab approved. The only thing you are doing is swapping out one strand of mRNA for a slightly different strand. In theory you should only need relatively small scale trial data to show efficacy and safety, and not a full blown set of clinical trials up to phase 3. 

And part of the shake up is that if govt money has been the main funder of research leading to a new drug (e.g. public universities, or govt research grants, even govt tax breaks. Then the govt (on behalf of the people) should own the IP and licence manufacture non-exclusively and take only a small royalty.

[Impmk2]

5 minutes ago, The Anti-Targ said:

Doing that is effectively the same process, or similar, to getting the annual flu jab approved. The only thing you are doing is swapping out one strand of mRNA for a slightly different strand. In theory you should only need relatively small scale trial data to show efficacy and safety, and not a full blown set of clinical trials up to phase 3. 

I imagine the pathway to getting a variant vaccine would be to do the plasmid/viral vector modification, which should take very little time for either the mRNA or adenovirus vaccine. Manufacture a small batch to test there's a decent immune response & protection as well as the initial safety check in whatever the animal model they're using (believe early on they were using mice with humanised ACE-2 receptor, but not sure now). Then a relatively small scale human testing similar to phase 1/2 for safety and checking immune response. Then large scale production should be pretty much exactly the same as the moment.

Would be very surprised if they haven't already started animal trials. So I'd speculate sometime in the middle of the year? But I've been constantly surprised, both pleasantly and otherwise with the timeline of this stuff vs small scale lab work.

I also wonder whether they'll just go with an booster shot with the major changes (believe E484K is the big one), or if they do some kind of heterologous mixture of a different varients + the wild type.