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

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)

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).

After the noise is filtered -<p>It&#x27;s atleast 60% effective with no hospitalizations for the remaining 40% and it&#x27;s scalable due to requiring refrigerator level storage.<p>The only concern is 2 adverse events of spinal inflammation and 1 of brain inflammation out of around 20,000 tests.

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?<p>Is it simply safe to assume nearly equal &quot;average exposure&quot; over say 90 days randomly, or are all participants encouraged to follow identical lifestyles.

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&#x2F;3 the size of the former. Even before taking into account the lack of 55+ patients, it&#x27;s possible that the half-full could be a lot less effective than it seems and&#x2F;or the full-full dose a bit more. Rather than stealing his statistics and pretending I can do the math, I&#x27;ll quote liberally from Derek Lowe&#x27;s write-up[0]:<p>&gt; In the larger cohort who got the two regular doses, vaccine efficacy was 62% (<i>with a 95% confidence interval of 41% to 75%</i>). 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% (<i>with a 95% confidence interval of 67% to 97%</i>). 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.<p>[0]<a href="https:&#x2F;&#x2F;blogs.sciencemag.org&#x2F;pipeline&#x2F;archives&#x2F;2020&#x2F;12&#x2F;09&#x2F;the-oxford-astrazeneca-vaccine-efficacy-data" rel="nofollow">https:&#x2F;&#x2F;blogs.sciencemag.org&#x2F;pipeline&#x2F;archives&#x2F;2020&#x2F;12&#x2F;09&#x2F;th...</a>

What&#x27;s shocking in all of this is how they handled two conflicting potency results.<p>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&#x27;re different and which one is wrong.<p>These guys just said &quot;We&#x27;ll just trust the results from OUR measurements over THEIR measurements&quot;, which is the height of arrogance and stupidity. These kinds of mistakes can have dire consequences because you&#x27;re no longer testing based on how the vaccine will be used in the real world once approved. To say &quot;Well, it worked out in the end so no harm&quot; is also incredibly arrogant and foolish.

Not properly blanking your UV&#x2F;Vis measurement is an amateur mistake, that really should not happen in this kind of setting. UV&#x2F;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&#x27;re measuring the right thing.<p>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.

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:<p>- 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.<p>- 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.<p>- the validity of the pooling of the data was approved with the regulator well before anyone knew how it would affect results<p>- 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.<p>Please correct if I’m wrong in the above?<p>The paper in the lancet: <a href="https:&#x2F;&#x2F;www.thelancet.com&#x2F;journals&#x2F;lancet&#x2F;article&#x2F;PIIS0140-6736(20)32661-1&#x2F;fulltext" rel="nofollow">https:&#x2F;&#x2F;www.thelancet.com&#x2F;journals&#x2F;lancet&#x2F;article&#x2F;PIIS0140-6...</a>

Do I understand correctly that so far it&#x27;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?

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<p><a href="https:&#x2F;&#x2F;www.theguardian.com&#x2F;world&#x2F;2020&#x2F;dec&#x2F;11&#x2F;oxford-covid-vaccine-to-be-combined-with-sputnik-jab-for-trial" rel="nofollow">https:&#x2F;&#x2F;www.theguardian.com&#x2F;world&#x2F;2020&#x2F;dec&#x2F;11&#x2F;oxford-covid-v...</a>

Experts: What&#x27;s the next step? Wouldn&#x27;t they need to test the half&#x2F;full dose combo on over-55&#x27;s before approving this vaccine?

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

This is a very good illustration on how that claim that &quot;the FDA is taking to long, you could run the efficiency trial data in a couple of hours&quot; is exaggerated<p>Approving a vaccine goes way beyond running numbers and in the end a process that&#x27;s pretty much opaque to us is full of gotchas and thorny details

It&#x27;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?

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?<p><a href="https:&#x2F;&#x2F;www.nytimes.com&#x2F;interactive&#x2F;2020&#x2F;science&#x2F;coronavirus-vaccine-tracker.html" rel="nofollow">https:&#x2F;&#x2F;www.nytimes.com&#x2F;interactive&#x2F;2020&#x2F;science&#x2F;coronavirus...</a><p>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.

From the article - referring to mRNA - Adrian Hill is quoted:<p>“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.”

If one has access to the Pfizer vaccine why bother with AZ&#x27;s vaccine?

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&#x27;s what a wire service is supposed to do tho?

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

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&amp;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.<p>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.

&gt; 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.<p>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&#x27;s absorbing the light - only that it&#x27;s happening. If other materials that absorb at the same UV wavelengths are present, you&#x27;ll think the concentration of what you&#x27;re measuring was higher than it actually was.<p>According to the article, Polysorbate 80 (an &quot;emulsifier&quot; used to stabilize the vaccine) and the virus absorb at the same wavelength being used to quantitate the virus.<p>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.<p>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.