How a British Covid-19 vaccine went from pole position to troubled start

https://www.reuters.com/article/us-health-coronavirus-britain-vaccine-sp-idUKKBN28Y0XU

by respinal • 6 years ago

157 168 6 years ago

ggm6• 6 years ago

Having done spectrophotometry for water quality analysis 40+ years ago I was somewhat surprised it was being used but it has some advantages: it's mechanistic and easy, without risking the integrity of the sample, but as the story here shows it depends on certainty of the solvents and related conditions under test (we had to use specific optical refractive index glass measurement vials with their own cleansing routine and there was a rigmarole around calibration i still suspect was hugely subjective. I would hope by now the human eyeball is replaced by some digital light sensor, I think my subjective view skewed the sampling method)

exmadscientist• 6 years ago

I would hope by now the human eyeball is replaced by some digital light sensor

It has been! But if my lab experience was any guide, it's not necessarily a good light sensor. Spectrophotometry is great for getting coarse accuracy results out of. True precision... that is, and will remain, difficult.

5440• 6 years ago

It works just fine. The samples are tested in the UV-VIS at 280nm.

refurb3• 6 years ago

UV visible does have all those benefits you mention. What went wrong here is what is called “validation” and is a big part of pharmaceutical analytical analysis.

You not only describe how you measured your drug concentration, but you also test the limits. And those limits should go beyond anything you might encounter in actual manufacturing.

If your aim is to confirm a concentration of 5mg/mL, then you test all the way down to 0mg/mL and then 50mg and 500mg/mL. Then if you have a saline mixture, you test different concentrations of NaCl.

You’re basically trying to break the analysis to show where it doesn’t work.

The fact they did a UV vis and didn’t account for a different emulsifier is a big miss.

ketamine__4• 6 years ago

If one has access to the Pfizer vaccine why bother with AZ's vaccine?

stonogo• 6 years ago

αἴκα.

umeshunni• 6 years ago

AZ's vaccine is, I believe, easier to transport due to being storable at higher temperatures.

muffa2• 6 years ago

It does not have the same strict criteria in terms of keeping it at a very cold temperature which makes it interesting for developing countries.

ketamine__4• 6 years ago

That's great but irrelevant to my question.

belltaco• 6 years ago

A billion doses or so have already been manufactured around the world or are very close to. It's also substantially cheaper and as others said, way easier to store and transport. It will make a huge difference in the non-rich countries.

Leaked prices from the EU:

-Oxford/AstraZeneca: €1.78

-Johnson & Johnson: $8.50

-Sanofi/GSK: €7.56

-BioNTech/Pfizer: €12

-CureVac: €10

-Moderna: $18

c1505• 6 years ago

Where are you getting that information about a billion doses already manufactured? Would be great if true!

wyldfire• 6 years ago

Is the price a result of the cost to produce it, or is it price adjusted, reflecting the relative demand? Perhaps there's limited demand for a vaccine if the mixed results undermines confidence.

Also, it would be interesting to understand the global pricing. Due to market segmentation, there could be inconsistent local pricing among the manufacturers.

angry_octet6• 6 years ago

This is a bit confused with different currencies being used with implied ordering...

USD 0.82 -> €1.00

Oxford/AstraZeneca: €1.78

-Johnson & Johnson: US$8.50 €6.97

-Sanofi/GSK: €7.56

-CureVac: €10

-BioNTech/Pfizer: €12

-Moderna: US$18 €14.76

ketamine__4• 6 years ago

Your points don't address my question.

hashmash• 6 years ago

The mRNA vaccines aren't currently being produced at a high enough volume. Having more types of vaccines available means more vaccinations are possible in a shorter period of time.

jsnell• 6 years ago

Right. Where I live, there are enough orders for the three main vaccines to vaccinate all adults. But half of that is for the AZ option. Just like vaccines in general are going to be prioritized for at-risk demographics and essential workers, I'd sure hope they're also prioritizing the more effective vaccines for them.

Given the current data, of course I'd personally prefer of the mRNA vaccines. But that's unlikely to be something I have any agency over. It's either nothing for an indefinite amount of time, or accept whatever they have even if it is one of the less effective options.

ketamine__4• 6 years ago

Except my question was based on having access to an mRNA vaccine...

JumpCrisscross2• 6 years ago

If one has access to the Pfizer vaccine why bother with AZ's vaccine?

You wouldn’t. Poorer people in poorer countries will get the less effective vaccines. Richer people in richer countries will get the better ones. There is a difference therein. But nothing compared to the vaccinated-unvaccinated gulf.

ggm6• 6 years ago

It's going to be used by rich Western economies too. Britain and Australia will use it. Dont believe this is only an inferior treatment compared to others, wait for better stats to emerge. This stuff is 5x cheaper and easier to ship and store. It will be used by every economy be it rich or poor.

rossriley• 6 years ago

Less effective is perhaps a misleading word choice, remember the Phase 3 trials are measuring efficacy in preventing any cases (as defined in the study endpoint).

Despite the efficacy being lower the Oxford vaccine is extremely effective, not a single vaccinated recipient was hospitalised once 21 days had passed from the first dose.

gpm• 6 years ago

I'm not confident I have a full understanding of the tradeoffs / I will be doing more research once I can actually access either / availability will probably be the deciding factor anyways, but with that said:

As I understand the state of things I'd be more comfortable getting the AZ/oxford vaccine than the Pfizer/BioNTech vaccine because the underlying technology is less novel, and therefore there is less potential for unknown long term side effects (of the unknown unknowns variety).

tempestn• 6 years ago

The nice thing about the mRNA vaccines is that while that tech hasn't been used in an approved vaccine before, it has been used in other treatments, and there's no real mechanism for there to be long term side effects. The vaccine and the proteins it causes to be produced are only in your system for a limited time period. Long term side effects are more of a concern for medications that are taken on an ongoing basis.

Currently if I had the choice I'd go for the Pfizer vaccine hands down, given the superior efficacy in testing. (That said, beggars can't be choosers, so I'd take any approved vaccine I could get...)

hn_throwaway_992• 6 years ago

I'm the exact opposite - given how the technology works (and I think mRNA vaccines are truly ingenious and amazing), it seems the potential for negative side effects would be much greater (but, to emphasize, still not that high) with a modified-adenovirus-vector vaccine than an mRNA vaccine. I mean, the pathway for the AZ vaccine is to get a modified chimp adenovirus to infect your cells where they will generate spike proteins. The mRNA vaccines really are just snippets of RNA wrapped in lipids - they're about as simple and direct a mechanism as you can get.

rurban• 6 years ago

Because it would actually help.

As of currently there is a huge production backlog for Moderna and Pfizer, but not the simpler AZ and Sputnik vector vaccines. Mass vaccinations need to happen last month, not in May to be effective. In May/June when our batches will be ready, the wave would already be over and you would be protected for the next 6 months with almost no risk. The next useful vaccination period would be fall 2021.

With the two simpler vector vaccines you could start now for everybody, as did Russia, Hungary and Argentina weeks ago. Well, with Sputnik not the elderly.

muffa2• 6 years ago

This is interesting, the article suggest the vaccine at a half dose might be 90% effective for people below the age of 55. And might be more effective then previously thought for people above the age of 55 using half dose as well. Good news this means more vaccine is available to the public

pkaye2• 6 years ago

I think the US trial is testing both the half and full dose approaches to confirm these results.

m12k• 6 years ago

Do you have a source? My googling only found references to a full-dose US trial, and speculation that an additional half-dose trial would have to be paid by AZ themselves with no govt funding.

jancsika• 6 years ago

Experts: What's the next step? Wouldn't they need to test the half/full dose combo on over-55's before approving this vaccine?

jseliger• 6 years ago

I'm not an expert but the obvious solution is to give the Oxford/AstraZeneca vaccine to the 18-55 population and the mRNA vaccines to those 65+. The mRNA vaccines also have stringent and extreme freezing requirements that the Oxford one doesn't.

hn_throwaway_992• 6 years ago

Moderna's vaccine's refrigeration requirements are not extreme. It just needs -20 C (i.e what a kitchen freezer can do) for shipping, and then will be good for a month at 2-8 C, i.e. kitchen fridge temps.

StavrosK2• 6 years ago

Why not give the mRNA vaccines to everyone?

randcraw5• 6 years ago

Yes. The original trial required a total number of X people spanning the full range of ages and co-morbidities. But with the blunder, fewer than X people were assessed. Until the missing portion of the patients receives the nominal regimen of two full doses, the study, as it was designed, remains incomplete. The diminished number of patients will reduce the statistical power of the results, presumably to fall below what was deemed necessary and approved for the trial.

It's still possible that regulators will decide that 1) a sufficient number and range of ages and co-morbidies have in fact been assessed and that 2) the differential outcomes of the two groups is big enough to show the necessary level of efficacy and safety. But the 90% efficacy group clearly does NOT yet satisfy constraint #1, so until more 55+ year old subjects are added to the 90% efficacy part of the study, I suspect authorization will have to be based only on the 62% efficacy portion of the study.

sthnblllII• 6 years ago

I dont understand the combative and critical tone and direction of the article. Nothing mentioned in the article justifies it. When piecing together a story from second hand or off the cuff remarks of course people will say different things because their own knowledge is incomplete. It seems like the author threw her hands up in the air and just dumped everything she had gathered into a heap. I guess that's what a wire service is supposed to do tho?

dannyw• 6 years ago

You have a dosing error that resulted in some participants getting half the dose initially, and this group turned out to have substantially better resistance (~90%) than the one receiving the full dose (~60%).

This is completely mysterious, in the opposite direction of every other vaccine candidate, and should we be following normal safeguards, there is zero chance this vaccine would be approved.

It also raises concerns of rushedness/negligence. When you get two conflicting measurements of the dosages, the correct response is to test it a third time, not assume the second is correct. This failure mechanism was the same in Boeing.

Not that we need to be: we already have Pfizer and Moderna, that did their trials properly and showed proper results.

Exmoor5• 6 years ago

I disagree with your general conclusion that the vaccine should not be approved as-is. The efficacy results are certainly disappointing compared to the near-miraculous results with the two mRNA vaccines, but 60%+ efficacy is still enough to save many, many lives and bring the world back to normalcy. Remember, the 60% number doesn't mean 60% see improvement, it means of the people who would've gotten COVID without the vaccine, 60% didn't get it at all and 40% got it with significantly less negative effects. In all likelihood it will also greatly reduce the ability to spread the virus.

They have already begun testing the half-full dose as another trial, so if that works better than full-full we may see the approval modified down the line.

we already have Pfizer and Moderna

Unfortunately production constraints are going to mean that it will take a long time for those two vaccines to be produced in enough quantity to vaccinate most of the rich world. The cost for them and temperature requirements mean that they'd be impractical for most countries even in a few years.

angry_octet6• 6 years ago

It isn't actually completely mysterious. If you listen to what immunologists/ & virologists they can explain a number of mechanisms which might be responsible. Obviously I'm not qualified to give a good explanation, but there's plenty of good exposition if you look.

https://www.nature.com/articles/d41586-020-03326-w

- Statistical effects, which might decrease the difference as the trial progresses. - A bigger dose causing an over-effective suppression of the carrier adenovirus, suppressing it's ability to make the COVID spike protein, and hence the production of COVID targetting T cells.

There is also a huge flaw in the testing of the Pfizer and Moderna vaccines: they didn't test everyone. Only people with symptoms (whatever that means) were tested (PCR). Whereas with the Oxford AZ vax all participants were tested, so we can actually get an idea of asymptomatic infection.

refurb3• 6 years ago

The article is mostly based off the 1,000 pages of supporting documents Oxford released with their paper, no?

dbcooper• 6 years ago

I've worked with nucleic acids (DNA and RNA) in my postdoc, and now in my own lab, and I'm quite shocked that anyone would rely on UV absorption measurements. They're inherently insensitive, and suffer from unreliability and reagent interference. Especially when they were taken over PCR based methods.

It's a remarkable f*ck up for a clinical trial. These decisions should have been made with data from gold standard analytical methods.

freeflight• 6 years ago

I don't really see a tone like that in the article.

I'm also pretty convinced if a "mishap" like that came to light about the Russian Sputnik, or one of the Chinese vaccines, then the combative and critical tone would go straight to "How Putin/Xi personally wanted to kill millions of people!" with news outlets all over the planet constantly regurgitating headlines along that line and Hanlon's Razor given zero consideration.

While this article ends on the notion of how this is just some kind of "oddity" and yet somehow at the same time allegedly a universal problem of "reporting having slightly nationalistic tone".

The article is so muddled up, and long-winded, the result of which is that it barely gains any traction in the online sphere, can't a find a single submission about this on Reddit with more than a dozen upvotes. The few there are the top-comments are very ad-hominemy "Good thing journalists never make mistakes!", which is a reminder that stuff like this [0] is a very real thing.

[0] https://theintercept.com/2014/02/24/jtrig-manipulation/

fabian2k3• 6 years ago

The mistake that happened here is the kind of thing you explain to students the first time they're in the lab. It's really obvious and something everyone should know that uses a UV/Vis spectrometer.

And of course the method itself is suspect, as the main benefit is that it is cheap and quick, not accurate. And then taking the wrongly performed measurement with the worse method over the qPCR by the manufacturer (who likely has much more robust QC than someone in academia) is just insane.

porpoise• 6 years ago

It's become increasingly common to refer to this vaccine as the AstraZeneca vaccine or simply the AZ vaccine even though before concerns were raised I only saw it refered to as the Oxford vs vaccine. Does this mean that the alleged issues mostly lie with AZ as opposed to Oxford?

technics256• 6 years ago

You should read the article, it elaborates on this and lays the issues mostly auto the Oxford team.

garmaine• 6 years ago

Huh?

samb17292• 6 years ago

lays the issues mostly auto the Oxford team.

Could you explain what 'auto' means in this context? I can't establish whether it's a typo or not.

0-_-0• 6 years ago

In good news it's usually called the Oxford vaccine, in bad news the AstraZeneca vaccine.

rational_indian• 6 years ago

Typical British reporting.

cowsandmilk2• 6 years ago

All the issues were caused by the team at Oxford.

The naming change is likely due to who is leading the charge. The vaccine was developed at Oxford, so at the first news, there was no AZ involvement. As we move towards approval and production, the vast majority of work is being done by the team at AZ. The resources and experiences for manufacturing and distribution are the reason Oxford partnered with a pharma company.

Exmoor5• 6 years ago

Important to remember that the 62% full-full dose and 90% half-half dose do not have the same statistical power as the later group was less than 1/3 the size of the former. Even before taking into account the lack of 55+ patients, it's possible that the half-full could be a lot less effective than it seems and/or the full-full dose a bit more. Rather than stealing his statistics and pretending I can do the math, I'll quote liberally from Derek Lowe's write-up[0]:

In the larger cohort who got the two regular doses, vaccine efficacy was 62% (with a 95% confidence interval of 41% to 75%). There were 27 cases in the 4440 treatment patients, compared to 71 cases out of 4455 patients in the controls. Meanwhile, in the half-dose-first group, efficacy comes out at 90% (with a 95% confidence interval of 67% to 97%). Both of those 95% CIs are a bit of a spread. In this group, 3 out of 1367 patients in the treatment group came down with coronavirus, compared to 30 out of 1374 in the controls. That control-group infection rate is definitely higher than what was seen in the two-full-dose group, which makes you wonder if it’s running randomly high (which would make the half-dose group look better than it really is) or if the larger full-dose group was running randomly low (which would make it look worse than it really is, but remember, with its larger sample size there’s correspondingly somewhat less room to believe that it was that far out of whack). We need to add in to these calculations the news that the half-dose group included no patients older than 55, and to wonder what effect that had on the numbers, too. The paper reports a combined overall efficacy of 70.45 (95% CI between 54.8% and 80.6%), but how much you trust that one comes down to how different you think these two groups are.

[0]https://blogs.sciencemag.org/pipeline/archives/2020/12/09/th...

dash2• 6 years ago

We need to add in to these calculations the news that the half-dose group included no patients older than 55, and to wonder what effect that had on the numbers, too.

I’m struggling to understand that. It can’t be random, with so many people in each treatment. So why are their treatment arms unbalanced? And how do they control for that in the analysis?

ggm6• 6 years ago

When you run a large cohort experiment, i would imagine you balance the age profile to population after you do things. If you can get 1000 students in one day but spend three weeks hunting over 60s willing to be injected.. do you refuse to test 1000 students? No. You'd do something akin to Monte-Carlo random sampling into the age bins to get a distribution of experiments to match your needs. Maybe by the time they learned they had a fuckup on their hands, they'd only tested with the bodies available?

Kliment• 6 years ago

Half-dose group was unplanned and they switched everyone to full dose when they found out. It was in the beginning of the trial and they had only administered it to young healthy UK people by then.

StavrosK2• 6 years ago

Minor correction, the groups were "full full" and "half full" (for optimists).

raverbashing2• 6 years ago

Ok cool so the questions for the regulators are:

Would you rather have something that works at best at 75% or something that works at 67%?

Are there any risks in giving a smaller dose to the older cohorts (besides maybe smaller efficiency?)

woeirua2• 6 years ago

There’s an increasing likelihood that the AZ vaccine will arrive too late to the party in the US and will be the least effective of all the vaccines approved by the FDA. We don’t know the latter yet for sure, J&J’s data is supposed to come out in a few weeks, but if that comes to fruition it will be a HUGE misstep for AZ.

It’s unclear at what level herd immunity will be reached with Covid, more recent estimates are trending towards the 80-90% of the population range. If that’s the case then the AZ vaccine may not be good enough to eradicate the disease, even with full vaccination of the population.

ggm6• 6 years ago

I don't think you appreciate the economics of vaccination or the time it will take to get through the population on current rates. A 4C storage vaccine can be deployed in drugstores, carparks, by clinicians with normal training. The -60C vaccine demands ridiculously low wastage rates and a 30min hold time in case of anaphylaxis which is running anywhere up to 5x normal expected rates because of PEG.

There is an increasing likelihood several vaccines will be used by every country, almost continuously for the next decade.

woeirua2• 6 years ago

Both the J&J and moderna vaccines can be stored at much warmer temperatures. Pfizer likely can as well but they haven’t done the testing to verify that yet.

I’m not saying that AZ’s stocks of vaccine are going to be thrown out by any measure.

cm2187• 6 years ago

In my mind having some diversification in vaccines is a good thing. I understand we never used a mRNA vaccine on humans at scale before, so it is still somewhat experimental. It may work great but we can’t completely exclude an unexpected side effect in the long term.

Also a few weeks shouldn’t change anything. We are talking about a 6-12 months vaccination campaign.

I suspect the 80% number you mention is to eradicate the virus. I think at this stage it is a bit unrealistic. Between poorer countries that will not be able to vaccinate everyone and animals which can carry this disease, I would imagine the virus is here to stay. I think the primary objective is for it to cease to be a major public health issue. That it keeps contaminating people at low intensity in the background shouldn’t be a major concern.

SomeoneFromCA6• 6 years ago

Herd immunity rate is directly dependendent on Rt. If something spreads faster, and Rt is therefore higher herd threshold will be higher too. I think the UK variant is the cause of recent updates on herd immunity percentage.

irq114• 6 years ago

And nobody has any idea if that variant actually affects the transmission rate, let alone what impact it might have on “Rt”.

Speculation about this is irresponsible, at the very least. Moreover, we have eradicated exactly one human disease in all of history, and it took a couple hundred years of effort. Eradication is not the goal.

Immunize the most vulnerable people in the population (those over 65 and/or with certain co-morbidities), and the death rate for this virus will be dramatically reduced long before any herd immunity threshold is achieved.

onetimemanytime• 6 years ago

Can a person (in poorer countries) get this first and then Moderna /Pfizer a year or so later? Will the second vaccine cause problems?

Even 60% is better than nothing. Add the percentage that already passed the virus and you get a decent % that no longer get sick or transmit. Not a bad thing, for now.

brmgb2• 6 years ago

Unlikely to cause problem.

Giving people multiple vaccines using different vectors is common and tend to help in reaching immunity. Tests are currently under way for dual inoculation of the Oxford and Russian vaccines.

A multi-vaccines protocol is unlikely to include any of the RNA based one however. They are just too expensive and too difficult to store. But a combination of the more traditional is likely.

pts_• 6 years ago

After the noise is filtered -

It's atleast 60% effective with no hospitalizations for the remaining 40% and it's scalable due to requiring refrigerator level storage.

The only concern is 2 adverse events of spinal inflammation and 1 of brain inflammation out of around 20,000 tests.

neves3• 6 years ago

They made mistakes, but worked with integrity. It is a well known technology, safe and cheap.

Maybe another problem is that it won't provide absurd profits to big pharma companies.

fabian2k3• 6 years ago

Not properly blanking your UV/Vis measurement is an amateur mistake, that really should not happen in this kind of setting. UV/Vis spectroscopy is a rather unspecific method, many things can absorb the same wavelengths. You need to have a very good idea of what is in your sample to be sure that you're measuring the right thing.

In this case there are two things that absorb at the same wavelength, the vaccine and the polysorbate. The proper reference measurement would be all components except the vaccine, which you then compare to the full vaccine. It reads a bit like the used water or another buffer as blank here, which is really inexcusable.

_Wintermute• 6 years ago

What amazes me more is when they got this huge discrepancy they didn't confirm it with qPCR, or contact the supplier who would likely point out the polysorbate.

You must really feel for AZ at this point, and wonder how much they want to partner with academic scientists at such a critical stage.

Closi5• 6 years ago

You must really feel for AZ at this point, and wonder how much they want to partner with academic scientists at such a critical stage.

Considering this looks like the most promising vaccine candidate for large-scale global rollout and has by far the most orders, I'm sure they are still happy they are working with the world-class Oxford vaccine team.

afarrell3• 6 years ago

amateur mistake

You wouldn't believe how many software engineers with years and years of experience make amateur mistakes during interviews.

Pressure does weird things to people's performance.

fabian2k3• 6 years ago

That kind of decision must have involved a whole bunch of people. And I really can’t understand why you would trust the UV/Vis data over qPCR in this case. An additional component absorbing at the same wavelength the first thing you would suspect if you see a difference in this direction.

hedora• 6 years ago

This is a classic communications breakdown.

One group mixed the vaccine, and the other tested. The first group added a filler that throws off the UV measurement. They didn’t tell the second group about the additive because they didn’t realize the second group would use UV to measure the concentration.

Neither group could have avoided the problem without access to information they did not have. Both groups under-communicated. This sort of screwup is by far the leading cause of software bugs (most bugs occur at the interfaces between teams).

cblconfederate• 6 years ago

Not mentioned in the article, but AZ is also going to run a trial using a different viral vector for the second dose, taken from the Russian sputnik vaccine. The latter have claimed rather impressive results which will be published soon

https://www.theguardian.com/world/2020/dec/11/oxford-covid-v...

raverbashing2• 6 years ago

This is a very good illustration on how that claim that "the FDA is taking to long, you could run the efficiency trial data in a couple of hours" is exaggerated

Approving a vaccine goes way beyond running numbers and in the end a process that's pretty much opaque to us is full of gotchas and thorny details

kstenerud• 6 years ago

What's shocking in all of this is how they handled two conflicting potency results.

A rational person would see two conflicting measurements and then stop to figure out why they are different, and then re-run measurements to verify the results until they know why they're different and which one is wrong.

These guys just said "We'll just trust the results from OUR measurements over THEIR measurements", which is the height of arrogance and stupidity. These kinds of mistakes can have dire consequences because you're no longer testing based on how the vaccine will be used in the real world once approved. To say "Well, it worked out in the end so no harm" is also incredibly arrogant and foolish.

afarrell3• 6 years ago

A rational person

In what setting have you _ever_ encountered a rational person?

I've met people who were capable of calmly evaluating a situation rationally -- sometimes even under a decent amount of pressure. But in my undergrad at MIT or in my career as a software engineer, I have never met a rational person.

addicted4• 6 years ago

You do realize that scientific studies are not the same as an interview right? You have time to reflect on your observations and you also have sizable teams to discuss those observations with, including the wider scientific community.

Everyone understands pressure does funny things to people. That’s why, for example, making mistakes is not considered bad when doing scientific research. However, not revealing those mistakes is considered terrible form, in an incentive to encourage open sharing as opposed to secretive misleading.

randcraw5• 6 years ago

Agreed. After observing such a huge disparity in outcomes (90% vs 62% efficacy), any honorable scientist should have been shocked, immediately asking, “How is this possible?”.

Once the outcome disparity was noted, it's unimaginable that BOTH blunders would not be revealed: 1) low concentration in the first dose, and 2) exclusion of age 55+ patients.

More troubling is error #2. That degree of mistake is unforgivable. Heads should roll, and that should include the subsequent apologists who blithely dismissed the gravity of their team's carelessness.

MrAlex942• 6 years ago

Once the outcome disparity was noted, it's unimaginable that BOTH blunders would not be revealed: 1) low concentration in the first dose, and 2) exclusion of age 55+ patients.

The regulator was aware at every step and recommended Oxford should continue the study with the half dose.

The Italian manufacturers used a different technique to Oxford to check the concentration of the vaccine - effectively how many viral particles are floating in each dose. When the Oxford scientists used their method, it appeared that the Italian vaccine was double strength. What to do? Calls were made to the medical regulators. It was agreed that volunteers should be given a half measure of the vaccine, on the basis that it was likely to equate to something more like a regular dose. This was partly a safety issue - they preferred to give them too little rather than too much.
But after a week, the scientists became aware that something unusual was going on. The volunteers were getting none of the usual side-effects - such as sore arms or fever. About 1,300 volunteers had only received a half-dose of the vaccine, rather than a full one. The independent regulators said the trial should continue and that the half-dose group could remain in the study.

https://www.bbc.co.uk/news/health-55308216

The amount of speculation in this thread is appalling.

solarkraft• 6 years ago

Do I understand correctly that so far it's not really known which dosage is good and there has been virtually no large enough scale testing to confirm the efficacy of any dosage?

Closi5• 6 years ago

My understanding was that there was enough scale at the main dosing regimen, however the 'mistake' dosing regimen showed additional promise.

randcraw5• 6 years ago

True, except for patients age 55+. They did not receive the initial half-concentration dose. That's almost certainly why those receiving the half-concentration dose experienced much higher efficacy (90% vs 62%) — they were younger and had fewer co-morbidities.

addicted4• 6 years ago

No, the mistake is not showing additional promise. The “mistake” is a clue that the study was completely botched.

tgsovlerkhgsel• 6 years ago

For people misled by the headline: No new issues seem to have been discovered; the article just seems to explain why some study participants received a half dose (which was already reported and actually turned out to likely be _more_ effective than the full dose).

rebuilder• 6 years ago

The article says more than that:

"Some experts say the dosing discrepancy raises doubts about the robustness of the study’s findings. And they worry about another acknowledged peculiarity of the study: The half-dose regimen wasn’t tested on anyone over 55 - the group considered at high risk from COVID-19."

randcraw5• 6 years ago

Exactly. When you remove the patient group that experiences 90% of the severe cases, voila, your efficacy rate skyrockets.

Until SOMEONE ELSE completes trials on that missing age 55+ cohort, this vaccine should be accepted ONLY for ages 0 to 54. And given its likely low efficacy (62%), NOT for anyone with co-morbidities.

happymellon3• 6 years ago

Which is why we are not going to use the half dose.

60% efficiency which has been peer reviewed, is still as good as the flu vaccine, it can be stored in a normal fridge so will work better for distribution outside of major cities, and costs significantly less.

There are very few downsides, apart from not generating American news.

addicted4• 6 years ago

The half dose being more effective than the full one is a potential red flag that the study results are off.

IgorPartola2• 6 years ago

From what I read it’s a lot more complex than that. One theory is that it’s due to how the AZ vaccine is constructed. It is a neutered chimp adenovirus that cannot reproduce but is able to infect cells and cause them to produce the COVID spike protein that the immune system can detect and react to. So it is a two stage process: infect the cell, make it produce the spike protein, have the spike protein attach to another cell, and finally have the immune system respond to the spike protein. The idea is that if you inject too high a dose initially, the immune system will instead respond to the adenovirus and kill it before it can carry out its intended job here. Having a slower initial response will allow for enough COVID spike protein to be produced to develop an immunity to that.

I am absolutely not an expert on this. Just paraphrasing something I read.

ulfw2• 6 years ago

The fact it was an error and they can't really explain why it's better, but have some ideas why it could be, is a red flag.

athriren• 6 years ago

the immune system is where intuition goes to die and it is not uncommon for lower potency vaccines to provoke more effective immune responses.

i do agree oxford and astrazeneca have not handled this well. it seems quite clearly an error based on a volume of documentation but leadership at both institutions appear to be insisting it was not, which degrades trust at a time when many members of the public do not trust health officials to tell them which way is up.

radycov2• 6 years ago

A question I rarely see addressed during double-blind placebo studies is: how do you ensure both groups encounter the same virus exposure during the study period?

Is it simply safe to assume nearly equal "average exposure" over say 90 days randomly, or are all participants encouraged to follow identical lifestyles.

joshgel• 6 years ago

This is the beauty of randomization and blinding. Because both the participants and the doctors (the ‘double’ in double blind) don’t know who got the vaccine or placebo, anything you tell them to do is told equally to both sides. You can’t alter the trajectory of one group over the other because you don’t know the groups.

sokoloff• 6 years ago

A close friend of mine is in one of the double-blind trials here in the US. He experienced symptoms 36-48 hours after the injection that have him convinced that he got an active vaccine dose. He has (by my judgment not his words) altered his routines as a result. That seems a mechanism by which the blinding can be undone (though in this case, it would seem to work against computed vaccine efficacy rather than for it).

TomK32• 6 years ago

I guess you ensure exposure by having many test subjects during an ongoing pandemic...

Now that the UK have already over 500k doses of the other vaccine administered we will see new data on the effectiveness and safety of the vaccine (in comparison to CoVid-19, don't forget that!).

mortehu• 6 years ago

Randomization will on average prevent confounding variables from being unbalanced. For known and suspected confounding variables you can use blocking on top of that. For example you can randomly split each age group in half in order to ensure the intervention and control arms have similar age distributions.

Blinding and placebo control helps prevent behavior modification from the intervention itself, but it's possible that people who receive the saline placebos behave differently, since they don't get any side effects. I believe AstraZeneca's trial in the US uses a saline placebo, presumably because an active placebo might accidentally also work against the virus.

radycov2• 6 years ago

Anecdotally, since March I have been travelling on public transport and going into crowded central city locations almost on a daily basis, yet appear to have (extremely fortunately) avoided infection. This includes over the past few weeks with new highly infections mutations.

Equally anecdotally, I know of several friends who have caught it from young children in school settings or crowded groups.

randcraw5• 6 years ago

The people who prepare and distribute the drug vials are obviously not blinded; each vial (or batch) has a serial number that is known to be positive or control. Only the drug's administrators in the clinic are blinded.

ulfw2• 6 years ago

Of course not. You can't tell people what life to live. That's why the studies are generally 30,000+ people big to get enough randomisation in.

I think the ChAdOx study wasn't quite as large. Someone know ?

brmgb2• 6 years ago

The US press still pilling up on the far cheaper and extremely easier to store and distribute UK vaccine. Color me surprised.

timmb• 6 years ago

It’s worth reading the peer reviewed paper in the Lancet. It’s been a PR disaster which is significant when you’re talking about persuading people to take vaccines. But from what I see:

- a mistake was made on standardising measurements, but a decision was made that erred on the side of caution (diluting the batch that may have had too high a dose). I can appreciate these decisions being decided based on balancing what is needed to measure efficacy vs. the number of additional people who die due to delaying the trials. In hindsight it was wrong and something apparently simple was overlooked but the decision process seemed to have integrity and be based on what was known at the time.

- The accidentally modified dosing trial was just tested on younger people but the improvement was the same even if you only compare it against the same age range on the original dosage. This dosage I guess needs more data which will probably be forthcoming. However the original dose efficacy of ~60% is still useful given the affordability and practicalities of distribution.

- the validity of the pooling of the data was approved with the regulator well before anyone knew how it would affect results

- However a key thing looks to be that the reduced dosing increased the vaccine’s efficacy on Asymptomatic cases from ~4% to 60% - But at this stage more data is needed because to give a confident picture. This is big news as this is the only vaccine so far with an indication of efficacy against asymptomatic.

Please correct if I’m wrong in the above?

The paper in the lancet: https://www.thelancet.com/journals/lancet/article/PIIS0140-6...

IgorPartola2• 6 years ago

Wasn’t the reason this vaccine looks to work so well on asymptomatic cases simply because they bothered to test people with no symptoms while other trials didn’t?

throwaway4good3• 6 years ago

Why is the west persuing the never before used mRNA designs instead of proven designs such as inactivated virus vaccine which have been around for ages?

https://www.nytimes.com/interactive/2020/science/coronavirus...

I fear that the approval and quality control process have been politicized and is prone to errors of both the white and the black swan type.

SomeoneFromCA6• 6 years ago

Because adenoviral vaccine are unreliable, and there is a big concern that humans have become so adjusted to them, so that immune response will be very fast and the embedded Covid proteins won't have a chance to make the antibodies against themselves.

throwaway4good3• 6 years ago

We understand this because this type has been in use for decades.

We do not have a similar level of understanding for the mRNA type. And yet we are pushing it out at a never seen before scale and speed.

throwaway4good3• 6 years ago

From the article - referring to mRNA - Adrian Hill is quoted:

“Why would you take a vaccine technology that is new, unproven, maybe quick to manufacture, but expensive to manufacture - and has never been scaled up and has never been shown to protect against anything in humans, and prioritize that in a global emergency?” he asked. “It’s very odd.”

elcomet• 6 years ago

Cause it's very fast to find the vaccine.

aazaa• 6 years ago

The documents published in The Lancet confirm that the error lay with the Oxford researchers. A common emulsifier, polysorbate 80, used in vaccines to facilitate mixing, had interfered with the ultraviolet-light meter that measures the quantity of viral material, according to the documents. As a result, the vaccine’s viral concentration was overstated and Oxford ended up administering half doses of vaccine, believing they were full doses.

To recap, you need a way to know the vaccine concentration so that you can draw the correct amount from the vial when dosing patients. Oxford was using a technique called UV spectroscopy. Place a sample of liquid in a UV light beam with a source on one end and a detector on the other. The relationship between absorbance and concentration is linear. BUT: you have no idea what's absorbing the light - only that it's happening. If other materials that absorb at the same UV wavelengths are present, you'll think the concentration of what you're measuring was higher than it actually was.

According to the article, Polysorbate 80 (an "emulsifier" used to stabilize the vaccine) and the virus absorb at the same wavelength being used to quantitate the virus.

Someone, somewhere forgot to do take the absorbance of UV light by Polysorbate 80 into account. This led to overestimation of the concentration of virus present in the batch received from the manufacturer by 2x. This 2x too high concentration was then mistakenly used in the study to determine the volume of vaccine to administer to patients. The patents only got half of the dose they should have.

This is a fundamental error that no experienced chemist would ever make. If all of this is correct, I would immediately start thinking about other fundamental errors that may have occurred in the study.

How a British Covid-19 vaccine went from pole position to troubled start

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