This discussion was recorded on February 1, 2022. This transcript has been edited for clarity.
Robert D. Glatter, MD: Hello and welcome. I’m Dr Robert Glatter, medical advisor for Medscape Emergency Medicine. Today we have a distinguished panel joining us to discuss the current data about boosters for COVID-19.
Dr Paul Offit is director of the Vaccine Education Center and professor of pediatrics in the Division of Infectious Diseases at Children’s Hospital of Philadelphia. Also joining us is Dr Paul Sax, clinical director of the Division of Infectious Diseases at Brigham and Women’s Hospital and professor of medicine at Harvard Medical School. Welcome, gentlemen.
Paul A. Offit, MD: Thank you.
Paul E. Sax, MD: Thanks.
Glatter: The current CDC data indicate that about 64% of the US population is now fully vaccinated or up-to-date, with about 42% of this group having received a booster (ie, third shot).
We have three recent studies from the CDC that indicate the importance of the booster, or third shot, to protect against the Omicron variant. Let’s talk about recent studies from the US and overseas that indicate this ability of boosters of preventing infection, hospitalizations, and deaths. We’ll start with Dr Offit.
Offit: We have to ask ourselves the question, what’s the goal of this vaccine? I think the goal of this vaccine — what the goal should be for every vaccine — is to protect against serious illness, meaning the kind of illness that causes you to go to the doctor’s office, the hospital, the ICU, or the morgue.
You could argue that the two doses of mRNA-containing vaccine have done that for the most part. I’ll get to the specific groups where that hasn’t been true. For example, if you look at young, healthy people, protection against moderate to severe disease is mediated by immunologic memory cells — like memory B cells, memory T-helper cells, memory cytotoxic T cells.
The immunologic component (ie, epitope) that’s recognized by those cells is generally conserved. Even though the vaccine was made against the original strain — the so-called Wuhan 2020 strain, the ancestral strain — and we’ve had four different variants that have come into this country, including D614G, Alpha, Delta, and then Omicron, protection against serious illnesses has held up.
Now, you can argue that this is a three-dose vaccine for certain groups (people over 65 and for people who live in long-term care facilities). The data are clear.
The data are also pretty good for people who have comorbidities and are over 50. Where I think it’s less clear is how a booster dose in an otherwise healthy young person increases protection against moderate to severe disease. I don’t think those data, frankly, exist.
While it’s a good idea to have a permissive recommendation for people over 12 to arguably get a third dose, making that a formal recommendation (which is meant for a lot of mandates to get third doses) on people who probably aren’t going to benefit from it in terms of protection against serious illness…
Now, on the other hand, if your goal is to try to prevent against all symptomatic disease, or mild disease, that’s mediated by neutralizing antibodies, which fade. The seduction that we had back in December, when the FDA Vaccine Advisory Committee considered the Pfizer or Moderna vaccine, was that protection against mild disease was more than 90% for those two vaccines. That’s because those were 3-month trials, so people had just gotten a second dose. The neutralizing antibodies had to fade, and did.
I think the communications error that we made was ever calling a mild illness a breakthrough infection. That’s not a breakthrough. A breakthrough is when you’re hospitalized despite being vaccinated. To expect that these mucosal vaccines are going to protect you against mild disease is a lot to ask. I think it’s an unrealistic bar.
Glatter: Dr Sax, how would you respond to Dr Offit’s comment?
Sax: There is a cost to breakthrough cases no matter how mild they are in the current pandemic, which is that they’re tremendously destabilizing for workers, families, and kids in school. If there is a potential benefit of reducing the risk for infection — symptomatic infection, even mild — then that would be a worthwhile goal, especially if it does translate into reduction in risk for transmission.
Now, I’m not saying that people with breakthrough are less likely to transmit than people who are unvaccinated, but that might be the case. If you can reduce the risk for transmission and there’s some evidence that within vaccinated households transmission risk is lower…
Glatter: We should talk about children. The 5- to 11-year-old age group is a concern, and 12- to 15-year-olds. These are important populations that are well undervaccinated. Dr Offit, you can understand this as a pediatrician. We need to reach these groups. How can we do that better? What are we not doing right now?
Offit: The largest group of people who are unvaccinated in this country are people under 30. I hear from parents, “When are we going to have a vaccine for the 12- to 15-year-olds? When are we going to have a vaccine for the 5- to 11-year-olds?”
We had a vaccine for the 12- to 15-year-olds in May, and about 55% of people in that age group were vaccinated. We had a vaccine for the 5- to 11-year-olds by the beginning of November — 3 months ago — and about 20% of that group is vaccinated. Presumably, we may have a vaccine for the less than 5-year-olds soon, but I suspect that the immunization rate will be even lower in that group than in the 5- to 11-year-olds.
We talk about wanting a vaccine, but when we have them, we don’t use them. How do we get people less than 30 to get vaccinated? They are the largest group that’s unvaccinated. I think that it really comes from the pediatrician. Generally, people trust their pediatricians. We maybe need to be a little more proactive about this.
Glatter: Dr Sax, how would you follow that up?
Sax: Well, I’m married to a pediatrician, so I have some credentials here. I was going to say that immunization is sort of front and center of the preventive health that they do. One of the crowning glories of the American public health system has been school mandates for vaccinations. It’s one of the reasons why we have smaller, less frequent outbreaks of things like measles in the United States than they do, for example, in Western Europe.
At some point, if the decision is made that the benefit of vaccinating children outweighs the risk, and it’s better for society as a whole, then I think we’ll move in that direction. I’m hopeful that we will, just because I do think it will stabilize things.
This last Omicron wave — the number of pediatric cases was just astronomical. Way higher than any of the previous waves. That’s partially because schools were open. What do you expect? Kids transmit viruses. Fortunately, most of the time, they were very mild illnesses.
Glatter: Did you see an increased incidence of multisystem inflammatory syndrome of children (MIS-C) in this cohort?
Offit: It seemed to me that months ago, when we were seeing children come in with COVID-19, we saw a lot of MIS-C. It was one of the most common diseases to come in to the hospital. It’s primarily a disease of the 5- to 13-year-olds and peaks at about 9 years of age.
With the Omicron wave, I’m sure there are data published on this, but we haven’t seen as much MIS-C. Omicron is different. I think it is less virulent.
There are two studies, one out of California and another out of Cleveland, that show you are less likely to be admitted to the hospital, the intensive care unit, or be mechanically ventilated if you’re infected with Omicron as compared with Delta. It’s always hard to separate out population immunity, which has obviously increased over time. I think it is somewhat less severe and it’s also immune evasive. That’s the problem. Even if you’ve been vaccinated — and arguably even to some extent, boosted — you’re off-target for protection against mild disease, because this virus is different.
Delta had a certain number of mutations in the receptor-binding domain and the N-terminal domain, but this virus has more than 30. It was like a leap upwards. Virologists talk about how coronaviruses aren’t flu viruses and how they don’t drift. This is a drifted virus. This virus acts like flu, which makes it a little scary.
Sax: One thing interesting about Omicron is that the place where it preferentially seems to infect and replicate is in the bronchus, the upper airways — not in the lungs. I’ve heard anecdotally that children are more likely to have crouplike illness from Omicron than with previous variants. I will say that for adults, at least, the fact that it may not replicate as well in the lungs would be very much welcome because the cause of lethal COVID-19 almost always is pulmonary disease.
Glatter: That brings up a key question of mucosal immunity in terms of vaccine development. Maybe both of you could weigh in on where we are in terms of vaccines that target mucosal immunity.
Offit: I was fortunate enough to be part of a team at Children’s Hospital of Philadelphia that developed the strains that became the bovine human rotavirus vaccine, RotaTeq. I have a fair amount of experience with mucosal immunity. The rotavirus vaccine is given by mouth because it then can stimulate immunity at the intestinal mucosal surface for a virus that really replicates, almost solely, at the intestinal mucosal surface.
Viremia is not an important part of pathogenesis. You can make the same case for this virus, too. This virus really doesn’t have viremia, meaning virus in the bloodstream, as an important part of pathogenesis. You need good mucosal immunity.
It’s not as easy to generate for the respiratory viruses as people think. For example, FluMist is a nasal spray, live-attenuated vaccine, which people assume would be dramatically better in terms of inducing that response than was the inactivated vaccine or the purified protein vaccine that’s given parenterally. It wasn’t so dramatically better.
It’s not so easy to make these things. Dr Fauci recently talked about a pan-coronavirus vaccine, a sarbecovirus vaccine, where you can target all coronaviruses. Now, SARS-CoV-2 is really the seventh pathogenic coronavirus that’s entered the human population. It’s not easy to do.
Glatter: In a 60 Minutes broadcast a few months ago, they said the US Army is close to having this pan-coronavirus vaccine. Interestingly, I’m not sure who they’re collaborating with, but it seems like, from what they’re describing, they’re close.
Offit: With the way they work, they’re able to create a structure that looks like a small soccer ball onto which they can then put all these different SARS-CoV-2 spike proteins. When people think about pan-coronavirus vaccine, I think what they’re really thinking about is trying to figure out a way to develop an immune response against conserved parts of this virus, that then will protect you against all, say, seven coronaviruses that have those conserved regions. That’s not easy to do because the natural infection doesn’t do it that well.
Glatter: Is that part of a mosaic approach, essentially, that you’re describing when you say “conserved”?
Offit: Yeah, the conserved regions. There are conserved regions that are recognized by T-helper cells, CTLs, and B cells on the SARS-CoV-2 spike protein. For the most part, they’ve remained conserved even for Omicron, so that’s good.
What you worry about is that you really would need a variant-specific vaccine. I’ll take a step back. When there was an outbreak in Provincetown, Massachusetts, where thousands of men got together to celebrate July 4th, 79% were vaccinated, but nonetheless, 346 got COVID-19. Of those 346, four were hospitalized, for a hospitalization rate of 1.2%.
Those, by the way, were breakthrough illnesses. Unfortunately, the CDC called all of those mild infections breakthrough illnesses. If that 1.2% becomes 10%, 20%, or 30%, then you have a failed vaccine. Now you’re talking about a new vaccine — a variant-specific vaccine, if that happens.
Waiting Time for a Booster
Glatter: I want to switch gears and talk about the ideal time to get vaccinated if you’re immunocompetent and if you’re immunosuppressed. There was a Wall Street Journal article recently that looked at this and really drew attention to the fact that people are confused. Do they get their booster, or third shot, right after they get better — after they’re convalescent? Do they wait 2 months, 3 months, 4 months? I want both of you to weigh in on this because maybe you can help settle the confusion to some degree.
Sax: I think one of the most confusing aspects of COVID-19 for our patients — and actually for doctors, too — is how durable protection is after natural infection. Part of the reason it’s so confusing is because it varies from person to person, it varies depending on the severity of the illness, and it probably varies based on when you had it. The durability and the protection are all over the map.
There are plenty of people who get reinfection. Sometimes the reinfection is more severe than the first infection. I wish that I could say that infection protects you and you’ll never get severe disease again, but that’s clearly not the case.
There are immunologists who feel like, yes, once you get infected, you can wait. You have 3 months at least and you’re not going to get reinfected. There are other immunologists who feel like the infection actually harms some of the immune responses and you should probably get vaccinated as soon as you can. I don’t think we have enough data to say what the optimal time to wait is.
Glatter: Dr Offit, any thoughts on that?
Offit: When the Pfizer and Moderna vaccines launched back in December, you had 3- or 4-week intervals between doses. The thinking at the time was that had this not been a pandemic, this would have been a three-dose vaccine. You would have wanted to have a 4- to 6-month interval between doses, whether it was the first or second, or second and third, based on what we had learned about purified protein vaccines and what we’d learned about inactivated viral vaccines, where in order to get really high frequencies of memory B and T cells, you needed that interval.
I’m not sure how this is going to play out. When you look at studies by John Wherry or Shane Crotty at La Jolla, when they look at frequencies of memory T-helper cells or memory cytotoxic T cells, they have, for the most part, held up. Maybe that’s because this is more like a live-attenuated viral vaccine in that you’re making the viral proteins in your own cell. You’re not being given passively those proteins.
I don’t know. I think we’re going to learn over time. It does look like the so-called hybrid immunity, which is induced by a combination of natural infection and immunization, provides maybe a broader protection and possibly longer-lasting protection. We’ll see, but it is confusing.
When the virus first came into this country back in January 2020, what people were looking at was whether natural infection protected against at least moderate to severe disease associated with reinfection. The answer was, for the most part, yes. There certainly were people who got seriously ill twice, but this wasn’t like a pathogen-like strep.
You can get strep throat or gonorrhea again and again, and natural infection doesn’t protect you. That wasn’t true here. Natural infection does, to some extent, protect.
As Dr Sax said, absolutely accurately, the dose is variable. When you’re getting a vaccine, you’re getting a defined dose. When you’re getting naturally infected, it’s an undefined dose. Therefore, there’s variability in protection. I think that the combination of natural infection and vaccination is probably your best bet in terms of broad immunity.
Sax: There are already data suggesting that these mild Omicron cases may not actually induce as much protective immunity as other infections. That’s a sad thing. You’d like for a mild case to be very protective, but it seems to be very much like the Goldilocks phenomenon: You don’t want to get severe disease because that’s life-threatening; you don’t want to get mild disease because it’s not very protective; you want something that’s sort of just right, but you can’t titrate that.
That’s why I think that natural infection as a strategy for protection doesn’t make much medical sense. The advice I give people is that once they’ve recovered from COVID-19, then they should go ahead and get their booster when they’re ready. It’s not urgent, but they also don’t have to wait 3 months.
Glatter: I thought there were some data showing that waiting is better in the sense of having a more robust effect. I guess we don’t have the data. Is that what you’re trying to say?
Sax: I don’t think we have the data, looking at waiting strategies after infection to see which vaccine strategy is most effective. I’d be very surprised if those data exist, but maybe Dr Offit knows.
Offit: No. There are papers now showing that if you’ve been naturally infected and you get a dose of an mRNA vaccine, it does act as if it’s your second dose.
When you have people who are naturally infected, they’ve received two doses of the vaccine, and now they’re being asked to get a third dose (haven’t been boosted), I think that’s a little silly. By making that a mandate (eg, to get on to university campuses), we’ve created a fair amount of angst there.
Glatter: The CDC steps out of it and says that you can get it at any time. They’re saying once you’re recovered, so they kind of step out of the ring, in my opinion.
Sax: People look for specific guidance. In this very fast-moving area, many things change very quickly. One of the things that’s so challenging about COVID-19 is that the data are coming at us very quickly and we must keep revising what we are recommending. We’re not revising it because we’re being capricious; we’re revising because there’s new information. Nobody expected a virus as diverse as this when Omicron appeared on Thanksgiving Day in 2021.
What About the Stealth Variant?
Glatter: Now we have the stealth variant. Where do we go from here? Are we looking at a more transmissible variant than the original Omicron?
Offit: Well, it looks to be somewhat more transmissible, yes. The good news is it still retains those epitopes that are recognized by memory cells. It looks like you still are going to be protected against serious disease if you’ve been vaccinated. It doesn’t appear to be more virulent, but it does appear to be somewhat more contagious. At least those are the data from Denmark.
Sax: A very interesting study from Denmark. I feel like I always should cite the specific numbers because their household transmission for this B2 variant of Omicron was up at around 40%. People think household transmission is virtually guaranteed with these more transmissible viruses, but they really aren’t.
Anyone who’s in clinical practice knows that there are households where, for whatever reason, one person gets infected and the other four living there, even in close settings, don’t get it. There are other households where everyone gets it. It almost certainly has to do with the amount of virus in the source patient.
Should We Focus on Cases or Hospitalizations?
Glatter: How about a few key takeaways from both of you?
Offit: I think that we’re getting there. If you look at population immunity, defined as being naturally infected, vaccinated, or both, you’re probably at about 90% of people who are, for the most part, protected against moderate to severe disease. That’s good.
I do think that there is a seasonal component to this. If you look at last year, when we had a very small percentage of the population that was vaccinated or naturally infected, when you hit mid-February and then late February, you clearly saw a decline in hospitalizations and deaths. I imagine, as we move into spring, that you would see that now, also.
Even when you look at last summer, we were way down in hospitalizations. That should be the focus. I really don’t think cases should be the focus, especially with Omicron. There are going to be many cases. We’re driving ourselves crazy a little bit.
In the end, we’re not going to boost our way out of this pandemic, I don’t think we’re going to mask our way out of this pandemic, and I don’t think we’re going to test our way out of this pandemic. I think we’re going to have to vaccinate our way out of this pandemic.
Over the next couple of years, you’re going to have two choices, which is to be vaccinated or be naturally infected, and vaccination is always the better choice.
Sax: In a very practical level, if you’re a doctor, or a nurse, or a PA caring for someone who’s over the age of 50, especially if they have medical comorbidities, and they haven’t received their third dose, I would strongly recommend that they do so, because in our hospitals that’s still the population. Of the vaccinated people who are sick enough to be hospitalized, it’s predominantly people with medical comorbidities or who are older.
And so, protect them. Focus on that group and tell them it’s a three-dose vaccine. It may require an annual or frequent top-up or maybe require modification. For now, it’s a three-dose vaccine.
Offit: I completely agree with that. In the adult hospital hub, next door to the Children’s Hospital of Philadelphia, when they see adults there who would have benefited from a booster, it’s because they have usually more than one comorbidity or they’re older.
I think it is a three-dose vaccine for that group. The thing that just upset me a little bit was when we sort of had a universal recommendation for healthy young people for a third dose because I just didn’t think the data were as strong for that. I seem to be an outlier there.
Glatter: Well, thank you, again. I really appreciate you both taking the time. It was a great discussion.
Robert D. Glatter, MD, is assistant professor of emergency medicine at Lenox Hill Hospital in New York City and at Zucker School of Medicine at Hofstra/Northwell in Hempstead, New York. He is an editorial advisor and hosts the Hot Topics in EM series on Medscape. He is also a medical contributor for Forbes.
Paul A. Offit, MD, is director of the Vaccine Education Center and professor of pediatrics in the Division of Infectious Diseases at Children’s Hospital of Philadelphia. He is the Maurice R. Hilleman Professor of Vaccinology at the Perelman School of Medicine at the University of Pennsylvania. He is an internationally recognized expert in the fields of virology and immunology, and was a member of the Advisory Committee on Immunization Practices to the Centers for Disease Control and Prevention.
Paul E. Sax, MD, is clinical director of the Division of Infectious Diseases at Brigham and Women’s Hospital (BWH), where he is the Bruce and Robert Beal Distinguished Chair, and is professor of medicine at Harvard Medical School. He is the associate program director for the Mass General Brigham fellowship in Infectious Diseases, is on the core faculty of the International Antiviral Society–USA, and teaches regularly on HIV and infectious diseases locally, nationally, and internationally.
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