Developing the Covid-19 vaccine

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raven
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Re: Developing the Covid-19 vaccine

Post by raven » Thu Apr 15, 2021 4:58 pm

Herainestold wrote:
Tue Apr 13, 2021 10:38 pm
Still, Paul Offit, the director of the Vaccine Education Center at Children’s Hospital of Philadelphia and a veteran of discussions about vaccine safety, rattled off a list of questions even before the news about the J&J vaccine broke. Why, he asked, would a vaccine lead to the production of antibodies against platelet factor 4? He emphasized that even when the FDA authorized the vaccine, the plan had been to carefully monitor for cases of thromboses. Offit sits on a key FDA committee involved in reviewing vaccine data.

“What you really would love to know,” Offit said, “is what is causing the immune response to platelet factor 4?”

Is some part of the adenovirus mimicking platelet factor 4? If so, would that same mimicry occur with other adenoviruses? There’s no clear answer. But Offit suspects it’s a class-wide problem, meaning the same phenomenon associated with AstraZeneca’s vaccine is associated with Johnson & Johnson’s.

“There is going to be something about the adenovirus — whether it’s adenoviral DNA or an adenovirus protein — that complexes with platelet factor 4. So that will be determined, I suspect soon.”
If it is related to an adenovirus then it should occur with the Sputnik V vaccine..

https://www.statnews.com/2021/04/13/res ... ome-clues/
Interesting figures at the end of that article, giving numbers for vaccines and then a background rate:

Pfizer -35 serious blood clots in 54m doses (world wide? EU? not sure)
Moderna - 5 serious blood clots in 4m doses (EU)
J&J - 4 blood clots with low platelet levels* in 4.5million (world wide?)

And then background: 169 cases of CVST and 53 similar clots in abdominal vessels in 34m people. Over what time frame it doesn't say.

* Note it doesn't say 'with low platelet levels' for the Pfizer & Moderna stats, so I'm assuming those might be more run of the mill clotting events & so more likely not related to the vaccination.

A google of adenovirus & low platelet levels brought me to this paper about using adenovirus to deliver gene therapy: Adenovirus-Platelet Interaction in Blood Causes Virus Sequestration to the Reticuloendothelial System of the Liver

If I skim-read it right they found the adenovirus binds to platelets, activates them, and then the resulting platelet/virus aggregates are cleared from the blood. And it says (my bold):
Although a role for platelets in the removal of blood-borne infectious agents has not been proposed, it is known that many viral infections (including those caused by hepatitis C virus, human immunodeficiency virus, mumps virus, Dengue virus, human T-cell leukemia virus, human cytomegalovirus, severe acute respiratory syndrome virus, swine fever virus, hantavirus, parvovirus B19, influenza virus, and Epstein-Barr virus) induce thrombocytopenia, and that viruses are frequent contaminants of platelet concentrates used for transfusion. Platelet activation, aggregation, and subsequent degradation in the reticuloendothelial system have been seen during infections with swine fever virus. For Ad, studies with animal models and humans describe decreases in platelet number and circulation time, indicating that the platelet-mediated pathway of Ad clearance that we discovered in our mouse model is also relevant for humans. This is supported by observations of thrombotic thrombocytopenic purpura or deep venous thrombosis in patients with disseminated adenoviral infections. Furthermore, it is feasible that removal of activated/pathogen-loaded platelets could involve phagocytosis by tissue macrophages, as has been described for idiopathic thrombocytopenic purpura
So if clots & low platelet levels are rare complications of adenovirus infection, that might explain it happening after vaccines based on adenovirus. (And if that complication of infection was known, why the countraindications for AZ were blood thinners & any bleeding/bruising problems.)

I'll be relieved if it's to do with the adenovirus, tbh. My immediate thought was it was the spike protein, as Covid itself causes thrombosis. If it's just the vector, we can switch to a different one or stick to mRNA vaccines.

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Re: Developing the Covid-19 vaccine

Post by tom p » Fri Apr 16, 2021 9:55 am

Herainestold wrote:
Tue Apr 13, 2021 10:38 pm
Still, Paul Offit, the director of the Vaccine Education Center at Children’s Hospital of Philadelphia and a veteran of discussions about vaccine safety, rattled off a list of questions even before the news about the J&J vaccine broke. Why, he asked, would a vaccine lead to the production of antibodies against platelet factor 4? He emphasized that even when the FDA authorized the vaccine, the plan had been to carefully monitor for cases of thromboses. Offit sits on a key FDA committee involved in reviewing vaccine data.

“What you really would love to know,” Offit said, “is what is causing the immune response to platelet factor 4?”

Is some part of the adenovirus mimicking platelet factor 4? If so, would that same mimicry occur with other adenoviruses? There’s no clear answer. But Offit suspects it’s a class-wide problem, meaning the same phenomenon associated with AstraZeneca’s vaccine is associated with Johnson & Johnson’s.

“There is going to be something about the adenovirus — whether it’s adenoviral DNA or an adenovirus protein — that complexes with platelet factor 4. So that will be determined, I suspect soon.”
If it is related to an adenovirus then it should occur with the Sputnik V vaccine..

https://www.statnews.com/2021/04/13/res ... ome-clues/
Gamelya/RDIF reckon it won't affect Sputnik
How much trust one places in pronouncements from the RIDF is entirely at the reader's discretion


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Re: Developing the Covid-19 vaccine

Post by Herainestold » Tue Apr 20, 2021 3:15 pm

It will be interesting to compare the incidence of rare blood clots between the AZ and J&J vaccines. Also curious that the adenovirus based Sputnik does not have this problem.

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Re: Developing the Covid-19 vaccine

Post by tom p » Tue Apr 20, 2021 3:34 pm

Herainestold wrote:
Tue Apr 20, 2021 3:15 pm
It will be interesting to compare the incidence of rare blood clots between the AZ and J&J vaccines. Also curious that the RDIF claims the adenovirus based Sputnik does not have this problem.
FIFY. I remain to be convinced about the veracity of that claim, but would be pleasantly surprised if it were true.

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Re: Developing the Covid-19 vaccine

Post by Herainestold » Tue Apr 20, 2021 3:47 pm

tom p wrote:
Tue Apr 20, 2021 3:34 pm
Herainestold wrote:
Tue Apr 20, 2021 3:15 pm
It will be interesting to compare the incidence of rare blood clots between the AZ and J&J vaccines. Also curious that the RDIF claims the adenovirus based Sputnik does not have this problem.
FIFY. I remain to be convinced about the veracity of that claim, but would be pleasantly surprised if it were true.
Okay< I take your point. Is anybody looking at it?

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Re: Developing the Covid-19 vaccine

Post by tom p » Tue Apr 20, 2021 4:02 pm

It is not an authorised medicinal product in the EEA* and there is as yet no formal application for authorisation.
The same is true in the USA & the UK.
I do not know about the rest of the world.
Because of this, I do not know which regulators are able to see side effect data relating to the sputnik vaccine.

*emergency distribution has been authorised in some member states. that is not the same thing as authorisation. a request for rolling review has been submitted to the EMA. I do not know how much data the relevant reviewers have yet received or reviewed.

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Re: Developing the Covid-19 vaccine

Post by tom p » Tue Apr 20, 2021 4:03 pm

Herainestold wrote:
Tue Apr 20, 2021 3:15 pm
It will be interesting to compare the incidence of rare blood clots between the AZ and J&J vaccines. Also curious that the adenovirus based Sputnik does not have this problem.
JnJ ~1 in a million. AZ a handful in a million.

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Re: Developing the Covid-19 vaccine

Post by Herainestold » Tue Apr 20, 2021 4:37 pm

Thanks for that. I was under the impression that Sputnik was being evaluated by the EMA. I guess that is the rolling review thingy.
Also thanks for the AZ/J&J comparison.


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Re: Developing the Covid-19 vaccine

Post by tom p » Wed Apr 21, 2021 8:05 am

Herainestold wrote:
Tue Apr 20, 2021 4:37 pm
Thanks for that. I was under the impression that Sputnik was being evaluated by the EMA. I guess that is the rolling review thingy.
Also thanks for the AZ/J&J comparison.
A rolling review isn't exactly the same as a marketing authorisation application. It's a new thing that comes before the application. Once an application has been made, then the rules for the drug company change & they have to report each side effect report direct to the EMA. Until then, it's data from trials in an aggregated format.

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Re: Developing the Covid-19 vaccine

Post by Herainestold » Wed Apr 21, 2021 1:35 pm

tom p wrote:
Wed Apr 21, 2021 8:05 am
Herainestold wrote:
Tue Apr 20, 2021 4:37 pm
Thanks for that. I was under the impression that Sputnik was being evaluated by the EMA. I guess that is the rolling review thingy.
Also thanks for the AZ/J&J comparison.
A rolling review isn't exactly the same as a marketing authorisation application. It's a new thing that comes before the application. Once an application has been made, then the rules for the drug company change & they have to report each side effect report direct to the EMA. Until then, it's data from trials in an aggregated format.
Thank you for the explanation.

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snoozeofreason
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Re: Developing the Covid-19 vaccine

Post by snoozeofreason » Fri Apr 23, 2021 6:13 pm

From Medscape (https://www.medscape.com/viewarticle/949636)
Scientists in Germany say they've worked out the two-step mechanism by which the AstraZeneca vaccine causes rare but devastating blood clots that gobble up the body's supply of platelets.

IANAD, so I don't know how plausible the explanation is.
In six days the Lord made the heavens and the earth, the sea, and all that is in them. The human body was knocked up pretty late on the Friday afternoon, with a deadline looming. How well do you expect it to work?

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Re: Developing the Covid-19 vaccine

Post by shpalman » Mon Apr 26, 2021 2:04 pm

Has anyone got the Johnson & Johnson publications to hand, only I've only been following the Pfizer and (mainly) AstraZeneca ones?

In particular, the Johnson & Johnson stipulates only a single dose, whereas much was made of pointing out that AstraZeneca works well with one dose for 3-12 weeks after that dose, at which point you need another one, which contradicts to some degree their dose protocol which they'd worked out after Phase II I presume. Of course, really long-term stuff is hard to know since these things have only recently been invented. But if AstraZeneca had assumed that a single dose would have been enough and stopped looking at Phase III data after 10-12 weeks in order to get the paper published then also they would be saying that a single dose was fine. So, over what timescales were the Johnson & Johnson trials run?
molto tricky

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Re: Developing the Covid-19 vaccine

Post by Herainestold » Mon Apr 26, 2021 11:01 pm

WHO to evaluate Chinese covid vaccines.
Two Chinese Covid-19 vaccines
are to be reviewed by a global regulator for the first time,
a decision that could have far-reaching implications for worldwide vaccine roll-outs.

China’s pharmaceutical companies have faced intense scrutiny for not releasing detailed data about how well the vaccines work before they came into use, but now the World Health Organization will decide whether they can be licensed for emergency use - a globally recognised stamp of approval.

A decision to authorise the products from Sinopharm and Sinovac Biotech would have far-reaching implications because shortages have crippled a WHO global vaccine distribution programme, prompting some countries to turn to China.
Good news for the rest of the globe that can't afford the western mRNA vaccines

https://www.scmp.com/news/china/diploma ... nese-covid

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Re: Developing the Covid-19 vaccine

Post by Millennie Al » Tue Apr 27, 2021 12:04 am

shpalman wrote:
Mon Apr 26, 2021 2:04 pm
Has anyone got the Johnson & Johnson publications to hand, only I've only been following the Pfizer and (mainly) AstraZeneca ones?

In particular, the Johnson & Johnson stipulates only a single dose, whereas much was made of pointing out that AstraZeneca works well with one dose for 3-12 weeks after that dose, at which point you need another one, which contradicts to some degree their dose protocol which they'd worked out after Phase II I presume. Of course, really long-term stuff is hard to know since these things have only recently been invented. But if AstraZeneca had assumed that a single dose would have been enough and stopped looking at Phase III data after 10-12 weeks in order to get the paper published then also they would be saying that a single dose was fine. So, over what timescales were the Johnson & Johnson trials run?
Is this what you're looking for: https://www.nejm.org/doi/full/10.1056/NEJMoa2101544 ? The magic search term is Ad26.COV2.S see also https://www.nejm.org/doi/full/10.1056/NEJMoa2034201

It says:
The trial began enrollment on September 21, 2020, and the data-cutoff date for the present analysis was January 22, 2021.
Covid-19 - Don't catch it: don't spread it.

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bob sterman
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Re: Developing the Covid-19 vaccine

Post by bob sterman » Tue Apr 27, 2021 6:03 am

Herainestold wrote:
Mon Apr 26, 2021 11:01 pm
WHO to evaluate Chinese covid vaccines.
Two Chinese Covid-19 vaccines
are to be reviewed by a global regulator for the first time,
a decision that could have far-reaching implications for worldwide vaccine roll-outs.

China’s pharmaceutical companies have faced intense scrutiny for not releasing detailed data about how well the vaccines work before they came into use, but now the World Health Organization will decide whether they can be licensed for emergency use - a globally recognised stamp of approval.

A decision to authorise the products from Sinopharm and Sinovac Biotech would have far-reaching implications because shortages have crippled a WHO global vaccine distribution programme, prompting some countries to turn to China.
Good news for the rest of the globe that can't afford the western mRNA vaccines

https://www.scmp.com/news/china/diploma ... nese-covid
So a newspaper owned by Alibaba Group (SCMP) writes a positive article about the future prospects of vaccine produced by company which Alibaba Health has a strategic partnership with. Nice!!

Alibaba Health, Sinovac in deal to build platform for coronavirus vaccine inoculation
https://www.reuters.com/article/health- ... SKBN26819C

Herainestold
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Re: Developing the Covid-19 vaccine

Post by Herainestold » Tue Apr 27, 2021 2:39 pm

bob sterman wrote:
Tue Apr 27, 2021 6:03 am
Herainestold wrote:
Mon Apr 26, 2021 11:01 pm
WHO to evaluate Chinese covid vaccines.
Two Chinese Covid-19 vaccines
are to be reviewed by a global regulator for the first time,
a decision that could have far-reaching implications for worldwide vaccine roll-outs.

China’s pharmaceutical companies have faced intense scrutiny for not releasing detailed data about how well the vaccines work before they came into use, but now the World Health Organization will decide whether they can be licensed for emergency use - a globally recognised stamp of approval.

A decision to authorise the products from Sinopharm and Sinovac Biotech would have far-reaching implications because shortages have crippled a WHO global vaccine distribution programme, prompting some countries to turn to China.
Good news for the rest of the globe that can't afford the western mRNA vaccines

https://www.scmp.com/news/china/diploma ... nese-covid
So a newspaper owned by Alibaba Group (SCMP) writes a positive article about the future prospects of vaccine produced by company which Alibaba Health has a strategic partnership with. Nice!!

Alibaba Health, Sinovac in deal to build platform for coronavirus vaccine inoculation
https://www.reuters.com/article/health- ... SKBN26819C
What does that mean "build a platform"? SCMP used to be a Murdoch paper. Did that make it more credible?
The more non western covid vaccines out there, the better< is what I think

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shpalman
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Re: Developing the Covid-19 vaccine

Post by shpalman » Tue Apr 27, 2021 2:48 pm

Millennie Al wrote:
Tue Apr 27, 2021 12:04 am
shpalman wrote:
Mon Apr 26, 2021 2:04 pm
Has anyone got the Johnson & Johnson publications to hand, only I've only been following the Pfizer and (mainly) AstraZeneca ones?

In particular, the Johnson & Johnson stipulates only a single dose, whereas much was made of pointing out that AstraZeneca works well with one dose for 3-12 weeks after that dose, at which point you need another one, which contradicts to some degree their dose protocol which they'd worked out after Phase II I presume. Of course, really long-term stuff is hard to know since these things have only recently been invented. But if AstraZeneca had assumed that a single dose would have been enough and stopped looking at Phase III data after 10-12 weeks in order to get the paper published then also they would be saying that a single dose was fine. So, over what timescales were the Johnson & Johnson trials run?
Is this what you're looking for: https://www.nejm.org/doi/full/10.1056/NEJMoa2101544 ? The magic search term is Ad26.COV2.S see also https://www.nejm.org/doi/full/10.1056/NEJMoa2034201

It says:
The trial began enrollment on September 21, 2020, and the data-cutoff date for the present analysis was January 22, 2021.
Yes thanks. In Fig. 2A you can see how it starts working after 2 weeks; in the 10-12 week period there are 7 placebo cases and 2 vaccine cases so probably still working, but after 12 weeks there are so few cases (looking at the numbers under the graph rather than the graph itself) that you can't really tell, i.e. from 12 weeks to the end of the graph there are two cases in the placebo group and two cases in the vaccine group.

I don't immediately understand the "No. at risk" and why it decays during the trial though.
molto tricky

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bob sterman
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Re: Developing the Covid-19 vaccine

Post by bob sterman » Tue Apr 27, 2021 2:48 pm

Herainestold wrote:
Tue Apr 27, 2021 2:39 pm
bob sterman wrote:
Tue Apr 27, 2021 6:03 am
So a newspaper owned by Alibaba Group (SCMP) writes a positive article about the future prospects of vaccine produced by company which Alibaba Health has a strategic partnership with. Nice!!

Alibaba Health, Sinovac in deal to build platform for coronavirus vaccine inoculation
https://www.reuters.com/article/health- ... SKBN26819C
What does that mean "build a platform"? SCMP used to be a Murdoch paper. Did that make it more credible?
The more non western covid vaccines out there, the better< is what I think
I think it's a data platform - for managing vaccine roll-out, bookings, proof of vaccination - that sort of thing.

The more effective vaccines out there the better - certainly! And it sounds like independent evaluations of Sinovac's effectiveness will be available soon.

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Re: Developing the Covid-19 vaccine

Post by Herainestold » Tue Apr 27, 2021 4:13 pm

bob sterman wrote:
Tue Apr 27, 2021 2:48 pm
Herainestold wrote:
Tue Apr 27, 2021 2:39 pm
bob sterman wrote:
Tue Apr 27, 2021 6:03 am
So a newspaper owned by Alibaba Group (SCMP) writes a positive article about the future prospects of vaccine produced by company which Alibaba Health has a strategic partnership with. Nice!!

Alibaba Health, Sinovac in deal to build platform for coronavirus vaccine inoculation
https://www.reuters.com/article/health- ... SKBN26819C
What does that mean "build a platform"? SCMP used to be a Murdoch paper. Did that make it more credible?
The more non western covid vaccines out there, the better< is what I think
I think it's a data platform - for managing vaccine roll-out, bookings, proof of vaccination - that sort of thing.

The more effective vaccines out there the better - certainly! And it sounds like independent evaluations of Sinovac's effectiveness will be available soon.
Okay, I see. The EMA should undertake to evaluate all these different vaccines, as it is the gold standard authority. If they were all evaluated by the same agency, it would give greater confidence.

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bob sterman
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Re: Developing the Covid-19 vaccine

Post by bob sterman » Tue Apr 27, 2021 4:32 pm

Herainestold wrote:
Tue Apr 27, 2021 4:13 pm
bob sterman wrote:
Tue Apr 27, 2021 2:48 pm
I think it's a data platform - for managing vaccine roll-out, bookings, proof of vaccination - that sort of thing.

The more effective vaccines out there the better - certainly! And it sounds like independent evaluations of Sinovac's effectiveness will be available soon.
Okay, I see. The EMA should undertake to evaluate all these different vaccines, as it is the gold standard authority. If they were all evaluated by the same agency, it would give greater confidence.
Huh? I thought it was the WHO who were about to evaluate Sinovac??? Who said anything about the EMA? (Sorry - getting a bit "who's on first").

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Re: Developing the Covid-19 vaccine

Post by Herainestold » Tue Apr 27, 2021 5:04 pm

bob sterman wrote:
Tue Apr 27, 2021 4:32 pm
Herainestold wrote:
Tue Apr 27, 2021 4:13 pm
bob sterman wrote:
Tue Apr 27, 2021 2:48 pm
I think it's a data platform - for managing vaccine roll-out, bookings, proof of vaccination - that sort of thing.

The more effective vaccines out there the better - certainly! And it sounds like independent evaluations of Sinovac's effectiveness will be available soon.
Okay, I see. The EMA should undertake to evaluate all these different vaccines, as it is the gold standard authority. If they were all evaluated by the same agency, it would give greater confidence.
Huh? I thought it was the WHO who were about to evaluate Sinovac??? Who said anything about the EMA? (Sorry - getting a bit "who's on first").
I said the EMA should evaluate it. The WHO is seen by some as too political and the EMA is the gold standard regulatory agency.

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bolo
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Re: Developing the Covid-19 vaccine

Post by bolo » Tue Apr 27, 2021 6:00 pm

I presume that if all the other vaccine manufacturers came to the EMA with safety and efficacy data and license applications, it would happily evaluate them. The fact that it hasn't already is presumably because the manufacturers haven't asked it to, or haven't provided adequate data.

At least, that's how most regulatory agencies work.

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Re: Developing the Covid-19 vaccine

Post by Herainestold » Tue Apr 27, 2021 7:32 pm

bolo wrote:
Tue Apr 27, 2021 6:00 pm
I presume that if all the other vaccine manufacturers came to the EMA with safety and efficacy data and license applications, it would happily evaluate them. The fact that it hasn't already is presumably because the manufacturers haven't asked it to, or haven't provided adequate data.

At least, that's how most regulatory agencies work.
I think you're right. My point is that the EMA is the most esteemed regulator and if all vaccines were evaluated by them, it would be easier to compare them and there would be no stigma applied to vaccines that didnt have the check mark of any particular regulator.

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