Results for “first doses first”
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How Slowly ‘First Doses First’ Came to America

Yesterday I pointed out How Rapidly ‘First Doses First’ Came to Britain. The United States is also moving in that direction but more slowly. First we ended holding second doses in reserves. Now the CDC has new policies:

CNBC: The Centers for Disease Control and Prevention quietly changed its guidance on Covid-19 vaccine shots, saying it’s now OK to mix Pfizer’s and Moderna’s shots in “exceptional situations” and that it’s also fine to wait up to six weeks to get the second shot of either company’s two-dose immunization.

We will see what happens if new variants start to takeoff in the US, as seems likely, and as the number of people immunized starts to slow as we move from first does to having to vaccinate people for the second dose. More second doses means fewer resources for first timers. Biden’s 100 million in 100 days, for example, was already under-ambitious but it’s not even 100 million people it’s 100 million doses or only about 67 million people given that some will be in line twice.

How Rapidly ‘First Doses First’ Came to Britain

Tim Harford writes about the whiplash he experienced from the debate over delaying second doses in Britain.

What a difference a couple of weeks makes. In mid-December, I asked a collection of wise guests on my BBC radio programme How to Vaccinate the World about the importance of second doses. At that stage, Scott Gottlieb, former head of the US Food and Drug Administration, had warned against stockpiling doses just to be sure that second doses were certain to be available, Economists such as Alex Tabarrok of George Mason University had gone further: what if we gave people single doses of a vaccine instead of the recommended pair of doses, and thus reached twice as many people in the short term? This radical concept was roundly rejected by my panel

…. “This is an easy one, Tim, because we’ve got to go with the scientific evidence,” said Nick Jackson of the Coalition for Epidemic Preparedness Innovations. “And the scientific evidence is that two doses is going to provide the best protection.”

My other guests agreed, and no wonder: Jackson’s view was firmly in the scientific mainstream three weeks ago. But in the face of a shortage of doses and a rapidly spreading strain of “Super-Covid”, the scientific mainstream appears to have drifted. The UK’s new policy is to prioritise the first dose and to deliver the second one within three months rather than three weeks…..the recommendation comes not from ministers but from the Joint Committee on Vaccination and Immunisation (JCVI).

Strikingly, many scientists have given the move their approval.

See also Tyler’s previous post on this theme.

By the way, if the J&J single-dose vaccine comes in at say 80% effective it is going to be interesting to see how people go from ‘a single-dose at 80% effective is too dangerous to allow for 8-12 weeks’ to ‘isn’t it great we have a single-dose 80% effective vaccine!’.

First Doses First, coming soon to a state near you…

Of course on this particular issue, Alex was the one who started the intellectual campaign…

A legal and regulatory question about First Doses First

It isn’t clear to me who in the United States is legally entitled to make this decision.  An FDA EUA is required before a vaccine can be used in the U.S.  But once an EUA has been issued, is “off-label use” permitted?  The CDC’s Advisory Committee on Immunization Practices recommends how scarce vaccine doses should be prioritized, but “states” (governors?) are free to make contrary prioritization decisions.  Can states also decide to give half-doses or lengthen the interval between first and second doses?  Can a hospital, a nursing home, or an individual doctor make such a decision?  (If so, can it also deviate from its state prioritizations?)  Can HHS or the President specify how these decisions must be made, or alternatively can they explicitly free lower-level decision-makers to use their own judgment?

You’re not a specialist in pharmaceutical law, I realize.  But I doubt you’ll let that stop you!  When you recommend a less risk-averse approach to COVID-19 vaccination, to whom are you addressing the recommendation?  Who has a right to implement it?

That is from MR reader Peter Sandman.  Can any MR reader inform us on this?

First Doses First and Herd Immunity

The simplest argument for First Doses First (FDF) is that 2*0.8>.95, i.e. two vaccinated people confers more immunity than one double vaccinated person. But there is more to it than that. Perhaps more important is that with FDF we will lower R more quickly and reach herd immunity sooner. Here’s an extreme but telling example.

Suppose you have a pop of 300 million, need 2/3 to get to herd immunity and you have 100m doses and can vaccinate 100m a month. Then with FDF you vaccinate 100m in first month and a new 100m in the second month and then you are “done.” i.e. you can then do 2nd doses more or less at leisure since you are at herd immunity (yes, I know about overshooting, this is a simple example). If instead you do second doses you vaccinate 100m in first month and the same 100m in the second month which leaves 100 million at risk for another month. Under second doses you don’t reach herd immunity until the third month. Thus, under FDF you save a 100m infection-month which is a big deal.

Now when you put this into a more sophisticated SEIR model you won’t get as strong a result but the result will be in the same direction. Note also that getting to herd immunity sooner is probably the best thing we can do to prevent further mutations.

See also Youyang Go’s thread where he discusses his modeling of similar ideas. He notes:

Reaching herd immunity two or three months sooner will have profound benefits throughout society, ranging from fewer cases & deaths to faster economic recovery.

Addendum: Please read Tyler’s post, FDF?-Show Your Work! before you comment.

First Doses First? — show your work!

Alex has been arguing for a “First Doses First” policy, and I find his views persuasive (while agreeing that “halfsies” may be better yet, more on that soon).  There are a number of numerical attempts to show the superiority of First Doses First, here is one example of a sketched-out argument, I have linked to a few others in recent days, or see this recent model, or here, here is an NYT survey of the broader debate.  The simplest numerical case for the policy is that 2 x 0.8 > 0.95, noting that if you think complications overturn that comparison please show us how.  (Addendum: here is now one effort by Joshua Gans).

On Twitter I have been asking people to provide comparable back-of-the-envelope calculations against First Doses First.  What is remarkable is that I cannot find a single example of a person who has done so.  Not one expert, and at this point I feel that if it happens it will come from an intelligent layperson.  Nor does the new FDA statement add anything.  As a rational Bayesian, I am (so far) inferring that the numerical, expected value case against First Doses First just isn’t that strong.

Show your work people!

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.

When you offer your expected value calculation, or when you refuse to, here are a bunch of things you please should not tell me:

f. “There just isn’t any data!”  Do read that excellent thread from Robert Wiblin.  Similar points hold for “you just can’t calculate this.”  A decision to stick with the status quo represents an implicit, non-transparent calculation of sorts, whether you admit it or not.

g. “This would risk public confidence in the vaccine process.”  Question-begging, but even if true tell us how many expected lives you are sacrificing to satisfy that end of maintaining public confidence.  This same point applies to many other rejoinders.  It is fine to cite additional moral values, but then tell us the trade-offs with respect to lives.  Note that egalitarianism also favors First Doses First.

h. “We shouldn’t be arguing about this, we should be getting more vaccines out the door!”  Yes we should be getting more vaccines out the door, but the more we succeed at that, as likely we will, the more important this dosing issue will become.  Please do not try to distract our attention, this one would fail in an undergraduate class in Philosophical Logic.

i. Other fallacies, including “the insiders at the FDA don’t feel comfortable about this.”  Maybe so, but then it ought to be easy enough to sketch for us in numerical terms why their reasons are good ones.

j. All other fallacies and moral failings.  The most evasive of those might be: “This is all the more reason why we need to protect everyone now.”  Well, yes, but still show your work and base your calculations on the level of protection you can  plausibly expect, not on the level of protection you are wishing for.

At the risk of venturing into psychoanalysis, it is hard for me to avoid the feeling that a lot of public health experts are very risk-averse and they are used to hiding behind RCT results to minimize the chance of blame.  They fear committing sins of commission more than committing sins of omission because of their training, they are fairly conformist, they are used to holding entrenched positions of authority, and subconsciously they identify their status and protected positions with good public health outcomes (a correlation usually but not always true), and so they have self-deceived into pursuing their status and security rather than the actual outcomes.  Doing a back of the envelope calculation to support their recommendation against First Doses First would expose that cognitive dissonance and thus it is an uncomfortable activity they shy away from.  Instead, they prefer to dip their toes into the water by citing “a single argument” and running away from a full comparison.

It is downright bizarre to me — and yes scandalous — that a significant percentage of public health experts are not working day and night to produce and circulate such numerical expected value estimates, no matter which side of the debate they may be on.

How many times have I read Twitter threads where public health experts, at around tweet #11, make the cliched call for transparency in decision-making?  If you wish to argue against First Doses First, now it is time to actually provide such transparency.  Show your work people, we will gladly listen and change our minds if your arguments are good ones.

“Second Doses” post-mortem

The most striking thing about the Biden administration shift to a version of “First Doses First” is how little protest there has been.  Given how many public health experts were upset about the idea only a few days ago, you might expect them to organize a Wall Street Journal petition from hundreds of their colleagues: “Biden administration proposal endangers the lives of millions of Americans.”

But of course they won’t do that.  Some of that is pro-Democrat partisanship, but that is not even the main factor.  One reason is that public health experts, with their medical and quasi-medical backgrounds, typically have very little sense of how to respond in the public arena if challenged.  For instance, not a single one stepped forward with a calculation to defend “Second Doses.”  They are not especially good at “the internet rules of the game,” which of course are now supreme (not always for the best, to be clear).

The second and probably most important reason is that, as I had explained, sins of omission are treated as far less significant than sins of commission.  Now that a version of “First Doses First” is on the verge of becoming policy, to do nothing about that is only a sin of omission, and thus not so bad.  Remarkable!  Status quo bias really matters here.

I haven’t seen a single peep on Twitter opposing the new policy.

Just keep all this in mind the next time you see a debate over public health policy.  There is often less behind the curtain than you might think.

Half-Doses as Good as Full?

NYTimes: A top official of Operation Warp Speed floated a new idea on Sunday for stretching the limited number of Covid-19 vaccine doses in the United States: Halving the dose of each shot of Moderna’s vaccine to potentially double the number of people who could receive it.

Data from Moderna’s clinical trials demonstrated that people between the ages of 18 and 55 who received two 50-microgram doses showed an “identical immune response” to the standard of two 100-microgram doses, said the official, Dr. Moncef Slaoui.

Dr. Slaoui said that Operation Warp Speed was in discussions with the Food and Drug Administration and the pharmaceutical company Moderna over implementing the half-dose regimen. Moderna did not respond immediately to a request for comment.

Each vaccine would still be delivered in two, on-schedule doses four weeks apart, Dr. Slaoui said in an interview with “CBS’s Face the Nation.” He said it would be up to the F.D.A. to decide whether to move forward with the plan.

Half dosing would double Moderna doses permanently rather than temporarily (as with First Doses First). Thus, I would be very happy to see half-dosing and it would obviate the need for FDF.

I and a handful of others started to discuss and advocate First Doses First on Dec. 8 and many times since then. The advocacy was then joined by Tony Blair and by many epidemiologists, immunologists, vaccine researchers, physicians and public health experts as well, of course, by the British experts on the Joint Committee on Vaccination and Immunisation. It’s clear that the FDA and Operation Warp Speed are now feeling the pressure to take some serious actions to increase supply. If so, my small efforts will have had a very high return.

Keep the pressure on.

Addendum: By the way, the British have yet to approve the Moderna vaccine (probably because they can’t get doses for some time anyway) and the AstraZeneca vaccine appears to work better with a longer dosing interval. So FDF makes sense for the British and we can do half-dosing on Moderna, potentially setting a new and beneficial standard for the entire world.

First Dose First

Writing on twitter Keith Klugman, world expert on infectious diseases and director of the Gates Foundation Pneumonia program, supports a policy I have argued for–First Doses First.

First doses of Pfizer/Moderna vaccines are 90%+ effective after 14 days. Most high risk lives will be saved by giving all these limited early supplies of vaccine as first doses – second doses can be given later if first dose effectiveness wanes or when supply improves

Here’s a way of thinking about this policy. Suppose you are scheduled for your second dose of the Pfizer or Moderna vaccine but you have the option of giving your second dose to your spouse as their first dose. Would you?

If the answer is yes then can you ethically deny this to someone else’s spouse?

Keep in mind that we have at least three more vaccines that could be available in as little as 12 weeks, Astra-Zeneca, Johnson & Jonson and Novavax. We are also pushing for more doses from Pfizer and we should be willing to pay top-dollar for those doses. As those vaccines come online we can deliver second doses.

Addendum: If you are 75 and your spouse is 25 then maybe you wouldn’t give your second dose to your spouse and that too ought to help us think about the larger questions of allocation.

The case for geographically concentrated vaccine doses

Here goes:

A central yet neglected point is that vaccines should not be sent to each and every part of the U.S. Instead, it would be better to concentrate distribution in a small number of places where the vaccines can have a greater impact.

Say, for the purposes of argument, that you had 20,000 vaccine doses to distribute. There are about 20,000 cities and towns in America. Would you send one dose to each location? That might sound fair, but such a distribution would limit the overall effect. Many of those 20,000 recipients would be safer, but your plan would not meaningfully reduce community transmission in any of those places, nor would it allow any public events to restart or schools to reopen.

Alternatively, say you chose one town or well-defined area and distributed all 20,000 doses there. Not only would you protect 20,000 people with the vaccine, but the surrounding area would be much safer, too. Children could go to school, for instance, knowing that most of the other people in the building had been vaccinated. Shopping and dining would boom as well.

Here is one qualifier, but in fact it pushes one further along the road to geographic concentration:

Over time, mobility, migration and mixing would undo some of the initial benefits of the geographically concentrated dose of vaccines. That’s why the second round of vaccine distribution should go exactly to those people who are most likely to mix with the first targeted area. This plan reaps two benefits: protecting the people in the newly chosen second area, and limiting the ability of those people to disrupt the benefits already gained in the first area.

In other words, if the first doses went (to choose a random example) to Wilmington, Delaware, the next batch of doses should go to the suburbs of Wilmington. In economics language [behind this link is a highly useful Michael Kremer paper], one can say that Covid-19 infections (and protections) have externalities, and there are increasing returns to those externalities. That implies a geographically concentrated approach to vaccine distribution, whether at the federal or state level.

Here is another qualifier:

…there will be practical limits on a fully concentrated geographic distribution of vaccines. Too many vaccines sent to too few places will result in long waits and trouble with storage. Nonetheless, at the margin the U.S. should still consider a more geographically concentrated distribution than what it is likely to do.

Do you think that travel restrictions have stopped the spread of the coronavirus? (Doesn’t mean you have to favor them, all things considered.)  Probably yes.  If so, you probably ought to favor a geographically concentrated initial distribution of the vaccine as well — can you see why it is the same logic?  Just imagine it spreading out like stones on a Go board.

Of course we are not likely to do any of this.  Here is my full Bloomberg column.

Extreme carcinogenic doses for rats

Here is a defense of using those rat tests to judge what will cause cancer in humans:

The "junk science" they are referring to is the long-standing and
well-confirmed practice of identifying chemicals likely to cause cancer
in humans by testing them in animals. The animals (rodents) are a
standard model for biological processes of relevance to humans (which
is why drug companies and medical researchers have been using them for
a century). They are well understood and are the only sentinels for
detecting carcinogenicity of any use to public health. Since chemically
induced cancer has a latency period of decades (typically 20 years or
more), waiting for it to appear in human populations would meant that
once detected, even if exposure would cease instantly (which can never
happen), it would take another 20 or more years to eliminate the
cancers from exposure (all the cancers induced in the 20 years exposure
prior to detection). But even then, the chances of detecting any but
the most powerful carcinogens in human populations (via epidemiology)
is small. Epidemiology is a very insensitive tool. I say this with some
authority, as I am a cancer epidemiologist specializing in chemical
exposures and have authored numerous peer reviewed studies in that area
over many years.

The main rhetorical lever ACSH employs is the
use of high doses in the animal studies, doses that are much higher
than usually faced by humans. But as ACSH knows well (but didn’t
divulge) there is a technical requirement for using these doses. If one
were to use doses in animals predicted to cause cancer at a rate we
would consider a public health hazard, we would need tens of thousands
of animals to test a single dose, mode of exposure and rodent species
or strain. This makes using those doses infeasible. Thus a Maximum
Tolerated Dose is used, one that causes no other pathology except
possibly cancer and doesn’t result in more than a 10% weight loss. The
assumption here is that something that causes cancer at high doses in
these animals will also do so at low doses. This is biologically
reasonable. It is a (surprising) fact, that most chemicals, given in no
matter how high a dose, won’t cause the very unusual and specific
biological effect of turning an animal cell cancerous. Cancer cells are
not "damaged" cells in the individual sense but "super cells," capable
of out competing normal cells. It is only in the context of the whole
organism that there is a problem. It is not surprising, then, that very
few chemicals would have be ability to turn a normal cell into a
biological super cell of this type. Estimates are that is far less than
10%, perhaps only 1% of all chemicals that have this ability. Thus
western industrial civilization doesn’t have to come to a screeching
halt if we eliminate industrial chemical carcinogens from our
environment.

We know of no false negatives with this process.
Every chemical we know that causes cancer in humans also does so in
rodents (with the possible exception of inorganic trivalent arsenic,
which is equivocal).

Here is the full post.  I’m not close to having the expertise to evaluate these claims, but two points.  First, the author is highly qualified; as a blogger he is anonymous but I can vouch for his credentials.  Second, it should be the self-appointed task of bloggers to pass along arguments which either struck them or which might shake up their readers.

We Will Get to Herd Immunity in 2021…One Way or Another

By July it will all be over. The only question is how many people have to die between now and then?

Youyang Gu, whose projections have been among the most accurate, projects that the United States will have reached herd immunity by July, with about half of the immunity coming from vaccinations and half from infections. Long before we reach herd immunity, however, the infection and death rates will fall. Gu is projecting that by March infections will be half what they are now and by May about one-tenth the current rate. The drop will catch people by surprise just like the increase. We are not good at exponentials. The economy will boom in Q2 as infections decline.

If that sounds good bear in mind that 400,000 people are dead already and the CDC expects another 100,000 dead by February. We have a very limited window in the United States to make a big push on vaccines and we are failing. We are failing phenomenally badly.

To understand how bad we are failing compare with flu vaccinations. Every year the US gives out about 150 million flu vaccinations within the space of about 3 months or 1.6 million shots a day. Thus, we vaccinate for flu at more than twice the speed we are vaccinating for COVID! Yes, COVID vaccination has its own difficulties but this is an emergency with tens of thousands of lives at stake.

I would love it if we mobilized serious resources and vaccinated at Israel’s rate–30% of the population in a month. But if we simply vaccinated for COVID at the same rate as we do for flu we would save thousands of lives and hundreds of billions of dollars in GDP. The comparison with flu vaccinations also reminds us that we don’t necessarily need the National Guard or mass clinics in stadiums. Use the HMOs and the pharmacies!

And let’s make it easier for the pharmacies. It’s beyond ridiculous that we are allowing counties to set their own guidelines for who should be vaccinated first. We need one, or at most 50, set of guidelines and lets not worry so much at people jumping the queue. (The ones jumping the queue are probably the ones who want to get back to the bars and social life the most so vaccinating them first has some side benefits.)

Of course, the faster we vaccinate the more vaccine quantities will become the binding constraint which is why we also need to approve more vaccines, move to First Doses First (delay second doses like the British), and use Moderna half-doses. Fire on all cylinders!

Time is of the essence.

Hat tip: Kevin Bryan and Witold Wiecek.

Thursday assorted links

No Learning Without Risk

Here’s something from a paper that I am working on. The context is why first doses first makes more sense the greater the uncertainty but the point made is larger. No indent.

An important feature of First Doses First (FDF) and other policies such as fractional dosing is that they are reversible. In other words, FDF contains an option to switch back to Second Doses First (SDF). Options increase in value with uncertainty (Dixit and Pindyck 1994). Thus, contrary to many people’s intuitions, the greater the uncertainty the greater the value of moving to First Doses First. Indeed, the value of the option can be so high that one might want to move to First Doses First even if it were worse in expectation. For example, if the expected efficacy of the first dose were just 45% then in expectation it would be worse than Second Doses First (95% efficacy) but if there were lots uncertainty around the 45% expected efficacy it might still be better to switch to First Doses First. If there was a 75% chance that the efficacy of the first dose was 30%, for example, and a 25% chance that it was 90% (.75*.3+.25*.90=45%) then under reversibility one would still want to switch to First Doses First to learn whether the true efficacy was 30% or 90%.*

Put differently shifting away from the default strategy to an alternative such as FDF or fractional dosing might be considered to be “risky”. But in this context, learning requires risk. When learning is desirable, it is also desirable to take on risk. Risk aversion can prevent learning and thus can be dangerous.

If FDF is worse in expectation than SDF then it would be optimal to switch to the most minimal form of FDF necessary to learn about the true efficacy rate. In other words, to run an experiment. If FDF is superior in expectation to SDF then it might also be better to run an experiment before switching but not necessarily. If FDF is superior in expectation to SDF then the cost of running the experiment is keeping the policy with lower expected value while the experiment is running. If these costs are high then switching immediately is better.

It would take at least 16 weeks, for example, to run an experiment on extending dosing from 3 weeks to 12 weeks (including, optimistically, just 1 week to setup the experiment). As of early January 2021, confirmed cases in the United States are increasing at the rate of 200,000 per day or 1,400,000 per week. Thus there could be 22,400,000 new confirmed cases in the time it takes to run the experiment. At a case fatality rate of 1.7% that means 380,800 new deaths. If First Doses First reduces the infection rate in expectation by 10% that would imply that running the experiment has an expected cost of 38,080 lives.

At these rates, more lives could be saved in expectation by switching to the policy with higher expected value and simultaneously running experiments. Randomized trials that explicitly test the impact of dosing timing, fractional dosing and different timings of additional doses on severe, symptomatic and asymptomatic infections, and also on transmission should be incorporated as part of roll-out plans (Kominers and Tabarrok 2020, Bach 2021). However, roll-out of modified plans should not wait until these trial results are known; instead, plans should be adjusted as new information emerges. Most notably the British moved to First Doses First and they approved the AstaZeneca vaccine on December 30, 2020 and the consequences of both of these decisions should be monitored very closely to help improve decisions in other countries.

*This assumes that one could learn the true efficacy rate quickly enough relative to the ongoing pandemic to benefit from the new information. One might respond that in principle SDF also contains an option to switch to FDF but this option is valueless since Second Doses First provides no opportunity to learn. Only under First Doses First do we learn valuable new information.