Results for “half doses” 45 found
Half Doses of Pfizer Work Well
New paper published in Vaccines from Polish group showing that half doses of Pfizer generate strong immune responses.
In the context of the ongoing COVID-19 pandemic, using a half-dose schedule vaccination can help to return to normalcy in a cost-efficient manner, which is especially important for low and middle-income countries. We undertook a study to confirm that in adults up to 55 years old, the humoral response to the half-dose (15 µg, 35 participants between 18 and 55 years old) and to the recommended dose (30 µg, 155 participants) in the two-dose three-week interval schedule would be comparable. Antibody levels were measured by the Elecsys Anti-SARS-CoV-2 S assay (Roche Diagnostics, upper detection limit: 2570 BAU/mL) on the day of dose 2 of the vaccine and then 8–10 days later to assess peak response to dose 2. The difference in proportions between the participants who did and did not exceed the upper detection limit 8–10 days after dose 2 was not statistically significant (p = 0.152). We suggest that a half-dose schedule can help to achieve widespread vaccination coverage more quickly and cheaply.
See my previous piece A Half Dose of Moderna is More Effective Than a Full Dose of AstraZeneca.
Half Doses of Moderna Produce Neutralizing Antibodies
A new phase II study from Moderna shows that half-doses (50 μg) appear to be as good as full doses (100 ug) at generating correlates of protection such as neutralizing antibodies.
In this randomized, controlled phase 2 trial, the SARS-CoV-2 vaccine candidate mRNA-1273, administered as a two-dose vaccination regimen at 50 and 100 μg, exhibited robust immune responses and an acceptable safety profile in healthy adults aged 18 years and older. Local and systemic adverse reactions were mostly mild-to-moderate in severity, were ≤4 days of median duration and were less commonly reported in older compared with younger adults. Anti-SARS-CoV-2 spike binding and neutralizing antibodies were induced by both doses of mRNA-1273 within 28 days after the first vaccination, and rose substantially to peak titers by 14 days after the second vaccination, exceeding levels of convalescent sera from COVID-19 patients. The antibodies remained elevated through the last time point assessed at 57 days. Neutralizing responses met criteria for seroconversion within 28 days after the first vaccination in the majority of participants, with rates of 100% observed at 14 and 28 days after the second vaccination. While no formal statistical testing was done, binding and neutralizing antibody responses were generally comparable in participants who received the 100 μg mRNA-1273 and the 50 μg dose at all time points and across both age groups. Overall, the results of this randomized, placebo-controlled trial extend previous immunogenicity and safety results for mRNA-1273 in the phase 1 study in an expanded cohort including participants older than 55 years of age [16, 19].
[These data] confirm that a robust immune response is generated at both 50 and 100 ug dose levels.
As I wrote earlier, halving the dose is equivalent to instantly doubling the output of every Moderna factory.
See my piece in the Washington Post on getting to V-day sooner for an overview of dose stretching strategies.
Addendum: France says one dose is sufficient for previously COVID infected.
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.
They had better hurry up and distribute those AstraZeneca doses
Movement data from last weekend show Melburnians engaging in what experts have called thousands of small transgressions with the potential to drive COVID-19 infections higher, as the effect of 200 days of lockdown takes an emotional toll.
Google mobility data compiled by The Age reveals that across the state last Friday and Saturday, people were moving more than at any time since mid-July last year when complacency prompted Premier Daniel Andrews to plunge the state into stage-four lockdown and mandatory mask-wearing.
Last weekend saw a spate of breaches including an organised takeaway pub crawl in Richmond and an engagement party in Caulfield North attended by 69 guests. The couple involved in the illegal party have received $5400 fines. Two of their parents were also fined and other guests are being interviewed.
Some metropolitan municipalities including Glen Eira and Bayside recorded their highest lockdown movement levels last week, ahead of a number of mystery cases appearing in St Kilda.
Professor Mike Toole from Melbourne’s Burnet Institute, who lives in a mobility hotspot in the inner south, said he was shocked to witness large groups of people gathering in parks at the weekend.
Here is the full article, via Rich Dewey. And the Sydney lockdown is now extended until the end of September, with masks mandated for outside as well. Elsewhere:
Walmart, Target and Lowe’s, by contrast, all lifted sales forecasts this week after beating expectations for the three months to the end of July. While demand for toilet paper and cleaning supplies has cooled after 2020s pantry hoarding, the appetite for other products was broad-based. Party supplies, apparel and travel gear flew off Walmart’s shelves. At Home Depot, an early cache of Halloween decorations sold out almost immediately. Swimsuits and children’s clothing were similarly popular at Target and, in another sign of confidence, more customers returned to Walmart and Target store aisles after a year of browsing online.
Here is the associated FT article. Which set of values do you prefer? Which do most people prefer?
A Half Dose of Moderna is More Effective Than a Full Dose of AstraZeneca
Today we are releasing a new paper on dose-stretching, co-authored by Witold Wiecek, Amrita Ahuja, Michael Kremer, Alexandre Simoes Gomes, Christopher M. Snyder, Brandon Joel Tan and myself.
The paper makes three big points. First, Khoury et al (2021) just published a paper in Nature which shows that “Neutralizing antibody levels are highly predictive of immune protection from symptomatic SARS-CoV-2 infection.” What that means is that there is a strong relationship between immunogenicity data that we can easily measure with a blood test and the efficacy rate that it takes hundreds of millions of dollars and many months of time to measure in a clinical trial. Thus, future vaccines may not have to go through lengthy clinical trials (which may even be made impossible as infections rates decline) but can instead rely on these correlates of immunity.
Here is where fractional dosing comes in. We supplement the key figure from Khoury et al.’s paper to show that fractional doses of the Moderna and Pfizer vaccines have neutralizing antibody levels (as measured in the early phase I and phase II trials) that look to be on par with those of many approved vaccines. Indeed, a one-half or one-quarter dose of the Moderna or Pfizer vaccine is predicted to be more effective than the standard dose of some of the other vaccines like the AstraZeneca, J&J or Sinopharm vaccines, assuming the same relationship as in Khoury et al. holds. The point is not that these other vaccines aren’t good–they are great! The point is that by using fractional dosing we could rapidly and safely expand the number of effective doses of the Moderna and Pfizer vaccines.
Second, we embed fractional doses and other policies such as first doses first in a SIER model and we show that even if efficacy rates for fractional doses are considerably lower, dose-stretching policies are still likely to reduce infections and deaths (assuming we can expand vaccinations fast enough to take advantage of the greater supply, which is well within the vaccination frontier). For example, a half-dose strategy reduces infections and deaths under a variety of different epidemic scenarios as long as the efficacy rate is 70% or greater.
Third, we show that under plausible scenarios it is better to start vaccination with a less efficacious vaccine than to wait for a more efficacious vaccine. Thus, Great Britain and Canada’s policies of starting First Doses first with the AstraZeneca vaccine and then moving to second doses, perhaps with the Moderna or Pfizer vaccines is a good strategy.
It is possible that new variants will reduce the efficacy rate of all vaccines indeed that is almost inevitable but that doesn’t mean that fractional dosing isn’t optimal nor that we shouldn’t adopt these policies now. What it means is that we should be testing and then adapting our strategy in light of new events like a battlefield commander. We might, for example, use fractional dosing in the young or for the second shot and reserve full doses for the elderly.
One more point worth mentioning. Dose stretching policies everywhere are especially beneficial for less-developed countries, many of which are at the back of the vaccine queue. If dose-stretching cuts the time to be vaccinated in half, for example, then that may mean cutting the time to be vaccinated from two months to one month in a developed country but cutting it from two years to one year in a country that is currently at the back of the queue.
Read the whole thing.
The Becker-Friedman center also has a video discussion featuring my co-authors, Nobel prize winner Michael Kremer and the very excellent Witold Wiecek.
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? — 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.
Most Popular MR Posts of the Year!
As measured by page views here are the most popular MR posts of 2021. Coming in at number 10 was Tyler’s post:
10. Best non-fiction books of 2021
Lots of good material there and well worth revisiting. Number 9 was by myself:
9. Revisionism on Deborah Birx, Trump, and the CDC
TDS infected many people but as the Biden administration quickly discovered the problems were much deeper than the president, leading to revisionism especially on the failures of the CDC and the FDA. Much more could be written here but this was a good start.
Number 8 was Tyler’s post:
8. The tax on unrealized capital gains
which asked some good questions about a bad plan.
7. We Will Get to Herd Immunity in 2021…One Way or Another
Sadly this post, written by me in January of 2021, had everything exactly right–we bottomed out at the end of June/early July as predicted. But then Delta hit and things went to hell. Sooner or later the virus makes fools of us all.
6. Half Doses of Moderna Produce Neutralizing Antibodies
One of my earlier pieces (written in Feb. 21) on fractional dosing. See also my later post A Half Dose of Moderna is More Effective Than a Full Dose of AstraZeneca. We have been slow, slow, slow. I hope for new results in 2022.
5. A few observations on my latest podcast with Amia Srinivasan
Listener’s took umbrage, perhaps even on Tyler’s behalf, at Srinivasan but Tyler comes away from every conversation having learned something and that makes him happy.
4. The Most Impressive AI Demo I Have Ever Seen
Still true. Still jaw-dropping.
3. Patents are Not the Problem!
I let loose on the Biden administration’s silly attacks on vaccine patents. Also still true. Note also that as my view predicts, Pfizer has made many licensing deals on Paxalovid which has a much simpler and easier to duplicate production process (albeit raw materials are still a problem.)
2. A Nobel Prize for the Credibility Revolution
A very good post, if I don’t say so myself, on this year’s Nobel prize recipients, Card, Angrist and Imbens.
1. How do you ask good questions?
Who else but Tyler?
To round out the top ten I’d point to Tyler’s post John O. Brennan on UFOs which still seems underrated in importance even if p is very low.
Erza Klein’s profile of me still makes me laugh, “He’s become a thorn in the side of public health experts…more than one groaned when I mentioned his name.” Yet, even though published in April many of these same experts are now openly criticizing the FDA and the CDC in unprecedented ways.
UFOs going mainstream or Tabarrok’s view of the FDA going mainstream. I’m not sure which of these scenarios was more unlikely ex ante. Strange world.
Let us know your favorite MR posts in the comments.
Use Fractional Dosing to Speed Vaccination and Save Lives
I’ve been shouting about fractional dosing since January, most recently with my post A Half Dose of Moderna is More Effective Than a Full Dose of AstraZeneca and the associated paper with Michael Kremer and co-authors. Yesterday we saw some big movement. Writing in Nature Medicine, WHO epidemiologists Benjamin Cowling and Wey Wen Lim and evolutionary biologist Sarah Cobey title a correspondence:
Fractionation of COVID-19 vaccine doses could extend limited supplies and reduce mortality.
Exactly so. They write:
Dose-finding studies indicate that fractional doses of mRNA vaccines could still elicit a robust immune response to COVID-192,3. In a non-randomized open-label phase 1/2 trial of the BNT162b2 vaccine, doses as low as one third (10 μg) of the full dose produced antibody and cellular immune responses comparable to those achieved with the full dose of 30 μg (ref. 4). Specifically, the geometric mean titer of neutralizing antibodies 21 days after the second vaccine dose was 166 for the group that received 10 μg, almost the same as the geometric mean titer of 161 for the group that received 30 μg, and 63 days after the second dose, these titers were 181 and 133, respectively4. For the mRNA-1273 vaccine, a dose of 25 μg conferred geometric mean PRNT80 titers (the inverse of the concentration of serum needed to reduce the number of plaques by 80% in a plaque reduction neutralization test) of 340 at 14 days after the second dose, compared with a value of 654 for the group that received the standard dose of 100 μg (ref. 5). According to the model proposed by Khoury et al.6, if vaccine efficacy at the full dose is 95%, a reduction in dose that led to as much as a halving in the post-vaccination geometric mean titer could still be in the range of 85–90%. Although other components of the immune response may also contribute to efficacy, these dose-finding data are at least indicative of the potential for further exploration of fractionation as a dose-sparing strategy. Durability of responses after fractional doses should also be explored.
…Concerns about the evolution of vaccine resistance have been posited as a potential drawback of dose-sparing strategies. However, vaccines that provide protection against clinical disease seem to also reduce transmission, which indicates that expanding partial vaccination coverage could reduce the incidence of infection. As described in a recent paper, lower prevalence should slow, not accelerate, the emergence and spread of new SARS-CoV-2 variants8.
…In conclusion, fractionated doses could provide a feasible solution that extends limited supplies of vaccines against COVID-19, which is a major challenge for low- and middle-income countries.
Also a new paper in preprint just showed that 1/4 doses of Moderna create a substantial and lasting immune response on par with that from natural infection.
Here we examined vaccine-specific CD4+ T cell, CD8+ T cell, binding antibody, and neutralizing antibody responses to the 25 ug Moderna mRNA-1273 vaccine over 7 months post-immunization, including multiple age groups, with a particular interest in assessing whether pre-existing crossreactive T cell memory impacts vaccine-generated immunity. Low dose (25 ug) mRNA-1273 elicited durable Spike binding antibodies comparable to that of convalescent COVID-19 cases. Vaccine-generated Spike memory CD4+ T cells 6 months post-boost were comparable in quantity and quality to COVID-19 cases, including the presence of TFH cells and IFNg-expressing cells.
Finally, an article in Reuters notes that Moderna are preparing to launch a 50 ug dose regimen as a booster and for children. Thus, contrary to some critics of our paper, the technology is ready.
Frankly, governments are way behind on this–they should have been pushing the vaccine manufacturers and funding trials on alternative dosing since at least January. Indeed, imagine how many lives we might have saved had we listened to Operation Warp Speed advisor Moncef Slaoui who advocated for half doses in January. On a world scale, we could have vaccinated tens even hundreds of millions more people by now had we ramped up fractional dosing.
At this point, it’s my view that there is enough knowledge to justify rolling out alternative dosing in any hot spot or in any country worried about outbreaks. Roll it out in a randomized fashion (as Kominers and I discussed in the context of the US vaccination rollout) to study it in real time but start the roll out now. Lives can be saved if we speed up vaccination, especially of the best vaccines we have, the mRNAs. Moderna and Pfizer have together pledged to deliver (mostly Pfizer and mostly through the US) some 250m vaccine doses to COVAX in 2021 for delivery to less developed countries. If we go to half-doses that becomes 500m doses–a life saver. And recall these points made earlier:
Judging by neutralizing antibodies, a 50 ug dose of, for example, Moderna looks to be more effective than standard dosing of many other vaccines including AZ and J&J and much better than others such as Sinovac. Thus alternative dosing is a way to *increase* the quality of vaccine for many people.
A 50 ug dose vaccine available today is much higher quality than a 100 ug dose vaccine available one year from now.
If we have the will, we can increase vaccine supply very rapidly.
Fractional Dosing Study in Brazil
Fiocruz, the Brazilian public health institute, will test half doses of the AstraZeneca vaccine. Not much information available yet. From a Google Translate article.
BANDNews: Fiocruz, in partnership with the government of Espírito Santo, is going to carry out a study with the application of half a dose of the Astrazeneca vaccine to the entire population of the municipality of Viana, in Greater Vitória.
The city has about 35 thousand inhabitants.
The immunization will take place on Sunday, June 13, and residents will be able to choose whether they want to participate in the study.
According to the state secretary of Health, Nésio Fernandes, there is already evidence of the effectiveness of the application of half a dose of the vaccine in immunization against Covid-19.
If the experience is successful, it will be possible to double the number of people vaccinated in the country with the immunizing agent produced by Fiocruz.
See my previous posts on fractional dosing for why this is very important.
Hat tip: Cisco Costa.
Bigger Is Better When It Comes to Vaccine Production
My co-authors, Eric Budish and Chris Snyder, have an excellent piece in the WSJ:
We recently published a paper in the journal Science that aimed to quantify the enormous value of Covid-19 vaccine capacity: both existing and the value of building more. We worked with a team of economists, statisticians and policy experts led by the University of Chicago’s Michael Kremer.
While vaccines are intuitively very valuable, the numbers are mind-boggling. The value of three billion courses of annual vaccine capacity—enough to vaccinate rich countries by the end of 2021 and the world by the end of 2022—is $17.4 trillion, or $5,800 for every course. This reflects the value of getting people back to work and school, avoiding unnecessary deaths and preserving health. If anything, we suspect our figure is conservative.
We estimate that another billion courses of vaccine capacity is worth $1 trillion of additional global benefits, and could accelerate vaccination by two months for rich countries and five months for the world. This $1 trillion—$1,000 for each additional course—would be much higher if the pandemic takes a turn for the worse—if, say, new variants require fresh vaccination or some vaccine manufacturers hit production snags.
Is it physically possible to build more capacity? We don’t know how much more can be built and how quickly, but the global benefits of capacity—$5,800 for every vaccination course overall, and $1,000 for incremental capacity—far exceed the prices paid to firms in deals to date, between $6 and $40 a course. This means that private incentives are a fraction of the social value at stake.
Private incentives may be particularly poor when it comes to speed. Consider a firm that will vaccinate one billion people at a fixed price of $40 each. The firm earns the same $40 billion whether it supplies the billion courses in a single month or stretched over a year. But doing it in a month requires 12 times the capacity costs. If you are wondering why vaccination is taking so long, this is the basic economic reason.
…The recent announcement that Merck will produce the Johnson & Johnson vaccine is a great example of finding a creative way to build more capacity. We don’t have specific production numbers for this deal. But suppose deals like this one could create an additional 40 million courses a month for the U.S., starting in April. Our analysis suggests that such a capacity increase is worth $136 billion to the U.S. and allows Americans to be vaccinated by June instead of August. If this new capacity is donated to the world after the U.S. is finished using it, it would generate more than $500 billion in total global benefits and accelerate global vaccination by nearly three months.
There are also options for stretching what exists: delaying the second of two doses, giving only one dose to those previously infected, or using lower-dose regimens. If it turns out that half doses are almost as effective as full doses, or a single dose is almost as effective as a two-dose course, capacity would effectively double overnight—which our analysis suggests is worth several trillion dollars.
Market Design to Accelerate Vaccine Supply
Market design to accelerate COVID-19 vaccine supply is my new paper in Science, co-authored with Camilo Castillo, Michael Kremer, Eric Budish, Susan Athey and others. We make three vital 
points. First, governments invested much less than our group advised. We spent trillions on fiscal support and maybe $20 billion or so on vaccines, far too little. Nevertheless, the 3bn courses we have (conservatively) in 2021 capacity is worth on the order of $17.4 trillion or $5800 per course. If advance market commitments moved us from 2 billion to 3 billion courses then they were worth 2.4 trillion dollars. I feel pretty good about the work we did to encourage Operation Warp Speed and other advance purchases.
Second, it’s not too late to do more. If we could get an additional billion courses in capacity online by July 2021 that would speed up vaccination in high-income countries by 1.4 months and in the world by 4.3 months. A few months might not seem like much but that speed-up is worth half a trillion to the world economy. If we could get additional capacity online by April it would be worth a trillion dollars.
You might think that getting more capacity online by April isn’t possible but you can do a lot for a trillion dollars. Moreover, we can increase capacity not just by building more factories but by using the doses we have now more wisely. Low-dose syringes, for example, can increase supplies by 20%. I think the health authorities know this now (although they should have been prepared) but even at this late stage almost everyone is under-estimating how much it would be worth spending to get 20% more vaccine capacity. Similarly, going to half-doses is equivalent to doubling the number of Moderna and Pfizer factories. Even if we did half doses for the young alone, that’s a big increase in supply. We calculate that additional capacity is worth $576 to $989 per annual course, far higher than the price.
Third, we also give advice on how to structure contracts. Buying doses isn’t optimal because companies can just agree and put you to the back of the queue. Optimal rewards and penalties are very difficult to implement, especially when optimal penalties could bankrupt firms many times over (because the social value of vaccines is much greater than the private value.) So it’s much better to subsidize capacity with an option to buy doses at a discount produced from that capacity–this is similar to what Operation Warp Speed did with Moderna and Novavax.
Finally, here’s a fourth important point I haven’t made earlier. We suggest procurement auctions to surface prices on necessary inputs. Ordinarily, an increase in demand to a final producer such as a vaccine manufacturer is transmitted along the entire supply chain through the signaling and incentive mechanism of prices. When final goods prices are limited socially or by law, however, the supply chain can become dis-coordinated. Capacity contracts could be fulfilled, for example, and the producer could yet claim an inability to produce because raw materials are in short supply. Thus, we need a mechanism to coordinate supply chains.The US Defense Production Act is one such mechanism. An alternative procedure that may work more quickly is to organize procurement auctions for all the inputs and complementary goods required for vaccine production. The advantage of a procurement auction is that it can attract and incentivize firms globally, firms that are well beyond the reach of the DPA.
Read the whole thing and the appendix with details on methods and calculations.
How to Double the Number of Moderna and Pfizer Factories
Theory and data both suggest that a much smaller dose–perhaps as low as 1/4 the current dose—of both the Moderna and Pfizer vaccines are as effective as a larger dose. Half doses of Moderna and Pfizer would be equivalent to instantly doubling the number of Moderna and Pfizer factories and would save hundreds of thousands of lives and be worth hundreds of billions of dollars in world GDP. Clinical data from adults 18-55 from the Moderna Phase II trial already suggest that quarter-doses are effective, which is why Operation Warp Speed chief, Moncef Slaoui has advocated for half-doses (leaving plenty of margin).
“We know that, for the Moderna vaccine, giving half of the dose to people between the ages of 18 and 55, two doses [at] half the dose … we know it induces identical immune response” to the currently authorized dose, Slaoui added.
Another way of putting this is that new clinical trials on dosing would be tremendously valuable. Ideally, we could use correlates of protection and do a bridging trial to infer the effectiveness of half-doses. The FDA has already said they will accept a bridging trial for new mRNA vaccines for variants, which is the right decision. The FDA should also accept a bridging trial for new dosing.
If new clinical trials are deemed necessary, dosing trials could be run as challenge trials but instead of comparing half-doses to placebo we would compare full-doses to half-doses. Thus, everyone in the challenge trial would be vaccinated, massively lowering risks. If we can’t do challenge trials even with vaccinated volunteers (!) then let’s get started on clinical trials. The NIH created the ACTIV program to speed clinical trials. Use it.
New clinical trials are valuable not just for dosing but also for approving new vaccines. Equivalence trials on the Sputnik and Sinopharm vaccines, for example, could be very valuable. In other words, we would trial Sputnik and Sinopharm against Pfizer and Moderna. A lot of people would be quite willing to join a trial in which the worst outcome is most likely getting a somewhat less effective vaccine–that’s much better than no vaccine!
The value of experiments, or let’s call them pilot studies, right now is immense. We can do pilot studies on half dosing for Moderna and Pfizer vaccines much faster and cheaper than we can build twice as many factories. So let’s do it!
Dose Optimization Trials Enable Fractional Dosing of Scarce Drugs
During the pandemic, when vaccines doses were scarce, I argued for fractional dosing to speed vaccination and maximize social benefits. But what dose? In my latest paper, just published in PNAS, with Phillip Boonstra and Garth Strohbehn, I look at optimal trial design when you want to quickly discover a fractional dose with good properties while not endangering patients in the trial.
[D]ose fractionation, rations the amount of a divisible scarce resource that is allocated to each individual recipient [3–6]. Fractionation is a utilitarian attempt to produce “the greatest good for the greatest number” by increasing the number of recipients who can gain access to a scarce resource by reducing the amount that each person receives, acknowledging that individuals who receive lower doses may be worse off than they would be had they received the “full” dose. If, for example, an effective intervention is so scarce that the vast majority of the population lacks access, then halving the dose in order to double the number of treated individuals can be socially valuable, provided the effectiveness of the treatment falls by less than half. For variable motivations, vaccine dose fractionation has previously been explored in diverse contexts, including Yellow Fever, tuberculosis, influenza, and, most recently, monkeypox [7–12]. Modeling studies strongly suggest that vaccine dose fractionation strategies, had they been implemented, would have meaningfully reduced COVID-19 infections and deaths [13], and perhaps limited the emergence of downstream SARS-CoV-2 variants [6].
…Confident employment of fractionation requires knowledge of a drug’s dose-response relationship [6, 13], but direct observation of both that relationship and MDSE, rather than pharmacokinetic modeling, appears necessary for regulatory and public health authorities to adopt fractionation [15, 16]. Oftentimes, however, early-phase trials of a drug develop only coarse and limited dose-response information, either intentionally or unintentionally. A speed-focused approach to drug development, which is common for at least two reasons, tends to preclude dose-response studies. The first reason is a strong financial incentive to be “first to market.” The majority of marketed cancer drugs, for example, have never been subjected to randomized, dose-ranging studies [17, 18]. The absence of dose optimization may raise patients’ risk. Further, in an industry sponsored study, there is a clear incentive to test the maximum tolerated dose (MTD) in order to observe a treatment effect, if one exists. The second reason, observed during the COVID-19 pandemic, is a focus on speed for public health. Due to ethical and logistical challenges, previously developed methods to estimate dose-response and MDSE have not routinely been pursued during COVID-19 [19]. The primary motivation of COVID-19 clinical trial infrastructure has been to identify any drug with any efficacy rather than maximize the benefits that can be generated from each individual drug [3, 18, 20, 21]. Conditional upon a therapy already having demonstrated efficacy, there is limited desire on the part of firms, funders, or participants to possibly be exposed to suboptimal dosages of an efficacious drug, even if the lower dose meaningfully reduced risk or extended benefits [16]. Taken together, then, post-marketing dose optimization is a commonly encountered, high-stakes problem–the best approach for which is unknown.
…With that motivation, we present in this manuscript the development an efficient trial design and treatment arm allocation strategy that quickly de-escalates the dose of a drug that is known to be efficacious to a dose that more efficiently expands societal benefits.
The basic idea is to begin near the known efficacious dose level and then deescalate dose levels but what is the best de-escalation strategy given that we want to quickly find an optimal dosage level but also don’t want to go so low that we endanger patients? Based on Bayesian trials under a variety of plausible conditions we conclude that the best strategy is Targeted Randomization (TR). At each stage, TR identifies the dose-level most likely to be optimal but randomizes the next subject(s) to either it or one of the two dose-levels immediately below it. The probability of randomization across three dose-levels explored in TR is proportional to the posterior probability that each is optimal. This strategy balances speed of optimization while reducing danger to patients.
Read the whole thing.
One Reason Why American Health Care is Expensive
tl/dr; Canadian woman is diagnosed with cancer, told she has 2 years to live at most, that she is not a candidate for surgery but would she like medical help committing suicide? She declines, comes to the United States, spends a lot of money, and is treated within weeks. Her health insurance is refusing to pay.
Global News: Ducluzeau said her family doctor told her that with this type of cancer, they usually do a procedure called HIPEC, which involves delivering high doses of chemotherapy into the abdomen to kill the cancer cells. But when she saw the consulting surgeon at the BC Cancer Agency in January, she said she was told she was not a candidate for surgery.
“Chemotherapy is not very effective with this type of cancer,” Ducluzeau said the surgeon told her. “It only works in about 50 per cent of the cases to slow it down. And you have a life span of what looks like to be two months to two years. And I suggest you talk to your family, get your affairs in order, talk to them about your wishes, which was indicating, you know, whether you want to have medically assisted dying or not.”
…Her brother contacted his mother-in-law who lives in Taiwan and she was able to get some advice from an oncologist there, after only waiting an hour. That oncologist confirmed that HIPEC was the treatment for Ducluzeau’s cancer. She set up a Zoom call with that oncologist later that week but then she found out about Dr. Armando Sardi at the Mercy Medical Center in Baltimore, Maryland.
“I had an appointment to speak with him via Zoom as well within a week and then also in Washington State,” she explained. “So there were two hospitals in Taiwan, one in Washington State and one in Baltimore that were able to take me as a patient.”
Ducluzeau decided to get treatment with Sardi in Baltimore.
…“I had to fly to California to get one of my diagnostic scans done there, a PET scan, because I wasn’t getting in here and I had to pay to have another CT scan done when I got to Baltimore because they couldn’t get it in time before I left,” she said.
Before she left, Ducluzeau said she called BC Cancer to ask how long it might be to see the oncologist was told it could be weeks, months, or longer, they had no idea.
“And I said, ‘Well, will it help if my doctor phones on my behalf?’ And they said, ‘no’. And my doctor submitted my referral again and still no word. No word at all from (BC Cancer) until after I flew to Baltimore, had my surgery and got home.”
With the help of a surgeon in Vancouver, Ducluzeau finally got a telephone appointment with an oncologist at BC Cancer for the middle of March – two-and-a-half months after receiving her diagnosis and the news that she may only have two months to two years to live.
…The BC Cancer Agency is refusing to provide documentation that would allow Ducluzeau to be reimbursed for the cost of out-of-country care, citing she did not proceed with additional investigations, such as a colonoscopy and laparoscopy.
“Universal healthcare really doesn’t exist,” Ducluzeau said. “My experience is it’s ‘do it yourself’ health care and GoFundMe health care.