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

157 points by respinal 6y ago

ggm 6y 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 6y 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 6y ago
    It works just fine. The samples are tested in the UV-VIS at 280nm.
- refurb 6y 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__ 6y ago
If one has access to the Pfizer vaccine why bother with AZ's vaccine?
- muffa 6y 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__ 6y ago
    That's great but irrelevant to my question.
- stonogo 6y ago
  αἴκα.
- umeshunni 6y ago
  AZ's vaccine is, I believe, easier to transport due to being storable at higher temperatures.
- belltaco 6y 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 6y ago
    Where are you getting that information about a billion doses already manufactured? Would be great if true!
    - rtx 6y ago
      There is a company called Serum Institute they have been doing production for sometime now. https://www.businesstoday.in/current/corporate/serum-institute-to-double-covishield-vaccine-production-to-100-million-month/story/423301.html https://www.businesstoday.in/current/corporate/serum-institu...
muffa 6y 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
- pkaye 6y ago
  I think the US trial is testing both the half and full dose approaches to confirm these results.
  - m12k 6y 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.
    - pkaye 6y ago
      I think you maybe right. I had read this a while back so maybe it didn't end up getting implmeented.
jancsika 6y 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 6y 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_99 6y 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.
    - estaseuropano 6y ago
      From the leaked EU prices the Moderna vaccine is 10x the price of the Oxford one. I guess that will be a key factor.
      - beojan 6y ago
        Everything's been pre-ordered (at least in the west) so I doubt price will be a key factor.
      - rualca 6y ago
        First of all, your "10x the price" means a price point between 10$ and 50$. That's hardly a blocker. Some people, when facing the choice of having a shot at a vaccine sometime in the future and have a reliable vaccine right now, would gladly pay 10x to speed it up.
  - StavrosK 6y ago
    Why not give the mRNA vaccines to everyone?
sthnblllII 6y 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 6y 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.
  - deleted 6y ago
    [deleted]
  - Exmoor 6y 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.
mchusma 6y ago
These hit pieces on the Astrazeneca vaccine are frustrating. In a peer reviewed paper in the Lancet, with a large phase III trial, the vaccine was found safe and effective enough to end the pandemic, which seems like a good enough bar. >95% effective at preventing severe disease. This is a standard far beyond what we should be having during a pandemic. Yet it's still banned for use in the US and most of the world. There is no rational utilitarian reason for this to be banned. Lift the ban on Astrazeneca and in the US we can be close to normal in 60 days.
- jsnell 6y ago
  > banned As you very well know (because you've been corrected on this inflamatory phrasing a bunch of times on HN), it has not been "banned". It has not yet been approved, which is very different.
- mhh__ 6y ago
  No it's the scientists who are wrong! If it's deemed safe it'll come, I assume it's only a matter of time, but you really can't rush these things (One fuckup anywhere in the world, and you bet Alex Jones will be on it straight away)
- InTheArena 6y ago
  AZ has not been banned, but clearly has issues with their quality control and scientific reporting. Thankfully there is a USA trial coming up which should provide numbers that are not contaminated by the mistake. Until the various governments review and approve the vaccines, they don’t go to market. It’s that simple.
  - respinal 6y ago
    Exactly. "BREAKING—95%—new data from Oxford/AstraZeneca vaccine shows 95% efficacy & is “100% effective” in preventing severe Hospital illness, says AZ CEO. That’s on par w/ Moderna & Pfizer. No official data yet, but UK said to likely approve in days." https://twitter.com/DrEricDing/status/1343047055078551554?s=20 https://twitter.com/DrEricDing/status/1343047055078551554?s=...
porpoise 6y 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 6y ago
  You should read the article, it elaborates on this and lays the issues mostly auto the Oxford team.
  - garmaine 6y ago
    Huh?
    - refurb 6y ago
      ”Oxford’s measurement showed that the batch was more potent than the Italian manufacturer had found, the documents show.” The Italian manufacturer’s analysis was correct. Oxford’s was wrong. They decided to stick with it and got the regulator to approve it. The fact that the more sensitive and selective PCR test result was ignored isn’t a good sign. Someone should have followed up to confirm which test was correct.
  - samb1729 6y 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 6y ago
  In good news it's usually called the Oxford vaccine, in bad news the AstraZeneca vaccine.
  - rational_indian 6y ago
    Typical British reporting.
Exmoor 6y 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/the-oxford-astrazeneca-vaccine-efficacy-data https://blogs.sciencemag.org/pipeline/archives/2020/12/09/th...
- dash2 6y 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?
  - ggm 6y 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?
woeirua 6y 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.
- ggm 6y 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.
  - woeirua 6y 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.
    - ggm 6y ago
      Its too early to say, basically. Enough locked in sales that absent a huge problem in the field, all the six to ten leading vaccines are going to be used at high scale for years. There's massive competition in fluvax. We don't all use a single source, never have. Since the days of penicillin there was a standard to measure against for efficacy and you can source it as you see fit.
- cm2187 6y ago
pts_ 6y 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.
- neves 6y 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.
fabian2k 6y 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 6y 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.
  - Closi 6y 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.
- afarrell 6y 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.
  - fabian2k 6y 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.
cblconfederate 6y 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-vaccine-to-be-combined-with-sputnik-jab-for-trial https://www.theguardian.com/world/2020/dec/11/oxford-covid-v...
raverbashing 6y 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 6y 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.
- afarrell 6y 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.
  - addicted 6y 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.
    - afarrell 6y ago
      > scientific studies are not the same as an interview Sure. Only one family's livelihood depends on the outcome of an interview. That is little weight on one's shoulders compared to stalling the response to a global pandemic. > You have time to reflect on your observations and you also have sizeable teams to discuss those observations with, including the wider scientific community. I would be interested to know what actual social dynamics looked like to the participants in this edge case. > Everyone understands pressure does funny things to people In theory, yes -- it is "common sense". In practice, no. Sadly, people generally scoff at "excuses" and look to place blame rather than understand contributing causes.
solarkraft 6y 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?
- Closi 6y ago
  My understanding was that there was enough scale at the main dosing regimen, however the 'mistake' dosing regimen showed additional promise.
  - randcraw 6y 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.
  - addicted 6y ago
    No, the mistake is not showing additional promise. The “mistake” is a clue that the study was completely botched.
    - Closi 6y ago
      Not completely botched, they approached the regulator with an error and followed their advice on how to continue. The regulators advice was how the final results were presented in the published paper (i.e. with the accidental dosing as a separate group).
tgsovlerkhgsel 6y 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 6y 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."
  - randcraw 6y 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.
    - happymellon 6y ago
      This statement is moronic. The vaccine has been tested on 55+. We are not doing a half initial dose because that hasn't been studied in detail.
    - DanBC 6y ago
      > patient group that experiences 90% of the severe cases, 43% of the patients going into ICUs in the UK[1] are under 60 years old. Most of the patients going into ICUs (including the older people) needed no assistance in their day to day lives before going into ICU.
      - Engineering-MD 6y ago
        But that is also a selection bias. The very elderly or those who need lots of assistance in day to day lives or those with multiple comorbidities are much less likely to benefit from an ICU stay (ie they will likely die with or without support) so don’t get admitted at all.
radycov 6y 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 6y 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 6y 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).
    - disgruntledphd2 6y ago
      Yeah, ideally you'd use an active placebo (same side effects as the active drug) but that's hard to do well and presumably wasn't a priority.
      - tim333 6y ago
        For at least some of the Oxford trials they used a "widely available meningitis vaccine."
- TomK32 6y 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!).
brmgb 6y ago
The US press still pilling up on the far cheaper and extremely easier to store and distribute UK vaccine. Color me surprised.
timmb 6y 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/PIIS0140-6736(20)32661-1/fulltext https://www.thelancet.com/journals/lancet/article/PIIS0140-6...
- IgorPartola 6y 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?
throwaway4good 6y 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-vaccine-tracker.html 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.
- SomeoneFromCA 6y 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.
  - throwaway4good 6y 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.
    - rualca 6y ago
      > 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. It's my understanding that the Pfizer/BioNTech vaccine is the first vaccine that is demonstrably reliable, safe, and able to be mass produced. Mankind may have a track record with another kind of technology, but until someone is able to come up with a vaccine that is reliable, safe, and able to be mass produced, they will remain in the hypothetical territory. It's better to have a vaccine in the hand than two in the theoretical textbooks.
throwaway4good 6y 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 6y ago
  Cause it's very fast to find the vaccine.
aazaa 6y 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.

157 points by respinal 6y ago

ggm 6y 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 6y 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 6y ago
  It works just fine. The samples are tested in the UV-VIS at 280nm.
refurb 6y 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__ 6y ago

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

muffa 6y 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__ 6y ago
  That's great but irrelevant to my question.
stonogo 6y ago
αἴκα.
umeshunni 6y ago
AZ's vaccine is, I believe, easier to transport due to being storable at higher temperatures.
belltaco 6y 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 6y ago
  Where are you getting that information about a billion doses already manufactured? Would be great if true!
  - rtx 6y ago
    There is a company called Serum Institute they have been doing production for sometime now. https://www.businesstoday.in/current/corporate/serum-institute-to-double-covishield-vaccine-production-to-100-million-month/story/423301.html https://www.businesstoday.in/current/corporate/serum-institu...

muffa 6y 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

pkaye 6y ago
I think the US trial is testing both the half and full dose approaches to confirm these results.
- m12k 6y 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.
  - pkaye 6y ago
    I think you maybe right. I had read this a while back so maybe it didn't end up getting implmeented.

jancsika 6y 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 6y 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_99 6y 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.
  - estaseuropano 6y ago
    From the leaked EU prices the Moderna vaccine is 10x the price of the Oxford one. I guess that will be a key factor.
    - beojan 6y ago
      Everything's been pre-ordered (at least in the west) so I doubt price will be a key factor.
    - rualca 6y ago
      First of all, your "10x the price" means a price point between 10$ and 50$. That's hardly a blocker. Some people, when facing the choice of having a shot at a vaccine sometime in the future and have a reliable vaccine right now, would gladly pay 10x to speed it up.
- StavrosK 6y ago
  Why not give the mRNA vaccines to everyone?

sthnblllII 6y 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 6y 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.
- deleted 6y ago
  [deleted]
- Exmoor 6y 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.

mchusma 6y ago

These hit pieces on the Astrazeneca vaccine are frustrating. In a peer reviewed paper in the Lancet, with a large phase III trial, the vaccine was found safe and effective enough to end the pandemic, which seems like a good enough bar. >95% effective at preventing severe disease. This is a standard far beyond what we should be having during a pandemic. Yet it's still banned for use in the US and most of the world. There is no rational utilitarian reason for this to be banned. Lift the ban on Astrazeneca and in the US we can be close to normal in 60 days.

jsnell 6y ago
> banned As you very well know (because you've been corrected on this inflamatory phrasing a bunch of times on HN), it has not been "banned". It has not yet been approved, which is very different.
mhh__ 6y ago
No it's the scientists who are wrong! If it's deemed safe it'll come, I assume it's only a matter of time, but you really can't rush these things (One fuckup anywhere in the world, and you bet Alex Jones will be on it straight away)
InTheArena 6y ago
AZ has not been banned, but clearly has issues with their quality control and scientific reporting. Thankfully there is a USA trial coming up which should provide numbers that are not contaminated by the mistake. Until the various governments review and approve the vaccines, they don’t go to market. It’s that simple.
- respinal 6y ago
  Exactly. "BREAKING—95%—new data from Oxford/AstraZeneca vaccine shows 95% efficacy & is “100% effective” in preventing severe Hospital illness, says AZ CEO. That’s on par w/ Moderna & Pfizer. No official data yet, but UK said to likely approve in days." https://twitter.com/DrEricDing/status/1343047055078551554?s=20 https://twitter.com/DrEricDing/status/1343047055078551554?s=...

porpoise 6y 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 6y ago
You should read the article, it elaborates on this and lays the issues mostly auto the Oxford team.
- garmaine 6y ago
  Huh?
  - refurb 6y ago
    ”Oxford’s measurement showed that the batch was more potent than the Italian manufacturer had found, the documents show.” The Italian manufacturer’s analysis was correct. Oxford’s was wrong. They decided to stick with it and got the regulator to approve it. The fact that the more sensitive and selective PCR test result was ignored isn’t a good sign. Someone should have followed up to confirm which test was correct.
- samb1729 6y 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 6y ago
In good news it's usually called the Oxford vaccine, in bad news the AstraZeneca vaccine.
- rational_indian 6y ago
  Typical British reporting.

Exmoor 6y 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/the-oxford-astrazeneca-vaccine-efficacy-data https://blogs.sciencemag.org/pipeline/archives/2020/12/09/th...

dash2 6y 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?
- ggm 6y 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?

woeirua 6y 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.

ggm 6y 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.
- woeirua 6y 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.
  - ggm 6y ago
    Its too early to say, basically. Enough locked in sales that absent a huge problem in the field, all the six to ten leading vaccines are going to be used at high scale for years. There's massive competition in fluvax. We don't all use a single source, never have. Since the days of penicillin there was a standard to measure against for efficacy and you can source it as you see fit.
cm2187 6y ago

pts_ 6y 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.

neves 6y 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.

fabian2k 6y 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 6y 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.
- Closi 6y 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.
afarrell 6y 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.
- fabian2k 6y 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.

cblconfederate 6y 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-vaccine-to-be-combined-with-sputnik-jab-for-trial https://www.theguardian.com/world/2020/dec/11/oxford-covid-v...

raverbashing 6y 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 6y 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.

afarrell 6y 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.
- addicted 6y 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.
  - afarrell 6y ago
    > scientific studies are not the same as an interview Sure. Only one family's livelihood depends on the outcome of an interview. That is little weight on one's shoulders compared to stalling the response to a global pandemic. > You have time to reflect on your observations and you also have sizeable teams to discuss those observations with, including the wider scientific community. I would be interested to know what actual social dynamics looked like to the participants in this edge case. > Everyone understands pressure does funny things to people In theory, yes -- it is "common sense". In practice, no. Sadly, people generally scoff at "excuses" and look to place blame rather than understand contributing causes.

solarkraft 6y 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?

Closi 6y ago
My understanding was that there was enough scale at the main dosing regimen, however the 'mistake' dosing regimen showed additional promise.
- randcraw 6y 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.
- addicted 6y ago
  No, the mistake is not showing additional promise. The “mistake” is a clue that the study was completely botched.
  - Closi 6y ago
    Not completely botched, they approached the regulator with an error and followed their advice on how to continue. The regulators advice was how the final results were presented in the published paper (i.e. with the accidental dosing as a separate group).

tgsovlerkhgsel 6y 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 6y 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."
- randcraw 6y 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.
  - happymellon 6y ago
    This statement is moronic. The vaccine has been tested on 55+. We are not doing a half initial dose because that hasn't been studied in detail.
  - DanBC 6y ago
    > patient group that experiences 90% of the severe cases, 43% of the patients going into ICUs in the UK[1] are under 60 years old. Most of the patients going into ICUs (including the older people) needed no assistance in their day to day lives before going into ICU.
    - Engineering-MD 6y ago
      But that is also a selection bias. The very elderly or those who need lots of assistance in day to day lives or those with multiple comorbidities are much less likely to benefit from an ICU stay (ie they will likely die with or without support) so don’t get admitted at all.

radycov 6y 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 6y 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 6y 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).
  - disgruntledphd2 6y ago
    Yeah, ideally you'd use an active placebo (same side effects as the active drug) but that's hard to do well and presumably wasn't a priority.
    - tim333 6y ago
      For at least some of the Oxford trials they used a "widely available meningitis vaccine."
TomK32 6y 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!).

brmgb 6y ago

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

timmb 6y 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/PIIS0140-6736(20)32661-1/fulltext https://www.thelancet.com/journals/lancet/article/PIIS0140-6...

IgorPartola 6y 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?

throwaway4good 6y 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-vaccine-tracker.html 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.

SomeoneFromCA 6y 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.
- throwaway4good 6y 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.
  - rualca 6y ago
    > 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. It's my understanding that the Pfizer/BioNTech vaccine is the first vaccine that is demonstrably reliable, safe, and able to be mass produced. Mankind may have a track record with another kind of technology, but until someone is able to come up with a vaccine that is reliable, safe, and able to be mass produced, they will remain in the hypothetical territory. It's better to have a vaccine in the hand than two in the theoretical textbooks.

throwaway4good 6y 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 6y ago
Cause it's very fast to find the vaccine.

aazaa 6y 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.