Results for “half doses”
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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.

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.

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!

Patents are Not the Problem!

For the last year and a half I have been shouting from the rooftops, “invest in capacity, build more factories, shore up the supply lines, spend billions to save trillions.” Fortunately, some boffins in the Biden administration have found a better way, “the US supports the waiver of IP protections on COVID-19 vaccines to help end the pandemic.”
Waive IP protections. So simple. Why didn’t I think of that???

Patents are not the problem. All of the vaccine manufacturers are trying to increase supply as quickly as possible. Billions of doses are being produced–more than ever before in the history of the world. Licenses are widely available. AstraZeneca have licensed their vaccine for production with manufactures around the world, including in India, Brazil, Mexico, Argentina, China and South Africa. J&J’s vaccine has been licensed for production by multiple firms in the United States as well as with firms in Spain, South Africa and France. Sputnik has been licensed for production by firms in India, China, South Korea, Brazil and pending EMA approval with firms in Germany and France. Sinopharm has been licensed in the UAE, Egypt and Bangladesh. Novavax has licensed its vaccine for production in South Korea, India, and Japan and it is desperate to find other licensees but technology transfer isn’t easy and there are limited supplies of raw materials:

Virtually overnight, [Novavax] set up a network of outside manufacturers more ambitious than one outside executive said he’s ever seen, but they struggled at times to transfer their technology there amid pandemic travel restrictions. They were kicked out of one factory by the same government that’s bankrolled their effort. Competing with larger competitors, they’ve found themselves short on raw materials as diverse as Chilean tree bark and bioreactor bags. They signed a deal with India’s Serum Institute to produce many of their COVAX doses but now face the realistic chance that even when Serum gets to full capacity — and they are behind — India’s government, dealing with the world’s worst active outbreak, won’t let the shots leave the country.

Plastic bags are a bigger bottleneck than patents. The US embargo on vaccine supplies to India was precisely that the Biden administration used the DPA to prioritize things like bioreactor bags and filters to US suppliers and that meant that India’s Serum Institute was having trouble getting its production lines ready for Novavax. CureVac, another potential mRNA vaccine, is also finding it difficult to find supplies due to US restrictions (which means supplies are short everywhere). As Derek Lowe said:

Abolishing patents will not provide more shaker bags or more Chilean tree bark, nor provide more of the key filtration materials needed for production. These processes have a lot of potential choke points and rate-limiting steps in them, and there is no wand that will wave that complexity away.

Technology transfer has been difficult for AstraZeneca–which is one reason they have had production difficulties–and their vaccine uses relatively well understood technology. The mRNA technology is new and has never before been used to produce at scale. Pfizer and Moderna had to build factories and distribution systems from scratch. There are no mRNA factories idling on the sidelines. If there were, Moderna or Pfizer would be happy to license since they are producing in their own factories 24 hours a day, seven days a week (monopolies restrict supply, remember?). Why do you think China hasn’t yet produced an mRNA vaccine? Hint: it isn’t fear about violating IP. Moreover, even Moderna and Pfizer don’t yet fully understand their production technology, they are learning by doing every single day. Moderna has said that they won’t enforce their patents during the pandemic but no one has stepped up to produce because no one else can.

The US trade representative’s announcement is virtue signaling to the anti-market left and will do little to nothing to increase supply.

What can we do to increase supply? Sorry, there is no quick and cheap solution. We must spend. Trump’s Operation Warp Speed spent on the order of $15 billion. If we want more, we need to spend more and on similar scale. The Biden administration paid $269 million to Merck to retool its factories to make the J&J vaccine. That was a good start. We could also offer Pfizer and Moderna say $100 a dose to produce in excess of their current production and maybe with those resources there is more they could do. South Africa and India and every other country in the world should offer the same (India hasn’t even approved the Pfizer vaccine and they are complaining about IP!??) We should ease up on the DPA and invest more in the supply chain–let’s get CureVac and the Serum Institute what they need. We should work like hell to find a substitute for Chilean tree bark. See my piece in Science co-authored with Michael Kremer et. al. for more ideas. (Note also that these ideas are better at dealing with current supply constraints and they also increase the incentive to produce future vaccines, unlike shortsighted patent abrogation.)

Bottom line is that producing more takes real resources not waving magic patent wands.

You may have gathered that I am angry. I am indeed angry that the people in power think they can solve real problems on the cheap and at someone else’s expense. This is not serious. I am also angry that they are sending the wrong message about business, profits and capitalism. So let me end on positive note. Like the Apollo program and Dunkirk, the creation of the mRNA vaccines by Pfizer and Moderna should be lauded with Nobel prizes and major movies. Churchill called the rescue at Dunkirk a “miracle of deliverance,” well the miracle of Moderna will rescue many more. Not only was a vaccine designed in under a year, an entirely new production process was set up to produce billions of doses to rescue the world. The creation of the mRNA vaccines was a triumph of science, logistics, and management and it was done at a speed that I had thought possible only for past generations.

I am grateful that greatness is still within our civilization’s grasp.

Addendum: Lest I be accused of being reflexively pro-patent, do recall the Tabarrok curve.

India’s Pandemic and the World

Shruti Rajagopalan is right, helping India isn’t just about India.

India’s role in the global pandemic is unique. The developing world is counting on affordable Indian vaccine-makers such as Serum Institute of India Pvt. Ltd. for their supplies. With India now reserving virtually all its doses for domestic use, those countries will have to wait even longer to be vaccinated. And if the pandemic disrupts production at Indian pharmaceutical companies, it could affect crucial non-Covid medications as well. Half the world’s children have been vaccinated by Serum Institute.

The Biden administration can do two things to help. The first is to ease restrictions on critical exports, imposed under the Defense Production Act to prioritize the needs of U.S. companies.

Vaccine production requires very specific, medically approved inputs, which are difficult to substitute quickly in the middle of a pandemic. Currently, U.S. producers must secure permission before exporting such things as special sterile filters, disposable bags for cell cultures, cell culture media and single-use tubing. The embargo has led to major bottlenecks. Serum Institute says that without those inputs, it may not be able to deliver the 160 million vaccine doses it had planned to produce next month.

Second, the U.S. should immediately share doses from its own supply of Oxford-AstraZeneca and Johnson & Johnson vaccines.

I have three things to add. First, I have already noted the foreign policy implications which weigh strongly in favor of taking a more active role in the world pandemic.

Second, India should move immediately to delay the second dose of the AZ vaccine to 12 weeks. The federal government has already recommended a 6-8 week schedule, as this improves efficiency of the AstraZeneca (Covishield) vaccine, but many people so fear shortages that they are getting a less-effective second dose at four weeks. An enforced 12 week schedule would improve efficiency and might also reassure people that there will be supplies in 12 weeks.

Third, and this is more speculative, but the rising pandemic in India provides an opportunity to test fractional dosing of the Pfizer and Moderna vaccines in a real world setting. There is currently a small-scale Belgian trial testing Moderna at 50 mcg and Pfizer at 20 mcg. We already have reasonable information that 50 mcg of Moderna induces a robust immune response in adults. The mRNA vaccines wouldn’t work in all of India but would be fine in the cities and perhaps there is an opportunity for an exchange similar to what Israel promised to get early supplies.

Atul Gawande and Zeke Emanuel Now Support Delaying the Second Dose

Many people are coming around to First Doses First, i.e delaying the second dose to ~12 weeks. Atul Gawande, for example, tweeted:

As cases and hospitalizations rise again, we can’t count on behavior alone reversing this course. Therefore, it’s time for the Biden admin to delay 2nd vax doses to 12 weeks. Getting as many people as possible a vax dose is now urgent.

Now urgent??? Yes, I am a little frustrated because the trajectory on the new variants was very clear. On January 1, for example, I wrote about The New Strain and the Need for Speed (riffing off an excellent piece by Zeynep Tufekci).  Still, very happy to have Gawande’s voice added to the cause. Also joining Gawande are the power trio of Govind Persad, William F. Parker and Ezekiel J. Emanuel who in an important op-ed write:

If we temporarily delay second doses …that is our best hope of quelling the fourth wave ignited by the B.1.1.7 variant. Because we did not start this strategy earlier, it is probably too late for Michigan, New York, New Jersey and the other Northeastern states. But it might be just in time for the South and California — the next places the more infectious strain will go if historical patterns repeat.

…Drug manufacturers selected the three- or four-week interval currently used between doses to rapidly prove efficacy in clinical trials. They did not choose such short intervals based on the optimal way of using the vaccines to quell a pandemic. While a three- or four-week follow-up is safe and effective, there is no evidence it optimizes either individual benefit or population protection.

…Some complain that postponing second doses is not “following the science.” But the scientific evidence goes far beyond what was shown in the original efficacy trials. Data from the United Kingdom, Israel and now the Centers for Disease Control and Prevention shows that first doses both prevent infection and reduce transmission. In people with prior infection, experts are beginning to recognize that a second dose could provide even less benefit. Following the science means updating policies to recognize new evidence rather than stubbornly maintaining the status quo.

Emanuel is on Biden’s COVID-19 task force so consider this op-ed running the flag up the flagpole. I predict Topol will fall next.

I would be surprised, however, if the US changes course now–too many people would then ask why didn’t we do this sooner?–but dose stretching is going to be important for the rest of the world. Why aren’t we doing more to investigate fractional dosing? Even if we went to half-doses on the second dose–the full second dose appears to be strong–that would still be a significant increase in total supply.

Addendum: I have argued for sending extra doses to Michigan and other hot spots such as NJ. Flood the zone! The Biden administration says no. Why? Production is now running well ahead of distribution as more than 50 million doses have been delivered but not administered. It would be a particularly good idea to send more single-shot J&J to reach hard to reach communities–one and done.

In praise of Alex Tabarrok

Here’s a question I’ve been mulling in recent months: Is Alex Tabarrok right? Are people dying because our coronavirus response is far too conservative?

I don’t mean conservative in the politicized, left-right sense. Tabarrok, an economist at George Mason University and a blogger at Marginal Revolution, is a libertarian, and I am very much not. But over the past year, he has emerged as a relentless critic of America’s coronavirus response, in ways that left me feeling like a Burkean in our conversations.

He called for vastly more spending to build vaccine manufacturing capacity, for giving half-doses of Moderna’s vaccine and delaying second doses of Pfizer’s, for using the Oxford-AstraZeneca vaccine, for the Food and Drug Administration to authorize rapid at-home tests, for accelerating research through human challenge trials. The through line of Tabarrok’s critique is that regulators and politicians have been too cautious, too reluctant to upend old institutions and protocols, so fearful of the consequences of change that they’ve permitted calamities through inaction.

Tabarrok hasn’t been alone. Combinations of these policies have been endorsed by epidemiologists, like Harvard’s Michael Mina and Brown’s Ashish Jha; by other economists, like Tabarrok’s colleague Tyler Cowen and the Nobel laureates Paul Romer and Michael Kremer; and by sociologists, like Zeynep Tufekci (who’s also a Times Opinion contributor). But Tabarrok is unusual in backing all of them, and doing so early and confrontationally. He’s become a thorn in the side of public health experts who defend the ways regulators are balancing risk. More than one groaned when I mentioned his name.

But as best as I can tell, Tabarrok has repeatedly been proved right, and ideas that sounded radical when he first argued for them command broader support now. What I’ve come to think of as the Tabarrok agenda has come closest to being adopted in Britain, which delayed second doses, approved the Oxford-AstraZeneca vaccine despite its data issues, is pushing at-home testing and permitted human challenge trials, in which volunteers are exposed to the coronavirus to speed the testing of treatments. And for now it’s working: Britain has vaccinated a larger percentage of its population than the rest of Europe and the United States have and is seeing lower daily case rates and deaths.

Here is more from Ezra Klein at the New York Times.

Dose Stretching Policies Probably *Reduce* Mutation Risk

One objection to dose-stretching policies, such as delaying the second dose or using half-doses, is that this might increase the risk of mutation. While possible, some immunologists and evolution experts are now arguing that dose-stretching will probably reduce mutation risk which is what Tyler and I concluded. Here’s Tyler:

One counter argument is that letting “half-vaccinated” people walk around will induce additional virus mutations.  Florian Kramer raises this issue, as do a number of others.

Maybe, but again I wish to see your expected value calculations.  And in doing these calculations, keep the following points in mind:

a. It is hard to find vaccines where there is a recommendation of “must give the second dose within 21 days” — are there any?

b. The 21-day (or 28-day) interval between doses was chosen to accelerate the completion of the trial, not because it has magical medical properties.

c. Way back when people were thrilled at the idea of Covid vaccines with possible 60% efficacy, few if any painted that scenario as a nightmare of mutations and otherwise giant monster swarms.

d. You get feedback along the way, including from the UK: “If it turns out that immunity wanes quickly with 1 dose, switch policies!”  It is easy enough to apply serological testing to a control group to learn along the way.  Yes I know this means egg on the face for public health types and the regulators.

e. Under the status quo, with basically p = 1 we have seen two mutations — the English and the South African — from currently unvaccinated populations.  Those mutations are here, and they are likely to overwhelm U.S. health care systems within two months.  That not only increases the need for a speedy response, it also indicates the chance of regular mutations from the currently “totally unvaccinated” population is really quite high and the results are really quite dire!  If you are so worried about hypothetical mutations from the “half vaccinated” we do need a numerical, expected value calculation comparing it to something we already know has happened and may happen yet again.  When doing your comparison, the hurdle you will have to clear here is very high.

(See my Washington Post piece for similar arguments and additional references.).

Now here are evolutionary theorists, immunologists and viral experts Sarah Cobey, Daniel B. Larremore, Yonatan H. Grad, and Marc Lipsitch in an excellent paper that first reviews the case for first doses first and then addresses the escape argument. They make several interrelated arguments that a one-dose strategy will reduce transmission, reduce prevalence, and reduce severity and that all of these effects reduce mutation risk.

The arguments above suggest that, thanks to at least some effect on transmission from one dose, widespread use of a single dose of mRNA vaccines will likely reduce infection prevalence…

The reduced transmission and lower prevalence have several effects that individually and together tend to reduce the probability that variants with a fitness advantage such as immune escape will arise and spread (Wen, Malani, and Cobey 2020). The first is that with fewer infected hosts, there are fewer opportunities for new mutations to arise—reducing available genetic variation on which selection can act. Although substitutions that reduce antibody binding were documented before vaccine rollout and are thus relatively common, adaptive evolution is facilitated by the appearance of mutations and other rearrangements that increase the fitness benefit of other mutations (Gong, Suchard, and Bloom 2013; N. C. Wu et al. 2013; Starr and Thornton 2016). The global population size of SARS-CoV-2 is enormous, but the space of possible mutations is larger, and lowering prevalence helps constrain this exploration. Other benefits arise when a small fraction of hosts drives most transmission and the effective reproductive number is low. Selection operates less effectively under these conditions: beneficial mutations will more often be lost by chance, and variants with beneficial mutations are less certain to rise to high frequencies in the population (Desai, Fisher, and Murray 2007; Patwa and Wahl 2008; Otto and Whitlock 1997; Desai and Fisher 2007; Kimura 1957). More research is clearly needed to understand the precise impact of vaccination on SARS-CoV-2 evolution, but multiple lines of evidence suggest that vaccination strategies that reduce prevalence would reduce rather than accelerate the rate of adaptation, including antigenic evolution, and thus incidence over the long term.

In evaluating the potential impact of expanded coverage from dose sparing on the transmission of escape variants, it is necessary to compare the alternative scenario, where fewer individuals are vaccinated (but a larger proportion receive two doses) and more people recover from natural infection. Immunity developing during the course of natural infection, and the immune response that inhibits repeat infection, also impose selection pressure. Although natural infection involves immune responses to a broader set of antibody and T cell targets compared to vaccination, antibodies to the spike protein are likely a major component of protection after either kind of exposure (Addetia et al. 2020; Zost et al. 2020; Steffen et al. 2020), and genetic variants that escape polyclonal sera after natural infection have already been identified (Weisblum et al. 2020; Andreano et al. 2020). Studies comparing the effectiveness of past infection and vaccination on protection and transmission are ongoing. If protective immunity, and specifically protection against transmission, from natural infection is weaker than that from one dose of vaccination, the rate of spread of escape variants in individuals with infection-induced immunity could be higher than in those with vaccine-induced immunity. In this case, an additional advantage of increasing coverage through dose sparing might be a reduction in the selective pressure from infection-induced immunity.

…In the simplest terms, the concern that dose-sparing strategies will enhance the spread of immune escape mutants postulates that individuals with a single dose of vaccine are those with the intermediate, “just right” level of immunity, more likely to evolve escape variants than those with zero or two doses (Bieniasz 2021; Saad-Roy et al. 2021)….There is no particular reason to believe this is the case. Strong immune responses arising from past infection or vaccination will clearly inhibit viral replication, preventing infection and thus within-host adaptation…. Past work on influenza has found no evidence of selection for escape variants during infection in vaccinated hosts (Debbink et al. 2017). Instead, evidence suggests that it is immunocompromised hosts with prolonged influenza infections and high viral loads whose viral populations show high diversity and potentially adaptation (Xue et al. 2017, 2018), a phenomenon also seen with SARS-CoV-2 (Choi et al. 2020; Kemp et al. 2020; Ko et al. 2021). It seems likely, given its impact on disease, that vaccination could shorten such infections, and there is limited evidence already that vaccination reduces the amount of virus present in those who do become infected post-vaccination (Levine-Tiefenbrun et al. 2021).

I also very much agree with these more general points:

The pandemic forces difficult choices under scientific uncertainty. There is a risk that appeals to improve the scientific basis of decision-making will inadvertently equate the absence of precise information about a particular scenario with complete ignorance, and thereby dismiss decades of accumulated and relevant scientific knowledge. Concerns about vaccine-induced evolution are often associated with worry about departing from the precise dosing intervals used in clinical trials. Although other intervals were investigated in earlier immunogenicity studies, for mRNA vaccines, these intervals were partly chosen for speed and have not been completely optimized. They are not the only information on immune responses. Indeed, arguments that vaccine efficacy below 95% would be unacceptable under dose sparing of mRNA vaccines imply that campaigns with the other vaccines estimated to have a lower efficacy pose similar problems. Yet few would advocate these vaccines should be withheld in the thick of a pandemic, or roll outs slowed to increase the number of doses that can be given to a smaller group of people. We urge careful consideration of scientific evidence to minimize lives lost.

Against Regulatory Nationalism

I’ve long argued that if a drug or medical device is approved in another country with a Stringent Regulatory Authority it ought to be approved in the United States. But, of course, the argument is even stronger in the other direction. Drugs and devices approved in the United States ought to be approved elsewhere. Indeed, this is how much of the world actually works because most countries do not have capability to evaluate drugs and devices the way the FDA or say the EMA does. Although it’s the way the world works, few will admit it because that would violate pretensions of regulatory nationalism. Moreover, keeping up with pretenses means transaction costs and unnecessary delays.

The price of such regulatory nationalism can be very high as indicated in this interview with Adar Poonawalla, chief executive of the Serum Institute of India (SII), the world’s largest producer of vaccines.

Some people think the reason that rollout has been slow in many countries is because the developers who hold the patents on the vaccines have licensed too few manufacturers to make them. Do you agree?

No. There are enough manufacturers, it just takes time to scale up. And by the way, I have been blown away by the cooperation between the public and private sectors in the last year, in developing these vaccines. What I find really disappointing, what has added a few months to vaccine delivery – not just ours – is the lack of global regulatory harmonisation. Over the last seven months, while I’ve been busy making vaccines, what have the US, UK and European regulators been doing? How hard would it have been to get together with the World Health Organization and agree that if a vaccine is approved in the half-dozen or so major manufacturing countries, it is approved to send anywhere on the planet?

Instead we have a patchwork of approvals and I have 70m doses that I can’t ship because they have been purchased but not approved. They have a shelf life of six months; these expire in April.

Did you get that? Regulatory nationalism has added months to vaccine delivery and now threatens to put to waste millions of stockpiled doses.

Addendum: See also Scott Sumner on the costs of regulatory nationalism.

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.

The Experts are Very Worried

Here is an interview with Dr. Peter Hotez, dean of the National School of Tropical Medicine at Baylor College of Medicine and the lead developer of a COVID vaccine being produced in India. He thinks the AstraZeneca vaccine should be approved immediately, as I have long argued.

President Biden himself announced Tuesday that we’re going to have maybe enough additional doses of the mRNA vaccines to fully vaccinate 300 million Americans by the end of summer or fall.

I’m saying, “Well, no, that’s that’s not gonna work.” Telling us “by the fall” is like telling us “when the glaciers are gonna come back down from Quebec.” I mean, that’s not adequate.

We’re going to have to figure out a way to vaccinate the American people by late spring. That’s a tall order. To beat back the virus we need to give two doses to three-quarters of the population, to 246 million Americans. That’s half a billion immunizations. To get there, we’d need a rate of immunizations two or three times higher than what’s proposed.

….We need vaccinations now.

..things have been slowed down with the AstraZeneca-Oxford adenovirus vaccine. My understanding is that the FDA insisted that they conduct a full-scale Phase Three trial in the U.S., and we won’t have results for that until April. Meanwhile, the European Medicines Agency, the EMA, is going to make a ruling on the AstraZeneca Oxford vaccine on Friday based on studies done in Europe and also probably on data from Brazil and South Africa. [The EMA authorized, AT].

Those are large, reliable studies?

Yeah….Because of these new variants, there’s great urgency here in the U.S. So I’m saying that sometimes we have to do things that take us out of our comfort zone in order to save lives. That means, rather than focusing only on the new study that we’re doing in the U.S., we also look at the dossier presented to the EMA.

As a regulatory agency the EMA is up there with our U.S. FDA. They’re the two best regulatory agencies in the world. So if they sign off, I think we should say, “Look, let’s do it. Let’s use that vaccine.”

We’ve already bought 300 million doses of the AstraZeneca-Oxford vaccine. We’ve paid for it — over a billion dollars — so let’s use it.

…And there’s also the recombinant protein vaccine our lab has developed at Baylor College of Medicine and Texas Children’s Hospital. In India they’re scaling that up to a billion doses. Nobody from the White House has approached us to say, “Hey, Peter, what can we do to bring that vaccine in.”

There seem to be blinders: All they can see is getting the mRNA vaccines. I don’t quite know what’s driving that. We have to figure out a way to bring the other ones on board.

And soon! We’re in the eye of the hurricane.

Hat tip: Jim Ward.

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