Category: Medicine

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 end of the Swedish model

The government this week proposed an emergency law that would allow it to lock down large parts of society; the first recommended use of face masks came into force; and the authorities gave schools the option to close for pupils older than 13 — all changes to its strategy to combat the pandemic.

“I don’t think Sweden stands out [from the rest of the world] very much right now,” said Jonas Ludvigsson, professor of clinical epidemiology at Karolinska Institutet in Stockholm. “Most of the things that made Sweden different have changed — either in Sweden or elsewhere.”

…Sweden has reported more than 2,000 Covid-19 deaths in a month and 535 in the past eight days alone. This compares with 465 for the pandemic as a whole in neighbouring Norway, which has half the population. As Sweden’s King Carl XVI Gustaf said just before Christmas: “We have failed.”

Here is more from the FT.  U.S. Covid deaths per day have now exceeded 4,000 for some days, and they are running at about 50% of the normal number for total daily deaths.  And no, it is not that the payments to classify these as Covid deaths have increased, rather the virus and the deaths have increased.  So the “no big deal” question we now can consider settled?  The new and more contagious strains haven’t even started playing a major role yet in the United States.

“Second Doses” post-mortem

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

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

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

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

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

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

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

Be Prepared! Sars-COV-3

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

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

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

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

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

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

Hat tip: Daniel Bier.

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

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?

Mass vaccination for Virginia (from my email)

A vaccination center with 4 vaccination stations requiring 58 staff (only 16 of which seem to need medical training to prepare and administer vaccines and 1 EMT on hand for adverse reactions (I imagine med students and military/other governmental personnel could also be used in this endeavor)) working a total of 16 hours/day (i.e. 2 shifts) is estimated to be able to vaccinate 1900 people per day.

If there were 50 of these across Virginia, the entire population could be given one dose in 90 days. Given that 2 doses are required, you could get the vaccination done by summer (if there were no supply constraints). With 30 vaccination centers, Virginia could be done distributing its 317,000 remaining unadministered doses in 5 days. Instead, Virginia reported 828 vaccinations yesterday. (I’m hoping Virginia is already finished with nursing facilities since Kaiser estimates that Virginia only had 19,900 residents in skilled nursing facilities in 2019).

And staffing is easily solved. 30 vaccination centers require 480 medical personnel to prepare and administer the vaccine and 30 EMTs. There are about 120,000 nurses in Virginia. Chances are, more than 480 nurses were on vacation for longer than 5 days at some point this past year so it won’t cripple the healthcare system. Getting 1 percent of the nursing workforce for this should not be that hard (and that’s not including med students and military/other governmental personnel who could also aid in this endeavor).

What boggles my mind is the number of staff they have allocated for paperwork.

If the US had been prepared, it could’ve set up a system of vaccination tickets with QR codes (much like tickets for air travel or going to a sporting event) that could be handed out by primary care physicians, hospitals, etc. (or just based on administrative records of age). Those would transfer the relevant data that would have been collected by the paperwork people. People would schedule a slot via some app (even doctors’ offices have online scheduling now), show up, provide ID verification, and get the shot. So you could open up a vaccination center with less staff. I get that not everyone has a smartphone, but seriously, this is not that hard.

The more you think about how many times large logistics problems are solved every single day by 100s and 1000s of organizations, the performance of the US just looks worse and worse.

From a loyal (and anonymous) MR reader.

First Doses First and Herd Immunity

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

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

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

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

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

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

“New York’s mass-vaccination plans are shelved as Cuomo takes different path”

County officials who have for years been planning for a mass vaccination said they are seeing that training and preparation — much of it funded by millions of dollars in federal grants — pushed aside as the administration of Gov. Andrew M. Cuomo has retained control of the state’s coronavirus vaccination program, including having hospitals rather than local health departments administer the doses.

Interviews with multiple county officials over the past week confirm that many are unclear why the governor’s administration has not activated the county-by-county system, a plan that included recent practice sessions in which members of the public received regular flu vaccines at drive-thru sites.

…In Albany County, officials have privately said they could vaccinate the population of the southern half of the county in a few days if they were given the coronavirus vaccines and allowed to mobilize their plan.

Here is the full, gory story.  It is clear they have just begun thinking about this.  I really do not understand why Paul Krugman has been praising the New York State response for so many months, they have gone from one disgrace to another.  Ross Barkan offers further commentary.  And here is de Blasio on Cuomo.

As a side note this is interesting: “The Times Union is not disclosing the [vaccination] location because county officials contend the vaccination sites should not be publicly disclosed for security purposes.”

To be clear, other states are messing up too, some of them worse than NY.

The politics of Covid just got even more hellish

That is the title of my latest Bloomberg column, here is one excerpt:

Preliminary data indicate that the new strain in the U.K. allows the virus to spread from one person to another more easily. The practical upshot is that even the strict lockdowns of early 2020, such as the one just ordered in the U.K. by Prime Minister Boris Johnson, may not be enough to reverse the spread of the virus.

It is far from obvious that politicians will be able to sell voters on strict lockdowns if they still allow the virus to spread. Furthermore, vaccine distribution has been sufficiently slow that a full lockdown would have to last for many months, and that probably isn’t feasible or desirable. Yet not having lockdowns would lead to a much more rapid spread of the virus, overloading hospitals and public health facilities.

And:

The biggest moral dilemmas might come in those countries that to date have been fairly successful at containing the spread of the virus. Apart from restrictions on foreign travel, life in Taiwan has been normal for some time now, and Covid-related casualties have been miniscule. Other successful examples of virus containment can be found throughout Asia and the Pacific.

But how will those countries deal with the new strain? It has already appeared in both Taiwan and China. So far it has not taken over, but the previous tactics of quarantine and tracing may no longer suffice, should the new strain become more active. It is already spreading in Denmark, which did a good job against Covid-19 early on.

Imagine being a leader of a country that has successfully contained Covid, and now realizing that a single mistake could undo almost a year of very hard work. You also know that, precisely because your country has been so effective at fighting the virus, it is not on the verge of vaccinating your entire population. What if you let a single returning citizen pass through customs taking one Covid test rather than three? What if you then cannot control the subsequent spread of the strain that person is carrying?

When was the last time that stakes for such apparently minor decisions were so high? How will leaders deal with the extreme moral anxiety that their decisions will likely induce?

It is like we are living in a horror movie, and just when we think it’s over, the monster comes back, stronger than ever.

Important throughout.

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.

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.

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.

How will we interpret data on the new strain?

Instead of exploding relative to a baseline of 0 cases (like in March), the new strain will be exploding relative to a baseline of around 200,000 cases per day. As a result, day-to-day random noise will completely mask any increase in infections from the new strain until it becomes dominant — around day 40 in the above chart. This means that if people use the overall numbers to guide their levels of precaution, our reaction time could lag by two or three weeks compared to March — as if we had locked down in early April instead of mid-March.

Now, this isn’t entirely a correct comparison because the rate of exponential growth will be much below 1.36; a reasonable guess might be 1.12. (You can get this by assuming R = 1.6 and assuming a generation time of 4 days.) But the overall point is the same: because any increase in the prevalence of the new strain will be masked by noise in current COVID levels, the new strain won’t be evident in overall numbers until it starts contributing hundreds of thousands of daily infections.

That is from Eric Neyman, good points thought note we will have independent measures of the spread of the new strain, with shorter lags than is currently the case.