The FDA went ahead and did it, approving a fourth vaccine shot for those age 50 or older. This is a reference post for those wondering if it makes sense to get that second booster.

The FDA approved the second booster by bypassing some of the normal procedures. Usual never-amused suspects are not amused.

What do those meetings and ‘public discussions’ do?

  1. Delay.
  2. Get picky about lots of little details.
  3. List all the reasons not to do something.
  4. Voice objections for all to see.
  5. Show lots of concern over trivial risks.

The Official Public Health Position is that doing all this Enhances Trust In The Process.

They are incorrect. And here is where their idea of ‘trust’ has gotten us.

Are they working hard on earning our trust back? Not exactly.

Their ‘scientific rationale’ is exactly what you think it is.

None of that means the standard drug process is necessarily bad or worthless. The process is very good at sniffing out any little potentially wrong thing or reason not to do something, and hence good at avoiding false positives. Which is sometimes what you want.

If your goal is to do a cost-benefit analysis to decide what to do, then turning things over to people who think costs and benefits do not belong in the same magisterium, and allowing them to act Deeply Concerned about things, does not seem like The Way.

The process is hopelessly biased towards delay, inaction and risk aversion. It makes sense to bypass it.

Nor does it seem like The Way to get Enhanced Trust. Yes, a few people will say ‘look, you did not hold the Official Meetings’ but actual regular people do not care. If anything, those arguments are crowding out arguments regular people would care about more.

For those shouting from the rooftops that ‘they’ would have us take infinite boosters forever, this is vindication of a sort. Yet it remains not even approved for others, let alone required.

There are good arguments against the second booster. That is fine. We can let individuals make their own choices.

Review: Should You Get a First Booster?

My answer to this continues to be yes.

The original design of the vaccine, of two shots in rapid succession, makes sense if you are trying to quickly test and deploy a vaccine in the middle of a pandemic. Pfizer and Moderna absolutely did the right thing to test that protocol given the situation.

However, there is lots of evidence that spacing the two shots so close together hurts long term immunity. Many vaccines involve much longer times between shots. In the UK, there were debates worrying that some people might not understand the importance of waiting multiple months between shots one and two, because that would make the vaccine less effective. We really, really should have done First Doses First.

Tests reliably show the first booster getting antibody response to levels well above those from the first two shots.

While the full effect of the booster fades over time, there seems to be a persistent and substantial effect on one’s permanent level of immunity.

Thus, even if the short term side effects for you are relatively unpleasant and you are young and in good health, I would get the first booster shot.

If you know you have had Covid-19, that likely functions in many ways as if it were a booster, at which point boosting or not boosting would be a small mistake. I would still boost, and definitely still boost if I was at high risk, but it is no longer obvious.

Should You Get a Second Booster?

The more important question, of course, is: Should you get a second booster?

I want to emphasize that my current viewpoint is that both decisions here are at worst small mistakes.

If you do get a second booster, the costs are minimal, beyond the short term side effects of being knocked on your ass to some degree for 0-2 days. There is a small risk that you make your immune system slightly less flexible if things change, but that seems like a small downside as well.

If you do not get a second booster, you still have robust protection against Covid-19. For now risk is even lower because we are up against Omicron and case numbers are not so high. If there is a new more dangerous variant you can reconsider your decision.

Here is what Vincent Racaniello has to say when my father asked him about the second booster and the potential dangers of antigenic sin/seniority. He is a name-chair professor at CUMC and the first person ever to sequence an entire virus genome, as well as a family friend.

Hello Professor, good to hear from you. If you are not too afraid, we
should have lunch sometime. Teaching virology in person without masks!

Second vaccine booster for those over 50 – the science doesn’t support
it. Three doses is doing fine at controlling severe disease and
hospitalization. You will never prevent infection, unless you want to
boost every 6 months.  I’m not getting a second booster.

Original antigenic sin – it’s a possibility of course but we won’t
know until we deploy a variant-specific vaccine. In my opinion we are
not going to do this. Omicron is the most diverged of the variants,
escapes neutralization by serum from twice-vaccinated people, yet
severe disease is still controlled by the vaccine. I don’t see a
variant specific vaccine unless severe disease/hospitalization begins
to rise.

As you know, for influenza virus, once HAI titers go below a certain
level, we know that correlates with increased severe disease so we
change the vaccine. We have no correlation between antibodies and
severe disease for COVID. That’s because antibodies control infection,
while T cells control disease severity. And as you know, most of the T
cell epitopes are not changed in the variants like Omega.

It is my understanding that flu vaccines suck at inducing a good T
cell response, hence we depend on antibodies. Not the case for COVID.
The mRNA vaccines are great at inducing T cell responses.

He also had some harsh words about the Israeli data underlying the decision.

Here are the data in the Israel paper. If you think they mean anything
you’ve lost your mind. Plus they make no attempt to compare the two
populations with respect to co-morbidities. These data are
meaningless.

Among participants aged 60 to 69, death from Covid-19 occurred in 5 of
111,776 participants in the second-booster group and 32 of 123,786
participants in the rst-booster group (adjusted hazard ratio, 0.16;
95% CI, 0.06 to 0.41; P<0.001) (Table S2).

Among participants aged 70 to 79, death from Covid-19 occurred in 22
of 134,656 participants in the second-booster group and 51 of 74,717
participants in the rst-booster group (adjusted hazard ratio, 0.28;
95% CI, 0.17 to 0.46; P<0.001) (Table S3).

Among participants aged 80 to 100, death from Covid-19 occurred in 65
of 82,165 participants in the second-booster group and 149 of 36,365
participants in the rst-booster group (adjusted hazard ratio, 0.20;
95% CI, 0.15 to 0.27; P<0.001) (Table S4).

Really, 5 vs 32, 22 vs 51, 65 vs 149 and you are making policy for the
US based on this? This is insanity.

Those sample sizes certainly seem small, but I do not know what the alternative is when a decision has to be made. I do think they mean something, but I agree they do not mean all that much, and in the longer term they mean essentially nothing. Part of what they mean is that risk even for the group over the age of 80 was not so high, and for other groups it was much lower.

Andy Slavitt, former senior Biden White House advisor, comes out in favor of re-boosting (Twitter thread). Main arguments are potential reductions in Long Covid and in infecting others, and in getting back to ‘previous levels of protection’ in a future wave. No numbers that support getting re-boosted are cited, and I find the case here unconvincing.

I am not as down on the second booster or its supporting data as Racaniello is above. I also do not agree with the principle that we should wait for proof before allowing people to take potentially life-saving medicine, especially once safety has been established.

My guess is that if you take a second booster, the following things happen.

  1. You will have short term side effects similar to your first booster.
  2. For the next four to six months, you are more protected from Covid-19.
  3. This includes less infections, and less infecting others, less Long Covid.
  4. But from a baseline with robust protection versus hospitalization and death.
  5. Then the benefits will fade unless you boost again.
  6. No meaningful longer term impact, if anything tiny negative.

And that’s it.

Is it Worth It?

That depends on several factors.

  1. Severity of your side effects from the first booster.
  2. How old or unhealthy you are.
  3. Expected amount of Covid-19 in your area.
  4. Whether you already had Covid-19 especially recently.
  5. Whether there is a new variant worth worrying about.
  6. Whether we know the old vaccine works on that new variant.

My answer, for me, is no, I am not interested. The third shot was not too bad, but the next day was not especially fun, and I see little benefit. I do not intend to voluntarily get a fourth shot even if allowed and encouraged, unless we are facing:

  1. A new wave.
  2. From a new variant.
  3. Where the old vaccine works.
  4. But severity is higher.

That is also because I am young and healthy, so much so that I am not even currently eligible. If I was sufficiently old and/or unhealthy, I would have a lower threshold for boosting, but I would still wait until conditions were getting worse to better time the benefits.

Timing is Everything

Several times, I have heard people say that ‘trying to time the booster is like trying to time the stock market.’

And no, trying to time the booster is not at all like trying to time the stock market.

Trying to time the booster is more like trying to time buying a winter coat.

Stock market prices are anti-inductive. You can only time the market by outsmarting the market. Which is hard.

If there was a prediction market on future case numbers, and the only way to time your booster was to time that prediction market and make a good trade, that would also be hard.

You don’t have to do that. All you have to do is wait until cases are high and rising, and then get your booster. It takes a week to work. Noticing a wave at least a week before it gets bad, or at least a week before most of the cumulative danger you will face, is very easy.

The sense in which you have to ‘beat the market’ is the danger that everyone might be trying to get the booster at the same time when things are about to get bad, and fighting for limited appointment slots. That is potentially a concern, but given people’s reluctance to boost, I do not anticipate there being enough additional demand to cause much of an issue. Even if there is, you’ll have ample warning.

Bottom Line

  1. Cost of second booster is small.
  2. Benefit of second booster is small and temporary.
  3. If you’re at very high risk, maybe it makes sense.
  4. Either decision is at worst a small mistake.

65

17 comments, sorted by Click to highlight new comments since: Today at 5:41 AM
New Comment

For folks like myself interested in micro-optimizations that are very likely meaningless, but are nonetheless fun to think about: It's probably better to mix up boosters, right?

Currently scheduling the parents for theirs while I'm visiting (rather than trying to time it) and the current plan is to switch to Moderna from a history of only Pfizer. My understanding is the conventional wisdom is that it might be marginally better to get different vaccines instead of all one brand. The potential downside is they've both had excellent zero side-effect reactions from Pfizer, so switching to Moderna may be another roll-of-the-dice with side effects. Though I haven't looked at data as to whether side effects tend to differ between brands.

I fully realize the real answer is, it doesn't matter, but I'm on the web site and it's asking my which vaccine to get. I'm being forced to pick. It just feels silly to make a choice here without any recommendation, as a completely arbitrary decision.

Recommendation to mix: https://yourlocalepidemiologist.substack.com/p/fourth-dose-q-and-a?s=r

Consider mixing your fourth dose. If you got three doses of Pfizer then get Moderna for your fourth dose. Or vice versa.

While Moderna and Pfizer are both mRNA vaccines, they are not identical and have subtle but meaningful differences. (See my previous post: Moderna vs. Pfizer: Is there a difference?)

This was confirmed yesterday from another peer-reviewed study. Scientists found that while the two different shots have the same impact on neutralizing antibodies, they have a different impact on Fc-functional antibodies, which target the whole surface of the spike protein. They also had a different impact on T-cell mechanisms. If you mix vaccines you have the potential to maximize protection.

If you're not sure which to go for, or already mixed, I recommend defaulting to Moderna for additional doses. It seems to have slightly better durability. 

Both the parents are now 4th shot Moderna-fied. Interestingly, my mother had never had side effects from Pfizer doses but Moderna did produce one night of mild body aches.

I would perhaps also add that the first booster (which will be the third jab for many) seems to actually be important in the US?

I haven't fact checked the details (which come from a journalist maintained statistical model that I don't see how to access) but David Wallace-Wells of The Intelligencer writes:

In 2020, the U.S. had done a bit worse than average among its OECD peers. In 2021, when pandemic outcomes were often determined by the relative uptake of American-made vaccines, the U.S. did much, much worse than that. In country after country in Europe, the pandemic killed a fraction as many last year as it had the year before. In the U.S., it killed more. A year ago, it was possible to defend the American record as merely below average — worse than it should have been but not, judging globally, cataclysmically bad. Today, it is cataclysmically bad, which is both outrageous and ironic, given that it is largely American vaccine innovation that has changed the pandemic landscape for the rest of the world — the rest of the rich world, at least...

How did this happen? The answer is screamingly obvious, if also, in its way, confusing: The U.S. drove an unprecedented vaccine-innovation campaign in 2020, which empowered much of the world to turn the page on the pandemic’s deadliest phases, then, in 2021, utterly failed to take advantage of its power itself. But what is perhaps even more striking is that American vaccination coverage isn’t just bad, by the standards of its peers, but getting worse. About two-thirds of Americans have received two shots of vaccine, a level that is in line with Israel and not far off from the U.K., though below many other wealthy countries. (And even in the U.K., vaccination was more effectively directed toward the old.) But over the last six months, the country has had an opportunity to make up that gap with boosters and has simply not taken it. Only 29 percent of Americans have had a booster shot of vaccine, which puts us behind Slovenia, Slovakia, and Poland and means that less than half of those people happy to be vaccinated a year ago have chosen to get a third shot through Delta and Omicron. Booster campaigns seem like an obvious opportunity for easy public-health gains, yet remarkably few Americans seem to think it’s worth the trouble.

My own hunch is that "remarkably few Americans have adequate healthcare in our disaster of a health system (which is systematically broken (due to various modes of regulatory capture (because of visceral contempt for normal Americans by elite Americans)))"...

...however the article does a pretty decent job of dancing around offending anyone by saying too much that is too controversial.

Whatever the causation, as a practical upshot, it does seem worthwhile to notice that, in terms of Bravery Debates, it seems plausible to me that the median American probably still would be helped by hearing and being convinced that it would cost relatively little and lower the chances of serious symptoms (up to and including death or brain damage) to get their FIRST booster.

Most of my uncertainty about what might actually help people... is based on the possibility that quite a few people in the US have probably had no vaccine, but multiple covid infections, and I have a gap in my model about the "personalized healthcare outcome predictions" for subpopulation more like this than like the people I usually interact with in my social bubble (who have mostly already boosted, with many also not yet having definitely had covid even the once).

Are people really not getting boosters because we have a bad healthcare system? Boosters are free and available pretty much everywhere. It is not hard to get a booster, even if you're poor.

I think the lack of booster uptake has more to do with political and social attitudes than our bad healthcare system.

I admit that there's an element here of the question involving "macrofacts" and a sort of game of chicken between stupid voters and evil politicans.

My claim is something like: if the health care system's main challenges weren't trust, paperwork, followthrough, adherence, price discrimination, and other essentially economic and communication problems (which the US sucks at)...

...then the main problem might finally about medical technology (which the US is good at), and the is/ought gap between possible and actual health outcomes would be smaller, and achieved for a smaller percent of GDP.

I don't blame the wage slaves, I blame the wage masters. 

If you built a causal model, I think it would be possible to DO() some variables (that represent either or both of the choices of the wage slaves vs the wage masters) to CAUSE better aggregate outcomes.

But I think if you look back 20 years, or forward 20 years, total number and cost of the DO() operations to get better health outcomes would be minimized if we spend it on things like:

DO("congress passes and the president signs a repeal of the Kefauver-Harris amendment") and 

DO("the insurance industry and medical diagnosis processes and hospital systems are jointly reformed"),

and DO("we delete the CDC that works on 'whatever public health means to them now' and instead 'actually fight communicable diseases' by testing people at the border n'stuff")?

It would take more than 1 piece of structural legislation, I grant. 

The cost in bribes and threats to change the behavior of various negligently oblivious congress critters (to make them redirect trillions from "pointless waste and fraud" to "something sane") might be millions and millions of dollars.

And maybe the momentum has built up in the wrong direction and can't be fixed in a single 5 year period?

Image source.

Deciding that the problem is the stupid patients acting stupid is (to me) like deciding the government should elect a new people... it is fundamentally upside down.

The suffering of many people (which is, tragically, baked in at this point) should be used as the fuel to fix the bad laws that prevent us from building a new system while the old medical system burns to the ground.

Every time I hear someone start preaching to be about single payer, I want to say "Good idea, but maybe we can start with single regulator?"

It is a good one liner :-) I'm not sure how that unpacks into policies, or of those policies would cause more healthy life for less money. Is this a slogan for an extended idea that you can link to?

In our current landscape we've got an insurance/banking regulator in every state, plus DC and Puerto Rico. Then there's the US DOL, that regulates self-funded employer plans (ERISA). Then there are local, state, and federal employee/retiree plans. Then Medicare and Medicaid, which fall under CMS. Finally there's the wild west of plans offered by religious employers, which aren't under the jurisdiction of any administrative agency (if you exhaust your internal appeals your only recourse is the courts). This state of affairs is largely due to the McCarran-Ferguson Act, which asserted that insurance was the exclusive jurisdiction of the states (in response to a SCOTUS decision that said otherwise). So we're left with an insanely inefficient patchwork in which large insurance companies shop for jurisdictions that make it as easy as possible for them, and as opaque as possible for customers. I think if we simplified regulation of insurance, we'd have less of a pressing need for single payer.

I haven't seen booster net efficacy assessed in an honest way, since they often exclude events for the first 2 weeks post-boost. Agree that we should expect a small effect only; I would approve for whoever wants and leave it at that.

Epistemic status: I'm not particularly knowledgeable about this and haven't spent the time to dig into it to verify that my memory is correct, or to write it up well. I also don't remember what the specific Peter Attia podcast episode is. However, I do feel pretty confident (~95%) that my memory is correct, and similarly, that the broad strokes of what I'm saying is correct.

I remember listening to a Peter Attia podcast a few months ago. He and his guests were talking, and I remember them saying how the booster doesn't really protect against serious illness or death, just infection. They may have also been making this point about second doses as well.

Part of it was that they were saying that this is what the data show, but part of it was them saying how it makes sense at the gears level as well.

Thinking back to high school biology, the idea is that the first time your body sees something, it builds up those (memory?) B cells and T cells and stuff. If you subsequently get infected, it takes some time for those cells to mobilize, but once they do, they are extremely powerful and will prevent serious illness and death. But because they take a long time to mobilize, they won't prevent infection itself.

On the other hand, antibodies are like the opposite. They are weaker, but are always swimming around/fast to mobilize. So they help you not get infected at all (or I guess if you do get infected they fight it off so fast that it's like you weren't actually infected maybe). Second shots and boosters give a boost in antibodies, and thus protect against infection. But the antibodies only hang out for so long. Eventually after some amount of months they decide they're not needed and disappear. Hence the temporary benefits of boosters.

What would you estimate the severe (e.g. CFS, out of work) Long COVID risk to be conditional on infection, assuming no new variants that significantly increase risk and if you don't get a second booster?

Or, how much immunity to Omicron would we have in the long run?

To me the most compelling reason to let people go ahead and get all the boosters they want, at this point (as long as they're reasonably safe) involves going back to the basic function of government: managing human conflict. For over half a year now, the principal axis of conflict has been between people who won't get vaccinated and people who will (and want more protection from those thar won't get their shots). At this point, the best way to settle this would be to move towards a boosting-free-for-all, with clear communication that (1) You should really get your first shot if you haven't already, and if you haven't yet, that's a you problem (2) If you're worried about being beset on all sides by inadequately vaccinated people, that's also a you problem, help yourself to a shot (3) If there's a need for any sort of prioritization, make it "virtual" - if you book an appointment and someone in a higher priority score wants your slot with a 48 hour notice, you get bumped

My suspicion is that vaccine doses are way more fungible than we think they are, and the focus should always have been matching willing arms with doses. What was a hard public health problem is mostly a banal manufacturing problem - rapidly creating covid-hardy humans.

"The sense in which you have to ‘beat the market’ is the danger that everyone might be trying to get the booster at the same time when things are about to get bad, and fighting for limited appointment slots. That is potentially a concern, but given people’s reluctance to boost, I do not anticipate there being enough additional demand to cause much of an issue. Even if there is, you’ll have ample warning."

That, and it's not a zero sum game. If there's a mad rush to get boosted right before a wave, that's going to have the aggregate effect of making that wave into more of a ripple.

Stock market prices are anti-inductive.

-> The link for "anti-inductive" is broken, but should maybe link here.

I think finding the correct link required a good heart. In the hope Zvi will see you, I am commenting to further boost visibility.

The cost of Covid is not just unlikely chronic effects, nor vanishingly-unlikely-with-three-shots severe/fatal effects, but also making you feel sick and obliging you to quarantine for ~five days (and probably send some uncomfortable emails to people you saw very recently). With the understandable abandonment of NPIs and need to get on with life, the chance that you will catch Covid in a given major wave if not recently boosted seems pretty high, perhaps 50%? (There were 30M confirmed US cases during the Omicron wave, and at least for most of the pandemic confirmed cases seemed to undercount true cases by about 3x, which makes 27% of the US population despite recent boosters and NPIs.) 100% chance of losing one predictable day (plus perhaps 5% chance of losing five days) seems much better than 50% chance of losing five unpredictable days.

Which is why insurance companies should be encouraged to start underwriting the cost of quarantines. With a discount for people who get vaccinated.