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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.

The AstraZeneca Vaccine Works Well

A new study looking at essentially the entirety of the Scottish population finds that both the Pfizer and AstraZeneca vaccine work very well at preventing hospitalizations from the first dose.

UK policy for use of vaccines against COVID-19 involves an offer of a first dose followed by a second dose 12 weeks later. To our knowledge, this is the first study of COVID-19 vaccine effect against hospitalisation for an entire nation after a single dose of vaccine. We found that a single dose of BNT162b2 COVID-19 vaccine was associated with a vaccine effect (VE) of 85% (95% CI 76 to 91) for COVID-19 hospitalisation 28-34 days post-vaccination. A single dose of ChAdOx1 vaccine was associated with a vaccine effect 94% (95% CI 73 to 99) at 28-34 days post-vaccination. VEs increased over time with a peak at 28-34 days post-vaccination for both vaccines. Comparable VEs were seen in those aged ≥80 years for prevention of COVID-19 hospitalisation with a high combined VE of 81% (95% CI 65 to 90) at 28-34 days post-vaccination.

Arne Akbar, president of the British Society for Immunology, noted “…overall these new findings should provide reassurance around the UK’s decision to offer the two doses of the vaccine 12 weeks apart.”

Another important point is that the AstraZeneca vaccine actually shows a higher effectiveness than the Pfizer vaccine. The study wasn’t designed to compare the vaccines and the populations getting the vaccines aren’t random samples. Nevertheless, the AstraZeneca vaccine appears to work well and it was actually given to a greater proportion of elderly patients.

The new results from Scotland support the UK, EU, and WHO decisions to authorize the AstraZeneca vaccine. If the US had authorized the AstraZeneca vaccine in late December at the same time as did the UK, millions more Americans could have been vaccinated saving many lives.

Where is the FDA’s cost-benefit calculation?

Approve the AstraZeneca Vaccine Now!

Here’s Marty Makary, M.D., a professor of surgery and health policy at the Johns Hopkins University School of Medicine:

Finally, the FDA needs to stop playing games and authorize the Oxford-AstraZeneca vaccine.  It’s safe, cheap ($2-$3 a dose), and is the easiest vaccine to distribute. It does not require freezing and is already approved and being administered in the United Kingdom.

Sadly, the FDA is months away from authorizing this vaccine because FDA career staff members insisted on another clinical trial to be completed and are punishing the company for inadvertently giving a half-dose of the vaccine to some people in the trial.

It’s like the FDA is holding out, pontificating existing excellent data and being vindictive against a company for making a mistake while thousands of Americans die each day.

Ironically, those in the Oxford-AstraZeneca trial who inadvertently received half the initial vaccine dose had lower infection rates. And this week Dr. Moncef Slaoui, the chief adviser to Operation Warp Speed, acknowledged that using half a dose might be a good broader strategy for the U.S. to double our supply as long our supply is severely constrained. That’s a good strategy that makes sense.

See also my post The AstraZeneca Factory in Baltimore. Thousands of people are dying every day. We have a vaccine factory ready to go. The FDA should lifts its ban on the AstraZeneca vaccine.

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.

The AstraZeneca trial is allowed to resume

Federal health regulators have decided to allow the resumption of U.S. studies of a leading Covid-19 vaccine candidate from AstraZeneca PLC and the University of Oxford, according to a person familiar with the matter and materials reviewed by The Wall Street Journal.

Here is the WSJ article, no real explanation given by either the company or the FDA.

From the AstraZeneca comments

Transverse Myletitis has a background incidence of 4/million in the US. Currently there are 2 cases reported out of 18,000 people who have already been administered the vaccine. Of those two, one was diagnosed with concurrent MS (another neurodegenerative autoimmune condition known to cause TM and whose population has a 2000% relative risk increase in developing TM depending on criteria used) and one has not had details released.

With 18,000 data points, a “1%” risk would require there to be 178 missed cases. Odds of that are astronomically low. Much more likely, if there were any real correlation (which again seems rather unlikely) we are looking at something 80+) and would STILL result in fewer deaths than waiting. If the choice were this or letting Covid become endemic with just an influenza fatality rate, this would again be the more ethical choice. Economically 1.1 million being totally disabled would be somewhere around $3 trillion, which again would be vastly cheaper than ending transmission through current social policies. In terms of raw lives lost, a 1% incidence would easily be less than letting Covid run.

People say we need more numbers, but funny enough their doom and gloom scenarios invariably involve scenarios that are necessarily imply that all the trial data to date is spurious and/or that even if true are less deadly than waiting.

And note that this argument has no justification for pausing the trial. With 2 data points, 1 of which is almost certainly spurious for the general population, the solution is to keep administering it.

Reality is that regulators and drug companies are simply not doing a cost benefit calculation that weights the currently dying at all in the US. I am hoping that the drug companies are being amoral profit seekers and are hoping to just browbeat the FDA once the Brits get things settled and the US policy scene (one way or the other) stops being about Mr. Trump.

That is from MR commentator Sure.  And also from him:

The other thing to remember is that a lot of pharma’s actual business is not as much discovery of new entities, rather they buy up rights to a lot of those and then take somebody else’s work through the years long process of approval. For big pharma much of their comparative advantage is in navigating an expensive, byzantine approval process. Take that away and they might face far more competition from smaller firms and potentially foreign firms that can manage the new landscape better.

Lastly, pharma lives in fear of the regulators while trying to suborn them. Going against them FDA bureaucrats (who are unlikely to want to de facto kill their own jobs) risks one of them grinding an axe and slow walking a blockbuster approval or fast walking a biosimilar approval. Either of those actions will easily change the net profit for a pharma firm by more than they could possibly make off a Covid vaccine.

Currently, faster has very little upside for them. They have pre-commitment so they are going to get paid even if they are slow. There are dozen odd vaccines coming down the pike and one, maybe two, will take the lion’s share of the market once the immediate crisis is over. They are mostly doing this to win goodwill and being the guy whose vaccine kills 2,000 people is bad if your competitors kill only 5. From a public health perspective, we would be better with the less safe vaccine a month sooner than the safer vaccine a month later (and ideally we would get both and swap promptly). For the pharma firms, the calculus just goes towards being as slow as the rest of pack and being ungodly thorough.

Perhaps things will improve in a few weeks’ time.

From the comments, on AstraZeneca vaccine trial resumption

America is really, really messed up.

The only place with such intensely wasteful discussions about a disease is the U.S. And it is getting increasingly easy to ignore the U.S. as the world continues to respond to this pandemic.

And it is not just the British based trial. This is from Reuters on Sept. 14 – “Clinical trials for the coronavirus vaccine being developed by AstraZeneca PLC and Oxford University resumed in Brazil on Monday after the country’s health regulator got confirmation over the weekend that its British equivalent MHRA had approved the restart, a company representative said.

The Federal University of Sao Paulo, which is running the trials, said in a statement that 4,600 of the planned 5,000 volunteers have been vaccinated in Brazil without any of them reporting any serious health issues.”

This from the Times of India on Sept 20th -“The phase-III human clinical trial of the COVID-19 vaccine developed by Oxford University and being manufactured by the Serum Institute of India (SII) will begin at the Sassoon General Hospital in Pune next week. Dean of the state-run Sassoon General Hospital Dr Muralidhar Tambe told this to on Saturday.

“The phase-III trial of ‘Covishield’ vaccine will begin at Sassoon hospital from next week. It is likely to start on Monday. Some volunteers have already come forward for the trial. Around 150 to 200 volunteers will be administered the vaccine candidate dose,” he said.

Regulators in Japan and South Africa also have no problem with the trial continuing.

That is from Easy-Peasy.  And I did google to ensure that those claims about foreign trial resumption are correct, for instance Japan resumed no later than October 2.  This is one reason — not the only! — why I am puzzled when Derek Lowe claims on Twitter that American perhaps cannot go any faster with its vaccine.  If you think Japan and the Brits are irresponsible, by all means let us know.  Otherwise…it is time to speak up in favor of maximizing expected value.

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 [36]. 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 [712]. 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 [613], but direct observation of both that relationship and MDSE, rather than pharmacokinetic modeling, appears necessary for regulatory and public health authorities to adopt fractionation [1516]. 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 [1718]. 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 [3182021]. 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.

The Growing Market for Cancer Drugs

In my TED talk on growth and globalization I said:

If China and India were as rich as the United States is today, the market for cancer drugs would be eight times larger than it is now. Now we are not there yet, but it is happening. As other countries become richer the demand for these pharmaceuticals is going to increase tremendously. And that means an increase incentive to do research and development, which benefits everyone in the world. Larger markets increase the incentive to produce all kinds of ideas, whether it’s software, whether it’s a computer chip, whether it’s a new design.

…[T]oday, less than one-tenth of one percent of the world’s population are scientists and engineers. The United States has been an idea leader. A large fraction of those people are in the United States. But the U.S. is losing its idea leadership. And for that I am very grateful. That is a good thing. It is fortunate that we are becoming less of an idea leader because for too long the United States, and a handful of other developed countries, have shouldered the entire burden of research and development. But consider the following: if the world as a whole were as wealthy as the United States is now there would be more than five times as many scientists and engineers contributing to ideas which benefit everyone, which are shared by everyone….We all benefit when another country gets rich.

A recent piece in the FT illustrates:


AstraZeneca’s chief executive returned from a recent trip to China exuberant about an “explosion” of biotech companies in the country and the potential for his business to deliver drugs discovered there to the world….Many drugmakers are tempted by China’s large, ageing population, which is increasingly affected by chronic diseases partly caused by smoking, pollution and more westernised diets….the opportunity lies not just in Chinese patients, but also in the country’s scientists. “The innovation power has changed,” said Demaré. “It is no more ‘copy, paste’. They really have the power to innovate and put all the money in. There’s a lot of start-ups and we are a part of that.”

As I concluded my talk:

Ideas are meant to be shared, one idea can serve the world. One idea, one world, one market.

Dose Stretching for the Monkeypox Vaccine

Photo Credit: NIAD. https://www.flickr.com/photos/niaid/52103767506/

We are making all the same errors with monkeypox policy that we made with Covid but we are correcting the errors more rapidly. (It remains to be seen whether we are correcting rapidly enough.) I’ve already mentioned the rapid movement of some organizations to first doses first for the monkeypox vaccine. Another example is dose stretching. I argued on the basis of immunological evidence that A Half Dose of Moderna is More Effective Than a Full Dose of AstraZeneca and with Witold Wiecek, Michael Kremer, Chris Snyder and others wrote a paper simulating the effect of dose stretching for COVID in an SIER model. We even worked with a number of groups to accelerate clinical trials on dose stretching. Yet, the idea was slow to take off. On the other hand, the NIH has already announced a dose stretching trial for monkeypox.

Scientists at the National Institutes of Health are getting ready to explore a possible work-around. They are putting the finishing touches on the design of a clinical trial to assess two methods of stretching available doses of Jynneos, the only vaccine in the United States approved for vaccination against monkeypox.

They plan to test whether fractional dosing — using one-fifth of the regular amount of vaccine per person — would provide as much protection as the current regimen of two full doses of the vaccine given 28 days apart. They will also test whether using a single dose might be enough to protect against infection.

The first approach would allow roughly five times as many people to be vaccinated as the current licensed approach, and the latter would mean twice as many people could be vaccinated with existing vaccine supplies.

…The answers the study will generate, hopefully by late November or early December, could significantly aid efforts to bring this unprecedented monkeypox outbreak under control.

Another interesting aspect of the dose stretching protocol is that the vaccine will be applied to the skin, i.e. intradermally, which is known to often create a stronger immune response. Again, the idea isn’t new, I mentioned it in passing a couple of times on MR. But we just weren’t prepared to take these step for COVID. Nevertheless, COVID got these ideas into the public square and now that the pump has been primed we appear to be moving more rapidly on monkeypox.

Addendum: Jonathan Nankivell asked on the prediction market, Manifold Markets, ‘whether a 1/5 dose of the monkey pox vaccine would provide at least 50% the protection of the full dose?’ which is now running at a 67% chance. Well worth doing the clinical trial! Especially if we think that the supply of the vaccine will not expand soon.

Fractional Dosing Trials

My paper Testing fractional doses of COVID-19 Vaccines, co-authored with Kremer et al., has now been published at PNAS. I covered the paper in A Half Dose of Moderna is More Effective than A Full Dose of Astra Zeneca and other posts so I won’t belabor the basic ideas. One new point is that thanks to the indefatigable Michael Kremer and the brilliant Witold Wiecek, clinical trials on fractional dosing on a large scale have begun in Nigeria. Here are a few key points:

WHO SAGE Outreach: The authors have met and presented their work to the World Health Organization (WHO) Strategic Advisory Group of Experts on Immunization (SAGE), with follow-up meetings to present evidence coming from new studies.

DIL Workshop and Updates: In the fall of 2021, the Development Innovation Lab (DIL) at UChicago, led by Professor Kremer, hosted a workshop on fractional dosing, collecting updates from clinical researchers from multiple countries conducting fractional dosing trials for COVID-19 vaccines. The workshop also covered issues relating to trial design and included participants from Belgium, Brazil, Ghana, the Netherlands, Nigeria, Thailand, South Africa, UK and the US. 

CEPI Outreach: Professor Kremer has also presented this research to The Coalition for Epidemic Preparedness Innovations (CEPI), which is now pursuing a platform trial of fractional dosing.

Country Trials – Nigeria: With the support of DIL and the research team and generous support and advice from WAM Foundation, the charitable arm of Weiss Asset Management and Open Philanthropy, a trial is being conducted in Nigeria by the Nigerian Institute of Medical Research, National Institute of Pharmaceutical Research and Development, National Agency for Food and Drug Administration and Control, and the National Primary Health Care Development Agency, in coordination with the Federal Ministry of Health.

A comprehensive list of all the trials on fractional dosing conducted to date is at the link. Fractional dosing may come too late for COVID-19 vaccines but perhaps next time a shortage of a vaccine looms we will be more quick to consider policies to stretch supplies.

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.

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.

A new hurdle for vaccine development

Unless countries that have purchased vaccine doses and companies that have already brought vaccines into use agree to find ways to resolve the problem, manufacturers that trail the first wave of producers may not be able to prove that their vaccines work. Not only will that slow efforts to vaccinate the planet, it will block development of next-generation vaccines, and it will stymie efforts to answer key public health questions, like whether boosting with a different vaccine would generate better protection, or whether giving smaller — fractional — doses could protect more people more quickly…

The problem stems in part from the fact that at this point in the pandemic, it isn’t considered ethical to test new vaccines against placebos; instead they would have to be tested against one of the existing shots. But getting one’s hands on licensed or authorized vaccines for study purposes is nigh on impossible; all available doses have been snapped up by countries keen to vaccinate as many of their citizens as possible.

Contracts for those doses contain rigid stipulations about how the vaccines can be deployed. The doses often have to be used in the country that made the purchase; when the Biden administration wanted to share AstraZeneca doses with Canada and Mexico in March, it loaned the doses to get around the restrictions. Contracts also often stipulate that doses that have been purchased must be used for outbreak control, not for research purposes, Lurie said.

Here is the full story by Helen Branswell.  Obviously there is a market-oriented solution here, if only we care enough to implement it…