UKH

https://uk.reuters.com/article/health-coronavirus-vaccines-pfizer/pfizer-bi...

Pfizer claim a vaccine. No idea if it will come to fruition or not

Yeah, but is it carcinogenic if I'm stood near a 5G mast? Or will I end up voting for Bill Gates at the next election?

😉

The stock market likes it. FTSE100 up 5% at midday. 

They would not announce this news if it wasn't going to come to market....

Best news all year...

It's actually a method of tracking/controlling us all funded by George Soros/Bill Gates/The Illuminati*

*Delete as appropriate 

Will it give me an embarrassing erection as well?

Yes. They stated in October they wouldn’t release this data until after the US elections. 
 

Think it will now be mid Jan when roll out starts here. Local Councils are preparing centres for delivery. 

Biden bounce.

OP:

Small company with lots to gain, says its awesome!

Assuming that it is effective. How long before they can ramp up production to produce enough for a country. ( I guess it will be licensed by multiple partners for global production.) How long before they can get it out and get people immunised. How many people will reject the jab for various reasons?

This, along with the other ones from other companies, is good news. I don't expect you or I will get it before the summer.

This could be fantastic news. We could do with some good news.

Sound bite and not wholly accurate. The Biden bounce accounted for a 100 point rise, the Pfizer news added another 250 points. If you are going to post such a blasé riposte at least check out the facts first. 

"It's a great day for science and humanity"....

Said the Chairman of Pfizer. 

More like its a great day for their pockets! 

Yeah, but can you imagine Trump's reaction to this coming too late for him!?

This is the RNA vaccine from the Mainz Uni spin off company Biontech. Pfizer contribute clinical testing, mass production, and distribution.

It will probably still be the first vaccine to be licensed in the US and Europe, but is certainly not the ideal candidate for any world wide immunization campaigns (-80°C storage required, needs booster injection for full function, ...).

Fun fact, the Biontech headquarters in Mainz have the street address "An der Goldgrube", i.e. "At the gold pit". Probably a case of nominative determinism rarely seen in biotech startups!

CB

Please let it be. People want their lives back.

Given that most vaccines take around 5-10 years to make it through design, testing, and into production, should there be concerns that this is being rushed out? 

I've no idea, I'm not in biotech. I read some figure of 43,000 people tested which is quite a large sample size.

BioNTech had already planned to produce 1.2 billion doses next year and are in the process of buying another production facility from Novartis to increase capacity by 730 million doses.

A vaccine which works for some is better than nothing! Here's hoping we can either make this work for all nations or another more suitable one will be along soon. Anything is better than nothing though!

Small company??? Pfizer is one of the biggest pharaoh companies going.

I'm hoping that the vast sums of money thrown at it might knock a few days off.

Given it's been the best weekend of news of a crappy year, I'm gonna enjoy this news without cynicism, at least for a few days!

I believe this is mainly because the stages and manufacturing upscaling is done sequentially one after the other, with high confidence results before moving on to next stage to reduce financial risk to the company. If a stage trials fail then vaccines haven’t been made large scale and wasted, and needless experiments haven’t been carried out. 

As far as COVID goes, governments have Essentially underwritten the losses by pre-purchasing. So as soon as stage 1 results were showing promise it was all hands on deck.

Even after the vaccine starts delivery there will be follow up studies to ensure no problems. 

My Rolls Royce shares up 50% today. Crazy. 

They just bought the Novartis plants in Marburg (contract signed in September, handover planned for November).

"They" probably being Pfizer, at least in the background. BioNTech is not that small anymore, but still.

CB

if you are interested in the technical details, there was a huge review on the various coronavirus vaccines in Nature back in September:

Krammer, F. SARS-CoV-2 vaccines in development. Nature 586, 516–527 (2020). https://doi.org/10.1038/s41586-020-2798-3

If it is behind a paywall, scihub is your friend....

CB

Quite.

This.

Also, most of the ground work for the new generation "platform" coronavirus vaccines was done for SARS classic and MERS (e.g. which epitopes to pick to have the best chance of generating neutralizing antibodies, etc.), even if these vaccines never entered production as the epidemics were controllable using classic public health approaches.

CB

Having worked for Pfizer for a number of years, I suspect you are correct - very much their modus operandi (and indeed, how I came to work for them).

Pfizer the go to place if you need a rise

I thought the biggest was Ramses Pyramid Emporium.

Nice autocorrect!

CB

The story has been updated since it was originally posted. I read it as the announcement was by the smaller partner, working with the larger company. My bad.

There are some rumours flying round twitter that it might not be as great as it seems. 

I don't have any details - and probably wouldn't understand them if I did.  

Until they close down a site.. 

Is it right that it is a 2 dose vaccine and you have the second dose 3 weeks after the first??

If so how practical is that for mass vaccination?

Or is this really to get health workers protected and the over 85's.

I would have thought a one dose vaccine is far more practical for the rest of us.

OK, you hang on in there and wait till one comes along.

Well the logistics/practicalities  would suggest alot of us will be hanging on.......so I am sure most of us will be waiting.......so I would not get excited.

But I am sure you might have figured this out.

Less good news from the oxford / astra zenica pre clincial trial. https://www.immunology.ox.ac.uk/covid-19/covid-19-immunology-literature-rev...

The key message being "They reported antibody development by day 14 post vaccination and weak neutralizing antibody responses in all vaccinated animals. A SARS-CoV-2 challenge 28 days post vaccination led to clinical symptoms in 5 out of 6 vaccinated animals but improved disease progression compared to non-vaccinated animals." (SARS-CoV-2 challenge = exposed to covid)

Doesn't meant it def doesn't work, just doesn't look good in monkeys, might be different in people.

The main issue with the Pfizer one is that the requirement for a -80C cold chain - vastly colder than any normal cold chain that operates in volume. I'm sure money will be chucked at the problem, but I can't end up being deployed in doctors surgeries - more of a central hub thing. And that's only after they manufacture enough.

Once there is a vaccine, good luck with enforcing lockdowns / measures - even if required. And I doubt the subtly of different vaccines having different effectiveness is going to be easy to communicate...

So what sort of specialist fridges are available for that? Its not your average off the shelf type. Fascinating.

Haha I know right - left it because I enjoyed it after realising.

They're fairly standard laboratory kit but obviously not something you can buy at Currys. I wonder if they'll be couriered out packed in dry ice for use that day.

I would have thought they only need to vaccinate the people that would normally get the flu jab.

You're talking about delivering it to billions of people potentially. Couriering works when you're talking a few dozen, unfortunately doesn't scale very well. Imagine the difficulties for a tropical country with poor infrastructure.

Laboratory is not really practicla for lots of us. Dry ice for 2 shots?

Sounds to me like a logistical and practical nightmare .

I have no special knowledge but not enough seems to be known about the factors leading to serious illness from Covid, it still seems a bit capricious whether you get a mild version or an escalated, multi system attack. I think they’ll want to vaccinate most of us (given that anti Vaxers and lizard watchers will inevitably refuse it). Let’s hope this can give us a path back to “normal “ life!

-80°C freezers are bog-standard stuff in a bio lab.   I assume (but don't know) that they're pretty common in medical sites as well.

-80°C freezers have got more affordable and space efficient of late with the cycling "auto-cascade" designs; about £8k for a 100 litre freezer.  I suspect that every site performing vaccinations will need a few hundred litres of such capacity at least to store produce.

I doubt the supply of these freezers is immediately very scalable beyond the usual low levels, but there's nothing apparently exotic about them - an unusual but not difficult to make mix of refrigerant gasses, more complex microprocessor control than typical but not with uncommon parts, thicker insulation and so on.  The auto-cascade design really is very clever.  

The logistics and transport chain is going to need a lot of dry ice production - I can't imagine these freezers like to be moved about when operating so it'll be a case of shipping produce on dry ice.  With mass transport from production sites in Europe into England shipping on dry ice, it would be a disaster if for example lorries were sat in customs clearance carparks for 3 days due to the failure to agree a suitable Brexit deal.  

The shipping is really quite an interesting question - it's not normal to ship large samples at this kind of temperature - so it could well be worth designing a much larger, more insulated but safety gas venting, CO2 cooled storage chest than the normal transport containers.  I assume Pfizer have been on this - it's not a very challenging thing to design, and but it will need to be robust, to have sufficient temperature monitoring to guarantee the integrity of the produce, and to handle the potential CO2 gas hazard safely.

I suspect 70% would eliminate it. Depends if they’re looking to eliminate it. Even 40% would slow the spread enormously. I suspect a huge proportion already have immunity. 

Do you know why it needs to be so cold? What is happening to the vaccine at, -80C that isn't already happening in a regular freezer at -18C?  

A good time to invest in CO2 extraction plants and liquid nitrogen providers!

If they did, how do you explain the university outbreaks with doubling times of < 4 days?

When I used to work at an Air Products plant there was a GP who’d pop round for a flask of liquid nitrogen, I think for wart removal. God knows whether / how he vented it as it warmed up. I’d be nervous trusting my GP with either liquid nitrogen or a hypodermic needle under normal circumstances. 

They’ve put a load of students together from different parts of the country. We are pretty sure around 20% of London had it from the first wave. 

Exactly.  So if “a huge proportion already have immunity.“ as you claimed, it would not have spread in halls (where risk control measures are basically void) just as fast as it did in March.  It would have spread much slower.

So it seems a “huge proportion” of students did not have immunity.

Sure, and it’s lower everywhere else.  The last time I checked, 20% wasn’t a “huge proportion”, it’s a small proportion and not enough to significantly moderate covid without masses of other risk control measures.

Seriously F8ck off.

This is an extraordinary achievement that will be transformative for humanity and you're making cheap shots?

Why do people do this?  There's a study with over 40000 participants across 6 countries.  A >90% protection rate, but you choose to promulgate "some rumours on Twitter".

Not entirely sure, it's certainly colder than a lot of vaccines and they are working on a different version that is ok at higher temps. One of the other vaccines started off at -70 and is now at -20. I suspect a big part of the answer is because 'that's the temperature that we tested it at and it the studies used for approval were valid at that temperature'.

Without even a link to twitter to “substantiate” their claim, no less...  Twitter is basically infinite monkey territory so you can find anything stated there...

They started actually manufacturing it months ago. 

and Kalna Kaza

That's my (limited) understanding as well. Perhaps the others did stability trials at higher temperatures in parallel. I think the time need to to stability trials now would be significant, so sorting out the -80 distribution problems will be faster.

Re immunity, I’m on my second round of Covid 7 months apart so we’ll probably have to have further doses of any vaccine regularly if my experience is in anyway normal. 

That sucks for you, sorry.

I was doing some noddy guesswork the other day.  It's really crude and subjective, with a level of research described as "googling for numbers".

Say we're about 2.5 sigma from the mean time from first infection to reinfection (which is perhaps 18 months) - that is immunity hasn't faded for most people yet.   This gives a probability of 0.6% that a person who was infected in the first round is now subject to re-infection.

Around 10 m people were infected in the UK in the first round, that means around 10 m x 0.6% = 60 k people are now liable for reinfection.  Currently around 1% of the population is infected so if it's a random processes then 60 k x 1% = 600 people are re-infected in the UK.  Many of these won't havre noticed their infection the first or the second time around and so the re-infection won't be identified.  

There are 110 k registered users on UKC, approximately.  So we'd expect 600 / 66 m (population of the UK)  x 110 k = 1.0 users on the site who are re-infected.

So, I think there's good odds you're unique on the site, but I do not in any way agree with those on here who have dismissed re-infection on the grounds that there are only a handful of reported cases.  Reporting through journals takes months and I think we're at the point only the unlucky few are both susceptible to re-infection and exposed to it - this likely didn't even become possible for non-immunocompromised patients until the "second wave" hit, which is not enough time to be published.

Do they publish the number of forum posters? Presumably that is a tiny fraction of the 110k registered users.

I'm hoping my neighbour (who works on Covid vaccine research)  has a load in his suspiciously large shed

And all the 20 odd documented reinfected people were reinfected with the different strain. Either G or D. 

Sorry to hear that!

Your unfortunate second round is in agreement with a study that found antibody immunity to last no more than 2 months. Don't know if there are similar studies on T-cell immunity. Maybe wintertree knows?

There needs to be some caution - the number of people challenged is likely to be far far fewer than the number vaccinated and tested serologically.

2 observations from our experience is that it’s likely our school age child was the source both times as she had v mild symptoms before us and the symptoms second time were far milder. 

I don't know if they still do it, but it was very commonly used for verruca/wart removal by practice nurses and chiropodists when I was a kid.  It was also an effective torture mechanism, at least I can't recall anything I had done to me as a kid by a medical professional that hurt more than freezing a verruca off.

Why wouldn't you trust your GP with a hypodermic needle?  You don't even need to be a medical professional to use one, it's fairly obvious as long as you know where you're meant to stick it (!) and diabetics and people on things like dalteparin (a blood thinner), not to mention drug addicts, do it all the time.

When we spoke to 111 about it they admitted that they are seeing more cases of reinfection. So far I’m the only person I know of that has had it more than once. Am sure that will change in time though. 

And that surprises you?

Do these rumours come from anyone who looks vaguely reliable or informed, or just random rumours and anti-vax crap? I’ll take unsubstantiated Twitter rumours with a very large pinch of salt personally. 

Yeah and Trump claimed victory. Are they selling this vaccine or giving it away for humanity?

Off the top of my head, I think it may be much more likely than that because some individuals are many times more likely to be infected than others due to their connections or situation.

I think because you're looking at a compounding of the odds of infection, just using the average chance of infection won't work to project the average chance of reinfection.

I could be talking nonsense, of course.

Only the number of active posters I think, which is around 100 generally.  So sight flaw in my estimations!

No I think you make a good point.  Although my methodology was so shonky I think it’s beyond saving.  Sometimes it’s useful to do a noddy estimate though to give an idea of the sort of numbers involved.  Which are likely to grow rapidly over the coming month or two...

I think you’d need to ask an immunologist!  As I understand it a definitive test for T-cell immunity is a lot harder to come by, and good data is thin on the ground.  

T-cell assays are fickle. You can look at proliferation in the presence of antigen, quite old fashioned and laborious, and often compared to something non-specific like ConA or you can do cytokines measurements from stimulated cells with more discrimination as to the type of immunity. Measuring how many memory T-cells there are requires limiting dilution assays and these are utterly dire to perform. 

If there was a commercial test, I would guess the cytokines measurement format to be most able to be scaled up. However T cell assays may remain as research tools in this context. 

Thanks for the details.  I somethings think if I was to go back in time 20 years I'd have gone for immunology - it's fascinating and I sometimes think the most computationally complex part of a mammal after the brain.  More impressive in many ways.

By "proliferation in the presence of antigen" do you mean sticking some extracted T-cells in a culture with an immunoflouresence tag or another antibody based tag that'll show on a western blot?  That is orders of magnitude worse than a PCR to do at scale I imagine.   

I quite like the idea of designing a one-shot or refurbishable "shake and bake" immunoflouresence lab on a chip with integrated culturing and so on.  Just inject the relevant plasma fraction and press go...

Is enough know about which particular cytokines are important in the T-cell covid response to design or source antibody kits for immunogold or immunoflouresence?

I did this to myself a few times when I worked in the lab.  It smarts a bit for a second but is very effective if you know what you are doing (you don't inject it, for a start).

If you have a Dewar of liquid nitrogen handy at home, here's how you do it.  Big glove on the non- warty hand, long forceps holding a little wad of cotton wool (like just larger than the area of the wart).  Dip the cotton wool into the liquid nitrogen and then smartly apply gently to the wart until a frosty ring appears on the skin around it.  Assuming a roughly hemispherical tumour, this means it's frozen all the way down into stratum germinativum and should die.

Simples.  I got good at it and did it for other people too.   

Cells + antigen + culture medium - count the uptake of something over the incubation period - in my day it was tritium. Alternatively you can measure surface antigens that are expressed in activated or dividing cells using FACS (e.g. CD38).  No blotting required, but still pretty laborious. However I must say I love a little bit of western blotting - although acrylamide is not great stuff.

I see nothing in there that's expensive, slow and going to present a barrier to scaling.  Well, except maybe the tritium.  Or a high throughput FACS.  I wonder who is working on a scaled up diagnostic test?   Going to be a lot of research moving out of the lab as a result of this pandemic...

It's counter intuitive, but solids are still moving even when frozen, and big biomolecule is still going to jiggle about a bit even when in a frozen solution.

The active ingredient in this vaccine is a single strand of RNA. Single strands of D/RNA are pretty reactive and can be broken down really, really easily by all manner of things. 

The issue with a vaccine relying on a long strand of RNA is if you get one break in the chain in a molecule, you lose the sequence. So a couple of atoms reacting in a molecule of 10,000s atoms renders that molecule ineffective. 

So it doesn't take much for a sample to degrade, and lose its potency. Most of the RNA will still be there as the sample "goes off", but a lot of it won't be the full sequence that has the immune effect.

This sensitivity means that even the difference in the amount of energy the atoms have in a solid at -20°C and -80°C is enough to slow the reactivity down enough to make a difference to the amount of time you can store the vaccine before it goes off.

I think -80°C is a pretty standard storage temperature for molecular biology that's known to preserve mRNA samples well. I think I read somewhere today that they are doing trials at the moment to test whether you can get away with keeping it in a standard freezer for a couple of days, which would help with worldwide distribution in the long term. 

"Huge" is obviously over doing it but I do think there is likely to be a large proportion of the student population, and others in the same age group in the north west and London, who have now had Covid. Of course it isn't enough to achieve herd immunity but it could easily be 20-30% in that age bracket, maybe more if most are asymptomatic.

Why is this relevant? Because it changes the calculation about who you give a vaccine to. The priority will obviously have to be health and care workers, older people (not sure what age you'd cut that) and others in the extremely vulnerable category. But I think once those people are vaccinated the Govt will release all restrictions and a lot more younger and middle aged people might get the virus before they get a vaccine if it comes back for a third or fourth wave. There is also an ethical question in my mind about vaccinating middle aged people here before you have vaccinated older people in less fortunate countries. And we have signed up to (possibly very limited) international agreements with this sort of question in mind. It's certainly not a dead cert in my mind that people under 50 will be vaccinated in the medium term, maybe not under 40s, and I struggle to see why you would ever do it for the under 30s. 

All the above makes an assumption that manufacturing and distributing whatever vaccine(s) are successful is a difficult job. If one comes along that can be distributed super fast everywhere, great.

A friend of mine (no, really, it wasn’t me) couldn’t face going to the doctor to have the wart on his penis treated professionally so he improvised the procedure you describe. He isolated the area using electrical tape and chilled the end of something metallic using, I think, propane. It was a triumph in that the wart disappeared and he didn’t self-immolate. 

What?  Like thalidomide? 

Yes 43,000 is a large figure.  But they were only tested over several days.

-80c refrigeration isn't a particularily big issue.  

My daughter inseminates cows - and she collects the sperm!  Her transport is an ordinary van with a few containers in the back.  I think she's even used her very ordinary Vauxhall corsa too.  Everything is stored at -80c.

Most likely in liquid nitrogen for semen.

Indeed.  I've been known to put things in a -80°C freezer myself.  But, rolling out a new nation-wide supply chain with suitable storage at every end-point is going to need a lot more freezers.    Which need to come from somewhere.  I'm curious about how fast the supply chain can scale.

Sure; a bog-standard polystyrene box with dry ice chips in it is fine for moving things in a car; you can stick one on your lap in a car; but there's a lot more vaccine to be moved about than cow sperm I would have imagined, and it's got to go a much longer distance than the cow sperm.

I listened to the PM's Coronovirus briefing on this.

Lots of 'maybe, ifs, perhaps, caution, not approved, could, possibly be, in terms of whether it works.    (the tested individuals were only tested over, I think, several days - and not several months!!).

And lots of; 'maybe, 'ifs', 'perhaps', 'could be',  caution, 'possibly', and so on in terms of when (if) it will become available.

Remember our world class Test 'N Trace.  

But lets live in hope!!!  

Well my daughter and all the rest of the thousands(?) of others who do this sort of work and similiar work, which relies on -80c storage & transport wouldn't object to a slight change in duties whilst it was rolled out.

On second thoughts the signage on the side of the van might need a little tweaking before it starts rolling up at the GP surgery.

A pandemic driven in significant part by a super-spreading mechanic often from younger people who stand to benefit very little directly and personally from vaccination, people in their last decades likely to respond the least to the vaccine yet representing the bulk of the hospitalisations that are why we have to have severe, society wide control measures, and as yet unknown medium-term outcomes from the vaccine (say 18-month) as there hasn't been the time for studies.  Throw in a desperate need to improve things society wide and it's a real medical ethics conundrum.

I'd hope that the vaccine could be used in a targeted way to push R << 1 and allow for a short sharp elimination approach, but at some point I have to accept the reality that I'm just not going to get what I want.  Still, this virus and its future mutation potential represents enough unbound able risk that I think going for elimination is the safest approach.  It'll be very interesting to see how the governments of Western Europe shape policy around a widely available, effective vaccine.  

I think they'll use a few vaccines. The two step with 90% efficacy on high risk groups and a single dose one on lower risk members of the population - even if it's significantly less effective.

Yes and no. While government's fixated on the short term may be foolishly tempted to rush testing there's not much in it for the pharma companies or the regulators with billions of doses pre-ordered and incalculable reputational risk. If I understand correctly most of the massive development speed-up has come through building on previous work using tech that has only very recently matured and through the taxpayer carrying the risk of several parallel testing and production programs in the hope at least one will come to fruition. Normally given the costs this would all be done cautiously and sequentially to save money on many failed ventures.

jk

Windows open, right!

jk

 Not all parts of Britain have the same weather and willing females as Newcastle though Bill?

Well, quite... The vaccine is great news, however, the cynical side of me still wouldn't put it past our shower to use the shot in the arm to shoot themselves in the foot. 

Indeed. Fingers crossed. 

Okay, now I have more specifics there are two flags

- the study only reduces 'symptoms', which doesn't necessarily mean that these people aren't asymptomatic and can't spread it to more vulnerable people

- they haven't fully published any details of associated safety issues with the vaccine.

Does that satisfy your little 'rumours on twitter' problem?

See my previous reply. Having posted the original news report I felt I should counter with the fact that some people are sceptical at this point in time. 

I should have been more specific, by rumours I mean from a biotech analyst I know, not from some random rabid anti vaxer or the like. 

I didn't say "safe for some", obviously the trials are there to prioritise safety. I was replying to a post saying that the storage conditions would make it hard to use it in some parts of the world, and I am saying that hopefully we can overcome that, but if we can't then there's still reason to celebrate if it can help some people. Obviously, it would be even better if all nations can have equal access, but some is better than none.

You haven't though. You've posted vague unattributed text that sounds very like anti-vax bollocks.

I'm not going to be more specific than a biotech analyst who is a friend of mine. I'm not going to attribute it to him by name. I'm not anti vaxer, he's not anti vaxer. He's not saying it doesn't work, or people shouldn't have it per se, just that facets are still unclear. Make of it what you will but don't cast inaccurate aspersions. 

What exactly is cow sperm? 😁 Is this something new and wonderful that I've not heard of or has it been developed in cattle as a necessary research step in a secret move towards an Amazonian society? 😁

So rather than an "original news report" it actually  Ed's mate?

And I think everyone knows it still needs regulatory approval still.

Thanks for the additional detail, they are valid questions that hopefully are due to be addressed in the near future. 

But with all the agendas, misinformation, and “post truth” bollocks of recent times, you really shouldn’t be surprised if people question “rumours on Twitter” and “someone I know”.

It’s a bit rich to start snapping at people for having doubts about your sources, especially when the source seems to start change when questioned - “rumours flying around Twitter” makes it sound far grander and more widespread than it just being a single friend of yours. 

Fair enough. But the question could be 'can you give any more info' rather than 'that's probably anti vax bollocks'. 

On the subject of accuracy, you turned one person’s views into rumours plural...

A better way of presenting it might be “I read some tweets from one person who noted the valid points that the full results of the clinical trials have not yet been published.”

As it happens they are the same points that I’ve seen in several news stories.  They are entirely congruent with the stage the product is at in the trials pipeline.  The vaccine may or may not be as great as people are expecting but that is different to it not being what Pfizer have claimed.   Between the SEC, their corporate reputation and the medical licensing processes I think their statement will have had exceptional scrutiny from lawyers fully briefed in all the clinical trials’ findings.  So I see their statement as very positive.  Given how the vaccine works I would be surprised if it only reduces symptoms without going so far as conferring some immunity. 

I think it's very good news, not just because there seems a strong chance that it will be effective and safe and soon come into widespread use, but because it suggests that other vaccine candidates, which target the same bit of the coronavirus, will also work.  I think there are about 10 others in phase 3 clinical trials (i.e. having been shown to be safe, being tested to see how well they work), and many more in the pipeline.  Some of those may work better, they may be easier to manufacture and distribute, we shall see.

On the need for -80 storage, there are some tradeoffs here. It's an RNA vaccine, which means that the manufacturing can scaled up much faster than a conventional vaccine.  That's because it can be produced by essentially chemical, in-vitro processes, unlike a conventional vaccine that is based on a viral vector, which you have to culture in a cell line, which will take longer to scale up.  

But the bare RNA molecules need to be encapsulated in a lipid nanoparticle to protect them from degradation by enzymes as soon as they are injected, and to help them enter the patient's target cells.  I suspect it's the fact that those formulations aren't very stable that make it necessary to store them so cold, so the water they're suspended in goes into a glassy state.  I expect it's possible in principle to find a way of storing the formulations in less extreme conditions, maybe freeze-drying, but it will take a while to work it out and demonstrate the vaccine still works.

A group of people were discussing it in private messages on twitter. So rumours and people plural. You say tomato I say tomato. You may think I was misleading, I know I wasn't. 

The story evolves.

”Rumours” strongly implies claims (truthful or not) beyond what is public knowledge.  What you have passed on is public knowledge and has been covered in some of the news releases.   It amounts to noting what was and wasn’t covered in the Pfizer press release; it’s “analysis” not “rumours”.

It’s possible to mislead people entirely accidentally.  I think the word “rumours” has done exactly that.

Well I have clarified. So get back in your sanctimonious box

Maybe it’s like dog food. It’s food for dogs, not food from dogs. 

That was a drug, not a vaccine. 
 

There are funds set aside to help the very few victims of vaccine injury (these numbers far outweigh the numbers of people saved from permanent disability, from polio, measles, mumps etc), and there are procedures put in place to follow up on people who have been vaccinated to watch for unforeseen side effects.

We are not living in the 1960s. 

Online on Facebook and twitter its amazing to see how many think this vaccine is going to cause them damage or don't want it etc. If it gets normal back then let's get on with it. 

Tom Chivers has written a good summary on whether we should be excited about this:

https://unherd.com/2020/11/yes-the-vaccine-is-really-on-its-way/

(Spoiler: yes, but with a little caution and a bit more patience)

The virus based vaccines (e.g. Oxford) will be one shot and are not too far behind. Spring or early summer, presumably. My guess is they will come on the market before the two shot RNA vaccines can be distributed to everyone.

Personally I would opt for the much cleaner RNA vaccine (even if this is the first one coming on the market), even if I would have to go back to the vaccination centre (which are currently being set up at 60 sites plus satellite sites in Germany, essentially at existing testing sites) after two weeks. I just like the concept that, in my judgement, seems intrinsically safer.

CB

That article refers to a different vaccine (the Chimp Adenovirus based one from Oxford, not the RNA based one from BioNTech).

Also, -80°C is no issue at all in Europe (every biology lab or hospital department has several such freezers), but it will become a problem when rolling out the vaccine in poorer countries.

CB

The issue is what is NOT happening at -80°C that is very slowly happening at -20°C and within hours or days at 4°C.

RNA is not as unstable as most people in the lab think, but you don't want to see significant hydrolysis of the RNA vaccine or degradation of the lipid vesicles that serve as packaging delivering the RNA to the target cells.

Storing RNA libraries or lipid vesicle transfection kits (essentially the same thing as the vaccine!) at -80°C is bog standard practise in any molecular biology lab. Half of the reagents we buy is delivered on dry ice, more than we can store in our freezers.

When my children were small, I therefore used to bring some dry ice home and chuck it into the tub when they were having a bath. Best bubbles and stage fog ever!

CB

Liquid N2 is just carried in a standard Dewar flask with a loose lid. No issue at all!

CB

I’m very wary of Facebook and Twitter.
 

They seem to attract whackos. Whatever the subject. I have one friend who is ‘open minded’, basically a nut job and not representative of the hundreds of people I know and meet. 
 

There are people who troll for mischief. 
 

There are also people who make money from online subscribers - some of them believe the nonsense they’re pedalling but growing more common are the YouTubers who don’t believe what they’re saying and just making money out of vulnerable people.

I think something like 20% of people are on Twitter and of that 20%, 20% make 80% of the noise. Anti-vaxers are an even smaller proportion of that 4%, making even more noise at this time and attracted like bees to the honey pot. 

Not necessarily. Coronaviruses carry genes whose function is to interfere with immune memory formation, resulting in shorter immunity (which is of obvious benefit for the virus). That is obviously not true for the vaccines, whether the antigen is delivered by virus or a RNA.

Of course, this needs to be checked in longitudinal follow up studies, which by definition cannot have been performed yet.

Worst that can happen, though, is that risk groups needs half yearly or yearly boosters (same as with the flu shots but for a different reason).

CB

You seem suspiciously up on the detail😊

Ah, good old Swap Shop. 

https://www.bbc.co.uk/news/blogs-the-papers-54882074

The Telegraph has a table re initial roll out on it’s front page.

What's your take on the exchange of sub-domains of the spike trimer between different coronavirus strains?  These seems to have been a key part of how sars-cov-2 came to get its defining feature.  

How is the RNA vaccine protected against having its RNA for the spike being appropriated by other circulating coronavirus variants during in a vaccination program?  Are the widely circulating ones different enough to not exchange material, is is the vaccine RNA gimped to make the spike non-functional, or are the primers changed on the vaccine RNA to hide it from the exchange mechanisms in the spike?  Or is there other molecular biology stuff going on in a live donor virus that isn't in the vesicles that would be required to start an exchange process?

It has been a while, but I SEEM to remember that in CV replication first a full length  -sense RNA is transcribed from the viral genome. This - sense RNA then serves as a template both for synthesizing the full length + sense genome for packaging as well as for making subgenomic + sense mRNAs for translation using some ultra weird discontinuous mode of transcription.

Thus, I do not see how a virus superinfecting a cell transfected with the vaccine could "pirate" the + sense vaccine RNA (the viral RNA dependent RNA Pol recognizes leader sequences that are certainly missing in the vaccine), but even if there were some template switching or other bizarre thing happening, that would actually be beneficial: Any functioning virus made by picking up vaccine RNA would afterwards make precisely the spike protein targeted by the vaccine.

Correct me if I am talking crap, of if I have misunderstood your point!

CB

Thanks; that's exactly what I was asking and I'm not sure I'd spot it if you were talking crap although I assume you're not...  I hadn't considered the sense of the viral RNA and the permutations that goes through during a replication.   That combined with the missing primer or tag sequences does make my worry seem very low probability.  I assume this has all been given a lot of thought by the relevant boffins as well as extensive testing.  Still, biology does like to borrow and share; twice now I've not managed to reply to your comments on the viral origin of the nucleus theory - I'd not heard that before and it's fascinating.

Classic arms race...

I thought they targeted the spike protein because of its genome stability.

Yes, it seems very stable against mutation - but as I understand it, the other circulating coronaviruses don’t have this spike, and coronaviruses have a mechanism to exchange spike subunits between different lineages; this likely being how our current menace came to be.

No they target it because it is on the outside of virus particles and involved in attaching virus particles to cells. Both properties make it the prime target for neutralizing antibodies. The T cell response could just as well be raised against a protein hidden inside the virus.

CV genomes are indeed more stable than other RNA virus genomes because, unusually, their RNA dependent RNA polymerase has some proofreading capability.

CB

Yeah of course, sorry I just meant they know it's a good candidate. Presumably though they can just change the mRNA sequence in future vaccines of it does mutate, like the flu vaccines. It's such a cool development in vaccine technology.

I've got some worries about this and, not wanting to get sucked into a conspiracy rabbithole by searching Google and YouTube, I thought this might be the place to ask.

My understanding is this.

1) A virus does its damage by taking over the machinery of a cell to manufacture copies of itself. Those copies go and infect surrounding cells and can become fatal when the spread is so great that too much of a system that keeps you alive, e.g. lungs, has been infected. 

2) A traditional vaccine works by introducing a finite dose of dead or weakened virus that the defences of your body can practice fighting in preparation for when the real virus comes along.

3) This RNA vaccine is a new class of medical intervention that takes over the machinery of a cell to manufacture copies of the part of the virus that your body needs to practice fighting. 

3 is very like 1. What limits the spread of these copies?

How well do the Pfizer understand the genetic instructions that they will be giving our cells. Is there any danger of our cells manufacturing something unforeseen?

The genome of a virus is, like that of any organism, split into genes. Very roughly a gene is the instruction set (encoded in DNA or RNA) to make one protein.

In DNA based organisms with nucleated cells (such as ourselves), the DNA is translated into RNA, which is then exported from the nucleus as a portable form of that information. This so called mRNA or messenger RNA is then read by so called ribosomes, biological machines that assemble proteins according to the encoded information. After a while, the mRNA is naturally degraded.

RNA viruses like Coronaviruses have genomes made of RNA, they need to bring along or make an enzyme that can translate that genomic RNA into mRNA, something our own cells cannot do. Virus genomes typicallly encode this polymerase, usually a protein to package the DNA or RNA of the virus, some other structural proteins, and proteins that decorate the outside of the virus when it buds from the cell and that it uses to dock onto new cells it infects.

During virus replication, all these genes must be at some point translated into mRNA, since the host cell ribosomes cannot work with anything else to make more viral proteins.

This happens in all live vaccines, whether they are a weakened or engineered viruses  just as it does in a normal infection with a pathogenic virus.

The new RNA vaccines circumvent that step by directly delivering the mRNA encoding for one single protein (usually the surface or "spike" protein that is accessible to antibodies) to a target cells (e.g., muscle). There is no way this single mRNA can make copies of itself, as it does not encode the enzyme to copy RNA and our own cells cannot do this either.

This is why such vaccines are intrinsically safer than vaccines based  on a weakened virus that can, with a bit of bad luck, mutate back to become stronger.

You could also just deliver the protein as such (or killed viruses). However, this could only ever trigger antibody based immunity (or B cell immunity).

The equally important T-cell based immunity samples the proteins other, non-immune cells of the body produce. If it spots a cell making stuff it should not (i.e. virus proteins), it will kill that cell and alert the rest of the immune system to mount an antiviral response.

Hence, for a vaccination to also achieve T cell immunity, you have to get some cells of the body to produce a viral protein, either by infecting cells with a vaccine virus or by transfecting them with the appropriate mRNA. Anibody immunity will automatically also be raised by protein released from the infected cells.

CB

Part of the problem is stupid people on Facebook. They think theyve found a flaw in the scientists work in that this vaccine is do much more effective than the flu vaccine.. ignoring it's a vaccine for a different type of virus.

Here I'm hoping we just make it mandatory for school kids and those who don't want it can be taught remote.

Why should you have to go to the hassle of remote teaching foir vaccine refusers? just don't teach them.

I think the biggest incentive will be if countries make a certificate of vaccination a requirement for passing through passport control. So many people will want a holiday after all of this!! No vaccine, no entry!

I expect this may become an increasingly common requirement at passport control and possibly for accessing other services too.

In (some states of?) Australia, there is a requirement to either prove a child has had their vaccines or has a medical reason why they can't before they can be registered for school.

No vaccines means they have to be homeschooled.

No vaccine, no/reduced tax benefits.

https://www.dss.gov.au/our-responsibilities/families-and-children/benefits-...

We have religious exemptions.. every anti-vaxxer claims them. I really don't remember Jesus talking about the dangers of vaccines..

Thanks for the effort there. I'm still trying to digest the information if I'm honest. It's a language which relates to concepts that I find difficult to understand. 

I think you are saying though that my 1) is about correct as a summary. My 2) is incorrect as a traditional vaccine works like 1 as well but must do so less efficiently than the wild virus then.

For 3), the mRNA vaccine, I take it that it does take over the machinery of the cell to produce a viral protein but it cannot spread into another cell? Does the infected cell produce multiple units of the viral protein until detected and killed by the T cell or is it one single strand of protein?

I knew it sounded too good to be true!

The precedent of course being Yellow Fever.

Yes, I think this is very likely indeed.

Yes(ish). In many diseases the actual damage to organs comes from the virus killing cells, in others it comes from the immune reaction: We had to destroy Ben Tre in order to save it.....

Again yes(ish). You can vaccinate against some diseases with purified proteins or killed viruses, but then you can only get a B cell / antibody response. B cells look for foreign stuff floating around outside the cells, and will produce antibodies if they find something they are responsive to. Often this is enough.

If you also want a T cell response you need to make the protein you want a reaction against in some body cell, as T cells sample what non immune cells produce and kill cells that make foreign stuff, as they are likely infected. For this, you need to deliver the genetic information into some target cells that will then make the protein encoded by it.

This could be a weakened virus, a related virus (this is why the vaccinia virus that causes cowpox protects against smallpox caused by variola virus), a unrelated virus that has been modified so that it now also carries the information encoding the targte protein (this is how the Oxford vaccine works, a Chimp Adenovirus that does not replicate in humans, but is able to infect some cells and make them produce CV spike protein), or you deliver the genetic infomation as mRNA. This is cleaner, but of course virus particles are much more efficient in delivering genetic information to cells, this is what they have been selected and optimized for during evolution anyway. The fact that mRNA vaccines work is purely due to improvement in the delivery system (some type of artificial lipid vesicle that fuses with cell membranes). Conceptually it is trivial.

Again yes(ish). The vaccine does not "take over" the protein production machinery of the cell as some viruses do, which actively prevent the cell from making its own proteins at the expense of viral proteins (e.g. by chopping essential bits from the beginning of the cell's mRNAs). The mRNA vaccines are  simply translated into protein like any of the other mRNAs floating around in the cell. They will be read several times, making one protein molecule each round, and then decay or be degraded.

Hence, the technical challenges of mRNA vaccines include delivering as many RNA copies as possible to produce sufficient protein to raise an immune response, making the mRNA stable, ensuring that it is effectively translated, etc...

All this is easier if you deliver the information as DNA (i.e in a live virus), because it will be read many times before the virus particle is degraded or the cell killed, each time producing a mRNA that in turn can be translated several times before decaying. This is one of the reasons why the BioNTec/Pfizer will require a booster injection, but virus based vaccines are projected to be one shot.

The desired end point is indeed that the immune system recognizes the virus protein. Typically that will result in the cell being killed, but that is no big deal. Our bodies kill and replace billions of cells each day anyway.

CB

The percentage of population getting a serious case of the virus is still small comparatively, then the percentage of those dying is smaller still. Then you add a 90% or more effective vaccine to all people who want it. Why are you insisting people who object to it need it? 

I've read the WHO literature, it seems to say that if absolutely everyone has the vaccine then that's increasing the chance of protecting those who took it, but it didn't have the desired protective effects (eg. where the vaccine doesn't work as intended). Fine, makes sense. But Covid has a CFR of.. "About 0.23% for low-income countries with a population structure skewed towards younger individuals and about 1.15% for high-income countries with a population structure skewed towards older individuals". 

Those aren't figures that should be inspiring the sentiments I'm seeing in this thread  eg. shame those who object, stop teaching their children, refuse them the right to travel anywhere. This is pretty heavy stuff folks.

I'm not against vaccines, I've received all the same ones anyone else in the UK has, but I do get incredibly wary when I'm coerced into doing something 'for the greater good'. Why not allow all the people who want it take go first, allow for time to analyze the statistical data and then proceed with further measure as appropriate? Rather than rabidly demanding curtailing of freedoms before the vaccine has even been released?

In the interests of clarity so there is no confusion with a number of other posts on this forum I think it is important to say that you can not divide the immune response into B-cell (antibody) and T-cell (cellular) as without T-cells there will not be a B-cell response. The organism or vaccine manipulation (through adjuvants or the addition of bacteria DNA repeats in DNA vaccines) can skew the response to be more antibody rich or vice versa. You should be able to measure an increased T-cell response after vaccination. T-cells do go around killing cells expressing foreign proteins, but they also provide the cytokine stimulus to allow the clonal maturation of B-cells that produce antibodies. These antibodies will bind to organisms in the circulation (TypeIII), to cells (TypeII) and when coating mast cells and other effector cells (TypeI) mean that those cells react to the presence of viral protein in tissue. 

I think it should be a medically led decision, and so far the medical side seems to be leaning towards immunising those most at risk of suffering from the virus and workers whose profession puts them at high risk of contracting and communicating the virus, then working down a list ranked by vulnerability.

I think making a decision to mass immunise children when they have virtually no medical benefit and before sufficient longitudinal data is acquired and studied is going to be highly unlikely.

I know, but how complicated do you want to make it? My reply was tailored to CMs question, at least that is what I hope I did....

On a recent thread someone asked for a brief introduction to immunology. I did not reply, but good luck!

CB

Difficult, and sorry I wasn't trying to be a smart ****. Your answers on here are really valuable. People are quite confused about immunology and it is frustrating, but the theme of there being two separate types of immunity has been present in a number of questioning posts and I wanted to address that.

Bitesize immunology on the BSI site is quite good for the genuine enquirer.  

  https://www.immunology.org/public-information/what-is-immunology

  https://www.immunology.org/public-information/bitesized-immunology

No worries!

CB

I notice that the ceo of Pfizer sold a load of share just after the announcement. Watch that 90% tumble. 

A cynic is what an idealist calls a realist. 

Yes agreed that the most vulnerable should get priority and plans to mass immunise children are a bit early frankly, if required at all. 

Are you slightly concerned by the enthusiasm of some to start cheering for what are essentially peoples rights to be drastically and permanently withdrawn, or is it just me? I'm all for following medical guidance but the minute you demand I must comply I'm on alert. Last I checked we aren't subjects of a medical dictatorship that can withdraw your rights on a whim.

To quote a couple of lines regarding UK legal stance on this, as it stands:

"It is unlawful and unethical to force a vaccination or immunisation upon an individual against their will, even during a pandemic with the current laws.5

In situations such as pandemics therefore it is important to educate those who are susceptible and allocate the appropriate resources to them should they want it."

Seems reasonable to me. 

I think it's misguided from a medical ethics perspective, and I don't think we are going to go in that direction.  (Edit - not in the next 6-9 months anyhow; after that we'll see). 

I can understand why teachers in particular are so concerned - especially secondary and 6th form teachers - given that they're being asked to expose themselves to cohorts who are known to represent a high risk of symptom free transmission.  But vaccinating the children is not the way to go to make them safer.  Vaccinating them - as the ones at higher medical risk - is, and using the vaccine to drive prevalence of the virus low is.  

Maybe I'm wrong.  It's almost certainly too late to use the vaccine to push for total elimination.  But I think a caution and pragmatic approach is needed in the absence of longitudinal studies, starting with those at elevated risk.  The first job is to bring hospitalisations down to the point where the healthcare system isn't on the brink of doom.

I am teaching university students, my wife is teaching children. Even if we get vaccinated somewhat near the front of the queue we might belong to the 10% not protected.

Once a vaccine becomes generally available, I would take a refusal to immunize yourself (or a refusal to immunize your children) as a deliberate and direct attack on our health.

So, if anyone could get immunized but declines, they and their brood can f*ck right off from our place of work.

The same logic applies for the classmates or fellow students of my children.

I agree that CV19, at least for children/teenagers, poses not that much of a risk, but anti vaxxers don't do logic, they also tend to refuse MMR.

I am glad that following the latest measles outbreak facilitated by anti vaxxer scum Germany made MMR vaccination mandatory for kindergarten/pre school childcare as well as schools. You can of course keep your preschool children at home, bu since school is mandatory, parents will have to immunize their children once they reach school age or be fined €2500 to start with.

As I wrote previously on here, I have seen a child that caught measles when too young to get the vaccine herself die of SSPE.

Essentially she was murdered by anti vaxxer scum deciding to live out their idiocy in public.

Also, I would make Covid vaccination mandatory for anyone trying to enter Schengenland. Dealing with our own anti vaxxers is hard enough, but why should we import more idiots?

CB

They claim the sale of shares was automated. Doesn't look good though.

https://www.theguardian.com/business/2020/nov/11/pfizer-chief-sold-56m-doll...

Interestingly if this comes to fruition and the government can deliver 40M doses to the 20M most at risk from covid or of spreading it, that's only really enough doses for over 60s and maybe 2-3M health and care workers.

Assuming all goes well, delivery is rapid and not bungled then maybe early summer public and economic pressure to fully release restrictions and re-open everything will be becoming irresistible.

At that point, assuming we muddle through winter much like like we are currently maybe 1/2 to 2/3 of the population still lacks immunity so if we re-open suddenly for a few months it runs riot (bringing border, trade and summer holiday implications, our neighbours will be facing similar issues too of course) unavoidably exposing the unlucky 2M (not in the 90%) older folk for whom the vaccine maybe doesn't work and maybe 9M over 50s for whom covid is still a credible threat to life.

It's still going to be a rough spell, probably to the point where we still can't realistically unlock the economy fully in one hit with just 20M (-10%) of the most at risk vaccinated. Unless another vaccine delivers by spring or those 40M doses can become 60-80M I forsee 2021 still being dominated by distancing restrictions and possibly even the odd 'lockdown'.

Still, 40M doses of one working vaccine assuming the good news keeps coming is great news and interesting that it's an unconventional design.

jk

Some links - Pfizer have just started clinical trials in children aged 12 and over - https://edition.cnn.com/2020/10/26/health/covid-vaccine-pfizer-trial-kids/i...

Discussion on the UK plan - the youngest age being publicly considered/discussed is 50 - https://www.bbc.co.uk/news/health-54902909

I think the Oxford / AZ vaccine is being trialled in children.  Pfizer waited until they had early data from an exceptional large number of adults before moving on to a small number of children.  I think the trials with children will continue more gradually than the adult trials, and will be observed for longer before it gets to the approval and then policy stages.

I read that, the announcement of success would never have been timed to meet the automation criteria would it? 

All a bit fishy. 

Yep, but at least they waited until after the US election

Nonsense - Pfizer is SEC regulated. The sale will be completely above board. You don’t mess with the SEC.

More likely the shares were preset to sell at x price and the price increase on the day automatically triggered the sale order.

Still, there’s nothing like a good conspiracy theory.

I mentioned this a couple of days ago; the statement will have been carefully scrutinised by lawyers given that misleading investors or manipulating stock price would have the SEC - to use the American vernacular - crawling up their ass with a flashlight.   I very much doubt the key people were unaware of where the stock price was, what the triggering condition was, and what was likely to happen when the announcement was made.  Either this was entirely above-board or the SEC are going to have a field day.  They take very badly to this sort of thing.

Never mind the stock sale, but the timing (which was not in the hands of the company anyway) was perfectly picked to hack off the Trumpster...

I can very much magine that a release of the same news a week or month earlier would have won him reelection.

CB

That is quite reassuring because I'm getting that the mRNA is unstable and won't be reproduced inside the cell so even if something unforeseen was introduced, the amount that would be produced is limited. 

You're the type that's worrying me, with the 'scum', throwing anti-vaxxer out repeatedly and the clear anger and vitriol. This is not how complex medical and ethic decisions should be made, by people braying emotionally for compliance. You can rest assured if anyone in charge started speaking like this you'd see willingness to get the vaccine drop off sharply.

If I had a genuine ethical or safety concern surrounding it and was on the fence about this issue, and someone like you immediately started calling me an idiot-scum-murderer, am I likely to come round to your way of thinking? A large fine is nothing compared with having to comply with people who clearly think you're sub-human. 

I'm more in line with wintertrees thinking here, a slow and steady, evidence based approach that doesn't trample on peoples right and factors in who is in actual danger. If you're already having fantasies about banning people from entire sections of the globe, maybe take a step back. Drawing conclusions for covid based on personal experience with measles/SSPE death is not scientific, sad as it is.

 As I told you, I consider the anti vaxx stance (or refusing to wear a mask, or ignoring distancing in a checkout queue.....) a deliberate attack on my health. What am I supposed to do with such people, punch them in the mouth? Calling them scum is more than appropriate.

CB

edit: and it is not just personal experience, but professional training. How many papers have you published in the Journal of Virology? Not all opinions are of equal value.

I’m very much with your view on immunisations for childhood diseases and mask wearing.  Idiots walk amongst us and put the most vulnerable at risk.  Hard to know what to do about it without making the problem worse when you close the loop on their broken thinking.  

For the covid vaccinations I think it’s going to be next summer before there’s capacity to even consider immunising children (excepting high risk individuals) in the UK, and that the studies to give longitudinal data on child immunisation are only just beginning it seems.  I just can’t see a push to immunise children before late next summer, and I suspect lots about the situation is going to change by then...  I think there’s a much stronger case to wait for longitudinal studies on the leading vaccine candidates in children, compared to rushing to immunise those most at direct risk of death or serious health damage. 

For now the focus is on getting through winter without wrecking healthcare provision and ideally restoring some of what’s been postponed.  Then we’ll see.

Ultimately I believe my health is my responsibility. I need to ensure distance if I'm concerned, I need to wear more PPE if I'm worried. I don't go around making others responsible (within reason) for my health. If someone's in the supermarket without a mask, I don't automatically think this scum is deliberately trying to kill me, that would be insane. If someone coughed directly at me or spit on me, that's a whole different matter.

Sure it is, but my health is your responsibility, too. If you refuse a vaccine once it is available it is your duty to ensure that you do not even put me at a minimum of extra risk through your choice.

So, stay at home, don't go shopping or to the pub, and in particular, don't send your unvaccinated children into my lecture, forcing me to interact with them.

Unfortunately, because enough people do not give a shit about the health of others (else we should never see self sustaining measles outbreaks, ever) it is essential to make a set of standard vaccinations strictly mandatory for school children and university students.

I agree, though, that with CV19 child/student vaccinations should wait until some longitudinal data are available.

CB

But Covid is a notifiable disease so any magistrate or judge can order you to be hospitalised against your will.

Can perhaps, but has this been done at all so far? Does that suggest that it has been deemed disproportionate to take such a step by said authorities?

Are you suggesting they could order you hospitalised indefinitely for not getting a vaccine or hospitalisie you to receive a vaccine against your will? Neither sounds correct.

I'm suggesting you read the relevant legislation.

Happy to, but would like to know what point you are making before doing so.

"I'm all for following medical guidance but the minute you demand I must comply I'm on alert. Last I checked we aren't subjects of a medical dictatorship that can withdraw your rights on a whim."

It might not be 'on a whim' but you might be suprised at which of your rights they can withdraw on suspicion that you are an infectious danger to others.

That wouldn’t be on the basis of not having been vaccinated though. Part 2A orders have been used to make people with tuberculosis submit to treatment (or at least stay in hospital). 

Yes I'm more interested where such powers not only can, but are likely to be used in this (covid) instance. To my knowledge, so far no-one has been forcibly held in hospital, the government seems content with asking that you quarantine yourself. This suggests that the danger isn't perceived to be sufficiently great to enforce quarantine to any 'serious' level (eg. threat of long term imprisonment, armed personnel holding you in a sealed room, centers where infected people are sent).

And as you say, holding in hospital until such point that you are no longer contagious seems feasible, but holding you indefinitely for testing negative but refusing covid vaccination sounds pretty unlikely in the real world. 

It could be though, if say an outbreak was traced to a street it would be reasonable to require the people who are not vaccinated were tested and those who refused could be reasonably suspected to be infectious.

That’s pretty much it. Sounds like they have better treatments now and a vaccine that works for older people in the risk group should be able to bring it into Flu territory, add in extra controls for the care homes and I think the ‘by the spring’ comments are perfectly valid. 
 

I think arguing over who will be forced to have the vaccine are counterproductive, we don’t force anyone to have the flu vaccine. Bear in mind that without vaccines and antibiotics we would see Flu kill just as many people. 

Flu is less contagious and has a lower mortality rate. And it is a virus so antibiotics cannot be used to treat it.

 But your PPE protects me and mine protects you. My mask doesn't stop me becoming infected, but yours drastically reduces the risk of you passing it onto me if you are infected. So you are responsible for my health and I am responsible for yours, whether you like it or not!

It’s the pneumonia that kills people. The antibiotics stop that. That’s the only reason it has a lower mortality. 

Fine if we were discussing getting fat.

When we're discussing a dangerous infectious disease my health is also your responsibility and yours mine of course. And it's not just our health, until we figure out how to live our lives with this held in check our economy rots with good businesses failing or accruing debt which will stifle growth for years, our hospitals choke, staff burn out and backlogs grow, our education and grad employment pipeline chokes...

jk

That's because covid is currently everywhere, penalising the odd dickhead for carrying on going out boozing with a positive diagnosis achieves little because they're rare and covid is already everywhere being spread freely by accident anyway (the bigger problem so th eone to focus on for now). Anyway by the time you have identified and processed them the damage is done.

Instead of looking at the quagmire we're in, look to other reasonably civilised countries where covid is already eradicated or barely present, they're not messing about with people flouting the law. The Isle of Man has been quite busy jailing people for isolation violations this summer. Seems harsh from here but they're living all but normal lives and the policy is well supported.

jk

If you recall the Govt effectivley forced people to quarantine during the early stages.They used the law to do that.Remember those people returning form Cruise ships etc,

And in Aus and NZ they have effectively been doing that.In Aus you are when returning from an oversea trip forced to stay at Govt approved hotel whilst you quarantine and you have to pay for it. No ifs or buts.

Dead eay to resolve. Other countries will no doubt say unless you have a vaccination certificate then you are not allowed in.Almost inevitable this will be widespread global practise.It will be your choice in the end-- too travel or not.

Completely and utterly wrong, PPE is exactly what it says "Personal Protective Equipment" and protecting others comes nowhere in the legislation. My FFP2 masks and my full respirator do absolutely nothing to protect others from Covid as they have unfiltered exhausts.

"Community masks" do nothing to protect you but probably others.

Ok, I was using the term PPE as the poster to whom I was replying used the term. The general usage of the term is often incorrect, even in a health care setting (my understanding is that surgical masks are also not technically PPE, they also are designed to reduce the spread from the wearer to others?).

Assuming the poster to whom I was replying did mean basic face coverings, you do seem in agreement with my general point.

Interesting article on the subject.

https://arstechnica.com/science/2020/11/well-need-more-than-one-vaccine-to-...

Links to another article discussing problems scaling the supply chain for the glass ampules used to distribute the vaccine - it needs a special glass to survive the -80oC storage.  From covid to illegal sand mining and cutting edge manufacturing through internal surface coating.

https://www.wired.com/story/vaccine-makers-turn-to-microchip-tech-to-beat-g...

Surely they’ll be recycling the glass? 

I doubt it.  The fabrication process will be set up for specific feedstock (sand, dopants etc) and specialist industrial glass fabrication is a finicky process to get working reliably.  I doubt they can substantially change the feedstock without a long optimisation and validation process.  It’s not even clear to me if the final glass can be remanufactured in to more of the same kind of glass.

For pretty obvious reasons I doubt the ampules will be reused.

Sterilisation of glass and metal seems to work in other medical and science based contexts? 

Hmm, not sure that article is particularly accurate. Schott makes a lot of glass for ampoules and other medical uses and some ampoules themselves but only a few billion, mainly they are one of three primary tube producers. What they did do along with the other is agree not to take speculative orders from hopeful vaccine producers to avoid blocking the supply to succesful vaccine companies. Not suprisingly (since the big suppliers are not from the US) this isn't exactly popular in some quarters.

Schott themselves had already invested in new production line and say they expect to produce 2 billion next year and that the world production is of the order of 60billion. The normal vaccine delivery ampoules are 10 or 20 doses.

Related to this, BioNTech was working on a self-amplifying RNA vaccine as one of its four variants, although it seems that the variant now in phase 2/3 trials is the modRNA one.

The Shattock saRNA vaccine announced back in July (https://www.nature.com/articles/s41467-020-17409-9) could be a boon to the cold-chain problems if the 64-fold reduction in dose typical for these vaccines (https://www.cell.com/molecular-therapy-family/molecular-therapy/fulltext/S1...) translates to lower bulk to a significant degree.

I wonder why the various structural modifications that have given amazing thermostability to previous RNA vaccines (https://journals.plos.org/plosntds/article?id=10.1371/journal.pntd.0006108) haven't borne fruit in this case, or why they couldn't be done, whichever the case may be. This whole press-release drip-feeding is very frustrating—I thought we'd be doing things differently in 2020, but that's just naive idealism.

I think you may be underestimating the distances that semen its transported.

Samples can cross the globe on dry ice.  But I’m guessing the product of miles and kilograms travelled by vaccine doses is going to far outclass the cattle industry’s gunk.

Unless we find an alternative vaccine that can be stored at higher temperatures thenit will certainly be necessaryto move huge volumes around but it may well be easier to scale up the simple solutions than to procure and install a large number of both static and mobile freezers.

Or if a non-thermostable saRNA vaccine comes to fruition and the potency increase translates to a reduction in bulk.

That said, none of the vaccines in the WHO database (https://extranet.who.int/pqvdata/) exceed 20 doses per vial. I wonder if this is because of sharp drop-offs in dosing accuracy and increase in wastage beyond that point, or because that was typically the result of the upper potency bound for non-saRNA vaccines.

I think getting static freezers and having a well designed dry ice transport system is the simpler solution.  Reading around, Pfizer have designed a nice transport box that's very well insulted and has sufficient temperature logging and reporting to guarantee the integrity of the product to medical standards. 

The last time I had contact with things related to saRNAs was with some bizarre Semliki Forest Virus based protein expression systems. Not sure I would like to see these in a vaccine, even if they are split into two separate components. Better than nothing if it is the only kind that works, but a clean, lipid delivered, nucleoside modified and stabilized single ORF mRNA looks a bit more trustworthy if it is able to induce sufficiently high expression levels.

CB

Yes, it seems to me that once you start packing replication enzymes into these vesicles along with the other bits, you’re nudging towards synthetic virus territory - I wonder what the minimum viable complement of genes and ready-made polymerases etc is for a synthetic virus?  Sounds like much easier work than trying to build the first synthetic cell, and would could possibly go wrong?

Are there any immune components that target foreign ribosomes?

In theory, the risk of cell export will only be there for budding-competent viral glycoproteins and can in any case be avoided with the trans-amplifying approach you mention.

Still, I understand the hesistancy. The safety profiles look good, but it may be a case of saRNAs only engendering confidence once we feel like the unknown unknowns (ahem) have dwindled to negligibility. Opinions differ on whether we're there yet.

Keep in mind that the replicases aren't 'ready made' and packaged into the vesicles but are coded for by strands of RNA. Your approach would probably be even safer than the purely genetic one.

The porcine circovirus has just two ORFs coding for three proteins: https://en.wikipedia.org/wiki/Porcine_circovirus  

It's easy enough to make such antibodies in the lab, although I doubt this is ever a natural strategy since they're never presented on the cell surface. Stranger things have happened though.

Also, 'sarna' is scabies in Spanish, whose mental imagery feeds into my own prejudices.

I understand the theory behind these constructs, and do not obviously see how they would pose an immediate danger. However, the mRNA only ones are even "cleaner", at least conceptually, which is why I would prefer them if I had a choice. KISS and all that....

One thing one could imagine would be that they may also generate immunity against the viral enzyme, which may be contraproductive should you ever need another vaccine requiring that technology. If the non sa version works well, why potentially risk that?

CB

With suiatble transport arrangements it would seem wise to move it to the point of administration as it is required rather than storing large quantities at medical practices all over the place?

Thanks.  I'm bugging a lot of molecular biologists/immunologists on here lately...

When the RNA for the (viral mRNA amplifying) ribosome is translated by the human cell's machinery into an instance of the ribosome, presumably it goes through an mRNA stage?

If so, does this mean there is a "do-not-translate" tag on the mRNA encoding the ribosome so that extant instance of the ribosome know not to amplify the mRNA for their own class? (with this mRNA floating about whilst the process of building more ribosomes from the RNA is going on by the human cellular machinery)

Otherwise I can see some sort of exponential run-away as these mRNA amplifying ribosomes amplify their own mRNA when they're translated from RNA.  If there is such a do-not-copy tag, what happens if you deliberately remove it?  

I'm not sure if I explained that clearly enough?

Thanks; yes I didn't think that one though.  Not much sign they're at work is presented on the outside of the cell I suppose.

Yes I do recall back when keeping the virus out of public circulation seemed possible until that was grossly mishandled (eg. no checks at borders/airports). I'm specifically referring to instances where people are being forced to quarantine in hospitals or other non-household buildings. To my knowledge this isn't in practice anymore, but please tell me if I'm wrong.

Clearly quarantining infected people and quarantining non-infected but non-vaccinated people are different. It would be odd to have infected people trusted to self-quarantine for a year or more, but as soon as a vaccine became available to suddenly forcefully quarantine/imprison non-infected but non-vaccinated people until they comply. Seems unrealistic to me.

To your second reply, I don't necessarily think there is no doubt that all or most countries will adopt this viewpoint. At least you're drawing a theoretical line at travel rather than banning people from all public life like some others above.

Looks like this might be a game changer if -80 degrees is logistically impossible at the sort of scale required:

https://news.sky.com/story/covid-19-moderna-vaccine-shown-to-be-94-5-effect...

Having thought about it some more, the mRNA intended for amplification must have some specific primers, otherwise the ribosome would go wild amplifying all mRNA in the human cell and presumably mess everything up.  

So then the question is, what happens if you put those primers into the code for the amplifying ribosome so it does amplify its own mRNA.  Ribopocalypse?  

Looks promising doesn't it.  The same questions remain over the demographics as for the Pfizer one - I'm not a fan of this "headlines first, phase 3 clinician trial results some time latter" approach...  

Not for Britain though, AFAIK we didn't buy any.

Realistically for a year or two we're not going to be shopping around for the best option, we'll be making do with what we pre-bought.

jk

Bring the people to the vaccine, not the vaccine to the people?

Makes some sense from a rural/semi-rural perspective but in the cities it's going to drive a lot of public transport use and potentially unsafe car-sharing for the elderly. Could be quite counterproductive.

Glassware notwithstanding it can't be beyond the wit of man to develop a regional distribution system that can feed numerous local vaccination centres and community nurses insulated crates at their designed work rate.

jk

I am not sure I understand your question.

The alphavirus genome (from which saRNAs are derived) is made of a single plus strand RNA containing two cistrons. The first encodes the viral replicase (a single polyprotein that is cleaved into its different components post translation) that copies the RNA into full length - strand RNA and back into either subgenomic mRNAs for the structural stuff as well as new + strand genomes for packaging. The second cistron encodes all the structural proteins. The viral RNA in an infectious virion is present as a capped and polyadenylated RNA, and can thus be translated right away by a cellular ribosome.

A saRNA encodes the viral replicase plus the protein of interest. It will be translated, the replicase make first - then multiple + copies of the RNA, from which the POI will be translated. The idea is that transiently amplifiying low levels of the RNA encoding the protein of interest can help to achieve sufficient levels of protein to elicit the desired immune response. 

The viral replicase can be encoded either by the same RNA that also contains the protein of interest, or the RNAs are split, with one encoding the replicase and the other the protein of interest. If only the latter also contains the target sequences for the replicase, you cannot get runaway as amplification ends whe the first RNA is degraded.

Seems, though, from both the Biontech and Moderna vaccines, that improvements in RNA delivery have made such tricks obsolete.

Hope that makes sense,

CB

I think I follow all that.  Thanks!

My question was about how the viral replicase knows which mRNA to amplify - and why it doesn't go wild amplifying it's own type of mRNA that appears as the cell is busy making more viral replicase from the alphavirus RNA. 

I I follow, the replicase isn't actually an mRNA cloner, but something that spits out multiple copies of mRNA from the target RNA, and that the target is designated by coupling the replicase RNA to the target RNA.

I had - wrongly I now think - assumed from the term "mRNA amplification" that the viral replicase was a device for duplicating mRNA.  But it's not really "amplification" (as in an output being looped round to an input and copied)  so much as multiple production from the same template?

What I should do is stop asking stupid questions and sign up for a part-time distance learning microbiology degree...

Yes, the RNA specificity is driven by the replicase protein binding to some RNA structure (a stem loop or such binding to the protein), which works more efficiently for the minus strand than the plus strand that is the viral genome: You only ever make a few copies of the minus version as an intermediate, which are then more effectively copied back into the plus version, either full length as viral genome or subgenomic as mRNA for the structural proteins (in a virus) or protein of interest in the vaccines. At any time, an infected cell has much more + strand viral RNAs than- strand.

This is different from the "rolling circle" amplification seen in bacteriophages like T4 and certain human viruses such as Papillomaviruses, all of which are dsDNA based

CB

A second mRNA vaccine getting similar results.

Moderna: Covid vaccine shows nearly 95% protection

https://www.bbc.co.uk/news/health-54902908

I believe the Pfeizer one is ok for a few days in a normal fridge prior to use so it probably just needs deliveries to GP surgeries etc a couple of times per week.

We roll out flu vaccination programs every fall so I'm not sure this is beyond the capabilities.

What have the UK manufactured so far? The Oxford vaccine? They typically start (well should) start manufacturing a vaccine when it shows promise.

"Another advantage of Moderna's vaccine is that it can be kept for 30 days in the refrigerator, the company announced Monday. Pfizer's vaccine can last only five days in the refrigerator."

This was on the CNN page then. Assuming it is accurate of course but they are normally pretty good at correcting technical info.