M

Mr._Clark

Audioholic Chief
Multi-dose injectables specially those without preservative/s can lead to loss of sterility of the remaining doses in the vial unless handled very carefully. The Advisory Committee meeting materials did not include the list of contents of the vaccine. Ideally the stopper of unpreserved injectable should be punctured only once. I am not sure how the doses are being withdrawn from the vials at the vaccination sites and whether the operators have been properly trained.
That could be, but it's still puzzling that no one recognized the problem and potential solution earlier (if the NYT article is accurate).

A NYT article dated 2/2/21 (link below) states that Moderna asked regulators to allow more doses per vial after the company "found a bottleneck in the bottling, capping and labeling process" despite the fact that filling the vials "has been identified for years as a constraint on vaccine production" (according to the article).

My best guess is that it's partly due to Moderna being a relatively new company with no experience producing vaccines.

Having said that, I'm not convinced the NYT articles describe the situation completely and accurately. I found an interesting sciencemag.org blog post (link below) about vaccine production stating that "Step Four" ("take your mRNA and your lipids and combine these into lipid nanoparticles (LNPs)") is likely to be the real bottleneck. The sciencemag.org blog post links to a blog post by Jonas Neubert that is actually even more interesting and more detailed. With regards to lipid nanoparticle assembly, Neubert says "Welcome to the bottleneck of mRNA vaccine production! . . . The problem at hand is this: How do you get the four lipids and the mRNA to combine in such a way that they form the protective sphere of the LNP, in a reproducible way?"

Lipid nanoparticle assembly appears to be the main bottleneck, but the actual process seems to be a bit of a mystery. Just for the fun of it I tried some quick patent searches but I was not able to find anything that looked like a clear "hit." I'm not saying it's not out there, just that I was not able to locate it. US20180043320 looks interesting but my impression is that it is probably not the process/system used (https://patents.google.com/patent/US20180043320A1/en)

Perhaps Moderna made unexpectedly good progress on the lipid nanoparticle assembly bottleneck which resulted in filling the vials being the new bottleneck.




 
M

Mr._Clark

Audioholic Chief
Just for the heck of it I did some google searching to see if there are any experts who still think the virus might have escaped from the lab. There seem to be a few who are not convinced the WHO investigation revealed much of anything.

As a general rule, I don't believe anything the Chinese government says.

>>>“If the only information you're allowing to be weighed is provided by the very people who have everything to lose by revealing such evidence, that just doesn't come close to passing the sniff test,” said David A. Relman, a microbiologist at Stanford University.

Relman suggested that the WHO team should have sought complete, detailed records from the laboratories about their experiments and the raw genomic sequence data of their research going back a decade.

Raina MacIntyre, professor of biosecurity at the University of New South Wales in Australia, was also surprised to see the idea of a lab accident ruled out so quickly.

Without exploring all leads, she suggested, “we may never know the origins of this virus.”

NBC is reporting that the U.S. government has ruled out a human-made or intentional origin, but not a lab accident origin (i.e. an animal-to-human jump at a lab). The actions of the Chinese government sure make it look like they do have something to hide.

It is interesting that a host animal still has not been identified.


>>>A Western intelligence official who has seen classified material told NBC News the U.S. has substantial intelligence that has not been made public about actions the Chinese government took — related to the Wuhan lab and other issues — that were designed to obscure the origins of Covid-19 and conceal its early impact. A former U.S. official who has also seen the intelligence agreed that it was significant, if inconclusive.

Both sources said the material, which they did not detail, did not add up to evidence that a lab accident occurred. But they said it raised enough circumstantial questions that analysts have been unable to rule out the lab scenario. U.S. intelligence officials declined to comment. The intelligence, which includes documents, paints a picture of a Chinese government initially trying to hide the burgeoning pandemic from the outside world. . . .

The so-called lab theory refers to a hypothesis that the Covid outbreak emerged in Wuhan as a result of an accidental release from one of the labs working with coronaviruses in that city — perhaps from an improper disposal of lab waste or an employee who got infected at work and then infected others.

U.S. intelligence agencies and scientists say they have ruled out that Covid-19 was human-made or intentionally released. The lab theory hypothesizes an accidental release of a virus found in nature by researchers and brought in for study.

Scientists say that scenario is unlikely on its face, because animal-to-human transmission of viruses are common, while lab accidents are relatively rare. The key scientists studying viruses in Wuhan say they were not studying the Covid-19 virus, which had not been previously documented in nature before the outbreak.

Intelligence officials counter that one key lab, the Wuhan Institute of Virology, removed from public view a database of 22,000 virus samples for security reasons, and has not allowed a detailed look at the lab's notes or other records.

They say it's suspicious that the virus outbreak arose in Wuhan, a hub of virus research in China, while the bats that commonly carry coronaviruses are typically found in caves a thousand miles from that city.

They note that scientists also have not found a host animal that could have transferred the virus to humans, after a year of looking.<<<


 
Swerd

Swerd

Audioholic Warlord
NBC is reporting that the U.S. government has ruled out a human-made or intentional origin, but not a lab accident origin (i.e. an animal-to-human jump at a lab). The actions of the Chinese government sure make it look like they do have something to hide.
It is true that they cannot rule out a possible lab accident that resulted in the virus infecting the public. But at the same time, there is nothing to support the idea of the then-Secretary of State Mike Pompeo, that there was significant evidence to support the lab origin theory of the novel coronavirus. This idea was so frequently repeated by Trump & Pompeo, without any supporting evidence, that it became lost among the other political football claims during the 2020 election year.
 
Swerd

Swerd

Audioholic Warlord
TLSGuy gets his wish. The British start a challenge trial:

That is completely unnecessary. We already have very good data from those very large clinical trials. The results of those two placebo-controlled trials of the Pfizer or Moderna vaccines are so clear cut, and the N is so large (15,000 in each arm: vaccine & placebo), that we can confidently predict that vaccinated people have a 94-95% probability of being protected from viral infection. Running a challenge trial in only 90 volunteers cannot beat that kind of statistical power. (Is there a negative control group, 90 people who get no vaccine but do get the challenge?) Such a challenge trial may confirm the earlier clinical trial results, but only for the many people whose eyes glaze over when they hear statistical evidence.
 
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T

trochetier

Audioholic
It is true that they cannot rule out a possible lab accident that resulted in the virus infecting the public. But at the same time, there is nothing to support the idea of the then-Secretary of State Mike Pompeo, that there was significant evidence to support the lab origin theory of the novel coronavirus. This idea was so frequently repeated by Trump & Pompeo, without any supporting evidence, that it became lost among the other political football claims during the 2020 election year.
Pomp-ass is/was no more than a pompous ass.
 
M

Mr._Clark

Audioholic Chief
It is true that they cannot rule out a possible lab accident that resulted in the virus infecting the public. But at the same time, there is nothing to support the idea of the then-Secretary of State Mike Pompeo, that there was significant evidence to support the lab origin theory of the novel coronavirus. This idea was so frequently repeated by Trump & Pompeo, without any supporting evidence, that it became lost among the other political football claims during the 2020 election year.
I'm happier when I pretend Pompeo doesn't exist.
 
TLS Guy

TLS Guy

Audioholic Slumlord
That is completely unnecessary. We already have very good data from those very large clinical trials. The results of those two placebo-controlled trials of the Pfizer or Moderna vaccines are so clear cut, and the N is so large (15,000 in each arm: vaccine & placebo), that we can confidently predict that vaccinated people have a 94-95% probability of being protected from viral infection. Running a challenge trial in only 90 volunteers cannot beat that kind of statistical power. (Is there a negative control group, 90 people who get no vaccine but do get the challenge?) Such a challenge trial may confirm the earlier clinical trial results, but only for the many people whose eyes glaze over when they hear statistical evidence.
I disagree.

I heard the lead researcher on the BBC today.

This trial has multiple purposes.

1). To determine the infectious dose of the various strains, and get accurate data on the relative infectivity.

2). To test vaccines when the infection rate is low. This will happen as vaccines roll out.

3). To aid the rapid development of vaccines against emergent novel strains, that may cause vaccine resistance of severe degree. We have to be able to react to this situations fast, or we could lose gains rapidly.

Methods have to be developed against emerging pandemics at speed.

This pandemic has shown that current trialling of vaccines under pandemic conditions is clearly not fit for purpose. We can never ever allow this to happen again.
The death rate has been awful, the economic, social, mental health and educational issues have been essentially catastrophic. This phase I, II and III trialling is far too slow under pandemic conditions. This will now take years to get this pandemic under control world wide.

Systems must be found to shut down emerging pandemics in four months or less. That means a totally different approach to this problem.

The volunteers, will be carefully selected healthy individuals between 18 and 30 years of age. As soon as a subject shows evidence of symptomatic infections that will be treated with current state of the art aggressive treatment.

This is war, and we need to treat it as such. Like in other war situations it requires soldiers on the front line.
 
TLS Guy

TLS Guy

Audioholic Slumlord
We made it to Bemidji, the first city on the Mississippi, today, and received our first dose of the Moderna Vaccine on time at Walmart.

We left a little before 7:00 AM. There was a light blustery snow falling in a bitterly cold wind for the first 150 miles. That was all six or two lane highways, mainly four. When we turned North at Motley, we had sunshine, and made the 90 miles to Bemidji on two lane highways.

We arrived a little after 11:AM and had our jabs on time. It was very efficient. We left a little after noon, and headed to the Park to eat our packed lunch on the shore of Lake Bemidji, which is a lake the Mississippi runs through.



You can see the fish houses on the frozen lake.

We headed home, and had a good journey until about 40 to 50 miles from home, where the snow was heavier, and the roads got very icy. Lots of cars were ending up in the ditch. I kept a slow steady pace and kept my distance. So we had to slow to 40 to 45 mph, and got home safely just before 5:00 PM.

We are both feeling fine. Our only problem is very slight tenderness at the injection site, but no discomfort unless you touch it.

So our next doses are due around March 17. If we have to travel back to Bemidji we will.
 
GO-NAD!

GO-NAD!

Audioholic Spartan
NBC is reporting that the U.S. government has ruled out a human-made or intentional origin, but not a lab accident origin (i.e. an animal-to-human jump at a lab). The actions of the Chinese government sure make it look like they do have something to hide.

It is interesting that a host animal still has not been identified.


>>>A Western intelligence official who has seen classified material told NBC News the U.S. has substantial intelligence that has not been made public about actions the Chinese government took — related to the Wuhan lab and other issues — that were designed to obscure the origins of Covid-19 and conceal its early impact. A former U.S. official who has also seen the intelligence agreed that it was significant, if inconclusive.

Both sources said the material, which they did not detail, did not add up to evidence that a lab accident occurred. But they said it raised enough circumstantial questions that analysts have been unable to rule out the lab scenario. U.S. intelligence officials declined to comment. The intelligence, which includes documents, paints a picture of a Chinese government initially trying to hide the burgeoning pandemic from the outside world. . . .

The so-called lab theory refers to a hypothesis that the Covid outbreak emerged in Wuhan as a result of an accidental release from one of the labs working with coronaviruses in that city — perhaps from an improper disposal of lab waste or an employee who got infected at work and then infected others.

U.S. intelligence agencies and scientists say they have ruled out that Covid-19 was human-made or intentionally released. The lab theory hypothesizes an accidental release of a virus found in nature by researchers and brought in for study.

Scientists say that scenario is unlikely on its face, because animal-to-human transmission of viruses are common, while lab accidents are relatively rare. The key scientists studying viruses in Wuhan say they were not studying the Covid-19 virus, which had not been previously documented in nature before the outbreak.

Intelligence officials counter that one key lab, the Wuhan Institute of Virology, removed from public view a database of 22,000 virus samples for security reasons, and has not allowed a detailed look at the lab's notes or other records.

They say it's suspicious that the virus outbreak arose in Wuhan, a hub of virus research in China, while the bats that commonly carry coronaviruses are typically found in caves a thousand miles from that city.

They note that scientists also have not found a host animal that could have transferred the virus to humans, after a year of looking.<<<


In the fullness of time, the real scandal will be understood that once again, just like with SARS in 2003, China tried to keep the outbreak a secret. This resulted in it spreading farther and faster than it might have if the alarm had been raised promptly and action taken to contain it.

The regime is pathological in its primary priority, which is self-preservation. Allowing knowledge of the virus to escape would bring on "instability". Better to try to keep a lid on it and just hope it goes away. :rolleyes:
 
M

Mr._Clark

Audioholic Chief
Reuters (link below) is reporting that "A laboratory study suggests that the South African variant of the coronavirus may reduce protective antibodies elicited by the Pfizer Inc/BioNTech SE vaccine by two-thirds, and it is not clear if the shot will be effective against the mutation, the companies said on Wednesday."

This wording is a bit odd. I think they mean that the neutralizing antibodies produced in response to the vaccine appear to have reduced effectiveness against the South African variant. The NEJM study (second link below) says:

>>>Thus, as compared with neutralization of USA-WA1/2020, neutralization of Δ242-244+D614G virus was similar and neutralization of the B.1.351-spike virus was weaker by approximately two thirds. Our data are also consistent with poorer neutralization of the virus with the full set of B.1.351-spike mutations than virus with either subset of mutations and suggested that virus with mutant residues in the receptor-binding site (K417N, E484K, and N501Y) is more poorly neutralized than virus with Δ242-244, which is located in the N-terminal domain of the spike protein.<<<

The main stream media reports I've seen imply that the vaccines will be less effective against the SA variant. However, the NEJM study says it is unclear if this means the vaccines will provide reduced protection against the SA variant:

>>>The onset of protection after one dose of BNT162b2 precedes the development of high neutralizing titers, and BNT162b2 immunization also elicits CD8+ T-cell responses. Thus, it is unclear what effect a reduction in neutralization by approximately two thirds would have on BNT162b2-elicited protection from Covid-19 caused by the B.1.351 lineage of SARS-CoV-2.<< (emphasis added)




 
Swerd

Swerd

Audioholic Warlord
Reuters (link below) is reporting that "A laboratory study suggests that the South African variant of the coronavirus may reduce protective antibodies elicited by the Pfizer Inc/BioNTech SE vaccine by two-thirds, and it is not clear if the shot will be effective against the mutation, the companies said on Wednesday."

This wording is a bit odd. I think they mean that the neutralizing antibodies produced in response to the vaccine appear to have reduced effectiveness against the South African variant. The NEJM study (second link below) says: … …
Thanks! I couldn't have said it better. The conclusions in the Reuters report are unwarranted. The NEJM article makes it clear that this complex question is yet to be answered.

Studying neutralizing antibodies generated by the present vaccine on the South African variant only looks at part of the anti-viral effect of vaccination. It ignores the CD8+ killer T-cell response. Circulating antibodies can bind to circulating virus particles and cause them to be cleared from a person's circulation (blood and lymph). This is what's meant by the words "neutralizing antibodies". CD8+ killer T-cells directly kill host cells infected with the virus. Each infected cell can produce many thousands of circulating virus particles.

Which is better? The answer is "it depends". The history of vaccines that we presently know has clearly taught us that vaccines which develop a strong CD8+ killer T-cell response are more effective than vaccines which develop primarily a neutralizing antibody response. Most vaccines in use today develop both kinds of responses. Immune responses against infecting pathogens (viruses & bacteria) are clearly complex. News organizations reporting on the coronavirus pandemic must get a better handle on this.
 
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Swerd

Swerd

Audioholic Warlord
This trial has multiple purposes.

1). To determine the infectious dose of the various strains, and get accurate data on the relative infectivity.
This kind of information is only useful if you intend to do repeated challenge trials with one particular virus strain. If one of the more infectious variants dominates in the future, it must be repeated for each variant.
2). To test vaccines when the infection rate is low. This will happen as vaccines roll out.
Effective vaccines, such as the three that now are widely approved, can also accomplish this.
3). To aid the rapid development of vaccines against emergent novel strains, that may cause vaccine resistance of severe degree. We have to be able to react to this situations fast, or we could lose gains rapidly.

Methods have to be developed against emerging pandemics at speed. This pandemic has shown that current trialling of vaccines under pandemic conditions is clearly not fit for purpose. We can never ever allow this to happen again.

The death rate has been awful, the economic, social, mental health and educational issues have been essentially catastrophic. This phase I, II and III trialling is far too slow under pandemic conditions. This will now take years to get this pandemic under control world wide.
I do agree that speed is essential.

The primary major accomplishment of recombinant mRNA or adenovirus-vector DNA vaccines is their speed in development compared to the old methods that we had for many decades. But the other major benefit is that the gene sequences of these vaccines can be easily edited. The edited versions, once manufactured, are no different at the chemical level other than the nucleic acid gene sequences. They should not require full Phase 1, 2, and 3 clinical trials for each new edition.

At present in the USA, the FDA already does something similar with each year's new 'edition' of Influenza A vaccines. The N (neuraminidase) and H (hemeagglutinin) genes targeted by each year's flu vaccine may be different, but overall these vaccines are the same each year. The FDA does allow their immediate use without time consuming safety & efficacy testing. These flu vaccines are made the old-fashioned way, by injecting many thousands of chicken eggs with the appropriate strains of influenza. Although the FDA has not put this in writing yet for the SARS-CoV-2 vaccines manufactured by the new recombinant gene methods, it is widely hoped among virus vaccine scientists (including those within the FDA) that this same approach to regulation can be borrowed from the experience with annual flu vaccines.

If this does happen, the various mRNA and adenovirus-vector DNA vaccines directed against new SARS-CoV-2 variants may be rapidly manufactured and put into use without elaborate clinical testing.
 
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highfigh

highfigh

Audioholic Overlord
I also suspect they're using out-sourcing shops in India, where Javascript developers often make $10/hour or less. The requirements and overall design are probably still done in the US, so the poor interface and bad performance are probably still domestic problems. Great websites are difficult design and implementation problems.
You think they should pay people in India the same as what someone makes in the US? They outsource because the COL is far lower outside of the US.

 
Irvrobinson

Irvrobinson

Audioholic Spartan
You think they should pay people in India the same as what someone makes in the US? They outsource because the COL is far lower outside of the US.

How on earth did you come to the conclusion that I'm in some way confused about why engineering talent costs less in India than in the US? My statement was to emphasize for anyone who has not worked in the computer or software engineering fields why out-sourcing of many tasks to India is so popular with senior executives. Even the most junior javascript engineers in the US are likely to earn $75K or more per year. In California probably six figures. I could go on and on about the complexities of overseas out-sourcing for software engineering, but this is a thread about COVID19.
 
highfigh

highfigh

Audioholic Overlord
How on earth did you come to the conclusion that I'm in some way confused about why engineering talent costs less in India than in the US? My statement was to emphasize for anyone who has not worked in the computer or software engineering fields why out-sourcing of many tasks to India is so popular with senior executives. Even the most junior javascript engineers in the US are likely to earn $75K or more per year. In California probably six figures. I could go on and on about the complexities of overseas out-sourcing for software engineering, but this is a thread about COVID19.
But you didn't post anything related to the COL, just that the jobs were probably outsourced.
 
Swerd

Swerd

Audioholic Warlord
We made it to Bemidji, the first city on the Mississippi, today, and received our first dose of the Moderna Vaccine on time at Walmart.

We left a little before 7:00 AM …
Very glad to hear you got your first vaccine dose. I'm trying to say jab instead of dose, shot, or injection. It is simpler to say, but I just can't get used to it.

Ten hours of driving during mid-winter in Minnesota is quite a lot of driving for one day. It must have been dark when you left home, and dark when you returned. Considering the snow plus other driving conditions that slowed you down, doing that round trip in 10 hours is an accomplishment. If you go again to Bemidji for jab #2, I hope the daylight is longer and the weather is better.

In the meantime, get some rest. Those antigen presenting cells are just now getting busy, and all those rapidly dividing B and T cells will consume lots of energy.
 
TLS Guy

TLS Guy

Audioholic Slumlord
Very glad to hear you got your first vaccine dose. I'm trying to say jab instead of dose, shot, or injection. It is simpler to say, but I just can't get used to it.

Ten hours of driving during mid-winter in Minnesota is quite a lot of driving for one day. It must have been dark when you left home, and dark when you returned. Considering the snow plus other driving conditions that slowed you down, doing that round trip in 10 hours is an accomplishment. If you go again to Bemidji for jab #2, I hope the daylight is longer and the weather is better.

In the meantime, get some rest. Those antigen presenting cells are just now getting busy, and all those rapidly dividing B and T cells will consume lots of energy.
No, we left at dawn and arrived back over an hour before darkness. I only have very slight tenderness over the left Deltoid muscle today. I have just blown out three driveways, on my 1981 JD 214 tractor with the 36" blower on the front. We can still get terrible weather here in March. March storms can be among the worst.
 
TLS Guy

TLS Guy

Audioholic Slumlord
Thanks! I couldn't have said it better. The conclusions in the Reuters report are unwarranted. The NEJM article makes it clear that this complex question is yet to be answered.

Studying neutralizing antibodies generated by the present vaccine on the South African variant only looks at part of the anti-viral effect of vaccination. It ignores the CD8+ killer T-cell response. Circulating antibodies can bind to circulating virus particles and cause them to be cleared from a person's circulation (blood and lymph). This is what's meant by the words "neutralizing antibodies". CD8+ killer T-cells directly kill host cells infected with the virus. Each infected cell can produce many thousands of circulating virus particles.

Which is better? The answer is "it depends". The history of vaccines that we presently know has clearly taught us that vaccines which develop a strong CD8+ killer T-cell response are more effective than vaccines which develop primarily a neutralizing antibody response. Most vaccines in use today develop both kinds of responses. Immune responses against infecting pathogens (viruses & bacteria) are clearly complex. News organizations reporting on the coronavirus pandemic must get a better handle on this.
The problem is we just do not know how effective the vaccines really are against these variants in the real world. South Africa has stopped using the Astrazeneca vaccine based on in vitro data. This I think was premature. This is another reason for testing vaccines under challenge conditions, as these could answer these questions quickly.
 
TLS Guy

TLS Guy

Audioholic Slumlord
This kind of information is only useful if you intend to do repeated challenge trials with one particular virus strain. If one of the more infectious variants dominates in the future, it must be repeated for each variant.
Effective vaccines, such as the three that now are widely approved, can also accomplish this.
I do agree that speed is essential.

The primary major accomplishment of recombinant mRNA or adenovirus-vector DNA vaccines is their speed in development compared to the old methods that we had for many decades. But the other major benefit is that the gene sequences of these vaccines can be easily edited. The edited versions, once manufactured, are no different at the chemical level other than the nucleic acid gene sequences. They should not require full Phase 1, 2, and 3 clinical trials for each new edition.

At present in the USA, the FDA recognizes this with each year's new 'edition' of Influenza A vaccines. The N and A genes that each year's flu vaccine targets may be different, but overall these vaccines are the same each year. The FDA does allow their immediate use without time consuming safety & efficacy testing. These flu vaccines are made the old-fashioned way, by injecting many thousands of chicken eggs with the appropriate strains of influenza. Although the FDA has not put this in writing yet for the SARS-CoV-2 vaccines manufactured by the new recombinant gene methods, it is widely hoped among virus vaccine scientists (including those within the FDA) that this same approach to regulation can be borrowed from the experience with annual flu vaccines.

If this does happen, the various mRNA and adenovirus-vector DNA vaccines directed against new SARS-CoV-2 variants may be rapidly manufactured and put into use without elaborate clinical testing.
The UK do have ideas for further novel vaccine platforms apparently. This challenge process will speed up development fast. There is real fear that we may not be able to outpace mutations. This is especially true if borders are not shut tight. This is decimating the airline, cruise and travel industry. The UK border is closed to many countries now, and may like Scotland close its borders to all countries. Scotland is considering closing its borders to England, unless England seals its borders, like Australia and NZ.

It seems to me this can not go on for years, as some propose. The way out of this is novel vaccine development. Liverpool has a highly novel platform under development that will go after the nucleus of all corona viruses for instance.
 

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