Results for “fda”

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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.

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.

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.

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.

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.”

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.