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The Disastrous J&J Pause

We were told that the J&J pause was necessary to prevent vaccine hesitancy. I never understood the certainty people expressed on this point, even people who were relatively good on other issues. In anycase, as the excellent Daniel Bier argues, the best explanation for the data right now is that the J&J pause increased vaccine hesitancy.

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Could the plunge timing have been a coincidence? Perhaps the eager had already gotten their vaccinations, leaving only the less eager and more hesitant. Maybe. But note that younger people were getting vaccinated rapidly before the pause and at increasing rates in line with the rates of the older people who had been vaccinated before them. But then the vaccination rates of the young plummeted, just as for the old. In other words, the plunge started in all age groups at the same time but at very different levels of vaccination. The similar timing across age groups is easy to explain if it was the J&J pause (everyone saw the pause at the same time) but it requires multiple coincidences to explain why every age group would reach their hesitancy point at different levels of vaccination but at the same time.

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My view is that neither the CDC nor the FDA should be playing psychological games with the public. Just give it to us straight. In this case, since there was never much doubt that the J&J vaccine was much safer than COVID, a bulletin to physicians would have been appropriate to the circumstances. We don’t know for certain what would have happened under that counterfactual (although the data from Britain v. Europe on the AZ pause suggest a bulletin would not have generated the same hesitancy) but it would have been the right decision on the evidence.

See Bier’s tweet thread for further breakdown of the data.

India Authorizes Any Vaccine Authorized by a Stringent Regulator

Mint: In a move that could potentially pave the way for Pfizer and Johnson & Johnson’s covid-19 vaccines in India, the Centre on Tuesday said it would allow the granting of emergency licensure for vaccines that have received authorization in the US, UK, Europe, Japan or from the World Health Organization (WHO).

This is good news and a smart move. But what’s frustrating is that Pfizer was the first company to apply for an EUA from India in December of 2020 but India demanded that they conduct a clinical study on the Indian population and Pfizer pulled its application. In other words, India could have had a third vaccine approved and in use but “vaccine nationalism” reared its ugly head. Only now, as the bodies burn in the streets, has the Indian government acknowledged that the FDA and the EMA are reasonably careful judges of safety and efficacy.

It’s true that the cold storage requirements make the Pfizer vaccine somewhat difficult to use in India’s villages but it would have been fine to use in the major cities.

Naturally, the FDA and the EMA should also recognize each other as peer regulators.

Shout it From the Rooftops and Sometimes People Will Listen

Shout it from the rooftops and sometimes lots of other people will start shouting and then sometimes other people will listen!

The U.S. will begin sharing its entire pipeline of vaccine from AstraZeneca once the COVID-19 vaccine clears federal safety reviews, the White House told The Associated Press on Monday, with as many as 60 million doses expected to be available for export in the coming months.

The move greatly expands on the Biden administration’s action last month to share about 4 million doses of the vaccine with Mexico and Canada. The AstraZeneca vaccine is widely in use around the world but not yet authorized by the U.S. Food and Drug Administration.

…About 10 million doses of AstraZeneca vaccine have been produced but have yet to pass review by the FDA to “meet its expectations for product quality,” Zients said…That process could be completed in the next several weeks. About 50 million more doses are in various stages of production and could be available to ship in May and June pending FDA sign-off.

Let’s also get our J&J vaccine factories up and running and soon we will have Moderna and Novavax to export as well. Keep it coming! An American plan to vaccinate the world.

The petty narcissism of small vaccine differences

That is the topic of my latest Bloomberg column, here is one excerpt:

My survey of the cultural vaccine landscape in the U.S. includes the four major vaccines — from Pfizer, Moderna, AstraZeneca and Johnson & Johnson.

Pfizer, distributed by one of the largest U.S. pharmaceutical firms, is the establishment vaccine. Since it initially had a significant “cold chain” requirement, it was given out at established institutions such as big hospitals and public-health centers with large freezers. It is plentiful, highly effective and largely uncontroversial.

Moderna — the very name suggests something new — is the intellectual vaccine. The company had no product or major revenue source until the vaccine itself, so it is harder to link Moderna to “Big Pharma,” which gives it a kind of anti-establishment vibe. Note also that the last three letters of Moderna are “rna,” referring to the mRNA technology that makes the vaccine work. It is the vaccine for people in the know.

Moderna was also, for a while anyway, the American vaccine. It was available primarily in the U.S. at a time when Pfizer was being handed out liberally in the U.K. and Israel. As a recipient of two Moderna doses myself, I feel just a wee bit special for this reason. You had to be an American to get my vaccine. Yes, the European Union had also approved it, but it failed to procure it in a timely manner. So the availability of Moderna reflects the greater wealth and efficiency of the U.S.

Then there are the AstraZeneca and Johnson & Johnson vaccines…

And:

To the extent vaccines turn into markers for a cultural club, vaccine hesitancy may persist.

It might be better, all things considered, if vaccines were viewed more like paper clips — that is, a useful and even necessary product entirely shorn of cultural significance. Few people refuse to deploy paper clips in order to “own the libs” or because they do not trust the establishment. They are just a way to hold two pieces of paper together.

To be clear, the primary blame here lies with those who hesitate to get vaccinated. But behind big mistakes are many small ones — and we vaccinated Americans, with our all-too-human tendency to create hierarchies for everything, are surely contributing to the mess.

Recommended!

My Congressional Testimony

I thought the meeting went well. I made four points.

  • It is not too late to do more.
  • We should invest in nasal and oral vaccines.
  • We should vaccinate the world.
  • We should stretch doses through fractional dosing and delaying the second dose, this will be important to vaccinate the world quickly.

One observation. Lots of people are talking about vaccine hesitancy but I am one of the few people who have been talking about nasal and oral vaccines which are the only really solid approach to the issue that I have seen.

My best line:

The unvaccinated are the biggest risk for generating mutations and new variants. You have heard of the South Africa and Brazilian variants, well the best way to protect your constituents from these and other variants is to vaccinate South Africans and Brazilians.

I also got in the last word in Q&A when discussing the pause of J&J:

For the rest of the world it is important to underline that it is most important to get vaccinated now. Use the AstraZeneca vaccine, use the Johnnson & Johnson vaccine…don’t wait for Moderna or Pfizer, it is going to take too long…start your vaccination program early…vaccinate as quickly as possible, that is the route to health and wealth.

See Western Warnings Tarnish Vaccines the World Badly Needs for the beginnings of a disaster. Note that if J&J and AZ are tarnished or knocked out of the vaccine arsenal then dose stretching and investing in more capacity are going to be even more important.

I also submitted five excellent and important pieces to Congress:

Canadian statement on delaying the second dose.

National Advisory Committee on Immunization (NACI) Canada. 2021. “COVID-19 Vaccine Extended Dose Interval for Canadians: NACI Recommendation.” Government of Canada. March 3, 2021. https://www.canada.ca/en/public-health/services/immunization/national-advisory-committee-on-immunization-naci/rapid-response-extended-dose-intervals-covid-19-vaccines-early-rollout-population-protection.html.

Value of vaccine capacity and additional investments.

Castillo, Juan Camilo, Amrita Ahuja, Susan Athey, Arthur Baker, Eric Budish, Tasneem Chipty, Rachel Glennerster, et al. 2021. “Market Design to Accelerate COVID-19 Vaccine Supply.” Science, February. https://doi.org/10.1126/science.abg0889.

Efficacy of the first dose from NEJM.

Skowronski, Danuta, and Gaston Serres De. 2021. “Letter to the Editor on Safety and Efficacy of the BNT162b2 MRNA Covid-19 Vaccine.” New England Journal of Medicine, February 17, 2021. https://doi.org/10.1056/NEJMc2036242.

Overview of dose stretching policies (with links in the online version).

Tabarrok, Alex. 2021. “What Are We Waiting For?” Washington Post, February 12, 2021, sec. Outlook. https://www.washingtonpost.com/outlook/2021/02/12/first-doses-vaccine-rules-fda/

A plan to vaccinate the world.

Agarwal, Ruchir, and Tristan Reed. 2021. “How to End the COVID-19 Pandemic by March 2022” SSRN. 2021. https://documents.worldbank.org/en/publication/documents-reports/documentdetail/181611618494084337/how-to-end-the-covid-19-pandemic-by-march-2022

The whole thing is here. My written testimony is here.

“RCTs for me but not for thee”?

Zeke Emanuel, a professor of healthcare management at the University of Pennsylvania and a former coronavirus adviser to US president Joe Biden, said: “I understand they wanted to be transparent, but did they really have to announce a complete pause? “My concern is this will unnecessarily undermine confidence in the vaccine, and possibly all [Covid-19] vaccines. Are people going to know the difference?”

Amesh Adalja, a senior scholar at the Johns Hopkins Center for Health Security in Baltimore, said: “The damage is done, this is going to be hard to resume. All [the CDC] can do is say how rare this is, show how safe and efficacious the J&J vaccine is. But this action is going to be hard to reverse.”

Here is the full FT piece.  Since lives are at stake, how about this for a proposal?  The FDA is allowed to suspend the use of any positive expected value vaccine only after running an RCT on their underlying theory of credibility and public risk communication in the relevant context.  (NB: asking about attitude change is not nearly good enough!)  And after they run the RCT, they have to wait three weeks to schedule the meeting on evaluating the data.  After all, that is how long it takes, right?

Estamos de acuerdo?

By the way, one reader wrote to me: “I submit to you that the credibility of the FDA on the relative safety of various vaccines may be a minor issue in the pool of issues that prevent the level of vaccinations we would like to see.”  Do we even know if that is true or false?

“Free-floating credibility” is underrated

The presence of a minuscule risk for some of the adenovirus platform Covid vaccines means that the FDA has put a hold on J&J and still won’t approve AstraZeneca.

In response to critics, the FDA says that their credibility is on the line.  If they allow vaccine use to proceed, and a modest number of people die as a result (with a big increase in net lives saved), the FDA and its defenders claim that people will lose faith in the FDA.  Yet that is exactly the wrong thing to say, it is self-serving, and it exacerbates the problem at hand.

When the FDA announces that they have to ban a vaccine because its credibility is on the line, that very announcement puts their credibility on the line.  It is a simple two-line proof.  Either they are lying about whether their credibility is on the line, in which case they have wrecked their credibility with the lie.  Or they are telling the truth, in which case by definition their credibility is indeed on the line.

One lesson is that you should not try to extend your credibility too far, because you will end up unduly constrained.

For purposes of contrast, consider alcoholic beverages.  At the federal level they are regulated by the Alcohol and Tobacco Tax and Trade Bureau (who are they again?), and also various state and local authorities.

As a result of this unusual, Prohibition-rooted distribution of authority, alcohol does not come with nutritional labeling.

Now, in that setting, if a bunch of kids die from binge drinking, the credibility of the Bureau is not much damaged.  The Bureau does not have to ban alcohol on the grounds that if it does not, the credibility of the Bureau will be ruined.  The Bureau simply never put its credibility on the line in this manner.

Now you might favor a tighter regulation of alcohol for some reason, but you could achieve such regulation without tying up the credibility of the ATTT Bureau in knots.  Similarly, the Department of Transportation regulates road safety (again with state and local authorities as well), but it has not put its credibility on the line when 40,000 or so Americans die each year on the roads.  Again, maybe they should enforce tougher safety standards, but they shouldn’t tie their credibility to getting road deaths down to one hundred, and indeed they do not.  They end up with more degrees of regulatory freedom.

Let’s say I were to announce that my credibility as a public intellectual were to depend at how I would fare at darts on British pub night.  That would be a big mistake, for multiple reasons.  It is like with the FDA.  If I am lying about that credibility tie, I hurt my credibility as a public intellectual.  If somehow I am telling the truth, well let’s just hope everyone else stays home that evening because my credibility is going to take a beating.

What I call “free-floating credibility” is underrated.

And that is precisely what defenders of the FDA destroy when they…defend the FDA.  They make the FDA worse.

NB: You are “out of your lane” commenting on this analysis unless you have studied game theory with Thomas Schelling.

Vaccine fact of the day

Moderna and BioNTech shares jumped 10.5 per cent and 6.1 per cent, respectively, on Tuesday as the vaccine makers benefited from news of the J&J pause.

Norway’s health authorities estimated that their vaccination plans could be delayed by eight to 12 weeks if they could not use either the J&J or the Oxford/AstraZeneca vaccine.

The biggest short-term loser here is Europe, not the United States.  Nor will this help Australia reopen.  But does the American median voter or median FDA senior bureaucrat care?  What will the CVS liability lawyers advise from here on out?  What will the French anti-vaxxers think?

Here is the full FT article.

In praise of Alex Tabarrok

Here’s a question I’ve been mulling in recent months: Is Alex Tabarrok right? Are people dying because our coronavirus response is far too conservative?

I don’t mean conservative in the politicized, left-right sense. Tabarrok, an economist at George Mason University and a blogger at Marginal Revolution, is a libertarian, and I am very much not. But over the past year, he has emerged as a relentless critic of America’s coronavirus response, in ways that left me feeling like a Burkean in our conversations.

He called for vastly more spending to build vaccine manufacturing capacity, for giving half-doses of Moderna’s vaccine and delaying second doses of Pfizer’s, for using the Oxford-AstraZeneca vaccine, for the Food and Drug Administration to authorize rapid at-home tests, for accelerating research through human challenge trials. The through line of Tabarrok’s critique is that regulators and politicians have been too cautious, too reluctant to upend old institutions and protocols, so fearful of the consequences of change that they’ve permitted calamities through inaction.

Tabarrok hasn’t been alone. Combinations of these policies have been endorsed by epidemiologists, like Harvard’s Michael Mina and Brown’s Ashish Jha; by other economists, like Tabarrok’s colleague Tyler Cowen and the Nobel laureates Paul Romer and Michael Kremer; and by sociologists, like Zeynep Tufekci (who’s also a Times Opinion contributor). But Tabarrok is unusual in backing all of them, and doing so early and confrontationally. He’s become a thorn in the side of public health experts who defend the ways regulators are balancing risk. More than one groaned when I mentioned his name.

But as best as I can tell, Tabarrok has repeatedly been proved right, and ideas that sounded radical when he first argued for them command broader support now. What I’ve come to think of as the Tabarrok agenda has come closest to being adopted in Britain, which delayed second doses, approved the Oxford-AstraZeneca vaccine despite its data issues, is pushing at-home testing and permitted human challenge trials, in which volunteers are exposed to the coronavirus to speed the testing of treatments. And for now it’s working: Britain has vaccinated a larger percentage of its population than the rest of Europe and the United States have and is seeing lower daily case rates and deaths.

Here is more from Ezra Klein at the New York Times.

The EU Vaccine Bungling

The EU vaccine rollout has been remarkably bungled even by the standards we have come to expect from Western governments. In advising governments I and the AHT team argued that vaccines were the world’s easiest cost-benefit test because Billions<<Trillions. Yet when manufactures offered the EU vaccines worth thousands of dollars a dose for just $5-$40 a dose the EU foolishly shouted “price gouging” and wasted weeks in dickering. I leave it to you as an exercise to calculate the value EU governments implicitly placed on European lives.

The latest bungling was the halt by over a dozen European governments of vaccination with the AstraZeneca vaccine due to fears that it might cause very rare blood clots (wisely Belgium and Great Britain continued vaccinations). After a review, the EMA has now cleared the vaccine:

The European Union’s drug regulator said on Thursday that the AstraZeneca vaccine was safe and effective, a finding that officials hope will alleviate concerns about possible rare side effects involving blood clots and allow more than a dozen countries that halted its use to add it back into their arsenal against the resurgent coronavirus.

The halt, however, was never justified. The EMA press release make this clear because it hasn’t added much more information it only underlines what we already knew. Namely, there was no increase in the overall risk of blood clots. There might be an increase in a very rare type of blood clot but that wasn’t obvious, especially when one takes into account that when you are monitoring hundreds of rare side effects it’s bound to be the case that some show statistically significant effects even if there are no true effects. As a result, the more conditions you test the higher standards you should apply to judge a difference as statistically significant (ala Bonferroni Correction which the EMA does not appear to have done). Moreover, even assuming that the rare vaccine effects were real they were thousands of times less than the effects of blood clotting from COVID itself so if you wanted to avoid blood clots the way to do so was to take the vaccine. Moreover, even assuming that the rare effects were real, they were not larger than those from other common activities such as flying or taking contraceptive pills. Moreover, and this point does not seem to have been made prominent, the most plausible argument for the vaccine creating blood clots is through the generation of the spike protein, which all the vaccines do, so there is little reason to believe that the Pfizer or Moderna vaccine would not also have the same problems (which they might). Thus, the focus on AZ seemed oddly misplaced. Draw your own conclusions on that.

The end result is that more people will die from the halt than could possible have been saved by the halt. Why did this happen? One reason is the absurd focus on doing anything to alleviate “vaccine hesitancy.” To alleviate vaccine hesitancy we have repeatedly sent the message that the vaccines are “safe, safe, safe.” When we should have said the vaccines pass a cost-benefit test (with flying colors!) and are much safer than many drugs people take for less serious conditions. But every drug or vaccine has side-effects. Tradeoffs are everywhere.

Unfortunately, vaccine hesitancy seems to have become a catch-all excuse for never having to show your work with a cost-benefit analysis. As I said in my post Don’t Delay a Vaccine to Allay Fear (should have said don’t halt one either!):

We should not let public policy be guided by the most risk averse, fearful, and scientifically illiterate among us.

[And]… rather than alleviating fear, delay may increase fear. People may reason, if the FDA is taking this long to review the evidence when thousands of people are dying every day it must be a hard decision.

The latter point, of course, is exactly what has happened. The EU halt has increased vaccine hesitancy rather than alleviating it.

Addendum:

  • Feb. 2: France restricts AstraZeneca vaccine to those aged less than 65 years of age.
  • March 2: France approves AZ vaccine for all ages.
  • March 19: France recommends AstraZeneca vaccine only to those aged more than 55 years.

I guess 55-65 years of age is the sweet spot.

How bad is EU bungling? So bad, Paul Krugman and I are in agreement. He almost quotes me on “Progressivism: The haunting fear that someone, somewhere, may be making a profit.”

What should I ask Daniel Carpenter?

I will be doing a Conversation with Daniel, who is a professor of political science at Harvard and one of the world’s leading experts on the history of regulation and also the FDA.  Here is part of his bio:

Professor Carpenter’s previous scholarship on regulation and government organizations appears in Reputation and Power: Organizational Image and Pharmaceutical Regulation at the FDA (Princeton, 2010), winner of the Allan Sharlin Memorial Award of the Social Science History Association; and of The Forging of Bureaucratic Autonomy: Reputations, Networks and Policy Innovation in Executive Agencies, 1862-1928 (Princeton, 2001), winner of the Gladys Kammerer Prize of the American Political Science Association and the Charles Levine Prize of the International Political Science Association.  With David Moss of Harvard Business School, he is the author and co-editor of Preventing Regulatory Capture: Special Interest Influence in Regulation and How to Limit It (Cambridge, 2013).

And coming out in May:

Professor Carpenter’s research on petitioning appears in his forthcoming book Democracy by Petition: Popular Politics in Transformation, 1790-1870 (Harvard University Press, 2021)

So what should I ask him?

Why vaccination passports probably won’t work well

That is the topic of my latest Bloomberg column, here is one excerpt:

One issue is what exactly constitutes proof of vaccination. For my vaccinations, I have been issued a rather flimsy, easy-to-forge paper document from the Centers for Disease Control. Unlike a passport or a dollar bill, it has no embedded watermarks or other protections. Anyone with a moderately sophisticated copy machine could create many fake documents, or perhaps steal an existing stash of these documents and sell them on the black market. Once you have the documents, you can simply note that you have been vaccinated, and it is not easy for outside parties to dispute such claims.

Soon enough, of course, it may be easier for most adults to get a vaccine than to forge a vaccine passport. Still, U.S. laws and regulations work better when they can refer to clear, verifiable standards of evidence. It is hard to imagine a set of laws or procedures based on criteria so loose that they basically allow anyone to claim they are vaccinated. A more stringent standard, however, would be hard for most vaccinated Americans to meet.

Another knotty question is which vaccines will count for the passport. Pfizer’s, Moderna’s and Johnson & Johnson’s for sure, but what if you are a U.S. citizen living in Canada who received AstraZeneca’s vaccine, which has been approved by some 15 nations but not the U.S.? Is the federal government willing to tell a whole class of responsible individuals that they cannot fly on U.S. planes? Or will the vaccine-passport bureaucracy be willing to approve vaccines that the Food and Drug Administration will not?

These dilemmas can become stickier yet. What about Sputnik, the Russian vaccine, or the numerous Chinese vaccines, which are being administered around the world, including in Mexico?

Do Americans really wish to create a country to which most foreigners would not be very welcome? Furthermore, what counts as proof of foreign vaccination? Some Asian countries, including China, are creating elaborate and supposedly secure vaccine verification systems, using advanced information technology. Good for them — but how would that connect with U.S. regulations? How many different passport systems would a flight attendant or gate agent have to read, interpret and render judgment upon?

The likely result of all this: Many foreign visitors to the U.S. would never quite know in advance whether they could board an airplane or attend a public event.

And how would the passport reflect any new vaccines deemed necessary? What if new Covid-19 strains require booster shots? What if you’ve had Covid and thus get only one shot for now rather than two, as many experts are recommending? What will happen as the number of vaccines around the world proliferates? Given the slowness of the FDA and CDC, it is hard to imagine any new U.S. approvals coming quickly. A vaccine passport system could end up being fetters not only for foreigners and anti-vaxxers but also for vaccinated Americans.

Recommended, there are additional arguments at the link.

Dose Stretching Policies Probably *Reduce* Mutation Risk

One objection to dose-stretching policies, such as delaying the second dose or using half-doses, is that this might increase the risk of mutation. While possible, some immunologists and evolution experts are now arguing that dose-stretching will probably reduce mutation risk which is what Tyler and I concluded. Here’s Tyler:

One counter argument is that letting “half-vaccinated” people walk around will induce additional virus mutations.  Florian Kramer raises this issue, as do a number of others.

Maybe, but again I wish to see your expected value calculations.  And in doing these calculations, keep the following points in mind:

a. It is hard to find vaccines where there is a recommendation of “must give the second dose within 21 days” — are there any?

b. The 21-day (or 28-day) interval between doses was chosen to accelerate the completion of the trial, not because it has magical medical properties.

c. Way back when people were thrilled at the idea of Covid vaccines with possible 60% efficacy, few if any painted that scenario as a nightmare of mutations and otherwise giant monster swarms.

d. You get feedback along the way, including from the UK: “If it turns out that immunity wanes quickly with 1 dose, switch policies!”  It is easy enough to apply serological testing to a control group to learn along the way.  Yes I know this means egg on the face for public health types and the regulators.

e. Under the status quo, with basically p = 1 we have seen two mutations — the English and the South African — from currently unvaccinated populations.  Those mutations are here, and they are likely to overwhelm U.S. health care systems within two months.  That not only increases the need for a speedy response, it also indicates the chance of regular mutations from the currently “totally unvaccinated” population is really quite high and the results are really quite dire!  If you are so worried about hypothetical mutations from the “half vaccinated” we do need a numerical, expected value calculation comparing it to something we already know has happened and may happen yet again.  When doing your comparison, the hurdle you will have to clear here is very high.

(See my Washington Post piece for similar arguments and additional references.).

Now here are evolutionary theorists, immunologists and viral experts Sarah Cobey, Daniel B. Larremore, Yonatan H. Grad, and Marc Lipsitch in an excellent paper that first reviews the case for first doses first and then addresses the escape argument. They make several interrelated arguments that a one-dose strategy will reduce transmission, reduce prevalence, and reduce severity and that all of these effects reduce mutation risk.

The arguments above suggest that, thanks to at least some effect on transmission from one dose, widespread use of a single dose of mRNA vaccines will likely reduce infection prevalence…

The reduced transmission and lower prevalence have several effects that individually and together tend to reduce the probability that variants with a fitness advantage such as immune escape will arise and spread (Wen, Malani, and Cobey 2020). The first is that with fewer infected hosts, there are fewer opportunities for new mutations to arise—reducing available genetic variation on which selection can act. Although substitutions that reduce antibody binding were documented before vaccine rollout and are thus relatively common, adaptive evolution is facilitated by the appearance of mutations and other rearrangements that increase the fitness benefit of other mutations (Gong, Suchard, and Bloom 2013; N. C. Wu et al. 2013; Starr and Thornton 2016). The global population size of SARS-CoV-2 is enormous, but the space of possible mutations is larger, and lowering prevalence helps constrain this exploration. Other benefits arise when a small fraction of hosts drives most transmission and the effective reproductive number is low. Selection operates less effectively under these conditions: beneficial mutations will more often be lost by chance, and variants with beneficial mutations are less certain to rise to high frequencies in the population (Desai, Fisher, and Murray 2007; Patwa and Wahl 2008; Otto and Whitlock 1997; Desai and Fisher 2007; Kimura 1957). More research is clearly needed to understand the precise impact of vaccination on SARS-CoV-2 evolution, but multiple lines of evidence suggest that vaccination strategies that reduce prevalence would reduce rather than accelerate the rate of adaptation, including antigenic evolution, and thus incidence over the long term.

In evaluating the potential impact of expanded coverage from dose sparing on the transmission of escape variants, it is necessary to compare the alternative scenario, where fewer individuals are vaccinated (but a larger proportion receive two doses) and more people recover from natural infection. Immunity developing during the course of natural infection, and the immune response that inhibits repeat infection, also impose selection pressure. Although natural infection involves immune responses to a broader set of antibody and T cell targets compared to vaccination, antibodies to the spike protein are likely a major component of protection after either kind of exposure (Addetia et al. 2020; Zost et al. 2020; Steffen et al. 2020), and genetic variants that escape polyclonal sera after natural infection have already been identified (Weisblum et al. 2020; Andreano et al. 2020). Studies comparing the effectiveness of past infection and vaccination on protection and transmission are ongoing. If protective immunity, and specifically protection against transmission, from natural infection is weaker than that from one dose of vaccination, the rate of spread of escape variants in individuals with infection-induced immunity could be higher than in those with vaccine-induced immunity. In this case, an additional advantage of increasing coverage through dose sparing might be a reduction in the selective pressure from infection-induced immunity.

…In the simplest terms, the concern that dose-sparing strategies will enhance the spread of immune escape mutants postulates that individuals with a single dose of vaccine are those with the intermediate, “just right” level of immunity, more likely to evolve escape variants than those with zero or two doses (Bieniasz 2021; Saad-Roy et al. 2021)….There is no particular reason to believe this is the case. Strong immune responses arising from past infection or vaccination will clearly inhibit viral replication, preventing infection and thus within-host adaptation…. Past work on influenza has found no evidence of selection for escape variants during infection in vaccinated hosts (Debbink et al. 2017). Instead, evidence suggests that it is immunocompromised hosts with prolonged influenza infections and high viral loads whose viral populations show high diversity and potentially adaptation (Xue et al. 2017, 2018), a phenomenon also seen with SARS-CoV-2 (Choi et al. 2020; Kemp et al. 2020; Ko et al. 2021). It seems likely, given its impact on disease, that vaccination could shorten such infections, and there is limited evidence already that vaccination reduces the amount of virus present in those who do become infected post-vaccination (Levine-Tiefenbrun et al. 2021).

I also very much agree with these more general points:

The pandemic forces difficult choices under scientific uncertainty. There is a risk that appeals to improve the scientific basis of decision-making will inadvertently equate the absence of precise information about a particular scenario with complete ignorance, and thereby dismiss decades of accumulated and relevant scientific knowledge. Concerns about vaccine-induced evolution are often associated with worry about departing from the precise dosing intervals used in clinical trials. Although other intervals were investigated in earlier immunogenicity studies, for mRNA vaccines, these intervals were partly chosen for speed and have not been completely optimized. They are not the only information on immune responses. Indeed, arguments that vaccine efficacy below 95% would be unacceptable under dose sparing of mRNA vaccines imply that campaigns with the other vaccines estimated to have a lower efficacy pose similar problems. Yet few would advocate these vaccines should be withheld in the thick of a pandemic, or roll outs slowed to increase the number of doses that can be given to a smaller group of people. We urge careful consideration of scientific evidence to minimize lives lost.

Detroit Fauci

The mayor of Detroit has turned down an allocation of the J&J vaccine.

Detroit Mayor Mike Duggan declined an initial allocation of the newly authorized Johnson & Johnson Covid-19 vaccine….”So, Johnson & Johnson is a very good vaccine. Moderna and Pfizer are the best. And I am going to do everything I can to make sure the residents of the city of Detroit get the best,” Duggan said during a news conference Thursday.

Sigh. What an error. Note, however, that the Detroit Mayor rejecting the J&J vaccine is exactly what the FDA has done with the AstraZeneca vaccine. Moreover none other than Anthony Fauci made exactly the same argument about AstraZeneca (an argument I criticized at the time):

But even if the vaccine ends up being approved, it will probably only have an efficacy of 60 to 70 percent. “What are you going to do with the 70 percent when you’ve got two (vaccines) that are 95 percent? Who are you going to give a vaccine like that to?” Anthony Fauci, the leading American expert on vaccines, recently wondered.

To be clear, I don’t blame Fauci for the actions of Detroit Mayor Mike Duggan. Duggan would probably have said the same had Fauci never made his error. Indeed, perhaps you might even read this as excusing Duggan (if even Fauci, “the leading American expert on vaccines”, could make this error then…).

Still, Fauci’s error has been much more costly for the United States.

Hat tip: JF.

Sins of omission vs sins of commission

That is the topic of my latest Bloomberg column, here is one excerpt:

To be clear, public health officials are encouraging additional vaccinations. But they don’t seem to realize how much their own ostensibly “careful” rhetoric makes vaccination sound unappealing. “Not talking up the vaccines” is a sin of omission, not a sin of commission, and so it is tolerated and is not a major issue for public debate.

Should public officials be allowed, indeed encouraged, to treat sins of commission and omission so differently, as private citizens (myself included) typically do?

I live near Arlington National Cemetery, where approximately 400,000 veterans (and family members) are buried. I suspect they would not care so much whether their deaths were the result of errors of commission or omission. Did a commanding general order a hill to be charged that should have been left alone? Or did he make the mistake of not charging a hill that could have been taken?

Most citizens care about the total number of military casualties from a battle and are only modestly concerned about the details of the mistakes that caused them. That seems like the right and rational attitude. Perhaps it is also the correct attitude for the war against the coronavirus — that is, an overriding concern with casualties and outcomes, regardless of the kind of error that led to them.

Recommended.