Results for “first doses”
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The Big Push: A Plan to Accelerate V-Day

In the Washington Post I have an extensive piece on accelerating progress to V-day, Vaccine or Victory day, the day everyone who wants a vaccine has gotten one. I cover themes that will be familiar to MR readers, including First Doses First, Fractional Dosing, Approving More Vaccines and DePrioritization to Expand Delivery. I won’t belabor these points here but the piece is useful at collecting all the arguments in one place and there are lots of authoritative links.

One point I do want to make is that all the pieces of the “Tabarrok plan,” if  you will, fit together. Namely, use First Doses First to make a big push to get as many people vaccinated with first doses as possible in the next 90 days. Approve more vaccines including Johnson & Johnson, AstraZeneca and others and make them available to anyone, anywhere–that is possible because these vaccines don’t require significant cold storage, J&J is a single shot and AZ is better with a second shot at 12 weeks or later all of which eases distribution.

…some people argue that adding a third (or fourth) vaccine might not help because of persistent delivery logjams at the state and local levels. But we know there is unused distributional capacity, even for the supply we do have. The United States is currently administering about 1.5 million coronavirus vaccine shots per day. While that sounds like a lot, for comparison consider that in September — during the pandemic, when social distancing measures were in full effect — we vaccinated for the seasonal flu in some weeks at the rate of 3 million people a day.

There are two main reasons the rollout has been so slow. First, the Moderna and especially the Pfizer vaccines require ultracold storage. (The Johnson & Johnson and AstraZeneca doses can be stored at ordinary refrigerator temperatures.) Second, we have tried to prioritize vaccinations using a confusing mishmash of age, health conditions and essential-worker status that differs by state and sometimes even by county. “Confirming such criteria is complicated at best, and it’s probably not even feasible to try under conditions of duress,” as Baylor’s Hotez puts it.

Arguments continue about prioritization lists, and the idea of tossing them entirely would cause a political fight. But there is a compromise at hand: Quickly approve the Johnson & Johnson and AstraZeneca vaccines and make them — and only them — available to anyone, anywhere. Keeping things simple is a sure way to increase total vaccinations. With no cold-storage requirement, the new vaccines could be administered by any of the 300,000 pharmacists and more than 1 million physicians in the United States authorized to deliver vaccines, most of whom are not now giving Pfizer or Moderna shots.

Canada Needs a New Vaccination Strategy

The US vaccination rollout has been deadly slow, inefficient, and chaotic. It has also been one of the best in the world. Canada, for example, is far behind the US on vaccination.

The Canadian deficit is mostly because they don’t have enough vaccine. Canada bought doses but they didn’t invest in capacity and a deal with China fell through. As a result, Canada won’t be getting lots of vaccine until March or April. Operation Warp Speed invested billions in the Modern vaccine and in early purchases of the Pfizer vaccine and thus got first dibs. The Americans are also not allowing vaccine to be exported to Canada. (We could at least give them access to our AstraZeneca factory!).

Regardless of blame, this puts Canada in a precarious situation. Death rates aren’t as high as in the United States but with new variants exploding, Canada is running a big risk. To get Canadians vaccinated more quickly–including my mother–Canada needs to find ways to stretch their vaccine supply–that means First Doses First, half dosing, intradermal delivery and other dose stretching strategies should be considered.

Many other countries are in a much more worse position than either the United States or Canada.

Had Covid? You May Need Only One Dose

The barriers are breaking. Step by step we move closer to First Doses First. New results from a small-scale study suggest that people who have had COVID have strong reactions to the first dose and may not need the second dose.

NYTimes: Based on these results, the researchers say, people who have had Covid-19 may need only one shot.

“I think one vaccination should be sufficient,” said Florian Krammer, a virologist at the Icahn School of Medicine at Mount Sinai and an author on the study. “This would also spare individuals from unnecessary pain when getting the second dose and it would free up additional vaccine doses.”

…People who have had Covid seem to be “reacting to the first dose as if it was a second dose,” said Akiko Iwasaki, an immunologist at the Yale School of Medicine. So one dose is probably “more than enough,” she said.

A study published earlier this month reported that surviving a natural infection provided 83 percent protection from getting infected again over the course of five months. “Giving two doses on top of that appears to be maybe overkill,” she added.

So for the 25 million to 100 million Americans who have already been infected by COVID it may be better for them personally to delay the second dose. In short, a significant fraction of second doses have little to no value. This (unsurprising) finding means that First Doses First is an even better strategy even if we can’t condition doses on previous infection.

Most important, First Doses First gets more people significant immunity faster which is good for the vaccinated and also drives down R which is good for society as a whole, even the unvaccinated.

The Biden administration has been more pro-active than the Trump administration on tests and vaccination and has already made some goods calls on getting more doses out faster. I hope they continue to be bold. We need quick, bold, and decisive action.

To Every One Who Has, More Will Be Given

From an email to Fairfax County teachers:

Due to a decrease in vaccine allocation, we are temporarily reducing appointment availability over the coming weeks. Vaccine supply is fluid across the country, and we are matching currently scheduled appointments to anticipated inventory.

We are pleased to share that more than 22,000 Fairfax County Public Schools teachers and employees have already been able to schedule their first shot.  At this time we are honoring those who have current appointments. Should our vaccine supply not be sufficiently replenished, we will suspend initial appointments (first doses) for eligible individuals in 1b and prioritize those who require their second vaccine dose in the weeks to come.

It’s really quite stunning when you think about it.

Hat tip: Max.

Preparing for a Pandemic: Accelerating Vaccine Availability

In Preparing for a Pandemic, (forthcoming AER PP), by myself and a host of worthies including Susan Athey, Eric Budish, Canice Prendergast, Scott Duke Kominers, Michael Kremer and others equally worthy, we explain the model that we have been using to estimate the value of vaccines and to advise governments. The heart of the paper is the appendix but the paper gives a good overview. Based on our model, we advised governments to go big and we had some success but everywhere we went we were faced with sticker shock. We recommended that even poor countries buy vaccines in advance and that high-income countries make large investments in vaccine capacity of $100b or more in total.

It’s now obvious that we should have spent more but the magnitudes are still astounding. The world spent on the order of $20b or so on vaccines and got a return in the trillions! It was hard to get governments to spend billions on vaccines despite massive benefit-to-cost ratios yet global spending on fiscal support was $14 trillion! Even now, there is more to be done to vaccinate the world quickly, but still we hesitate.

I went over the model for Jess Hoel’s class and we also had a spirited discussion of First Doses First and other policies to stretch the vaccine supply.

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.

Be Prepared! Sars-COV-3

The federal government was unprepared for the pandemic, despite multiple, loud and clear warnings. State and local governments were unprepared for vaccines, despite multiple, loud and clear warnings. The Capitol Police were unprepared for rioters, despite multiple, loud and clear warnings.

The record isn’t good but as a Queen’s Scout I persist. We now have multiple, loud and clear warnings that new variants of the SARS-COV II virus are more transmissible and thus much more dangerous. But we can do something. As wrote in The New Strain and the Need for Speed

One of the big virtues of mRNA vaccines is that much like switching a bottling plant from Sprite to 7-Up we could tweak the formula and produce a new vaccine using exactly the same manufacturing plants. Moreover, Marks and Hahn at the FDA have said that the FDA would not require new clinical trials for safety and efficacy just smaller, shorter trials for immune response (similarly we don’t do new large-scale clinical trials for every iteration of the flu vaccine.) Thus, if we needed it, we could modify mRNA vaccines (not other types) for a new variant in say 8-12 weeks.

Thus, let’s start doing much more sequencing to discover new strains–and also think about potential new strains–and start phase I and phase II trials of new vaccines. Florian Krammer suggested an even more ambitious plan to do the same thing for all potential pandemic viruses:

From each of the identified virus families, which should certainly include the Paramyxoviridae, Orthomyxoviridae, and Coronaviridae families, a handful of representative strains with the highest pandemic potential should be selected for vaccine production. Up to 50–100 different viruses could be selected and this would broadly cover all phylogenies that may give rise to pandemic strains….It should be possible to choose candidates that are close to viruses that might emerge in the human population. The idea is that once viruses are selected, vaccines can be produced in different platforms and tested in phase 1 and phase 2 trials with some of the produced vaccine being stockpiled. This would likely cost 20–30 million US dollars per vaccine candidate resulting in a cost of 1–3 billion US dollars.

What I am suggesting is less ambitious–just do this for Sars-COV-3, 4, 5 and 6. But do it now!

Hat tip: Daniel Bier.

Broken Record Addendum: We should make better use of our limited vaccine supply by moving to First Doses First and/or fractional dosing and approve the AstraZeneca vaccine immediately and spend billions to increase the rate of vaccinations and to speed new vaccines (such as those from J&J and Novavax) to market.

Wednesday assorted links

1. How to run a simple and fairly quick clinical trial on First Doses First.  It is funny how you do not hear the critics suggest the merits of further investigation.

2. “American Chess Magazine Releases Their List of the Top 1 Shows of 2020.”  You should not need to click on the link.

3. The redone Joshua Gans calculations (great praise to him for trying to put numbers on everything) now favor a policy of First Doses First.  And another useful model supporting First Doses First.  The silence on the other side of the debate is deafening.

4. Is peer-reviewed work increasingly boring?

5. Making policy for a low-trust world (so far the year’s best short essay).

6. Hail Palau, it might soon have all its people vaccinated.

The AstraZeneca Factory in Baltimore

Emergent BioSolutions has a factory in Baltimore that operates under an innovative long-term private-partnership agreement with BARDA. Essentially BARDA subsidized the factory in return for an option to use it in an emergency–Operation Warp Speed exercised that option and in June-July AstraZeneca signed a licensing agreement with Emergent for large-scale manufacturing of its vaccine.

According to the Baltimore Sun the AZ vaccine is already being made at the facility. I hope they are making millions of doses. I want the AZ vaccine approved in the United States immediately but if we won’t take it (yet) they can still export it to Britain and the many other countries which will approve the vaccine.

More generally, there are three vaccines in the near term pipeline. AstraZeneca, Johnson and Johnson and Novavax. If there is anything that we can do to speed these vaccines to people it would be worth billions. All of these vaccine manufacturers should be making and storing millions of doses now.

It’s important to understand that a policy like First Doses First works best when capacity is increasing rapidly so approving these additional vaccines is part of an integrated plan.

Here’s the factory in Baltimore. It’s capable of producing tens to hundreds of millions of vaccine doses a year. Isn’t it beautiful?

AstraZeneca’s coronavirus vaccine candidate is being manufactured at Emergent BioSolutions' facility in East Baltimore, shown in a 2017 photo.
The factory is ready to go. Are we?

Addendum: One more thing. Stop telling me that the problem is vaccine distribution not supply. Guess what? I am thinking ahead.

Hail Britannia!

The British approved the Pfizer vaccine, they approved the AstraZeneca vaccine, they moved to first doses first and now they are allowing (not yet encouraging they are running a trial) mix and match. Under the present circumstances, the British focus on doing what it takes to save lives is smart, admirable, and impressive.

As I wrote on Dec. 10, in Herd Immunity is Herd Immunity:

Mix and matching has two potentially good properties. First, mix and matching could make the immune system response stronger than either vaccine alone because different vaccines stimulate the immune system in different ways. Second, it could help with distribution. It’s going to be easier to scale up the AZ vaccine than the mRNA vaccines, so if we can use both widely we can get more bang for our shot.

Addendum: The CDC is projecting 80,000 COVID deaths in the United States over the next three weeks.

The New Strain and the Need for Speed

I was going to write a long blog post on the new strain but Zeynep Tufekci has written an excellent piece for The Atlantic. I will quote from it and add a few points.

One of the big virtues of mRNA vaccines is that much like switching a bottling plant from Sprite to 7-Up we could tweak the formula and produce a new vaccine using exactly the same manufacturing plants. Moreover, Marks and Hahn at the FDA have said that the FDA would not require new clinical trials for safety and efficacy just smaller, shorter trials for immune response (similarly we don’t do new large-scale clinical trials for every iteration of the flu vaccine.) Thus, if we needed it, we could modify mRNA vaccines (not other types) for a new variant in say 8-12 weeks. As Zeynep notes, however, the vaccines are very likely to work well for the new variant. It’s nice to know, however, that we do have some flexibility.

The real worry is not that the vaccines won’t work but that we won’t get them into arms fast enough. We were already going too slow but in a race against the new more transmissible variant we are looking like tortoises.

A more transmissible variant of COVID-19 is a potential catastrophe in and of itself. If anything, given the stage in the pandemic we are at, a more transmissible variant is in some ways much more dangerous than a more severe variant. That’s because higher transmissibility subjects us to a more contagious virus spreading with exponential growth, whereas the risk from increased severity would have increased in a linear manner, affecting only those infected.

Here’s a key example from epidemiologist Adam Kucharski:

As an example, suppose current R=1.1, infection fatality risk is 0.8%, generation time is 6 days, and 10k people infected (plausible for many European cities recently). So we’d expect 10000 x 1.1^5 x 0.8% = 129 eventual new fatalities after a month of spread. What happens if fatality risk increases by 50%? By above, we’d expect 10000 x 1.1^5 x (0.8% x 1.5) = 193 new fatalities.

Now suppose transmissibility increases by 50%. By above, we’d expect 10000 x (1.1 x 1.5)^5 x 0.8% = 978 eventual new fatalities after a month of spread.

the key message: an increase in something that grows exponentially (i.e. transmission) can have far more effect than the same proportional increase in something that just scales an outcome (i.e. severity).

I argued that the FDA should have approved the Pfizer vaccine, on a revocable basis, as soon as the data on the safety and efficacy of its vaccine were made available around Nov. 20. But the FDA scheduled it’s meeting of experts for weeks later and didn’t approve until Dec. 11, even as thousands of people were dying daily. We could have been weeks ahead of where we are today. Now the epidemiologists are telling us that weeks are critical. As Zeynep notes holding back second doses looks like a clear mistake and the balance of the evidence also suggests we should move to first doses first:

All this means that the speed of the vaccine rollout is of enormous importance.

…Meanwhile, the United States was reportedly planning to hold back half the vaccine it has in freezers as a hedge against supply-chain issues, and some states may be slowed down by murky prioritization plans. Scott Gottlieb—the former FDA chief and a current board member of Pfizer—has argued that the U.S. should also go ahead with vaccinating as many people as possible right now and trust that the supply chain will be there for the booster. Researchers in Canada—where some provinces decided to vaccinate now as much as possible without holding half in reserve, and will administer the booster with future supplies—estimate that this type of front-loading can help “avert between 34 and 42 per cent more symptomatic coronavirus infections, compared with a strategy of keeping half the shipments in reserve.” (Note that this strategy, which is different from the one the United Kingdom just announced it will adopt in prioritizing the first dose, does not even necessarily involve explicitly changing booster timing protocols in order to maximize vaccination now; it just means not waiting to get shots into arms when the vaccines are currently available.) These were already important conversations to have, but given the threat posed by this new variant, they are even more urgent.

Perhaps most critically, the FDA should approve the AstraZeneca vaccine if not as part of Operation Warp Speed then on a right to try basis. We need every weapon in the arsenal. How many times must we learn not to play with exponential matches?

Addendum: See also this excellent Miles Kimball post, How Perfectionism Has Made the Pandemic Worse.

Wise Canadians

On December 12 I wrote:

We should vaccinate 6 million people with first dose NOW. It is deadly cautious to hold second dose in *reserve*. Supply chain will be ok and the exact timing of the second dose is not magical and likely not critical.

Modelling by a group at the University of Toronto confirmed.

Ashleigh Tuite, an epidemiologist at U of T’s Dalla Lana School of Public Health….said she and her colleagues projected that frontloading vaccine doses would avert between 34 and 42 per cent more symptomatic coronavirus infections, compared with a strategy of keeping half the shipments in reserve.

“It makes much more sense to just get as many people their first doses as soon as possible,” Dr. Tuite said.

…everyone should get the second dose on schedule, but if supply issues delay that injection by a week or two, it shouldn’t hamper how well the vaccines work.

According to Abigail Bimman at Global News, Ontario will now switch to getting as many first doses out as possible:

NEW: Ontario is changing its vaccine policy and no longer reserving second doses, but getting all of the initial 90k out the door- they expect to finish them in the “next several days” – Health Minister’s office tell @globalnew. Change due to confidence in supply chain.

It’s not all the way to first doses first but it’s a minimally risky, smart move. Indeed, Nova Scotia, Saskatchewan and British Columbia already have said that they won’t hold back first doses.

The United States should listen to the wise Canadians.

Double the Inoculated Population with One Dose

I’ve been arguing that we should delay the second dose (or at least not hold back first doses) in order to hit the virus hard and inoculate more people on the first dose. I wrote:

We should vaccinate 6 million people with first dose NOW. It is deadly cautious to hold second dose in *reserve*. Supply chain will be ok and the exact timing of the second dose is not magical and likely not critical. In the accidental low-dose, standard-dose regime for the AZ vaccine, people got the second dose 7 to 8 weeks after the first dose and that was the 90% efficacious regime. [A different vaccine obviously but ] Exact timing of the second-dose does not seem critical, although everyone should get a second dose.

Today epidemiologist Michael Mina and writer Zeynep Tufekci, who has been ahead of the curve on much of the discussion, make the case even more strongly in the NYTimes:

First, the science. While the vaccine trials were designed to evaluate a two-dose regimen, some immunity might be acquired before a second dose is administered. We know, for instance, that a Covid-19 infection appears to yield protection for at least six months. While infections are not vaccinations, and while we need more data on this, it’s plausible that the immunity gained from a vaccination may turn out to be even stronger than what comes from an infection. The reason we do a second — booster — vaccination is that these later doses help to solidify immune memory, in part by giving extra training to the cells that produce antibodies, a process called affinity maturation. But this process begins with the single dose, and the evidence collected between the time of the first and second doses in tens of thousands of people in the Phase 3 trials suggests that the level of affinity maturation may provide enough protection to meet the standards we have set for vaccine approval during this pandemic even without the second dose.

While we know that the single dose can protect against disease, we don’t yet know how long this immune protection will last, and at what level. However, there is no rule that says that vaccines must be boosted within weeks of each other. For measles, the booster dose is given years after the first dose. If the booster dose could be given six months or a year after the first dose, while maintaining high efficacy before the second dose, that would allow twice as many people to get vaccinated between now and later next year, accelerating herd immunity — greatly helping end the crisis phase of the pandemic in the United States.

… we should begin immediate single-dose trials, recruiting volunteers from low-risk populations who are first in line for the vaccinations. For example, among health care workers protective equipment works, rates of infection among this group have fallen sharply and severe disease is much more rare.Younger essential workers without risk factors are less likely to be severely affected if they are exposed since this disease’s impact rises steeply with age. Just as tens of thousands of people volunteered for the earlier vaccine trials, many may well volunteer to test a placebo against a second dose, allowing us to quickly ascertain questions of durability and effectiveness of the single dose.

Two additional points. First, mix and match, as I argued earlier, may be beneficial:

…we could mix and match vaccines. The UK will run a trial on this question. Mix and matching has two potentially good properties. First, mix and matching could make the immune system response stronger than either vaccine alone because different vaccines stimulate the immune system in different ways. Second, it could help with distribution. It’s going to be easier to scale up the AZ vaccine than the mRNA vaccines, so if we can use both widely we can get more bang for our shot.

Second, an economics issue. If we want Pfizer and Moderna on board we need to pay them not just to run the clinical trials but to be happy with potentially selling half as many doses. Incentives matter.