Category: Medicine

Failure is the Mother of Success

New paper from Jeffrey E. Harris:

The decades-long effort to produce a workable HIV vaccine has hardly been a waste of public and private resources. To the contrary, the scientific know-how acquired along the way has served as the critical foundation for the development of vaccines against the novel, pandemic SARS-CoV-2 virus. We retell the real-world story of HIV vaccine research – with all its false leads and missteps – in a way that sheds light on the current state of the art of antiviral vaccines. We find that HIV-related R&D had more than a general spillover effect. In fact, the repeated failures of HIV vaccine trials have served as a critical stimulus to the development of successful vaccine technologies today. We rebut the counterargument that HIV vaccine development has been no more than a blind alley, and that recently developed vaccines against COVID-19 are really descendants of successful vaccines against Ebola, MERS, SARS-CoV-1 and human papillomavirus. These successful vaccines likewise owe much to the vicissitudes of HIV vaccine development.

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.

The mortality of scholars

After recovering from a severe mortality crisis in the seventeenth century, life expectancy among scholars started to increase as early as in the eighteenth century, well before the Industrial Revolution. Our finding that members of scientific academies—an elite group among scholars—were the first to experience mortality improvements suggests that 300 years ago, individuals with higher social status already enjoyed lower mortality. We also show, however, that the onset of mortality improvements among scholars in medicine was delayed, possibly because these scholars were exposed to pathogens and did not have germ theory knowledge that might have protected them. The disadvantage among medical professionals decreased toward the end of the nineteenth century.

Here is more from Robert Stelter, David de la Croix, and Mikko Myrskylä.  Via the excellent Kevin Lewis.

Are Americans getting worse?

Maybe so:

Morbidity and mortality have been increasing among middle-aged and young-old Americans since the turn of the century. We investigate whether these unfavorable trends extend to younger cohorts and their underlying physiological, psychological, and behavioral mechanisms. Applying generalized linear mixed effects models to 62,833 adults from the National Health and Nutrition Examination Surveys (1988-2016) and 625,221 adults from the National Health Interview Surveys (1997-2018), we find that for all gender and racial groups, physiological dysregulation has increased continuously from Baby Boomers through late-Gen X and Gen Y. The magnitude of the increase is higher for White men than other groups, while Black men have a steepest increase in low urinary albumin (a marker of chronic inflammation). In addition, Whites undergo distinctive increases in anxiety, depression, and heavy drinking, and have a higher level than Blacks and Hispanics of smoking and drug use in recent cohorts. Smoking is not responsible for the increasing physiological dysregulation across cohorts. The obesity epidemic contributes to the increase in metabolic syndrome, but not in low urinary albumin. The worsening physiological and mental health profiles among younger generations imply a challenging morbidity and mortality prospect for the United States, one that may be particularly inauspicious for Whites.

Here is the full article, via an excellent loyal MR reader.

Trypanophobia or How to Alleviate Vaccine Hesitancy

A significant share of vaccine hesitancy is driven by fear of needles, trypanophobia. Adults don’t like to admit a fear of needles and less so that they would avoid a vaccine for fear of a needle. But trypanophobia is common and does reduce flu immunizations:

Avoidance of influenza vaccination because of needle fear occurred in 16% of adult patients, 27% of hospital employees, 18% of workers at long‐term care facilities, and 8% of healthcare workers at hospitals. Needle fear was common when undergoing venipuncture, blood donation, and in those with chronic conditions requiring injection.

Aside from fear of the needle, I think there is also a perception that needles are “serious medicine” and thus anything that comes in needle form must be serious or dangerous. In fact, vaccines are safer than many commonly used drugs that are taken orally.

Needle hesitancy is bad for the hesitant who don’t get protection from COVID and bad for everyone else who are further subject to transmission from unvaccinated carriers.

The best way to alleviate needle hesitancy is to get rid of the needle. Operation Warp Speed made smart investments in a fairly widely range of vaccines (we advised going wider) including a pill vaccine from VaxArt. The VaxArt vaccine has completed a Phase I trial with modest results and is moving into Phase II. Nasal vaccines are in development. The RadVac open science vaccine, for example, is a nasal vaccine available to anyone with a scientific bent willing to give an unapproved vaccine a try. CodaGenix has a nasal vaccine in Phase I trials as does Altimmune.

Aside from ease of delivery, a COVID nasal or oral vaccine may also be better than intramuscular injection because it stimulates the immune system at the first point of viral attack, the mucosal tissues in the nose, mouth, lungs and digestive tract. In addition, the mucosal immune system has some unique elements so you get a potentially stronger immune response more capable of neutralizing the virus quickly.

Operation Warp Speed investments generated trillions in value for billions in cost, a few additional smart investments in accelerating nasal and oral vaccines could pay off highly in mopping up vaccine hesitancy and moving us more quickly to herd immunity. We could even do a human challenge trial with nasal vaccine v. intramusucalar injection. Oral and nasal vaccines will also be great for kids and for booster shots.

Even at this late stage we are spending trillions on stimulus/relief and not enough on investment, especially on highly successful investment in vaccines.

Addendum: I know it probably won’t help but fyi, it’s a painless shot. Nothing to fear! Get a superpower and a donut afterwards. It will be memorable.

Power Up!

Two weeks ago I was bitten by the equivalent of a radioactive spider and now I have superpowers! Including the power of immunity and the power to fly! Awesome. As I said earlier, the SARS-COV-2 virus killed more people this year than bullets “so virus immunity is a much better superpower than bullet immunity!”

I got the J&J vaccine–one of the first in the world to do so–which seemed appropriate as I have been calling for first doses first and the J&J vaccine is single dose. I will probably supplement with Novavax at a later date when supplies are plentiful.

Addendum: Also, I can get free donuts at Krispy Kreme.

The EU Vaccine Bungling

The EU vaccine rollout has been remarkably bungled even by the standards we have come to expect from Western governments. In advising governments I and the AHT team argued that vaccines were the world’s easiest cost-benefit test because Billions<<Trillions. Yet when manufactures offered the EU vaccines worth thousands of dollars a dose for just $5-$40 a dose the EU foolishly shouted “price gouging” and wasted weeks in dickering. I leave it to you as an exercise to calculate the value EU governments implicitly placed on European lives.

The latest bungling was the halt by over a dozen European governments of vaccination with the AstraZeneca vaccine due to fears that it might cause very rare blood clots (wisely Belgium and Great Britain continued vaccinations). After a review, the EMA has now cleared the vaccine:

The European Union’s drug regulator said on Thursday that the AstraZeneca vaccine was safe and effective, a finding that officials hope will alleviate concerns about possible rare side effects involving blood clots and allow more than a dozen countries that halted its use to add it back into their arsenal against the resurgent coronavirus.

The halt, however, was never justified. The EMA press release make this clear because it hasn’t added much more information it only underlines what we already knew. Namely, there was no increase in the overall risk of blood clots. There might be an increase in a very rare type of blood clot but that wasn’t obvious, especially when one takes into account that when you are monitoring hundreds of rare side effects it’s bound to be the case that some show statistically significant effects even if there are no true effects. As a result, the more conditions you test the higher standards you should apply to judge a difference as statistically significant (ala Bonferroni Correction which the EMA does not appear to have done). Moreover, even assuming that the rare vaccine effects were real they were thousands of times less than the effects of blood clotting from COVID itself so if you wanted to avoid blood clots the way to do so was to take the vaccine. Moreover, even assuming that the rare effects were real, they were not larger than those from other common activities such as flying or taking contraceptive pills. Moreover, and this point does not seem to have been made prominent, the most plausible argument for the vaccine creating blood clots is through the generation of the spike protein, which all the vaccines do, so there is little reason to believe that the Pfizer or Moderna vaccine would not also have the same problems (which they might). Thus, the focus on AZ seemed oddly misplaced. Draw your own conclusions on that.

The end result is that more people will die from the halt than could possible have been saved by the halt. Why did this happen? One reason is the absurd focus on doing anything to alleviate “vaccine hesitancy.” To alleviate vaccine hesitancy we have repeatedly sent the message that the vaccines are “safe, safe, safe.” When we should have said the vaccines pass a cost-benefit test (with flying colors!) and are much safer than many drugs people take for less serious conditions. But every drug or vaccine has side-effects. Tradeoffs are everywhere.

Unfortunately, vaccine hesitancy seems to have become a catch-all excuse for never having to show your work with a cost-benefit analysis. As I said in my post Don’t Delay a Vaccine to Allay Fear (should have said don’t halt one either!):

We should not let public policy be guided by the most risk averse, fearful, and scientifically illiterate among us.

[And]… rather than alleviating fear, delay may increase fear. People may reason, if the FDA is taking this long to review the evidence when thousands of people are dying every day it must be a hard decision.

The latter point, of course, is exactly what has happened. The EU halt has increased vaccine hesitancy rather than alleviating it.

Addendum:

  • Feb. 2: France restricts AstraZeneca vaccine to those aged less than 65 years of age.
  • March 2: France approves AZ vaccine for all ages.
  • March 19: France recommends AstraZeneca vaccine only to those aged more than 55 years.

I guess 55-65 years of age is the sweet spot.

How bad is EU bungling? So bad, Paul Krugman and I are in agreement. He almost quotes me on “Progressivism: The haunting fear that someone, somewhere, may be making a profit.”

A simple plan for sick leave

With Covid as a prompt, but not only because of Covid, it is worth thinking about the economics of sick leave more seriously.  How about this for a purely private solution for face-to-face workplaces?

Give each full-time worker three sick days each year.  It is not only “paid” sick leave, rather you are paid an extra bonus to take those days.  That way you do not bring a cold into the office.  On net, it now becomes more than culturally acceptable to plead sickness.  Most people will be doing it, and without shame.

Other components of the wage package can adjust to keep the net real wage constant.

Some very hardy individuals still won’t take any sick days at all, and many of them will love working.  In fact they should be “taxed” somewhat more, since their intangible benefits from working are so high.

If some individuals allocate their sick days to days when they are actually sick, workplace transmission of illness will decline, to the benefit of productivity.  And a general norm is set that may make it easier to deal with the next pandemic.

The importance of superspreading events

Empirical observation throughout the SARS-CoV-2 pandemic has shown the outsized role of superspreading events in the propagation of SARS-CoV-2, wherein the average infected person does not transmit the virus. Our results suggest the same dynamics likely influenced the initial establishment of SARS-CoV-2 in humans, as only 29.7% of simulated epidemics from the primary analysis went on to establish self-sustaining epidemics. The remaining 70.3% of epidemics went extinct…Furthermore, the large and highly connected contact networks characterizing urban areas seem critical to the establishment of SARS-CoV-2. When we simulated epidemics where the number of connections was reduced by 50% or 75% (without rescaling per-contact transmissibility), to reflect emergence in a rural community, the epidemics went extinct 94.5% or 99.6% of the time, respectively…The high extinction rates we inferred suggest that spillover of SARS-CoV-2-like viruses may be frequent, even if pandemics are rare.

Here is the paper, via the excellent Kevin Lewis.

Pandemic sentences to ponder

Of course, there are national health systems in Canada, Mexico, England, and France, among many others, and the uniformity of failure across this heterodox group suggests that structure may have made less of a difference than culture.

“One of the common features is that we are a medical-centric group of countries,” says Michael Mina, a Harvard epidemiologist who has spent the pandemic advocating for mass rollout of rapid testing on the pregnancy-kit model — only to meet resistance at every turn by those who insisted on a higher, clinical standard for tests. “We have an enormous focus on medicine and individual biology and individual health. We have very little focus as a group of nations on prioritizing the public good. We just don’t. It’s almost taboo — I mean, it is taboo. We have physicians running the show — that’s a consistent thing, medical doctors across the western European countries, driving the decision-making.” The result, he says, has been short-sighted calculations that prioritize absolute knowledge about everything before advising or designing policy about anything.

…in East Asia, countries didn’t wait for the WHO’s guidance to change on aerosols or asymptomatic transmission before masking up, social-distancing, and quarantining. “They acted fast. They acted decisively,” says Mina. “They made early moves. They didn’t sit and ponder: ‘What should we do? Do we have all of the data before we make a single decision?’ And I think that is a common theme that we’ve seen across all the Western countries—a reluctance to even admit that it was a big problem and then to really act without all of the information available. To this day, people are still not acting.” Instead, he says, “decision-makers have been paralyzed. They would rather just not act and let the pandemic move forward than act aggressively, but potentially be wrong.”

This, he says, reflects a culture of medicine in which the case of the individual patient is paramount.

Here is more from David Wallace-Wells, interesting throughout and with a cameo from yours truly.

The Chinese vaccine passport uses relative prices

China raised the stakes in the international vaccine competition on Saturday, saying that foreigners wishing to enter the Chinese mainland from Hong Kong will face fewer paperwork requirements if they are inoculated with Chinese-made coronavirus vaccines.

The policy announcement, which covers foreigners applying for visas in the Chinese territory, comes a day after the United States, India, Japan and Australia announced plans to provide vaccines more widely to other countries.

Here is more from Keith Bradsher (NYT).

FDA Postpones Inspections Delaying New Drugs and Creating Shortages of Old Drugs

NYTimes: The Covid-19 pandemic has forced the Food and Drug Administration to postpone hundreds of drug company inspections, creating an enormous backlog that is delaying new drug approvals and leading the industry to warn of impending shortages of existing medicines.

…In an interview, F.D.A. officials said they sharply curtailed the inspections to protect their investigators, following guidelines from the Centers for Disease Control and Prevention, which discouraged federal employees from travel during the pandemic.

But some people in both industry and public health communities say that federal drug inspections are essential, and that the agency should bypass travel restrictions by taking precautions, including wearing proper personal protective equipment.

…In interviews, F.D.A. officials denied that the dramatic drop in inspections has slowed drug approvals. But a number of drug companies, including Spectrum Pharmaceuticals, Biocon Biologics and Bristol Myers Squibb, has issued statements noting deferred F.D.A. action because of the agency’s inability to conduct inspections.

  • In October, Spectrum announced that the F.D.A. had deferred action on its application for Rolontis, a treatment for cancer patients who have a very low number of certain white blood cells, because it could not inspect the manufacturing plant the company uses in South Korea.

  • In late December, Biocon Biologics notified shareholders that the F.D.A. deferred action on its joint application with Mylan for a proposed biosimilar to Avastin, a cancer drug.

  • Bristol Myers Squibb announced in November that the F.D.A. would miss its November deadline for taking action on a lymphoma treatment, lisocabtagene maraleucel because it could not inspect a third-party Texas manufacturing plant. The agency eventually did complete its inspection and approved the drug last month.

Grocery store workers are working, meat packers are working, hell bars and restaurants are open in many parts of the country but FDA inspectors aren’t inspecting. It boggles the mind.

Let’s review. The FDA prevented private firms from offering SARS-Cov2 tests in the crucial early weeks of the pandemic, delayed the approval of vaccines, took weeks to arrange meetings to approve vaccines even as thousands died daily, failed to approve the AstraZeneca vaccine, failed to quickly approve rapid antigen tests, and failed to perform inspections necessary to keep pharmaceutical supply lines open.

I am a long-time critic of the FDA and frankly I am stunned at the devastation.

Why vaccination passports probably won’t work well

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

One issue is what exactly constitutes proof of vaccination. For my vaccinations, I have been issued a rather flimsy, easy-to-forge paper document from the Centers for Disease Control. Unlike a passport or a dollar bill, it has no embedded watermarks or other protections. Anyone with a moderately sophisticated copy machine could create many fake documents, or perhaps steal an existing stash of these documents and sell them on the black market. Once you have the documents, you can simply note that you have been vaccinated, and it is not easy for outside parties to dispute such claims.

Soon enough, of course, it may be easier for most adults to get a vaccine than to forge a vaccine passport. Still, U.S. laws and regulations work better when they can refer to clear, verifiable standards of evidence. It is hard to imagine a set of laws or procedures based on criteria so loose that they basically allow anyone to claim they are vaccinated. A more stringent standard, however, would be hard for most vaccinated Americans to meet.

Another knotty question is which vaccines will count for the passport. Pfizer’s, Moderna’s and Johnson & Johnson’s for sure, but what if you are a U.S. citizen living in Canada who received AstraZeneca’s vaccine, which has been approved by some 15 nations but not the U.S.? Is the federal government willing to tell a whole class of responsible individuals that they cannot fly on U.S. planes? Or will the vaccine-passport bureaucracy be willing to approve vaccines that the Food and Drug Administration will not?

These dilemmas can become stickier yet. What about Sputnik, the Russian vaccine, or the numerous Chinese vaccines, which are being administered around the world, including in Mexico?

Do Americans really wish to create a country to which most foreigners would not be very welcome? Furthermore, what counts as proof of foreign vaccination? Some Asian countries, including China, are creating elaborate and supposedly secure vaccine verification systems, using advanced information technology. Good for them — but how would that connect with U.S. regulations? How many different passport systems would a flight attendant or gate agent have to read, interpret and render judgment upon?

The likely result of all this: Many foreign visitors to the U.S. would never quite know in advance whether they could board an airplane or attend a public event.

And how would the passport reflect any new vaccines deemed necessary? What if new Covid-19 strains require booster shots? What if you’ve had Covid and thus get only one shot for now rather than two, as many experts are recommending? What will happen as the number of vaccines around the world proliferates? Given the slowness of the FDA and CDC, it is hard to imagine any new U.S. approvals coming quickly. A vaccine passport system could end up being fetters not only for foreigners and anti-vaxxers but also for vaccinated Americans.

Recommended, there are additional arguments at the link.

My excellent Conversation with John Cochrane

Here is the audio, transcript, and video.  So many good parts it is hard to excerpt, here is part of the summary:

John joined Tyler to apply that habit of mind to a number of puzzles, including why real interest rates don’t equalize across countries, what explains why high trading volumes and active management persist in finance, how the pandemic has affected his opinion of habit formation theories, his fiscal theory of price level and inflation, the danger of a US sovereign debt crisis, why he thinks Bitcoin will eventually die, his idea for health-status insurance, becoming a national gliding champion, how a Renaissance historian for a father and a book translator for a mother shaped him intellectually, what’s causing the leftward drift in economics, the need to increase competition among universities, how he became libertarian, the benefits of blogging, and more.

Here is one bit from John:

COCHRANE: You ask two questions here. One is active management, and the other is trading. I’d like to distinguish them. It’s a puzzle in the Chicago free market sense.

Let me ask your question even more pointedly. If you believe in efficient markets, and you believe in competition, and things work out right, we’ve scientifically proven since the 1960s, that high-fee active managers don’t earn any more than a proverbial monkey throwing darts in a well-managed slow index. So why do people keep paying for high-fee active management?

Chicago free market — we’re not supposed to say, “Oh, people are dumb for 40 years — 50 years now,” [laughs] but there’s a lot of it. It’s one of those things. Active management is slowly falling away. The move towards passive index investment is getting stronger and stronger.

There’s a strong new literature, which I’ll point to. My colleague here, Jonathan Berk, has written some good articles on it. This is the puzzle of efficient markets. If everybody indexed, markets couldn’t be efficient because no one’s out there getting the information that makes markets efficient. Markets have to be a little inefficient, and somebody has to do the trading.

Your second question is about trading. Why is there this immense volume of trading? When was the last time you bought or sold a stock? You don’t do it every 20 milliseconds, do you? [laughs]

I’ll highlight this. If I get my list of the 10 great unsolved puzzles that I hope our grandchildren will have figured out, why does getting the information into asset prices require that the stock be turned over a hundred times? That’s clearly what’s going on. There’s this vast amount of trading, which is based on information or opinion and so forth. I hate to discount it at all just as human folly, but that’s clearly what’s going on, but we don’t have a good model.

Self-recommending.