Podcast: What’s up with boosters?

Jim Dryden (host): Hello and welcome to “Show Me the Science,” conversations about science and health with the people of Washington University School of Medicine in St. Louis, Missouri … the Show-Me State. As we continue to detail Washington University’s response to the COVID-19 pandemic, in this episode we look at boosters. Although some cities and states have approved boosters for basically everyone, the official recommendations cover mainly older people, those with compromised immune systems, and people whose occupations put them at risk. Dr. Rachel Presti is the medical director of the Infectious Disease Clinical Research Unit and co-director of the Center for Vaccine Research at Washington University.

Rachel Presti, MD, PhD: Thus far, we’ve been pretty lucky. So of the variants that have circulated widely, the only one that, in the test tube, seems to be resistant to the immunity that you get from the vaccine is the beta, which for whatever reason isn’t actually circulating at very high rates. The immune response to the vaccine is effective against delta.

Dryden: Presti says people who qualify to get boosters, something that differs from city to city and state to state, should get them, especially as colder weather and holiday family gatherings approach. And Dr. Alfred Kim, a rheumatologist who treats people with weakened immune systems, says that although 90% of patients with compromised immune systems do make antibodies in response to vaccines, most don’t make quite as many.

Alfred Kim, MD, PhD: We don’t have clear definitions of immunologic sufficiency in terms of magnitude of responses. What we have shown is that roughly about 90% of the people who are immunosuppressed with a systemic autoimmune disease have antibodies post-vaccination. But when you look at the bulk of the people and the level of antibodies, it’s about threefold down.

Dryden: Recent data does show, however, that for people who don’t have compromised immunity, a third shot does improve protection, so much so that some states are now recommending that every adult get a booster. Presti says that’s still not the federal government’s official position, but that’s not because the boosters don’t help.

Presti: They could be beneficial, but I think they’re trying to balance equity — making sure we get the vaccine to everybody, including to people around the world, people in the U.S. that are not vaccinated — and protect the populations where it does look like the vaccines are not quite as effective. Looking at the data, it was not clear that if you were under 65 and you’d gotten Pfizer or Moderna that you needed a booster, you still appear to be very, very protected from severe disease. So while we’re seeing breakthrough infections, the vaccinated breakthrough infections tend to be quite mild, except in people who are older or people who have underlying medical conditions or people who have very, very high-risk exposures, where they might be exposed to a lot of the virus, so that’s where that came from. Now the situation is different for Johnson & Johnson, where the efficacy has always been a little bit lower, and they did do a second study looking at two doses of Johnson & Johnson in a general population, and that did seem to have more efficacy, and so the recommendation if you got Johnson & Johnson is to go and get another vaccine. The real question that we have very little definite data about is switching things up: if you got Johnson & Johnson, going and getting a different vaccine. There’s been some confusion about the reason the FDA and CDC recommended those mix-and-match. From what they said and from the data, the reason to get another vaccine is not because the other vaccine definitely will work better; it’s because the other vaccine might be easier to get. So if you show up to your pharmacy and all they have is Moderna and you got J&J, it’s perfectly reasonable to get Moderna. Should you go searching all over the county to find Moderna? No, you should just get the vaccine that’s most convenient.

Dryden: It’s also flu shot season. Can a person get a flu shot and a booster at the same appointment, for instance, or would you recommend that you do that a few days or a few weeks apart?

Presti: So in general, we’ve been recommending if you’re in the clinic and you need a booster for your COVID vaccine and you also need a flu shot, to just go ahead and get both at the same time and get it taken care of. So we do have a tendency to give the flu shot at pretty much any time. And there’s no real scientific reason that that would be harmful. You might have two sore arms instead of one sore arm, you might have a little bit more side effects. The reason that on the studies they wanted to separate other vaccines from a booster dose of their vaccine or from their vaccine isn’t a concern for safety or efficacy. It’s mainly a concern for confusing the picture. So if you want to know what the side effects are for the COVID vaccine, you want to make sure that somebody didn’t get another vaccine, which might cause side effects. You need both. If you had to pick, if you wanted to wait, you’re better off getting your COVID vaccinations up to date first, because we’re seeing COVID circulating at much higher rates than flu, and then get your flu vaccine later. But if you think you’re not going to be able to get back, then get them both at the same time.

Dryden: The vaccines we’re using were sort of designed to combat a virus that effectively, it’s not around anymore, the first version of the SARS-CoV-2 virus. The shots still work against delta, but is it necessary moving forward to try to tweak the vaccines to fight the virus that’s actually out there, or is the virus always going to be a step ahead so it’s not really worth the trouble. What about that?

Presti: This has always been the concern: that the virus would mutate away from the vaccines. And it’s very, very closely watched. And thus far we’ve been pretty lucky. So of the variants that have circulated widely, the only one that in the test tube seems to be resistant to the immunity that you get from the vaccine is the beta, which, for whatever reason, isn’t actually circulating at very high rates. The immune response to the vaccine is effective against delta, and we can see that both in the test tube but also in the real world, in who’s getting infected and vaccination status. So in reality, the boosters are probably going to wind up giving you a broader immune response. It doesn’t look like matching the vaccine to, say, the delta variant gives you a huge benefit over just boosting with the original vaccine, and this is a really active area of study. Thus far, it doesn’t look like you need to switch vaccines to get a good response, but it may be something that eventually might need to be done. And I think that’s where the real question comes about. Do we need a booster every year? The coronaviruses are not like influenza, they don’t have a built-in system where they are going to change and escape our immune response every year the way influenza viruses do. The coronaviruses don’t tend to change as much, they don’t have that built-in system. So they kind of drift and make mistakes when they copy themselves, and so they shift a little bit in the way they look, but unless they shift significantly, the question about whether or not we need another dose or an annual dose is really to be determined.

Dryden: You’re going to be involved in some of that research into tweaking those vaccines, is that correct?

Presti: Yes. We’re doing a study with Moderna looking at giving a booster vaccine that is tailored to target different variants — so the beta or the delta variant — as opposed to giving the regular original Moderna vaccine. I think this is interesting, I think it is important to do the research and find out if this actually is a better vaccine. In reality, it’s hard to get better than the original Moderna vaccine. It tends to give a very, very strong response and have very, very high efficacy that doesn’t appear to be decreasing significantly, even with delta circulating. One of the reasons we’re really excited about doing this study actually is a pure, basic science rationale. And that is this is a really unique opportunity to be able to look at how your immune system responds to a new antigen, so the new coronavirus that no one had seen before, so we have good data about how people’s antibodies, their T cells respond, how they develop, and how they change after you get the original vaccine. And so it’s really, really of scientific interest to find out if you vary that slightly, do you actually make new antibodies? And I think that’s an unanswered question. So to some extent, we’ve been able to take advantage of the fact that there’s this horrible experiment of nature in this pandemic that’s given us a real opportunity to understand how the immune system works in human beings and not just in animal models or tissue culture.

Dryden: With all of the various vaccines now approved for boosters for certain groups, if people need a booster and they get one in the next month, what is that going to mean regarding winter and the holiday season?

Presti: I think it is a little too early to tell. Coronaviruses tend to be winter viruses. We haven’t really seen that seasonality yet, but I think we’re getting closer to that, especially in populations that have a high level of exposure to the virus. So there have been a lot of people infected and a high level of vaccination. We’re seeing in Israel and in the U.K. that this virus is starting to be more like the endemic, not the pandemic, kind of viruses, where they may fall into sort of a seasonal pattern. So I think most of us are cautiously optimistic that we may see a little bit of a bump over the holidays but that it won’t be as bad as it was last year.

Dryden: Though our numbers are down in the region from where they were over the summer, if this was 30 or 40 people with influenza in a particular hospital, it would be like hair-on-fire time. Are we somewhat jaded by the fact that this doesn’t seem like a high number anymore?

Presti: I think if you look at the way things have progressed and the waves that have gone by in the state of Missouri, just for example, we were hair-on-fire panicked back in March, April of 2020 about how rapidly numbers were going up and how many cases we were seeing in the hospital. And we are not back down to those numbers yet. So there’s still a significant amount of disease out there, there’s still a lot of people getting sick and a lot of people dying from this virus. And while things are getting better, they are not back to where we want them. So things are better, and I think there’s a limit to how long you can run around with your hair on fire. We’re figuring out how to deal with this. It would be great to get it to influenza levels, it would be even more wonderful if we could get this to the kind of mortality you see with seasonal coronaviruses, which have very, very, very low rates of mortality in the U.S. So we still have a way to go, but I think we’re making good progress.

Kim: My name is Alfred Kim, I’m an assistant professor of medicine at Washington University School of Medicine within the Division of Rheumatology.

Dryden: Kim works with people who have compromised immune systems, and he has found that the vaccines elicit antibody responses in nearly nine out of 10 people with weakened immune systems, but their responses are not as strong as those mounted by healthy people.

Kim: The current estimates of the number of people who are immunosuppressed — and this is whether due to an immune deficiency that they were born with, or this is acquired because of either a malignancy like cancer or due to medications — it’s roughly about 3% of the U.S. population. So this roughly puts about 10, maybe 11 million Americans at risk of having attenuated responses to vaccination.

Dryden: Now, the vaccine is supposed to help the immune system mount challenges to the virus. But as you say, if a person is a cancer patient, an organ recipient, taking some kind of medication that interferes with the immune response, or has a compromised immune system for some other reason, how much can the vaccines help?

Kim: That is an excellent question, Jim, and I think the real problem that we have here is we don’t have clear definitions of immunologic sufficiency in terms of magnitude of responses. What we have shown is that roughly about 90% of the people who are immunosuppressed with a systemic autoimmune disease have antibodies post-vaccination. But when you look at the bulk of the people and the level of antibodies, it’s about threefold down compared to those who are immunocompetent. So the ultimate question is, “Is that threefold reduction going to mediate a reduced protection?” The nuance here is not just about levels but is also going to be potentially the quality of the antibodies in terms of how well they function. And also, can they bind to variants? Having said all that, I think there are early signs in terms of breakthrough infections within the immunosuppressed that have given us some clue about which type of medicines that may be driving the biggest risk of breakthrough infections and hospitalization.

Dryden: And when you say the types of medicines that may be driving risk, are you talking about some patients facing a choice here like, “There’s a lot of delta in this region now — let’s wait and start your chemotherapy in two months.” I mean, those sorts of decisions?

Kim: Yeah, so the topic of holding medications around the time of vaccination has been discussed before, especially in the context of influenza vaccination. Within the rheumatologic world, it’s actually recommended that methotrexate, which is a commonly used medication, should be held for up to two weeks after getting the flu shot in order to maximize and optimize flu vaccine responses. I think, though, in general, the real question is: Can the patient’s underlying condition or the reason for suppression tolerate a medication holiday? For transplant patients, this may not be the case. For cancer patients, this is going to be very case-specific, but there are going to be some people that may not be able to tolerate it, or basically they need the treatment sooner than later. For autoimmune patients, it’s much more varied and more nuanced. I think the majority of them may be able to tolerate it, but again, this is a very individual situation, and the guidelines that are being put out right now, particularly from the American College of Rheumatology, for holding certain medications could put some people at risk.

Dryden: Third shots have just been approved for various groups, including the immunosuppressed, but I’ve heard about even a fourth shot for people with immune system problems.

Kim: This is an interesting scenario. I was actually a little bit surprised by the CDC’s thought process here, largely because the cart is a little bit ahead of the horse. I think the theoretical benefits are very obvious, but I think there are a couple of issues here. If you have poor responses to the first three doses of vaccine, if you don’t change anything, there’s a high likelihood you’re going to have a poor response to the fourth dose. I don’t think it matters if you get eight doses; I don’t think these people are going to be generating very good responses at all. I think this goes back to the idea of the role of drug holidays and holding medications and the safety of that for the underlying disease versus then optimizing or even generating vaccine responses. It will be interesting to see how this all plays out.

Dryden: I’m thinking from this conversation that maybe the best way to protect people with compromised immune systems would have less to do with getting them vaccinated and more to do with getting everyone else vaccinated so there’s just less virus circulating, and they lower their risk that way.

Kim: Yeah, 100% agree, Jim. I think that right now, the best strategy, the strategy that we can do, at least in terms of what we’re allowed to do medically, is to make sure that we do reach this concept of herd immunity and basically attenuate the ability for the virus to spread rapidly. There are additional potential options in the future. Obviously, there are antivirals that have been coming out from Merck, there are antivirals being developed here at the School of Medicine in Washington University. And on top of that, there’s discussion at the FDA right now that I’m aware of that’s looking at the role of pre-exposure prophylaxis with monoclonal antibodies or PrEP. Right now, the FDA allows for post-exposure prophylaxis of monoclonal antibodies. In other words, if you’ve been exposed to someone with COVID-19, it doesn’t matter if you test positive or negative, you’re allowed to be able to get the Regeneron dual antibody cocktail, which essentially serves as, kind of, vaccine antibodies, except these are made within the lab setting. And this will then allow for short-term protection during that period where the virus could be attempting to infect. I think us, along with other groups globally, have shown that the vast majority of the people can generate a response, but like I said earlier, the magnitude of that response seems to be slightly attenuated. The real question here going into the future is going to be, “OK, if we’re starting to see differences in the magnitude of the response and quality of the response, can we help these people with the poor-quality responses with additional doses downstream?” And this is somewhat interestingly unique for SARS-CoV-2 because of its amazing ability to infect. I think that’s the thing that’s been so surprising is that it infects so readily. But it appears that a real good correlative protection against the infection itself would be high-quality antibodies.

Dryden: I’ll go with the sports metaphor. So what we’re looking at with the immune system in many people is they’re a baseball team and none of their pitchers are very good at throwing strikes, they walk a lot of batters. So the question is whether 12 pitchers who walk a lot of batters are any better than only eight pitchers who walk a lot of batters, if they’re all going to walk a lot of batters. It’s the quality of the stuff that the pitcher is throwing, rather than the quantity of pitchers that’s going to necessarily make a difference.

Kim: Yeah, I think that’s an interesting analogy. So if we kind of extend this, you do need a pitcher, all right, so there’s a certain level of sufficiency, whether it’s the level of antibodies, which is undefined, or the number of pitchers you need. Now, if they are throwing every pitch in the dirt, yeah, then the quality of the antibodies may not be there, even though the number of pitches are there. But I think this analogy also extends to the other eight players on the field in terms of the defense, and then those represent different aspects of the immune system response. And again, we’re still trying to characterize those other eight players right now in their role in terms of protection, in terms of supporting antibody responses, et cetera.

Dryden: Kim and Presti say extra shots probably can’t hurt, and with more and more people and agencies recommending third doses and even considering changing the definition of what qualifies as being fully vaccinated, we’ll soon be finding out how helpful those boosters will be for various groups of people. “Show Me the Science” is a production of the Office of Medical Public Affairs at Washington University School of Medicine in St. Louis. The goal of this project is to keep you informed and maybe teach you some things that will give you hope. If you’ve enjoyed what you’ve heard, please remember to subscribe and tell your friends. Thanks for tuning in. I’m Jim Dryden. Stay safe.