Journal of the Plague Years XVIII – AstraZeneca and the Unloved Vaccine

It was developed in record time and made available at cost price. It is easy to transport and store. It is being manufactured by the billion in India for the benefit of the developing world. So why does (almost) everybody hate AstraZeneca? Victor Hill inquires.

Origins

AstraZeneca (LON:AZN) is a pharmaceutical giant with global reach; but it has never been a vaccine maker. Rather, it excels in oncology medications. In contrast, the French regarded the failure of their own Sanofi SA (EPA:SAN) (the third largest vaccine producer in the world) to produce a coronavirus vaccine as a national humiliation. AstraZeneca is on track to deliver about three billion doses of its vaccine by the end of 2021 – one billion more than Pfizer-BioNTech. A significant proportion will be dedicated to the Covax programme operating in developing countries. Most people would regard that as impressive.

The Oxford-AZ vaccine came about because the Johnson government by May last year began to bang heads together. After high-level soundings, Sir John Bell, Regius Professor of Medicine at Oxford, who has had a long and distinguished career in the pharmaceutical industry and who knew AstraZeneca CEO Pascal Soriot personally, proposed a partnership between the pharma giant and the leading vaccine research powerhouse, the Jenner Institute in Oxford. The research involved was substantially taxpayer funded.

Most of the bio-pharmacological legwork in the development of the vaccine was undertaken by the Jenner Institute under the leadership of such luminaries as Professor Adrian Hill (no relation) and Professor Sarah Gilbert. AstraZeneca’s task was to commercialise the product – that is to manufacture and distribute it, which it would do at cost. From the outset, Monsieur Soriot thought that the collaboration would bring much more goodwill and prestige than profit to his firm. That has not turned out to be the case, at least outside of the UK itself.

The anatomy of efficacy

Ever since the advanced world entered the vaccination phase of the pandemic last December there has been a lingering suspicion that the Oxford-AZ vaccine was less effective than the Pfizer-BioNTech vaccine, and prospectively of others that became available, such as the Moderna and Sputnik-V vaccines. The Moderna vaccine is now being rolled out in the UK – it was first administered in Carmarthen, Wales on 07 April. However, supplies appear to be limited.

Leaving aside the political dimension – with EU leaders such as President Macron describing the Oxford vaccine as quasi-ineffective back in January – it is now clear that AstraZeneca got off on the wrong foot with both the European regulator (the EMA) and the US regulator (the FDA). The problem was that their trial data was unorthodox. AstraZeneca trialled the vaccine in four different countries (the UK, US, Brazil and South Africa) on heterogeneous populations and using different time lapses between the first and second jabs. The regulators did not care for the way in which the efficacy data was presented. And the original trials did not embrace a sufficient cohort of over-60s.

AstraZeneca then compounded the dismay of the regulatory establishment on 25 March by revising published data submitted to the FDA. Having announced a 79 percent efficacy, the company then admitted it was only 76 percent. That is regarded in regulatory corridors as unconscionable. One US official reportedly told CNN last week that the Oxford-AZ vaccine had a chequered past.

There are about 80 coronavirus vaccines in early-stage clinical trials and 23 in phase 3 trials. All of them will be submitting efficacy data in due course. Pfizer-BioNTech reported a 95 percent efficacy from its Phase-3 trial, while Johnson & Johnson (NYSE:JNJ) (the J&J-Janssen vaccine) reported an efficacy of just 66 percent. What, precisely, does that mean?

Most people think that a 95 percent efficacy implies that out of 100 people vaccinated, 5 people will go on to contract the virus symptomatically anyway. That is a misconception. A 95 percent efficacy states the relative chance of contracting the virus as between the vaccinated trial group and the placebo trial group. So, 95 percent efficacy means the number of vaccinated people who went down with the virus within a stated time frame was five percent of the those in the placebo group who subsequently contracted the virus.

There are problems with this methodology. The vaccinated group and the placebo group should be identical in size and with substantially similar demographic and personal health profiles. That is a tall order. Moreover, the J&J-Janssen trials were undertaken in Brazil after the new variant strain of CoV-SARS-2 was identified there. Can the J&J-Janssen data therefore be compared directly with the Oxford-AZ data?

Furthermore, a jab might have a relatively low efficacy percentage and yet be totally effective in preventing hospitalisation and death. That appears to be the case with the Oxford-AZ vaccine – so it is undoubtedly a powerful weapon in the fight against coronavirus. This week it was reported that the chance of catching Covid in any given week in the UK is down to one in half a million: at the peak it was one in 50. Last Sunday (11 April) the daily reported UK death toll from Covid-19 fell to just seven: that was the first single digit figure since 14 September last year. So, the UK is beating coronavirus – for now at least.

But how much of that success is due to the prophylactic effects of lockdown and how much from the vaccination programme is difficult to untangle. On Tuesday (13 April) Prime Minister Johnson intoned that “the bulk of the work in reducing the disease has been done by the lockdown”. This from man who likened the vaccine rollout to the arrival of the cavalry.

The fact that the death rate for the over-60s (around one in 100,000) has fallen dramatically since the vaccination programme began and is now akin to that of the under-60s (0.9 per 100,000) suggests that vaccination has had at least as big an impact as the lockdown. The causal chain between infections, hospitalisations and deaths seems to have been broken. And given that more than two in three jabs administered in the UK were the Oxford-AZ vaccine we should give credit where it is due.

Mr Johnson increasingly seems to be suffering from Stockholm Syndrome. Having been kidnapped by the scientific mandarinate he feels compelled to repeat their platitudes.

This is not to be complacent. SPI-M-O, a modelling team, thinks that there could yet be a third wave in the autumn. But if a third wave kills vulnerable people who have been doubly vaccinated (as it surely will a few) that will further undermine confidence in vaccination. Figures out yesterday show that out of 78 million fully vaccinated Americans, 5,800 still contracted the virus, and of those 74 have died^[i].

The subtle metrics of safety

Can vaccines harm? A lot of people seem to think so. Could the Oxford vaccine kill? Many Europeans are convinced of it. Though the fact that simultaneously they rail against AstraZeneca for not supplying it in sufficient quantity is confusing. It was the Norwegian and German regulators who first spotted rare blood clots in Oxford-AZ vaccine recipients; but now concerns are international.

Up to 21 March the UK medical regulator, the MHRA, had received 79 reports of blood clots accompanied by low platelet counts out of about 20 million people who had received the Oxford-AZ vaccine. Of those 79 cases, 19 people had died. But correlation is not causation: no causal link between the Oxford-AZ vaccine and blood clotting has yet been identified.

There are numerous hypotheses for why adenovirus vaccines might cause clots in rare cases. One is that particles of viral DNA in the vaccines are breaking apart and attaching to proteins in the body. Another is that the body’s immune system could be triggered to attack this type of vaccine because it regards it as a foreign entity^[ii]. A third hypothesis is that it’s the adenovirus vector itself (a modified monkey flu virus in the case of Oxford-AZ) that could be causing the clots.

On 07 April the Joint Committee on Vaccination and Immunisation (JCVI) announced that people under 30 would no longer be given the Oxford-AZ vaccine, though people who have already received their first Oxford-AZ jab will be given a second one when due. That represents a change of stance on the vaccine’s risk profile. The Deputy Chief Medical Officer, Professor Jonathan Van Tam (“JVT” – one of the few government scientists with excellent communication skills and a popular following), said: “This is a course correction”.

This is in line with what most European countries are doing. France banned the Oxford-AZ vaccine for the under-55s last week (they previously banned it for the over-60s). Germany has done the same. And now Denmark has now banned the vaccine entirely. This reflects the higher degree of risk-aversion in the EU combined with mistrust which I discussed in JPYXVII – with an MEP accusing AstraZeneca of having a culture of dishonesty.

For all this, the MHRA still believes that the benefits of this jab still far outweigh the considerable risks associated with getting Covid-19. About one fifth of patients admitted to hospital with Covid-19 experience blood clots. 

It seems that the next cohort of vaccinees in the UK – the under-40s – will disproportionately receive the Moderna vaccine now that safety concerns have also arisen around the J&J-Janssen too. On Tuesday (13 April) the FDA recommended that states pause the administration of the J&J-Janssen vaccine after six incidents of serious rare clots, all in women aged 18-48, were recorded in the USA out of 6.8 million jabs. The first deliveries of this vaccine arrived in Europe only last week. In the UK, Professor Anthony Harnden, deputy chairman of the JCVI said on Tuesday that the committee would have to review the latest J&J-Janssen safety data carefully. This vaccine was reportedly about to obtain approval by the MHRA imminently – but that is now unlikely to happen.

Sadly then, the 18-20s, due to be vaccinated in July, may not be able to get their one-jab wonder and then jet off to Ibiza for sun, sea and sangria. The risks from coronavirus in that age group simply don’t outweigh the potential risks from blood clots. Belgium, where the J&J-Janssen vaccine is manufactured announced that it would not stop the rollout of the vaccine at this stage.

Should we be worried?

Such has been the confusion surrounding the Oxford-AZ vaccine that even some ardent pro-vaxxers have been given pause. And the prevailing opinion, led by experts, towards a mix-and-match approach to vaccination (known in the trade as heterologous priming) has altered. There were always some scientists – not least Russian ones – who argued that greater immunity could be acquired by combining vaccines. The Chinese have now come to that conclusion too – partly because the efficacy of their vaccine, Sinovac, has been doubted. The idea of a cocktail of vaccines is not entirely new – it was trialled in the fight against the Ebola epidemic in west Africa (2013-16). The WHO still seems to be agnostic on the issue.

The Oxford-AZ and the J&J-Janssen vaccines on the one hand and the Pfizer-BioNTech and Moderna vaccines on the other work using quite different medical technologies and it is still not known what the effect is of combining them. Yet experts suspect that it will have beneficial consequences because each vaccine triggers slightly different immune responses and priming will make it harder for viruses to mutate.

Professor Tim Spector, chair of genetic epidemiology at King’s College London, declared that “the chances of dying from a blood clot caused by a vaccine are similar to the chances of being struck by lightning” – though he conceded that such a rare event was slightly more likely for the under-60s. Others have compared the risks from the Oxford-AZ vaccine to those for women taking the contraceptive pill. At one in a million, the chance of dying from a blood clot triggered by the Oxford-AZ vaccine is considerably less than the risk of drowning in the bath (one in 685,000).

The main concern is that the issues surrounding the safety of the Oxford-AZ vaccine could hinder the completion of the vaccination programme in the UK. Out of a total of 475 million vaccine doses ordered by the UK government, 100 million are from AstraZeneca. SAGE has already predicted that the speed of England’s vaccination programme will slow to 2.7 million jabs a week by the end of July. On the plus side, the Valneva vaccine, which is set to be manufactured in the UK, is showing promising trial data.

Personally, I shall have no compunction in receiving my second Oxford-AZ jab.

Share price hesitancy

Last week, AstraZeneca investors accused Monsieur Soriot, who has been in Australia visiting family since Christmas (though, apparently, he works round the clock), of having made a poor job of communicating the vaccine’s benefits. Their concern was that the negative sentiment surrounding the vaccine is now casting a cloud over the company’s growth prospects. There have even been reports that senior AstraZeneca executives bitterly regret getting involved in the vaccine project at all. Morale at the firm is said to be lagging, especially given the death of José Balsega, AZN’s head of oncology research, last month.

AstraZeneca’s share price has fallen from its peak of £93.20 last July to £73.70 at close yesterday – a drop of over 20 percent. The company has pledged to continue selling the vaccine at cost in developing countries indefinitely. That’s roughly €3 – as compared with Pfizer-BioNTech which now charges €19.50 a shot.

I’m probably not alone in thinking that by making the vaccine effectively free, AstraZeneca encouraged the notion that it was worthless. This is a classic case where charitable intentions have unintended consequences. Can we imagine European politicians berating the company over “breaking promises” if the vaccine had been sold at market price – the matter would just have gone straight to court. Reputational damage without profit is not a good deal. I’m also concerned that that reputational damage might extend to the Jenner Institute as well. Moreover, the Johnson government’s attempts to co-brand the vaccine with post-Brexit Global Britain has put noses out of joint.

Australia has now pivoted away from AstraZeneca and has placed an order for 20 million doses of the Pfizer-BioNTech vaccine. That could be the start of a trend.

One consequence of the whole affair is that large countries with life science bases (of which there are about eight) are going to strive to be vaccine sufficient in future. I doubt that Berlin or Paris will rely on Brussels in a public health emergency in the future. That will mean that certain pharmaceutical giants will become flag-carriers just like their much-subsidised airline counterparts. But the real beneficiaries of this sorry saga are the anti-science anti-vaxxers.

***

The late Prince Philip, Duke of Edinburgh, usually got the better of any exchange. But when he met Thurgood Marshall, the US Supreme Court Justice and civil rights activist, he asked him: “Would you like to know what I think about lawyers?” Marshall replied: “Only if you’d like to know what I think about princes”.

A good retort. Though I cannot think of a better example of a prince than Philip. He had no formal academic education – yet he became a universal man. His interests ranged from engineering to religion. He was way ahead of the curve in terms of the environment. A man of forceful opinions, he was sceptical of experts. He never felt trapped by duty – or if he did, he concealed it.

In the end, he aspired to simplicity. He spent the twilight of his life in a vernacular but well-appointed farmhouse, nestling in the woods on the Sandringham estate. There, he read, painted and listened to birdsong.

We shall miss him – but not as much as The Queen will.

^[i] See: https://www.businessinsider.com.au/infected-after-covid-vaccination-cdc-numbers-breakthrough-infections-2021-4?utm_source=Business+Insider+Australia+-+10+things+you+need+to+know+in+the+morning+in+Australia&utm_campaign=73bb70955d-businessinsider_2021_04_16&utm_medium=email&utm_term=0_8a990bd96b-73bb70955d-280737397

^[ii] See: https://www.forbes.com/sites/leahrosenbaum/2021/04/13/heres-what-scientists-know-about-covid-19-vaccine-blood-clots-and-how-the-risks-can-be-diminished/?utm_source=newsletter&utm_medium=email&utm_campaign=dailydozen&cdlcid=5d1670771802c8c524c81dd8&sh=15dcc40f51c4