PlagueWatch 2020-23 - Coronavirus

[LasVegas]

Perhaps you've addressed this somewhere else in this thread, but can you see any good reason for the FDA not having approved the Astrazeneca vaccine yet? My current opinion that it's criminal negligence, but I'd be interested if you can convince me otherwise."

From what I’ve read, they haven’t even applied for emergency use auth yet. Conducting another trial since they messed the first one up a bit. I’d link but the mobile format makes it tough.

[CDu]

Perhaps you've addressed this somewhere else in this thread, but can you see any good reason for the FDA not having approved the Astrazeneca vaccine yet? My current opinion that it's criminal negligence, but I'd be interested if you can convince me otherwise."

From what I’ve read, they haven’t even applied for emergency use auth yet. Conducting another trial since they messed the first one up a bit. I’d link but the mobile format makes it tough.

This. The FDA hasn’t approved the AZ vaccine because they have not reviewed it yet. And that is because AZ hasn’t submitted anything to the FDA yet. It most assuredly isn’t criminal negligence by the FDA.

As far as why AZ hasn’t submitted? Probably because their first trial wasn’t well-powered for the US and had some issues (inconsistent dosing, not sufficient data in the elderly, etc). So they will likely submit when their US-specific study has been completed.

[MChambers]

This. The FDA hasn’t approved the AZ vaccine because they have not reviewed it yet. And that is because AZ hasn’t submitted anything to the FDA yet. It most assuredly isn’t criminal negligence by the FDA.

As far as why AZ hasn’t submitted? Probably because their first trial wasn’t well-powered for the US and had some issues (inconsistent dosing, not sufficient data in the elderly, etc). So they will likely submit when their US-specific study has been completed.

It's also possible that AZ hasn't submitted because the FDA informally told them the data wasn't good enough.

[CDu]

It's also possible that AZ hasn't submitted because the FDA informally told them the data wasn't good enough.

Certainly possible. Their data aren’t THAT good (not bad, but below well the approved vaccines). And that is before the issues with trial design/administration.

So it could well be that the FDA said “we have questions/concerns” and AZ took the cue to hold off until they have addressed those issues.

Worth noting that the efficiency in those over 65 might well have been bad. And as such, they wouldn’t have been approved for use in the elderly anyway. Germany, for example has not recommended its use in elderly patients. The overall efficacy was 62%, but a subgroup of 18-55 year olds who got an incorrect first dose had 90% effectiveness. This would suggest that AZ’s effectiveness results in the elderly (only 1418 patients, 12%, were over 55; only about 4% were over 70) were perhaps below 50%.

In any of these cases (whether AZ acted on their own or at the hint by the FDA), criminal negligence by the FDA is not the reason. And given the uncertainty regarding its effect in older patients, it is probably moot as they wouldn’t be approved for the people eligible right now anyway.

[mph]

The author misrepresents the context and reasoning behind lab adaption of H5N1 flu in ferrets with out of context use the word "force". This process is routinely done with pathogenic avian flu viruses because the ferret infection model has been repeatedly shown to be a strong model for human infection. It helps scientists study what factors in the avian flu viruses make them more likely to "jump" into mammals for better surveillance. Flu virus transmission and pathology in birds bears little resemblance to that of humans. Same thing for SARS virus work. The mouse adaption studies that he described from Baric and Shi in 2015 was important work showing that we should definitely be monitoring betacoronaviruses more closely for the potential of exactly what did happen in 2019. I strongly disagree with the out-of-context comment that the author ends that section with from Mark Liptsch that Gain-of-function experiments “have done almost nothing to improve our preparedness for pandemics,” he said, “yet they risked creating an accidental pandemic.”.

Thank you for the detailed response. It was very helpful. Can you elaborate on the bolded sentence? Over the last 20 years my work has required me to do some off and on reading into the debate over gain of function. I don’t have enough information to have a strong opinion, but I’ll admit that my reading has made me skeptical that the benefits outweigh the risks. Where would you point someone who wanted to read more about the benefits of gain of function research?

[YmoBeThere]

I am also highly skeptical about this virus coming from a lab. I have not watched the Bill Maher clip but I did read the NYMag article linked up thread. To me the article is a bit disingenuous because it presents the 2 ideas (natural vs lab) in the first paragraph as equally likely. In fact, the author actually states that he thinks there was lab manipulation. As someone who works in this field I think that this disingenuous and I call hogwash. This whole article basically has the false premise that because we can't rule out something that is highly unlikely that it should treated with equal likelihood to occur as the much more likely explanation. A reverse Occam's Razor if you will. This article is written by someone with an agenda toward an OPINION that there was a lab origin.

Is there risk? Yes, of course. But I believe that this article is greatly skewed toward this risk having equal footing with the much more likely natural explanation. IMO, that is what conspiracy theorists do. Twist the plausible explanations for things and greatly amplify the very small likelihood that their theory is real. And amplify the fact that scientists will never rule anything out even if it has a 1% chance.

FULL DISCLOSURE: I have collaborated with Ralph Baric (on dengue not coronaviruses). The work that he does and that others do in this area are key to learning about pandemic preparedness in my professional opinion.
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More detailed rebuttal

IMO, it is MUCH more likely that the coronavirus combines with other coronaviruses in bats or pangolins and a variant that can then effectively infect humans occurs. Virologists and epidemiologists study this for viruses all the time. It is well documented for influenza that this occurs between waterfowl, pigs, and humans in a regular manner. And live wet markets are the perfect breeding ground for this.

The author fails to note that the lab accidents that might occur - a dropped flask, a needle prick, a mouse bite, an illegibly labeled bottle would also need about 10 other highly unlikely steps to occur for anyone of those accidents with a virulent virus to actually infect a human in the BSL3 or BSL4 lab conditions in which they are handled. Every one these incidents that occur are tracked and reported (the 1100 incidents cited in the US from 2008 and 2012 resulted in only 5 cases of workers actually being infected or sickened and all were properly quarantined and recovered).

When the article quotes a journalist who says "I’m just asking, Is it a complete coincidence that this outbreak happened in the one city in China with a BSL-4 lab?”. He misses the point entirely. This is, IMO, an example of the recent trend to give fringe beliefs equal footing with common sense. The BSL-4 lab was built in Wuhan precisely because that region in China has a well documented history of zoonotic transmissions. Would you build a lab that studies underground oil reserves in Oklahoma or in Vermont?

The author misrepresents the context and reasoning behind lab adaption of H5N1 flu in ferrets with out of context use the word "force". This process is routinely done with pathogenic avian flu viruses because the ferret infection model has been repeatedly shown to be a strong model for human infection. It helps scientists study what factors in the avian flu viruses make them more likely to "jump" into mammals for better surveillance. Flu virus transmission and pathology in birds bears little resemblance to that of humans. Same thing for SARS virus work. The mouse adaption studies that he described from Baric and Shi in 2015 was important work showing that we should definitely be monitoring betacoronaviruses more closely for the potential of exactly what did happen in 2019. I strongly disagree with the out-of-context comment that the author ends that section with from Mark Liptsch that Gain-of-function experiments “have done almost nothing to improve our preparedness for pandemics,” he said, “yet they risked creating an accidental pandemic.”.

The author constantly refers to the people on the side that lab experiments were related to this outbreak in a positive light. Calling them "thoughtful' and treating their assertions that something bad 'could' happen as basically the same as something bad has happened. Which there is absolutely no proof that it has. The author also casts Fouchier, Baric and Shi with terms like 'force", creepy paper" and Anarchist's Cookbook.

I am going to stop now, because I could go on all day. I'll agree with Ralph Baric's quote "(that) he still thought the virus came from bats in southern China, perhaps directly, or possibly via an intermediate host, although the smuggled pangolins, in his view, were a red herring. The disease evolved in humans over time without being noticed, he suspected, becoming gradually more infectious, and eventually a person carried it to Wuhan “and the pandemic took off.” Then he said, “Can you rule out a laboratory escape? The answer in this case is probably not.” As a scientist I agree with Dr. Baric's last direct quote that you probably can't rule out a lab escape. However, that doesn't mean that a lab escape was likely or even slightly likely. To a scientist if there was a 1-2% chance (what I personally would rate a lab escape) you would always say you can't rule it out.

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Must spread comments around...

Thank you for this.

[WillJ]

Certainly possible. Their data aren’t THAT good (not bad, but below well the approved vaccines). And that is before the issues with trial design/administration.

So it could well be that the FDA said “we have questions/concerns” and AZ took the cue to hold off until they have addressed those issues.

Worth noting that the efficiency in those over 65 might well have been bad. And as such, they wouldn’t have been approved for use in the elderly anyway. Germany, for example has not recommended its use in elderly patients. The overall efficacy was 62%, but a subgroup of 18-55 year olds who got an incorrect first dose had 90% effectiveness. This would suggest that AZ’s effectiveness results in the elderly (only 1418 patients, 12%, were over 55; only about 4% were over 70) were perhaps below 50%.

In any of these cases (whether AZ acted on their own or at the hint by the FDA), criminal negligence by the FDA is not the reason. And given the uncertainty regarding its effect in older patients, it is probably moot as they wouldn’t be approved for the people eligible right now anyway.

IMO, this thinking is part of the problem. The alternatives are not AZ versus a perfect vaccine. For the time being, the alternatives (for me at least) are AZ versus nothing. Roughly 100,000 people will die in the US over the next six months because we have not gotten enough vaccines, even imperfect vaccines, into arms. Approving the AZ vaccine for immediate use would save many lives and, also importantly, save hundreds of billions if not trillions of dollars. Great Britain has of course approved the vaccine and is well ahead of us in vaccinations per capita.

[CDu]

IMO, this thinking is part of the problem. The alternatives are not AZ versus a perfect vaccine. For the time being, the alternatives (for me at least) are AZ versus nothing. Roughly 100,000 people will die in the US over the next six months because we have not gotten enough vaccines, even imperfect vaccines, into arms. Approving the AZ vaccine for immediate use would save many lives and, also importantly, save hundreds of billions if not trillions of dollars. Great Britain has of course approved the vaccine and is well ahead of us in vaccinations per capita.

A few things in response:
1. We aren’t way behind the UK in vaccinations. They have vaccinated 12%, we are at 8%. We have vaccinated 22 million more people.
2. It isn’t a lack of doses that is driving the problem, but lack of infrastructure and coordination. The UK is tiny, and thus distribution and admin are easier. The US is vast, and our rollout plan was not great to start. We still have like 20 million doses that haven’t been administered. Adding more doses doesn’t magically improve our distribution and admin issues
3. The AZ trial had few elderly patients, and it appears the results in that age group weren’t good. We don’t know exactly how bad because AZ didn’t report it. If the drug doesn’t work in the elderly, how useful is it in preventing deaths?
4. They also didn’t have a population with many comorbidities, so even their younger population doesn’t provide much info in younger high-risk people.
5. And we still don’t know if the FDA is the reason AZ hasn’t filed for approval yet.

There may be a point (hopefully soon) at which we are prepared to mass-vaccinate, and at that point having more vaccines/doses will be important. But we are not quite there yet. And beyond that, it is unclear whether the AZ vaccine will actually save lives in the elderly. The FDA simply isn’t going to approve something unless it is both safe and effective. They aren’t going to let older people get a vaccine that isn’t effective for old people. The AZ drug would perhaps get approved in 18-55 ages, but probably not in 55+. And since we are struggling to administer the 50 million doses we have, I am not seeing how approval for a vaccine in 18-55 will make a dent.

But again it is moot because AZ hasn’t submitted to the FDA.

[CDu]

Up to 31.1 million doses administered, up 1.5 million from yesterday.

JnJ should submit to the FDA this week, which would give a nice boost as well. Novavax could submit soon as well based on their UK data, but that remains to be seen.

[tbyers11]

Thank you for the detailed response. It was very helpful. Can you elaborate on the bolded sentence? Over the last 20 years my work has required me to do some off and on reading into the debate over gain of function. I don’t have enough information to have a strong opinion, but I’ll admit that my reading has made me skeptical that the benefits outweigh the risks. Where would you point someone who wanted to read more about the benefits of gain of function research?

I am not overly familiar with the term gain-of-function with respect to its more literal genetics sense. So I should be clear that I don't know exactly what Liptsch was referring to in the "gain-of-function" quote. There may be areas of gain of function research I am not familiar with that have contributed little to knowledge. But since the author of the NYMag article did not specify the exact context of the quote I don't know. I was specifically referring to the article associating engineered viruses made via passage in cell lines or through infection in ferrets/mice as gain-of-function.

Many wild type viruses from natural reservoirs (non-mammalian and mammalian) do not easily replicate in commonly used cell lines or animal models (mice or ferrets). Models are needed to study pathogenesis or immunogenicity when the host has little relevance to mammals/humans (such as bats/birds) or the host is human itself and you can't ethically study in humans. Pathogenic avian strains of flu have been adapted to infect ferrets or cell lines. Here is a paper that engineered flu virus from avian strains and the 1918 Flu pandemic strain and compared how they infected human airway epithelial cells. This paper showed that differences in sialic acid binding linkages were not as important as previously thought for avian to human "jump" associated with pandemics.

The article's description of Baric's group using non-infectious VEEV replicons or liquid-air interface human airway epithelial models describe common lab techniques in the field to work towards the goal of a SARS-CoV-1 vaccine. This work along with the 2016 work describing engineered SARS virus replication in human transgenic ACE2 mice were all very important to understand how SARS betacoronaviruses interact with furin cleavage sites and the ACE2 receptor. The 2015 Nature Medicine article with Dr. Shi cited in the article details work that showed that an inactivated SARS vaccine did not protect mice challenged with this virus. If we had an mRNA vaccine at this point we could have tested in this model and we might have had an inkling that this was a good approach. As for a perspective on why this type of research is important I'd also refer you to the "long letter" by Drs. Baric and Denison linked in the article. I think it describes in 49 pages the scientific rationale and the safety considerations of these approaches.

[WillJ]

Up to 31.1 million doses administered, up 1.5 million from yesterday.

JnJ should submit to the FDA this week, which would give a nice boost as well. Novavax could submit soon as well based on their UK data, but that remains to be seen.

I'll shut up after this, but I disagree. You are correct that vaccine supply is not the only problem - as there are other parts of the delivery chain that have also been poorly managed and that need more supply (e.g., more efficient syringes). However, vaccine supply is still a huge problem - note that all three of the DMV "governors" pointed to vaccine supply as the main problem - https://www.washingtonpost.com/local...229_story.html. Even making adjustments for their desire to shift blame elsewhere, I don't think this supports the idea that more vaccine wouldn't help. Also, see this excerpt from a Baylor medical boffin on the AZ vaccine - https://marginalrevolution.com/margi...y-worried.html. It's misleading to exculpate the FDA because 'AZ has not submitted' when it's the FDA that is demanding a business-as-usual approach to drug approval at a time when hundreds of thousands of people are dying. I truly hope that the FDA's scandalous policy - on this and other isues in this epidemic gets a significant congressional review. Without that, there's no reason to believe that we'll do better next time.

[JasonEvans]

The NYTimes sent out a newsletter this morning talking about vaccines. There is a portion of it that EVERYONE NEEDS TO READ AND UNDERSTAND!!

Note: this excerpt is longer than we usually allow on DBR, but because it came in a newsletter there is no link to direct you to read. What's more, with the NYTimes making Coronavirus coverage free, I am sure they would not object to me posting this:

We don’t need to eliminate it for life to return to normal. We instead need to downgrade it from a deadly pandemic to a normal virus. Once that happens, adults can go back to work, and children back to school. Grandparents can nuzzle their grandchildren, and you can meet your friends at a restaurant.

As Dr. Ashish Jha, the dean of the Brown University School of Public Health, told me this weekend: “I don’t actually care about infections. I care about hospitalizations and deaths and long-term complications.”

By those measures, all five of the vaccines — from Pfizer, Moderna, AstraZeneca, Novavax and Johnson & Johnson — look extremely good. Of the roughly 75,000 people who have received one of the five in a research trial, not a single person has died from Covid, and only a few people appear to have been hospitalized. None have remained hospitalized 28 days after receiving a shot.

To put that in perspective, it helps to think about what Covid has done so far to a representative group of 75,000 American adults: It has killed roughly 150 of them and sent several hundred more to the hospital. The vaccines reduce those numbers to zero and nearly zero, based on the research trials.

Zero isn’t even the most relevant benchmark. A typical U.S. flu season kills between five and 15 out of every 75,000 adults and hospitalizes more than 100 of them.

I assume you would agree that any vaccine that transforms Covid into something much milder than a typical flu deserves to be called effective. But that is not the scientific definition. When you read that the Johnson & Johnson vaccine was 66 percent effective or that the Novavax vaccine was 89 percent effective, those numbers are referring to the prevention of all illness. They count mild symptoms as a failure.

“In terms of the severe outcomes, which is what we really care about, the news is fantastic,” Dr. Aaron Richterman, an infectious-disease specialist at the University of Pennsylvania, said.

What about the highly contagious new virus variants that have emerged in Britain, Brazil and South Africa? The South African variant does appear to make the vaccines less effective at eliminating infections.

Fortunately, there is no evidence yet that it increases deaths among vaccinated people. Two of the five vaccines — from Johnson & Johnson and Novavax — have reported some results from South Africa, and none of the people there who received a vaccine died of Covid. “People are still not getting serious illness. They’re still not dying,” Dr. Rebecca Wurtz of the University of Minnesota School of Public Health told me.

The most likely reason, epidemiologists say, is that the vaccines still provide considerable protection against the variant, albeit not quite as much as against the original version. Some protection appears to be enough to turn this coronavirus into a fairly normal disease in the vast majority of cases.

I hear people debating, "if you are offered the JnJ vaccine, would you take it or wait for Moderna/Pfizer?" Heck, have been among those talking about that debate. But, I have become more educated in recent days and I now think that there should be no hesitation to take any of these vaccines the moment you can. Let me put this in simple terms... taking the JnJ vaccine makes Covid much less harmful than a normal flu. It basically turns Covid into a mild common cold. Waiting for a more potent vaccine is just plain foolish and is harmful to society because you are allowing yourself to be a vector for virus spread for no good reason. There are enough idiots who are vaccine deniers who will refuse this. The last think we need is people who would get a vaccine waiting for a better vaccine when a perfectly good one is available.

-Jason "I swear, it is like some people want to keep us locked indoors and double-masking for as long as possible" Evans

[mph]

The NYTimes sent out a newsletter this morning talking about vaccines. There is a portion of it that EVERYONE NEEDS TO READ AND UNDERSTAND!!

Note: this excerpt is longer than we usually allow on DBR, but because it came in a newsletter there is no link to direct you to read. What's more, with the NYTimes making Coronavirus coverage free, I am sure they would not object to me posting this:



I hear people debating, "if you are offered the JnJ vaccine, would you take it or wait for Moderna/Pfizer?" Heck, have been among those talking about that debate. But, I have become more educated in recent days and I now think that there should be no hesitation to take any of these vaccines the moment you can. Let me put this in simple terms... taking the JnJ vaccine makes Covid much less harmful than a normal flu. It basically turns Covid into a mild common cold. Waiting for a more potent vaccine is just plain foolish and is harmful to society because you are allowing yourself to be a vector for virus spread for no good reason. There are enough idiots who are vaccine deniers who will refuse this. The last think we need is people who would get a vaccine waiting for a better vaccine when a perfectly good one is available.

-Jason "I swear, it is like some people want to keep us locked indoors and double-masking for as long as possible" Evans

I read the same newsletter this morning. 100% agree. VERY encouraging! Thank you for posting it in its entirety.

[Indoor66]

-Jason "I swear, it is like some people want to keep us locked indoors and double-masking for as long as possible" Evans

You just noticed your point in quotes? It has been going on for a year now.

[jtelander]

taking the JnJ vaccine makes Covid much less harmful than a normal flu. It basically turns Covid into a mild common cold.

This certainly sounds promising. What do we know about the long term effects of moderate/mild Covid infections?


It seems to often we understandably focus on Covid deaths, but tend to gloss over rather than dwell on non-lethal, potentially life altering Covid impacts.

[CDu]

This certainly sounds promising. What do we know about the long term effects of moderate/mild Covid infections?


It seems to often we understandably focus on Covid deaths, but tend to gloss over rather than dwell on non-lethal, potentially life altering Covid impacts.

Presumably the more severe but non-lethal long-term effects of COVID are also associated with more severe acute illness. But we don't know much at all about long-term effects yet as we haven't yet hit much long-term with any COVID cases.

[JasonEvans]

This certainly sounds promising. What do we know about the long term effects of moderate/mild Covid infections?

I think we should have some solid data on this in half a decade or so.

[PackMan97]

This certainly sounds promising. What do we know about the long term effects of moderate/mild Covid infections?


It seems to often we understandably focus on Covid deaths, but tend to gloss over rather than dwell on non-lethal, potentially life altering Covid impacts.

Exactly.

I am hoping that with a vaccine that reduces the severity of the disease it would also reduce the long term effects of the disease.

[PackMan97]

-Jason "I swear, it is like some people want to keep us locked indoors and double-masking for as long as possible" Evans

As a natural born introvert and a loner (it's amazing that I have a wife and two kids) I resemble that remark!

It's only on anonymous internet message boards that I'm a outspoken loud mouth.

[MChambers]

-Jason "I swear, it is like some people want to keep us locked indoors and double-masking for as long as possible" Evans

Hey, some of us look a lot better wearing masks!