Boosters and Nocebos

Harlan Krumholz: Hello everyone, welcome to Health & Veritas. I’m Harlan Krumholz.

Howard Forman: And I’m Howie Forman. Harlan and I are doctors and professors at Yale University and we’re trying to get closer to the truth about health, healthcare, and much more.

Harlan Krumholz: So, Howie, this is our first episode, maybe we should also share a little bit about why we’re doing this. I mean, there are a million podcasts out there, but you and I thought that maybe this could be helpful.

Howard Forman: I’ve always admired your work and scholarship in the area of understanding both the interpretation of and the generation of data to provide improvements and evidence. And I personally am a teacher at heart, and it’s really important to me that the public have a better understanding of everything around them and not just answering to physicians, public health officials, and others who tell them what to do, but to be able to ask and have answered questions that allow them to be more informed about why and what they do in their own health and healthcare and their family and friends’.

Harlan Krumholz: Oh my gosh, that was too nice about me. It makes me feel guilty like I was fishing for a compliment, but that was nice. But you know I have deep admiration for you and you’re an esteemed teacher who has influenced so many people.

I think both of us, as we got together, thought that there was space for a podcast that would explore the evidence and synthesize information and help people to understand the context in which this information is being generated and how it might be applied. We see so much misinformation—you and I are sort of the nexus of healthcare, just given our positions where we’re listening to people, other academics, industry, government; we’re privy to a lot of different conversations. And I think sometimes we’re frustrated that the kind of information that gets out there may not be in the best interest of people in society. And maybe this can be a small contribution that helps people to gain some insight into some of the news that’s coming across in health and healthcare and help everyone to make better choice about themselves or families, people they care about, and also just to learn.

Howard Forman: So, Harlan, one of the things that I hear about every day from friends, family, colleagues, from news media are questions about booster shots. What are you hearing and what are you thinking about now?

Harlan Krumholz: Well, isn’t this such a complex topic? It actually hit me personally a couple weeks ago when my mother called me and said that she was scheduled at CVS to get a booster shot. I was pretty surprised because the FDA had waited on this, the Biden administration had talked about that they would make a decision in October. The way it must have worked was she called up CVS and just said, “I want to get a vaccine.” I mean, I’m not sure that they even knew that this was a booster shot, but she sort of had scheduled herself that way. And my sister jumped in and said to her, well, she had heard from someone else who heard from someone else who knew someone at the CDC that people should hold off on the booster. So she told my mother not to do it. My mother calls me up, her son, the doctor, and says, “What should I do?”

And then we’re also in the midst of a lot of discussion around what’s it like for Americans to be boosting themselves when there’s so many people around the world who don’t even have the opportunity to get the first series. And by the way, meanwhile, we have people who aren’t even being vaccinated here in this country, even with an abundance of vaccines in the first place. So yeah, it’s a confusing topic.

Howard Forman: It’s amazing. It really brings up and highlights the issues of tradeoffs, both sort of individual tradeoffs and population health tradeoffs, and then global health equity tradeoffs. I saw somebody on Twitter making sort of a passionate argument about the fact that the first vaccination of an individual in Sub-Saharan Africa is so much more of a compelling healthcare and health argument than is the third shot for somebody in America. And I do think that we have an obligation as global citizens to be able to factor that in.

But similar to you, I have elderly parents, both of whom are very healthy and participate in life, thankfully, even in their advanced stage. And they too came to me with the question about boosters; almost everybody they knew had already gone for boosters at that point. And we did collectively, with me weighing in but them making the ultimate decision, have them go for boosters. I’ve also had people much, much younger, people down in their 30s asking about booster shots and my opinion on that end of it is fairly strong where I don’t think it’s necessary at this point. And as I said to someone yesterday, come back and talk to me in six weeks. I might change my opinion if the data starts to really become compelling to make that case. But I don’t see it there right now.

Harlan Krumholz: One thing that I have found reassuring is that at the individual patient level, the boosters seem safe. I know some people may say, “Well, what’s going to happen in 10 years? What happens in 20 years?” I mean, we don’t really have experience that giving vaccinations and boosters like this do end up with long-term issues. And I think in looking at the short term, I’m buoyed by the fact that the safety data seems pretty good. That doesn’t change the calculus, I think, for younger people, because the younger you are, the lower the risk you are at an individual level, the less you have to gain from the vaccine. And so I think this leads to a whole ’nother challenging discussion about the vaccination of children and what we should be doing there, but it’s all part of this same kind of conversation, which is more about society in deference to the individual and saying if we can get everybody vaccinated and we can slow the spread, then we can emerge from this pandemic in a different era.

And I’ve always thought maybe that we’re not going to eliminate the pandemic, but if we can get it down to a bad flu season, if the harm is something like flu season, we’re used to that. I mean, not that we tolerate, not that we wouldn’t want to get rid of it, but we can operate as a society in a bad flu season without shutting down or fundamentally changing our lives. Probably, by the way, after this in a bad flu season, we’ll be even more responsible than we’ve been in past flu seasons; we’ll wear masks or do other things to try to slow a bad flu season.

But we have a history in the country of people making sacrifices for the greater whole. I mean, the net benefit of somebody storming Normandy, I’ve said this many times, was not in that person’s favor, but they were part of something larger than themselves in order to protect the world from what we believed would’ve been a catastrophic, if we had lost, World War II.

Howard Forman: Look, from the beginning of the pandemic, we’ve had a very difficult time conveying to people that your actions are going to impact other people. And it’s not just about yourself, it is about the collective good, whether it’s about masking, social distancing, whether you go out to a community event when you already know you have symptoms of something, even if you don’t know that you have COVID—all those things have drastic impacts on people around you and ripple effects, right? One person could set off a chain that ultimately leads to 150 or more infections as we’ve seen throughout the world in super-spreader events. And now with the vaccine, it’s the same type of calculus. If we knew that the vaccine was offering sterilizing immunity, it would even be more compelling, but it does offer a substantial reduction in transmission based on the evidence that we have right now and we have to continue to do the work to convince people and help them understand what their role is in blocking the transmission chain.

One of the reasons why I do wonder about boosters for younger individuals in the future, not now, is what would happen if for instance we do start to see a massive wave building in the Northeast as fall progresses. If we see a massive wave building, it may become more necessary for us to advance the cause of boosters for everybody in order to reduce transmission more substantially. And so I wonder about how we’re going to make those decisions. Right now in the Northeast, we’ve got the outbreak relatively under control and so it’s a lot easier for me to sit here and say, elderly people need to look out for themselves, reduce their risk of severe disease, hospitalization, death, and those that are immune-compromised the same way. Perhaps those that have higher risk for severe disease, but are non-elderly, non-immune compromised. But everybody else, I can’t make a good case for booster shots when I know that those shots could be used elsewhere. But will that change over the next few weeks? I’m completely open to that possibility.

And this is why we have to continue to follow the evidence as it emerges. And we get more evidence every day about things like Pfizer’s efficacy, Pfizer’s effectiveness, Moderna same thing, and now Johnson & Johnson with new news yesterday.

Harlan Krumholz: So are you already sold completely on mandates for children for vaccination? Of course now we’re just getting new data on down to five years old now, but we’ve had data and in my town, I was surprised to see that the school aged kids above 12 and above, 90% had been vaccinated. So at least in my community it had been firmly embraced I think without a specific mandate, but with strong encouragement. But I don’t think we’ve gotten to the point where kids can’t go to school if they’re not vaccinated, but it’s become normative. But what do you think about that across the country? And do you have a view on this younger age group? We haven’t been in much debate about vaccines for a long time. I mean, there are mandates for vaccines for kids, I mean MMR and so forth.

Howard Forman: And so to me, when I look at the data right now, I’m convinced that 12 and above, the benefit to the individual outweighs the risk to the individual with a tiny asterisk that some people quarrel about 12-to-16 year old males. But I think the evidence is still compelling down to 12 years for all groups that the net benefit to the individual exceeds the net risk to the individual and therefore the compelling additional benefit to the community of them being vaccinated really swings things all the way over. And so I can be very supportive of mandates in that population as part of a public health strategy.

Below 12, I haven’t seen the data enough. So, for instance, we only have a few thousand cases, a few thousand vaccinated children, to really look at reference wise. I believe based on what I know that it’s going to be the same thing, that it’s going to be that the net benefit exceeds the risk; even though in children, the risk is really, really low of COVID, I think the risk of the vaccine is going to be similarly extremely low. So I think there too, it probably will be compelling, but I have not seen that actual data, even though I know that Pfizer released the beginning of the data from their trial on children. I do think that if we could get mandates in place for those to 12 and then allow it to be people’s options below that, we would still make a lot of progress.

Harlan Krumholz: As we roll out to younger kids, which I believe will be part of the next tranche, we need to strengthen our data systems in this country. So, we need clear early warning. If there is any indication of an issue, we ought to be able to get to it next day. And right now, our data systems and safety surveillance systems are just not strong enough. And so we’re depending on self-report—the VAERS system with CDC, it requires active data collection and reporting. It’s often not verified, it’s just hard to sort through and figure out what to make of it.

And if anything, I think this country has to realize that we need to strengthen these data systems in order to be able to give people up-to-the-minute feedback on what’s happening as we roll out to new populations, we start treating people. We should get smarter with every person vaccinated. We should be able to get that data in and be able to report it back to the public in a transparent way, and also manage expectations. It’s not going to be zero, but realize that the alternative is worse and that’s what we’re talking about.

Howard Forman: And just look, I mean, you look at places like the UK and Israel which have more nationalized forms of healthcare and collection of data, they’re lapping us in terms of analysis of cases, side effects, in terms of outcomes, they are providing some of the best information out there for us. We’re supposed to be the greatest nation on earth, but we’re constantly letting other nations lead us in this way, because we’re just not equipped to do that. So I completely share that opinion.

It reminds me, though, when you talk about the side effects and our ability to track side effects, you mentioned to me in the past week about this nocebo trial, this statin muscle pain trial. I’ve been on statins for, I think, probably almost 20 years now. Statins lower your cholesterol; they’ve been proven over time to have population health benefit, reducing cardiovascular disease. They’re really an important intervention, but a lot of people—and you know this much better than I do because I’ve always tolerated it—but you know as a clinician that some patients seemingly can’t tolerate it. And I loved hearing about this, you highlighted it for me. Do you want to speak a little about that trial and why it actually does relate to our tracking of vaccines and side effects?

Harlan Krumholz: Yeah. And I think this goes in this context of when people who don’t study this stuff for a living, and I’m just talking about now COVID for example, that sometimes individual reports get weighed very heavily and they’re not put in the context of what is exactly the rate that this is happening, and the need to sort of systematically generate the evidence that can lead you to make informed choices about your health and for those who depend on you. And you’re raising another issue, which is outside of a controlled study, sometimes things that are reported aren’t necessarily related to the things that they relate to. And so there’s a study published in one of the leading heart journals in circulation, which was a brilliant study that’s from a friend of mine, Darrel Francis, who’s a brilliant clinician and scientist.

As you may know, a lot of people who go on statin drugs—which are remarkable drugs, they reduce risk by maybe 25, 30%, lower risk of heart attacks and strokes and deaths and it’s one of the great breakthroughs of our time—but yet there are many people who discontinue them because they end up complaining of a wide variety of ailments and most prominently muscle aches or what we call myalgias, where they feel that they’re restricted in their exercise capacity.

What Darrel and his team did was they took a bunch of people who had discontinued statins and said, “I’m intolerant to them. When I took them, I had bad reactions,” and they enrolled them in a study and they convinced them to give this study a try. And what they did in this study was they said, “We’re going to treat you over a year and every month we’re going to give you a different pill.” And then they were going to randomize that so that on some months you’re getting the statins and on some months you weren’t, and then they would see, how did you feel that month? And then it had a third arm to it, which was in some months they didn’t give you anything. So when I didn’t get anything, I know I’m not taking a statin. When I’m getting a pill, I know I’m either taking a statin or placebo, but I don’t know which.

But when they were taking the pills, they had a marked increase in the number of these symptoms. Interestingly, they had them whether they were taking the statin or the placebo pill. And then when you call this word nocebo, it’s used to describe the fact of—placebo, we think of giving people a pill and sometimes having a beneficial effect; I thought I was on something that was going to make me feel better. Nocebo is sometimes you take something, you think it might be bad for you and you end up getting a side effect from it. And so sometimes the months were the same, discontinuing the nocebo pill and going into a no pill thing, actually their symptoms got better. And so it didn’t matter if it was a statin or it was the fake pill, when they stopped it, their symptoms improved.

So in practice, you might say, “I know this statin’s causing this problem because I put them on the statin and the symptoms started and I took them off the statin and it ended, and that’s pretty good evidence for me that the statin is causing the problem.” But in this study where people didn’t know if they discontinued the fake pill, they got better. If they started the fake pill, they got worse, just like they did on the statin.

So I guess all this is to say that it took a study like this to disentangle the fact that once people are starting to get worried that something might cause a problem, then the next thing you know, they’re actually complaining of that problem. And in this study, it showed even if it’s a fake pill, they started manifesting symptoms that people associated with statins. Bringing this back to vaccinations in everyday practice, if the people start hearing a lot about vaccinations causing this or that, it’s highly likely that some people would manifest symptoms. Actually, when you looked at the trials, that was true that people who didn’t get the vaccine, many of them had reactions that you would’ve associated with getting the vaccine. And you could only tell what the incremental issue of harm or benefit of the vaccine was because you had randomized them within the study.

So, sorry, that’s a little bit of a long explanation, but it’s just showing again why it’s so difficult to untangle these things and for a lay person just hearing about a single report of somebody who all of a sudden felt awful or whatever after a vaccine, you really have to look at this in a bit of a different way in order to get a sense of whether the vaccinations are really causing that and to what extent they’re causing it.

Howard Forman: In a future episode, I’d love to hear more about your thoughts about how we spend billions of dollars every year on clinical trials funded by private for-profit companies but we really don’t do nearly enough of this type of very small trial that gives us very important answers about, in this case, atorvastatin or what used to be called Lipitor, and probably applies to all the statin drugs.

Harlan Krumholz: So, Howie, I know we’re getting to the end here and we’re going to kind of leave with parting shots that we kind of divide this up. You were going to say what keeps you up at night and I was going to say what’s made me feel good in the last couple weeks. So let’s share a little bit, so what are the things? And let’s say non-health things, so we just leave the audience outside of all this discussion about health and maybe this is about wellbeing. So what’s disturbing your wellbeing these days? And I’ll tell you what’s elevating mine.

Howard Forman: Yeah. Look, the political division that prevents us from addressing climate change, immigration—which is a massive problem and too many people live day to day not knowing whether they get to stay here or they leave, we have a large number of people at the border as we speak right now. And even infrastructure, which is so obvious and necessary, is just in limbo because of political division. Those things drive me mad because I think that the vast majority of the population could easily come to consensus on solutions for those, even if they wouldn’t necessarily appease the extremes in either party, and we still can’t get there. And that frustrates me a lot. I spent a year working in the Senate 20 years ago, and people told me things were bad then, but things have just gotten so much worse. I’m hoping for better times ahead because I do think that this nation is a great nation and that we could tackle these big problems if we put our heads together, but division seems to prevent that right now.

Harlan Krumholz: Yeah. I think that’s in this theme of our biggest threat is ourselves. And our biggest limitations is ourselves. The question is whether the country can come together.

I was going to share with you, I thought the one thing that buoyed my experience, made me feel better in the last couple weeks, was that U.S. Open in New York, the tennis tournament. I’m, I guess, a casual fan, but I couldn’t help but to be drawn into the women’s bracket and to see that to the great surprise of everyone, one really low-ranked individual and another one who wasn’t ranked at all who came up through the qualifiers, surprised everyone. And so you had an 18-year-old and a 19-year-old that I think before the U.S. Open few people had noticed or talked about fighting for the championship and doing so with a verve and a fearlessness and a courage. I mean, they’re on the main court and they played a marvelous match.

And I just thought it was so funny at the end, they’re being interviewed and I’m thinking most people 18 and 19, I mean, you’re trying to be the best player on your high school tennis team, or you’re maybe trying to get to the state tournament and then these two people are… I found it a spark of happiness to see the unexpected triumph of youth. And I do believe that as you talk about these challenges for the future, the hope is in the youth and young people, and that they can have the good sense to be looking at the long game and trying to correct some of the errors and tribalism that has been so endemic throughout generations before them and help us move towards a society that’s fair, more just, and it is more together in what it’s trying to accomplish, recognizing that enemies like the pandemic are enemies that should unite us, not divide us. And too often, that’s just not the case, but hopeful still that the next generation will help.

Howard Forman: I’m back to teaching, in person right now, my undergrad class, and I’ll just echo that by saying that the young shall lead us, because I feel like when I talk to these students and I listen to their questions and I realize how capable they are, that they are up to this challenge. And I’m very optimistic of that.

We’ve come to the close right now and you’ve been listening to Health & Veritas with Harlan Krumholz and Howie Forman. How did we do? Give us your feedback, keep the conversation going. You can find us on Twitter. Harlan Krumholz is @hmkyale. And I’m @thehowie. Health & Veritas is produced with the School of Management at Yale. Talk to you soon, Harlan.

Harlan Krumholz: Yep, talk to you soon, Howie. It’s been fun to do it together and I look forward to future episodes.

Howard Forman: Thank you.