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AstraZeneca’s up-and-down quest to develop a vaccine for Covid-19 stands out from what has otherwise been a remarkably straightforward process in the U.S. And the latest twist for AstraZeneca’s vaccine, involving a contentious back-and-forth with federal authorities, only adds confusion to an already muddled process.

STAT’s Helen Branswell recently joined the “Readout Loud” podcast to talk about AstraZeneca’s current predicament, the implications for vaccine confidence, and how this affects the global effort to beat back the pandemic by getting doses into arms.

Excerpts from the conversation have been lightly edited and condensed for clarity.

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When discussing the AstraZeneca situation, experts consistently reach for the word “unprecedented.” Is that accurate? And how shocking was this back-and-forth compared to the normal process of developing a vaccine? 

I think it was quite shocking. I don’t know that I could go as far as unprecedented. I haven’t looked for, you know, precedents.

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But typically, when a sponsor of an experimental product, whether that’s a vaccine or a drug, and a DSMB [data and safety monitoring board] are going back and forth, that happens behind the curtain. We don’t see that. And if there’s a disagreement between the two on how to read the data, they resolve that before anybody goes public with the data. So to have this situation where AstraZeneca made their statement and then the DSMB made it known that they had they disagreed with the analysis, or the way that AstraZeneca had done its analysis by focusing on earlier cases only, that was quite a stunning rebuke. This kind of stuff doesn’t normally happen in the public eye.

It’s been a bit of a rollercoaster this week. As of Thursday morning, it appears that all the alarm was over a 3 percentage point relative difference in vaccine efficacy — 79% in AstraZeneca’s interim data announced Monday, versus 76% from the more up-to-date analysis we got more recently. Who do you think will get the blame for this bizarre news cycle taking place: AstraZeneca for releasing outdated data or the NIH for putting this all on the public record?

I don’t think it looks good on either party, to be honest. Given that it’s only 3 percentage points, you would be tempted to say, oh, the NIH looks worse from this. But there’s been so much drama around this vaccine, so much uncertainty about the the data, that the company and Oxford University have generated … they had a lot of baggage coming into this fight. So I don’t think anybody walks away from this looking particularly great.

We knew that within 48 hours we are going to get an updated set of results. When you saw that the results were only 3 percentage points different from the original results, did that make you feel better about what might have happened, or did it make you scratch your head even more about why it happened? 

I think I would say both, in a way. At the end of the day, we’re all fascinated by this fight, the drama. But the reality is this is a really important vaccine and the world needs it and needs it to work. And what the data show is that it does work. And so 76% is quite a bit better than the 62% the Oxford group originally reported out of their three Phase 3s, the ones that they did in the U.K. and Brazil and South Africa. So this trial has given us information we really need and it’s really good news. So in that respect, that’s great.

“This vaccine project has had more plot twists and turns than an Agatha Christie novel.”

Helen Branswell, STAT senior writer on infectious disease

But I would love to know more about why the DSMB two days ago thought that the more accurate figure should have been somewhere between 69 and 74. And why now? I mean, you know, there’s there’s part of this story that we just don’t know yet. And I’m really curious about what it is.

The stateside controversy over the vaccine comes just days after a host of European countries briefly paused its distribution to investigate some rare potential side effects. Because this vaccine is being made at a not-for-profit price and it’s easier to store than many of the others, its inventors at Oxford University have called it a “vaccine for the world.” So from the world’s perspective, is this recent news damaging confidence in the vaccine?

Certainly it is damaging confidence in the vaccine in North America, potentially in Europe.

A lot of countries have given emergency authorizations to this vaccine. Whether they are all following this to the same degree that we are, I don’t know. But certainly a lot of people, friends of mine who are not journalists and who are not reporting on this, have been asking me about this vaccine. A lot of my family and friends are in Canada and a lot of them anticipate that this will be the vaccine they’re going to be offered and they feel like they don’t really know what to believe about it, to be honest.

What should AstraZeneca do to rebuild some of the trust and confidence? Or I guess more accurately, what can they do at this stage? 

No more drama. This vaccine project has had more plot twists and turns than an Agatha Christie novel. What they need to do is just generate and disseminate good, reliable data. That’s obviously been done. Going forward, they’re going to be putting in an application for an emergency use authorization. And the FDA is going to be crunching their raw data and it will tell the world what it thinks of how well this vaccine works. And that will be an extraordinarily important step in the process for this vaccine.

Speaking of which, the trial that we’re talking about was meant to support this application to the FDA, but the vaccine likely won’t go before the regulator until a month or two from now, by which point the U.S. might have enough supply of other Covid-19 vaccines to meet its needs. So what do you think the odds are that despite all this contentious debate, AstraZeneca is vaccine never actually gets distributed in the U.S.?

You know, I think that’s a possibility. I guess I’m not sure that we know at this point. One of the things we have to see is, at some point in time, people are going to have to start to vaccinate children and trials are going to need to be done to test the various vaccines and kids. And there is a strong likelihood, I think, that one or two of the vaccines might be more useful in children than others. If they’re less reactogenic, for instance. Parents don’t like to see their kids having a rough go of it after getting a vaccine. So if you can find a vaccine, one of the vaccines, or two of the vaccines that are less reactogenic in children, then those will probably be the ones that would be used.

So would I shut the door on the possibility that this vaccine might have some use in the United States? No. Do I think it’s a possibility that it won’t be used or won’t be used much in the United States? Yeah, I do think that’s a possibility. Just from the point of view of what you just what you said yourself, the U.S. may not need much of this vaccine or any of this vaccine by the time it’s available for use here.

  • The risk of thrombosis in people vaccinated with AZ vaccine is not at all comparable with that of the population at large. How many thromboses occur in people of under 55, in the span of a few days? It is absolutely incorrect to compare incidence in the vaccinated population to the population at large. One has to compare the number of thrombosis incidence in populations of the same age, within the same interval of time. When that is done, one will see that the thrombosis events are vaccine induced.

    • There are already articles mentioning that it is likely vaccine related due to the type of thrombotic event, being akin to Heparin Induced Thrombocitopenia. There calling it VIPIT. Vaccine Induced Prothombic Immune Thrombocitopenia. Just hope when they are giving out the vaccine they are checking peoples platelet levels and having a non heparin bloodthinner available. I don’t like that just because a risk is low, that people who roll the dice unluckily might get written off because of the efficiency/innefficiency of preparing for the low risk event vs ignoring it. If I get the Vaccines with risk of PEG anaphylaxis I hope someone has an epipen handy, if I get the AZ one I hope someone has a non heparin blood thinner and is checking my platelet levels handy. Any thing else is wrong.

    • Guess I just read the time of onset is 4-20 days so u’ll likely have to assess your own symptoms, then go to a doctor and hope they take you seriously. Though the rate of incidence is supposed to be around 1 in 125,000 or greater.

      Also remembered the other vaccines had thrombocytopenia type of events. Immagine this would be difficult for doctors. You’d need to make a judgement between the one type of event where the platelet loss involves bleeding and hemmoraging, and the other type which due to its nature causes the opposite, significant clotting.

  • The small difference in reported efficacy percentage should not make a deciding difference. AstraZeneca intends to make no big-time profit off this vaccine, that is why Oxford partnered with AZN rather than Merck. The US has millions of doses of AZN already – and is “lending” 4 million doses to Canada and Mexico. So in a few months, the US will receive 4million AZN doses back from those 2 countries – whether the US approves it or not. Because this lending is not to be turned into “exchange for another”. (Should this however unfairly happen, then the US must pay Mexico and Canada the likely rather stiff difference in cost). Most countries that halted the AZN vaccine are now using it – except for the 4 Scandinavian countries. Is that political (Brexit) – or really for R&D? Have the other Covid vaccines not recorded any clotting events? It is very clear that AZN’s CEO has no control over his company’s disclosures – maybe he should come out of his Australian hide-out, and focus more on this product rather than large new acquisitions (Alexion) ?

  • Isn’t this all clear reflection of the fact EUA required information to obtain approval is significantly slacker slacked than the those required for actual vaccine approval? It’s all rush, rush, rush and everyone is under a lot of pressure including the company’s clinical operations, regulatory affairs staff and also the DSMB Board members and even he NIH scientists?

    Finally, would there be further refinements with the emerging variants similarly to monoclonal anitbodies and most importantly, who is in charge and who gets to call the decision?

    It’s so easy and convenient advocate” let the decision be made based on scientific evidence, but then when the scientists could not aggress…

    Did did the pre-eminent, authoritative, influential Dr. Anthoy Fauci say bout the data discrepancey. If so, can someone share a link or a news article?

  • There was also an understandably missing step. Investment bankers can get nervous about stock prices moving on preliminary data — data that is released before peer review and/or regulatory submission. They seem to have third parties take a quick look. I was one of a bunch of folks that did that for another vaccine, independent of the maker. But in this case, the success of a vaccine or drug at its low price would not tend to move the market significantly anyway. So the extra (always clumsy and weirdly choreographed) review was unlikely to have been done.

  • It may a bit incorrect to say ” rare potential side effects”.
    My understanding is, there a at least some serious reporting potential side effect, and some concern the are systemati.
    It is correct, they have not been seen in the clinical studies, but please understand the authorities collect and share ‘real life’ incidence. There are much more subjecrs wexposedto the vaccine in real life.
    I think it is correct there a not many, but it is worth analysing if it systematic and can beavoided for certain subsets.

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