Last week AstraZeneca announced demonstrated varying efficacy in two different dosing regimens of its candidate COVID-19 vaccine, AZD1222 (ChAdOx1 nCOV-19).
In a November 23rd press release [PDF] the company announced efficacy of 90% when AZD1222 was given as a half dose and followed by a full dose at least one month later. This sample group had 2,741 subjects. Vaccine efficacy of 62% was evident when two full doses of AZD1222 were given at least one month apart. This was observed in a sample group of 8,895. They also announced a “combined efficacy” averaging 70% in a sample of 11,636.
Problems emerge
Whilst this sounded like a positive outcome it soon became apparent that the Oxford-AstraZeneca team still had hurdles to clear. It emerged later that the dose regimen yielding efficacy of 90% was given by mistake. This wasn’t made clear in the press release. The first dose should have been a full dose but due to a “manufacturing issue” only half of the expected dose was given. Regulators were told at the time and agreed the trial could continue with the immunisation of more volunteers. It is problematic that the trial wasn’t designed to test this regimen and less than 3,000 subjects aged 55 or less were involved. In order to validate the results another study examining the efficacy of the regimen will take place.
The other problem was the notion of “combined efficacy”. These data come from two different trials with different dosing regimens. One trial arm in the UK began in May. The Brazilian trial arm began in late June. So this information has not come from a single large Phase III trial as was the case with Pfizer and Moderna. Averaging efficacy from two different trials to yield “combined efficacy” of 70% is not acceptable. This doesn’t provide a sound assessment of what level of efficacy, or regimen, the public can expect. So again, further trials are needed. Also press release is not the vehicle to present scientific information and the AstraZeneca issue is an example of how problematic this can be. Study specifics that have been peer reviewed carry far more weight.
Media coverage
Which raises a point made by Norman Swan on today’s Coronacast that rumours are circulating, apparently with very little confirmation, that suggest Oxford-AstraZeneca are rushing to publish. He referred to a Financial times article which reported on Saturday;
Regulators and the rest of the world will soon have the full data. The Oxford academics who developed the vaccine have submitted a paper setting out their full Phase 3 results to The Lancet medical journal. They will be working over the weekend to answer questions from the journal and its referees and the article could be published as early as Thursday [UK time].
Concern and criticism about transparency and trust has been raised, particularly in the USA. Natalie E. Dean, assistant professor of biostatistics at the University of Florida posted a series of tweets on November 25th. Apart from transparency, concern about scientific rigour was raised. Her tweets included;
AstraZeneca/Oxford get a poor grade for transparency and rigor when it comes to the vaccine trial results they have reported. This is not like Pfizer or Moderna where we had the protocols in advance and a pre-specified primary analysis was reported.
The point about protocols in advance, along with the fact that AstraZeneca was one of nine vaccine makers to sign a scientific rigour pledge in September was raised in a highly critical article by Hilda Bastian writing in Wired. The article goes into the Phase III trial arms in depth and the manner in which Oxford-AstraZeneca has deviated from their trial protocol. Comparisons are made to the BioNTech-Pfizer vaccine at 90% efficacy and the Moderna vaccine at almost 95% efficacy. Bastian certainly casts them in a positive light. These two companies use messenger-RNA as the vector in their COVID-19 vaccines. Oxford-AstraZeneca use an adenovirus vector in their vaccine. How variously each approach effects COVID-19 vaccine efficacy is presently unknown. The Moderna and Pfizer vaccine results were also made public by press release.
It’s important to note that the FDA has argued a vaccine must be at least 50% effective to be useful in combating the pandemic. Whilst concern has been raised about the AstraZeneca situation it is over efficacy and not safety. The fact that regulators will accept an efficacy of at least 50% was noted by Mene Pangalos, AstraZeneca’s executive vice president for research, who dismissed concerns. AstraZeneca also want to alter the specifics of the US trial under the auspices of Operation Warp Speed. The aim is to change the two full dose regimen to a half dose, full dose regimen.
Certainly further successful trials are well within AstraZenecas grasp. The BMJ recently published COVID-19 vaccines: where are the data? The article examines the position of the three recent candidate vaccines and what is expected through peer-reviewed publication. The UK government has asked the Medicines and Healthcare products Regulatory Agency to evaluate authorising supply of the Oxford-AstraZeneca vaccine.
The cold chain needs of each vaccine vary. The Pfizer candidate requires storage at -70 degrees Celsius. This alone provides a challenge difficult to meet in developed nations and impossible in nations without significant infrastructure. Moderna’s candidate vaccine can be stored at -20 degrees Celsius meeting most pharmacy and hospital freezer temperatures but providing transport challenges for developing nations. Moderna claims that after thawing the vaccine will remain stable for up to 30 days at 2 – 8 degrees Celsius. AstraZenecas candidate can be stored in a normal refrigerator at 2 – 8 degrees Celsius and thus meets conditions in present healthcare settings and realistic options in developing nations. A successful outcome for Oxford-AstraZeneca is significant for the management of a global pandemic.
Back to Norman Swan of Coronacast;
And remember, this is a vaccine that they promised not to make profits out of, that is cheap and they are committed to giving very large doses, I think something enormous like a third of the world’s doses of vaccines are relying on AstraZeneca. So there’s a lot riding on this vaccine.
Anti-vaccination lobby
The anti-vaccination community have taken the challenges faced by AstraZeneca as more evidence Big Pharma is always up to no good. A recent AVN Facebook post observed that maybe it wasn’t a good idea to let drug companies release their own study information without independent oversight.
So again we might consult the press release. It includes (para 3);
An independent Data Safety Monitoring Board determined that the analysis met its primary endpoint showing protection from COVID-19 occurring 14 days or more after receiving two doses of the vaccine. No serious safety events related to the vaccine have been confirmed. AZD1222 was well tolerated across both dosing regimens.
Reading information on the AstraZeneca board we see;
Our Directors are collectively responsible for the success of AstraZeneca. In addition, the Non-Executive Directors are responsible for exercising independent and objective judgement and for scrutinising and challenging management.
Quickly scattering the seeds of disinformation in this manner is what the AVN always do. One expects this manipulation of their members. What I’m more interested in is the inability of the group to acknowledge that the focus on COVID-19 vaccine development has revealed a number of long standing claims to be false. In September I posted on how the Oxford-AstraZeneca trial pause alone refuted long standing anti-vaccine claims. Namely transparent mainstream media coverage and the documented process of Phase III trials. Despite the ample criticism of AstraZeneca’s handling of data the AVN are even further from defending their claims than they were in September.
As a quick reminder it is the claim that vaccine manufacturers do not assess the safety or efficacy of vaccines. Ever. Added to this is the strange insistence that a placebo must always be inert. Let’s revisit quotes promoting these errors. Given that the COVID-19 candidates are new vaccines the following quote published in a response to a journalist is particularly relevant. See Proposition 4;
…there have never been double-blind, placebo-controlled prospective studies done on either the safety or efficacy of vaccines, not even when a new vaccine is introduced.
This piece on HPV is highly misleading. Yet it’s the claim in the second paragraph under Safety In Question I find compelling;
By definition, a placebo must be a totally inert substance which will never provoke a response.
That definition might be fine for the “sugar pill” placebo. As in when we think of the “placebo effect”. Yet in vaccine trials it is more important to sustain the double blind nature of the trial. Simply put a subject must not know what group they are in. The AVN are anti-HPV vaccination. Gardasil trials have used the amorphous aluminium hydroxyphosphate sulphate adjuvant, or AAHS as placebo. This, unlike saline, produces an injection site effect like a genuine vaccine. Thus members of the placebo group and those administering the dose are unaware they have received or given the placebo. The randomised double blind nature of the trial is preserved.
Double blind randomised control trials are what Meryl Dorey, founder of the AVN calls “the gold standard” insisting they are ignored in vaccine research. The claim is part of the AVN Did You Know? leaflet. In this case demanding only inert placebos be used helps to both refute the value of trials and contend a heavy metal neurological injury is potentially caused by adjuvant placebos. The impact of this rhetoric can be seen below in an image of an interviewee on the Vaxxed II bus (27 Nov. 2020). Her T-Shirt has the words “gold standard science” and “inert saline placebos” amongst others written on it in Texta.
Finally as discussed in this article, by contending that no vaccine trials using saline placebos have ever been conducted the insistence that vaccines are primed to harm persists. It’s a simple no true Scotsman anti-vaccine fallacy. Also when saline is used as the placebo in an HPV vaccine trial, there really is nowhere to hide. Vaccine studies using saline placebos abound. Period.
AVN devotee wearing T-shirt demanding ‘inert saline placebo’ trials
As it happens saline has been used in the USA arm of the AstraZeneca Phase III trials. In other groups a meningococcal vaccine is given as placebo. This won’t only create an injection site effect but a general feeling in line with being vaccinated. Not being aware they are receiving a placebo ensures subjects don’t introduce an unexpected variable to the trial. This fact, and the ethical nature of the approach is discussed in a well written article here. Finally in establishing the safety of vaccines a more convincing and in depth picture is gained through the application of more than just placebo controlled studies.
Conclusion
The more we see of Phase III trials for COVID-19 candidates, whether they be immediately accepted or controversial, the greater the refutation of the above anti-vaccine tropes. Senior members of the AVN are reading material that describes Phase III trials and their testing of both safety and efficacy. The above claim that double blind, placebo controlled trials don’t exist, “even when a new vaccine is introduced” still exists on the AVN website and in discussion. In the bright light of facts this is a true measure of the group.
The Oxford-AstraZeneca AZD1222 results have been met, understandably, with specific criticism. This relates to efficacy only. Safety is not being questioned. Some media reports have hinted that AstraZeneca will have difficulty getting the vaccine regulated for emergency use in the USA based on present data. Further, larger studies are needed to establish the veracity of the 90% efficacy finding in the smaller sample given a half dose followed by a full dose. This is entirely within reach of AstraZeneca.
Given the unscientific notion of a “combined efficacy” of 70% it is within AstraZeneca’s interests to pursue further research. Indeed everything being equal one may hope that the “combined efficacy” rate is not reinforced with further research. As STAT reported;
If it’s 70%, then we’ve got a dilemma,” said Fauci. “Because what are you going to do with the 70% when you’ve got two [vaccines] that are 95%? Who are you going to give a vaccine like that to?
AstraZeneca’s AZD1222 vaccine has enormous potential. The low cost, cold chain specifics and the company’s offer to not profit from the vaccine meets a global imperative for pandemic recovery. What the scientific community and the public need to see is a large robust Phase III trial that reproduces efficacy in the region of 90%.
References:
COVID-19 vaccines: where are the data? – BMJ
After admitting mistake AstraZeneca faces difficult questions about its vaccine – NYT
Oxford COVID vaccine: regulator asked to assess jab – BBC
Pfizer vaccine: what an efficacy rate above 90% really means – The Conversation
Moderna’s trial data shows its COVID-19 vaccine nears 95% efficacy – ABC
Placebo use in vaccine trials: Recommendations of a WHO expert panel – NCBI
There are no vaccines with saline placebo? – Vaccines Work blog
Last Update: 1 Dec. 2020
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Losing In The Lucky Country 