Developing the Covid-19 vaccine

Covid-19 discussion, bring your own statistics
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Woodchopper
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Re: Developing the Covid-19 vaccine

Post by Woodchopper » Sat Apr 03, 2021 7:29 am


The novel pandemic betacoronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has infected at least 120 million people since its identification as the cause of a December 2019 viral pneumonia outbreak in Wuhan, China. Despite the unprecedented pace of vaccine development, with six vaccines already in use worldwide, the emergence of SARS-CoV-2 variants of concern (VOC) across diverse geographic locales suggests herd immunity may fail to eliminate the virus. All three officially designated VOC carry Spike (S) polymorphisms thought to enable escape from neutralizing antibodies elicited during initial waves of the pandemic. Here, we characterize the biological consequences of the ensemble of S mutations present in VOC lineages B.1.1.7 (501Y.V1) and B.1.351 (501Y.V2). Using a replication-competent EGFP-reporter vesicular stomatitis virus (VSV) system, rcVSV-CoV2-S, which encodes S from SARS coronavirus 2 in place of VSV-G, coupled with a clonal HEK-293T ACE2 TMPRSS2 cell line optimized for highly efficient S-mediated infection, we determined that 8 out of 12 (75%) of serum samples from 12 recipients of the Russian Sputnik V Ad26 / Ad5 vaccine showed dose response curve slopes indicative of failure to neutralize rcVSV-CoV2-S: B.1.351. The same set of sera efficiently neutralized S from B.1.1.7 and showed only moderately reduced activity against S carrying the E484K substitution alone. Taken together, our data suggest that control of emergent SARS-CoV-2 variants may benefit from updated vaccines.
https://www.medrxiv.org/content/10.1101 ... 21254660v1


tl;dr Russian Sputnik vaccine appears to be less effective against the South Africa variant, but works ok against the UK variant.

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Re: Developing the Covid-19 vaccine

Post by Woodchopper » Sat Apr 03, 2021 7:37 am

Millennie Al wrote:
Sat Apr 03, 2021 1:59 am
jdc wrote:
Fri Apr 02, 2021 8:35 pm
The 30 cases figure is an update after a review and apparently the figures cover 9 December 2020 to 21 March. If we've done the review and updated the numbers then what makes you think there'll be "more and more"? We've gone from 0 to 5 to 30 but that doesn't mean the numbers will keep going up.
From media reports it seems that the supposed problem is cerebral venous sinus thrombosis (CVST), which wikipedia says has occurs at a rate of "3-4 cases per million annual incidence in adults". By 21st March, 27,997,976 people had received their first vaccination (from https://coronavirus.data.gov.uk/details/vaccinations). So over a year, we would expect 84-112 cases of CVST in that many people, or 21-24 per quarter. If we then halve it to allow for a linear rate of vaccination, we get around 11 expected cases. While this is below the 30 found so far, it is still a very small number and it's not at all clear that it's anything other than a statistical fluctuation, or maybe even a result of finding more of something that you're looking for. Obviously, it is worth careful monitoring, but it is far too small an effect to justify drastic action such as refusing to use the vaccine, which is likely to kill far more people.
You would though expect those 11 to occur throughout the year. Whereas we’ve seen the 30 within three months or so. If it is a rare side effect we’d expect to see many more.

Still, the possible side effect appears to be much less dangerous than getting Covid.

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Re: Developing the Covid-19 vaccine

Post by mediocrity511 » Sat Apr 03, 2021 7:56 am

Woodchopper wrote:
Sat Apr 03, 2021 7:37 am
Millennie Al wrote:
Sat Apr 03, 2021 1:59 am
jdc wrote:
Fri Apr 02, 2021 8:35 pm
The 30 cases figure is an update after a review and apparently the figures cover 9 December 2020 to 21 March. If we've done the review and updated the numbers then what makes you think there'll be "more and more"? We've gone from 0 to 5 to 30 but that doesn't mean the numbers will keep going up.
From media reports it seems that the supposed problem is cerebral venous sinus thrombosis (CVST), which wikipedia says has occurs at a rate of "3-4 cases per million annual incidence in adults". By 21st March, 27,997,976 people had received their first vaccination (from https://coronavirus.data.gov.uk/details/vaccinations). So over a year, we would expect 84-112 cases of CVST in that many people, or 21-24 per quarter. If we then halve it to allow for a linear rate of vaccination, we get around 11 expected cases. While this is below the 30 found so far, it is still a very small number and it's not at all clear that it's anything other than a statistical fluctuation, or maybe even a result of finding more of something that you're looking for. Obviously, it is worth careful monitoring, but it is far too small an effect to justify drastic action such as refusing to use the vaccine, which is likely to kill far more people.
You would though expect those 11 to occur throughout the year. Whereas we’ve seen the 30 within three months or so. If it is a rare side effect we’d expect to see many more.

Still, the possible side effect appears to be much less dangerous than getting Covid.
It's also worth pointing out that CVST is a condition that mainly occurs in people under 55. So whilst we have vaccinated care workers and the vulnerable, the bulk of vaccines have gone to the elderly and not the part of the population most at risk of CVST. If it is related, we can expect to see cases rise significantly as the roll out reaches more younger people.

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Re: Developing the Covid-19 vaccine

Post by Woodchopper » Sat Apr 03, 2021 10:23 am

mediocrity511 wrote:
Sat Apr 03, 2021 7:56 am
Woodchopper wrote:
Sat Apr 03, 2021 7:37 am
Millennie Al wrote:
Sat Apr 03, 2021 1:59 am


From media reports it seems that the supposed problem is cerebral venous sinus thrombosis (CVST), which wikipedia says has occurs at a rate of "3-4 cases per million annual incidence in adults". By 21st March, 27,997,976 people had received their first vaccination (from https://coronavirus.data.gov.uk/details/vaccinations). So over a year, we would expect 84-112 cases of CVST in that many people, or 21-24 per quarter. If we then halve it to allow for a linear rate of vaccination, we get around 11 expected cases. While this is below the 30 found so far, it is still a very small number and it's not at all clear that it's anything other than a statistical fluctuation, or maybe even a result of finding more of something that you're looking for. Obviously, it is worth careful monitoring, but it is far too small an effect to justify drastic action such as refusing to use the vaccine, which is likely to kill far more people.
You would though expect those 11 to occur throughout the year. Whereas we’ve seen the 30 within three months or so. If it is a rare side effect we’d expect to see many more.

Still, the possible side effect appears to be much less dangerous than getting Covid.
It's also worth pointing out that CVST is a condition that mainly occurs in people under 55. So whilst we have vaccinated care workers and the vulnerable, the bulk of vaccines have gone to the elderly and not the part of the population most at risk of CVST. If it is related, we can expect to see cases rise significantly as the roll out reaches more younger people.
Yes, good point.

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Re: Developing the Covid-19 vaccine

Post by jdc » Sat Apr 03, 2021 3:02 pm

Woodchopper wrote:
Sat Apr 03, 2021 7:37 am
Millennie Al wrote:
Sat Apr 03, 2021 1:59 am
jdc wrote:
Fri Apr 02, 2021 8:35 pm
The 30 cases figure is an update after a review and apparently the figures cover 9 December 2020 to 21 March. If we've done the review and updated the numbers then what makes you think there'll be "more and more"? We've gone from 0 to 5 to 30 but that doesn't mean the numbers will keep going up.
From media reports it seems that the supposed problem is cerebral venous sinus thrombosis (CVST), which wikipedia says has occurs at a rate of "3-4 cases per million annual incidence in adults". By 21st March, 27,997,976 people had received their first vaccination (from https://coronavirus.data.gov.uk/details/vaccinations). So over a year, we would expect 84-112 cases of CVST in that many people, or 21-24 per quarter. If we then halve it to allow for a linear rate of vaccination, we get around 11 expected cases. While this is below the 30 found so far, it is still a very small number and it's not at all clear that it's anything other than a statistical fluctuation, or maybe even a result of finding more of something that you're looking for. Obviously, it is worth careful monitoring, but it is far too small an effect to justify drastic action such as refusing to use the vaccine, which is likely to kill far more people.
You would though expect those 11 to occur throughout the year. Whereas we’ve seen the 30 within three months or so. If it is a rare side effect we’d expect to see many more.

Still, the possible side effect appears to be much less dangerous than getting Covid.
Nah, he's saying he'd expect 11 per quarter. He divided the annual figure by four before making his adjustment for the rate of vaccination.

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Re: Developing the Covid-19 vaccine

Post by jdc » Sat Apr 03, 2021 3:10 pm

That is a good point Medi. Time for me to start reading up on CVST epidemiology, I think.

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Re: Developing the Covid-19 vaccine

Post by Woodchopper » Sat Apr 03, 2021 4:11 pm

jdc wrote:
Sat Apr 03, 2021 3:02 pm
Woodchopper wrote:
Sat Apr 03, 2021 7:37 am
Millennie Al wrote:
Sat Apr 03, 2021 1:59 am


From media reports it seems that the supposed problem is cerebral venous sinus thrombosis (CVST), which wikipedia says has occurs at a rate of "3-4 cases per million annual incidence in adults". By 21st March, 27,997,976 people had received their first vaccination (from https://coronavirus.data.gov.uk/details/vaccinations). So over a year, we would expect 84-112 cases of CVST in that many people, or 21-24 per quarter. If we then halve it to allow for a linear rate of vaccination, we get around 11 expected cases. While this is below the 30 found so far, it is still a very small number and it's not at all clear that it's anything other than a statistical fluctuation, or maybe even a result of finding more of something that you're looking for. Obviously, it is worth careful monitoring, but it is far too small an effect to justify drastic action such as refusing to use the vaccine, which is likely to kill far more people.
You would though expect those 11 to occur throughout the year. Whereas we’ve seen the 30 within three months or so. If it is a rare side effect we’d expect to see many more.

Still, the possible side effect appears to be much less dangerous than getting Covid.
Nah, he's saying he'd expect 11 per quarter. He divided the annual figure by four before making his adjustment for the rate of vaccination.
Ah yes, ignore the comment.

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Re: Developing the Covid-19 vaccine

Post by Woodchopper » Mon Apr 05, 2021 2:53 pm

Development Laid the Groundwork for SARS-CoV-2 Vaccines

The decades-long effort to produce a workable HIV vaccine has hardly been a waste of public and private resources. To the contrary, the scientific know-how acquired along the way has served as the critical foundation for the development of vaccines against the novel, pandemic SARS-CoV-2 virus. We retell the real-world story of HIV vaccine research - with all its false leads and missteps - in a way that sheds light on the current state of the art of antiviral vaccines. We find that HIV-related R&D had more than a general spillover effect. In fact, the repeated failures of HIV vaccine trials have served as a critical stimulus to the development of successful vaccine technologies today. We rebut the counterargument that HIV vaccine development has been no more than a blind alley, and that recently developed vaccines against COVID-19 are really descendants of successful vaccines against Ebola, MERS, SARS-CoV-1 and human papillomavirus. These successful vaccines likewise owe much to the vicissitudes of HIV vaccine development.
https://www.nber.org/papers/w28587

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Re: Developing the Covid-19 vaccine - CVST papers

Post by jdc » Mon Apr 05, 2021 4:58 pm

Millennie Al wrote:
Sat Apr 03, 2021 1:59 am
jdc wrote:
Fri Apr 02, 2021 8:35 pm
The 30 cases figure is an update after a review and apparently the figures cover 9 December 2020 to 21 March. If we've done the review and updated the numbers then what makes you think there'll be "more and more"? We've gone from 0 to 5 to 30 but that doesn't mean the numbers will keep going up.
From media reports it seems that the supposed problem is cerebral venous sinus thrombosis (CVST), which wikipedia says has occurs at a rate of "3-4 cases per million annual incidence in adults". By 21st March, 27,997,976 people had received their first vaccination (from https://coronavirus.data.gov.uk/details/vaccinations). So over a year, we would expect 84-112 cases of CVST in that many people, or 21-24 per quarter. If we then halve it to allow for a linear rate of vaccination, we get around 11 expected cases. While this is below the 30 found so far, it is still a very small number and it's not at all clear that it's anything other than a statistical fluctuation, or maybe even a result of finding more of something that you're looking for. Obviously, it is worth careful monitoring, but it is far too small an effect to justify drastic action such as refusing to use the vaccine, which is likely to kill far more people.
Found a couple of papers:

Cerebral Venous Sinus Thrombosis Incidence Is Higher Than Previously Thought
The incidence of cerebral venous thrombosis (CVT) varies between studies, but it is estimated to be between 2 and 5 per million per year. A recent study in the Netherlands with comprehensive ascertainment suggested a much higher incidence. It is uncertain whether these differing estimates reflect the quality of ascertainment or true variation. The purpose of this study was to determine the incidence of CVT in Adelaide, using a novel clinical and radiological methodology.
One hundred five cases were, therefore, confirmed. In our population of 953 390 adults, this equates to an incidence of 15.7 cases per million per year (95% confidence interval, 12.9–19.0).
Our higher incidence rate more likely represents more complete ascertainment, rather than a higher incidence in our population. Using coding alone would have led to an incidence ≈40% lower than our final figure. Due to differing methodologies, it is not possible for us to compare directly with Coutinho et al’s1 study the proportion ascertained via CVT coding versus those ascertained by other means.
Coutinho et al is https://www.ahajournals.org/doi/10.1161 ... 112.671453 and they make it 13.2 per million person years:
The overall annual incidence of CVT among adults was 1.32 per 100 000 person-years (95% CI, 1.06–1.61; Table 1).




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Re: Developing the Covid-19 vaccine

Post by headshot » Tue Apr 06, 2021 4:45 pm

I have a conspiracy theory that the delays citing supply problems, that are now being extended for vaccinations for below-50s to July, are a cover for concern about the AZ blood clotting issues.

They're using supply issues as an excuse to push the rollout for under-50s later to wait and see what the evidence says...a potential way to halt vaccinations whilst not creating vaccine hesitancy problems.


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Re: Developing the Covid-19 vaccine

Post by OffTheRock » Tue Apr 06, 2021 8:24 pm

Is it just me, or are the words ‘Boris Johnson sought to reassure people’ at the start of that article not at all reassuring? If you’re trying to convince people that the benefits outweigh the risks keeping him as far away as possible seems like the best option.

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Re: Developing the Covid-19 vaccine

Post by raven » Tue Apr 06, 2021 10:17 pm

There's a guy on Newsnight talking about this, and he just implied as there's been no cases of CVST identified after Pfizer that sort of implies that CVST after AZ is 'not non-causal'. But does it? I read somewhere that women below 65 were at highest risk of clots (I think in general, not CVST in particular) and as Pfizer was mostly given to older groups and AZ to younger groups, that might perhaps account for a different incidence.

Whether his logical is right or not, it's still looking like these blood clots are a real albeit very rare side effect of AZ. The leaflet you get given with AZ says, under 'Warnings and precautions', to tell your doctor if you have a problem with bleeding or bruising, or if you're on blood thinners, so perhaps they were aware clotting might be an issue?

I didn't get chance to read that before I was vaccinate though. It was pretty much 'here's the paperwork; get jabbed & off you go', so I don't know how many people would realise that might apply to them in time to discuss it with anyone.

ETA: There was someone with a tablet going through a checklist of questions. They asked about blood thinners, but not about bleeding/bruising.

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Re: Developing the Covid-19 vaccine

Post by raven » Tue Apr 06, 2021 10:51 pm

Come to think of it, we think my sister got into group6 'cos of a blood clot years ago, and that's probably also why she got Pfizer not AZ like her partner did.

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Re: Developing the Covid-19 vaccine

Post by Millennie Al » Wed Apr 07, 2021 1:11 am

raven wrote:
Tue Apr 06, 2021 10:17 pm
There's a guy on Newsnight talking about this, and he just implied as there's been no cases of CVST identified after Pfizer that sort of implies that CVST after AZ is 'not non-causal'. But does it? I read somewhere that women below 65 were at highest risk of clots (I think in general, not CVST in particular) and as Pfizer was mostly given to older groups and AZ to younger groups, that might perhaps account for a different incidence.
Revisiting the papers found by jdc and mentioned in viewtopic.php?f=19&t=995&start=925#p76662 we have an expected incidence of 15.7 per million people per year, in the first and 13.2/Mp/y in the second. Reworking the figures I previously gave, 30 cases seen out of 27,997,976 people in a quarter is 4.3/Mp/y but if we assume that someone who got CVST before vaccination would have missed out the vaccine, we need to double it to get 8.6/Mp/y. That's lower than the expected number, so we should insted be rashly leaping to the conclusion that the vaccines have a protective effect against CVST rather than causing it.

Less rashly, we should be considering that there are three groups: unvaccinated, Pfizer/BioNTech, and AZ/Oxford. These should add up to the execpedt incidence, so if it's much lower in Pfizer/BioNTech than the average, that most likely means that a confounding factor is present - such as you mention whereby age matters. That then further means that if the cases are not falling into one group, the other groups must be seeing them.

As always, if we want to know what is really happening we need to run a trial. I'd suggest three arms: Pfizer/BioNTech, AZ/Oxford, and unvaccinated and you'd need to have 10,000,000 people in each arm to get decent statistical power, given how rare the effect is. If we're not worried enough to run such a trial, I'd suggest we shouldn't be worried enough to take any other action.
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Re: Developing the Covid-19 vaccine

Post by tom p » Wed Apr 07, 2021 1:35 pm

Millennie Al wrote:
Wed Apr 07, 2021 1:11 am
raven wrote:
Tue Apr 06, 2021 10:17 pm
There's a guy on Newsnight talking about this, and he just implied as there's been no cases of CVST identified after Pfizer that sort of implies that CVST after AZ is 'not non-causal'. But does it? I read somewhere that women below 65 were at highest risk of clots (I think in general, not CVST in particular) and as Pfizer was mostly given to older groups and AZ to younger groups, that might perhaps account for a different incidence.
Revisiting the papers found by jdc and mentioned in viewtopic.php?f=19&t=995&start=925#p76662 we have an expected incidence of 15.7 per million people per year, in the first and 13.2/Mp/y in the second. Reworking the figures I previously gave, 30 cases seen out of 27,997,976 people in a quarter is 4.3/Mp/y but if we assume that someone who got CVST before vaccination would have missed out the vaccine, we need to double it to get 8.6/Mp/y. That's lower than the expected number, so we should insted be rashly leaping to the conclusion that the vaccines have a protective effect against CVST rather than causing it.

Less rashly, we should be considering that there are three groups: unvaccinated, Pfizer/BioNTech, and AZ/Oxford. These should add up to the execpedt incidence, so if it's much lower in Pfizer/BioNTech than the average, that most likely means that a confounding factor is present - such as you mention whereby age matters. That then further means that if the cases are not falling into one group, the other groups must be seeing them.

As always, if we want to know what is really happening we need to run a trial. I'd suggest three arms: Pfizer/BioNTech, AZ/Oxford, and unvaccinated and you'd need to have 10,000,000 people in each arm to get decent statistical power, given how rare the effect is. If we're not worried enough to run such a trial, I'd suggest we shouldn't be worried enough to take any other action.
Observational studies at approaching that level are being done. Along with O-E analyses.
Also, thanks to spontaneous reporting, we actually have information on probably close to all the clots that happened to people post COVID vaccination from all over the world, being reviewed by a few different sets of experts. We also have the numbers vaccinated with each vaccine from most of the world, in close to real-time.

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Re: Developing the Covid-19 vaccine

Post by bob sterman » Wed Apr 07, 2021 1:46 pm

If there are going to be restrictions placed on the use of the AZ vaccine with younger age groups - this is going to cause massive problems for the developing world.

This was supposed to be the vaccine that was affordable - sold on a non-profit basis - to low and middle-income countries. And these countries - because of the age structure of their populations - are those where a larger proportion of vaccinations would be in younger age groups.


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Re: Developing the Covid-19 vaccine

Post by shpalman » Wed Apr 07, 2021 2:29 pm

Watching the UK-JVT-JVCI-MHRA briefing now but it's going to say that Under-30s in UK should be offered alternative to the AstraZeneca vaccine isn't it?
molto tricky

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Re: Developing the Covid-19 vaccine

Post by jdc » Wed Apr 07, 2021 5:14 pm

Herainestold wrote:
Fri Apr 02, 2021 7:13 pm
Maybe we don't stop administering the AZ vax, but younger people may not want to take it, as more and more blood clot cases are discovered in the health records.
This post has aged better than my more optimistic ones. That'll learn me.

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Re: Developing the Covid-19 vaccine

Post by jdc » Wed Apr 07, 2021 5:16 pm

shpalman wrote:
Wed Apr 07, 2021 2:27 pm
shpalman wrote:
Tue Apr 06, 2021 6:21 pm
shpalman wrote:
Tue Apr 06, 2021 3:41 pm

no we didn't
yes there is
and indeed they did
When I saw the headline, my first thought was "I hope shpalman was able to finish his series of posts".

Well done everyone else for not jumping in.

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Re: Developing the Covid-19 vaccine

Post by shpalman » Wed Apr 07, 2021 5:18 pm

molto tricky

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