In the second part of this two-part conversation, Jeremy Faust, MD, editor-in-chief of MedPage Today, and Paul Offit, MD, discuss the ambiguity of long COVID, the risks of pediatric COVID, and the “human price to pay for knowledge.”
Offit is director of the Vaccine Education Center at Children’s Hospital of Philadelphia (CHOP), attending physician in the division of infectious diseases at CHOP, and Maurice R. Hilleman Professor of Vaccinology at the Perelman School of Medicine at the University of Pennsylvania. He is also a member of the FDA Vaccines and Related Biological Products Advisory Committee. Watch part one of this two-part discussion here.
The following is a transcript of their remarks:
Jeremy Faust, MD: If you’re advising my parents, who are in their 70s, should they get their fourth dose right now because they haven’t gotten it yet? Or should they wait until the bivalent [vaccine] comes on in the fall because they’re trying to avoid infection or anything else? So what should they do? Should they just do it now? Or should they wait?
Paul Offit, MD: First of all, it’s really hard to avoid infection. It is. I mean, these are highly contagious viruses; they’re immune evasive. It’s a short incubation-period mucosal respiratory infection, so at some level, we’re going to have to try and find a way to accept mild infection. Even for those who are at highest risk, what are we going to do? Boost twice a year? It is just not a practical strategy, I think.
In answer to your question, I guess I would wait and see what the data show. Hopefully we’ll have much more vigorous data regarding this sort of bivalent vaccine that contains BA5 because it looks like that’s the way the [Biden] administration wants to go. We’ll have clear data on that, and if that’s true, then I would wait because I really do think people make a mistake when they give boosters very close together. You really should wait several months to do that. I disagree with the people who occasionally say, ‘Well, get it now and then you can get it again later.’ No, let’s wait; wait until later to see what this BA5 looks like.
Faust: Alright, let’s talk about vaccines and long COVID. We know that we know nothing, but there’s certainly a concern that this virus, this pandemic, is sort of a mass event for creating disability. Even if there’s a range of estimates on how much long COVID there is, and even if the lowest estimates are true, it’s still a ton of people. Do you think we’re going to get a readout on whether vaccines and boosts in particular help otherwise healthy people avoid long COVID, or is that just going to be impossible to sort out?
Offit: Well, you said it, we need to define this phenomenon of long COVID. Right now, you read estimates that range anywhere from 5% of people who suffer natural infection up to 50% of people. For example, the United States has a higher rate of long COVID than Europe does, so we have a definition problem. We clearly need to define it as objectively as possible because it’s a real entity, and the part of it that worries me is the vasculitis part. I mean, this is a virus that can cause you to make an immune response to your own endothelial cells that line blood vessels, so therefore all organs are at risk.
You do need to have a defined way of doing this because now if you look at these meta-analyses, the symptom that seems to come up to the top most frequently is fatigue, which is hard to define. Fatigue, pain, those are whatever you say they are. It’s not like measuring your blood pressure or temperature. It’s not so easily defined, so define it! Find a much clearer way of defining it than saying, ‘Are you tired when you get up in the morning? Have you been tired for weeks?’ because it sets itself up for just including far more people.
I feel sorry now for employers and for insurance companies that are now going to try and figure out how to deal with the massive amount of disability that no doubt is going to follow this virus. We need to define it immunologically, virologically, and at some level, psychologically. We have to do that. We have to because it’s going to be a big hit associated with this diagnosis.
Faust: Long COVID is obviously a concern across the age spectrum, but a lot of young people are worried about it. But there’s a group of people that are really maybe relatively low risk, but really of our concern and is an area of great interest in your career, and this is pediatrics; in kids. What’s your stance on pediatric vaccines? And how do you respond to the idea that COVID either isn’t that bad for kids and they don’t need a vaccine, or maybe even if it is on a population level, too many have been exposed anyway so why do it? Where are we on pediatric COVID vaccines?
Offit: Right. Well, we all have our biases. I guess mine is that I work at a children’s hospital, so I do see children come into our hospital who suffer this disease.
If you look sort of just at the data that we were presented at the FDA vaccine advisory committee when we made this decision in mid-June about vaccines for less than 5-year-olds, it is clear that there are at least millions of children who’ve been infected who are less than 5 years of age. It’s also clear that at least children have been hospitalized — and if you look at the CDC data, thousands and thousands have been hospitalized, and according to CDC data, about 200 have died from this virus.
Now, you want to make sure you have good data there. Is it that they’re getting hospitalized or dying with this virus or from this virus? We need to make that very clear, and I think that’s a little less clear. I can certainly say that we see children who come into our hospital because they have COVID or are treated because they have COVID; some of whom end up in the intensive care unit. It’s real, and for that reason it should be prevented.
So then the question becomes when is the best time to vaccinate, I think. Because if you make the assumption that the virus can cause death at any age — which is true — if you make the assumption that this virus is going to be with us for years, if not decades, which I think is also true, then the question is: When to vaccinate? Because every year in this country 3.5 to more than 4 million children are brought into this world who are fully susceptible to this virus, and this virus is going to be around for a long time. We are going to need to have a high level of population immunity to protect them. So [the question] when to vaccinate, is what I would argue.
Now, in the worst case scenario, it may be that if you find that memory responses, which were associated generally with protection against severe disease, fade after 5 years or 10 years and you need to re-vaccinate later, fine. But at least you’ve protected them during that period of time.
Faust: Can I ask you for a clinical impression? I’ll set it up by sharing a little bit of mine. In early 2020, COVID pneumonia was on every x-ray. They come in and it’s like, ‘Wow, this is a crazy x-ray. Why do I keep seeing this thing?’
And then in the Delta/Omicron period, where you had a lot of people coming into the hospital even though they were vaccinated, that group didn’t have COVID pneumonia. They were being hospitalized for emphysema, but COVID exacerbated it so it’s COVID’s fault, but it’s not COVID pneumonia.
What do you see in kids who are unvaccinated who get hospitalized? Are they having that COVID pneumonia like I was seeing in early 2020, or is it a kid who’s dehydrated who just can’t go home?
Offit: No. I was on service a few weeks ago and we saw an unvaccinated adolescent who came in, who clearly had COVID pneumonia. I mean, he was sick. He required supplemental oxygen; his oxygen saturation levels were low. If you looked at his x-ray and his CT scan, it was striking and clearly COVID pneumonia.
Faust: And what do you say to people who were out there saying, ‘Look, this is so rare [in kids]. We don’t need to make kids have to get vaccinated. They don’t have hypoxia.’ You know, the downplayers, how do you reach them? What do you say to them?
Offit: It’s not rare enough. I think if this was like rhinovirus, and it’s basically a common cold virus, and it’s not the kind of thing that’s going to cause you to be hospitalized or go to the ICU or die, fine. But it’s not that virus; this virus is much scarier.
The scariest aspect to me is this MIS-C, this multisystem inflammatory disease in children, which is striking. You have a child, typically between 5 and 13 years of age — an average 9 years of age — who comes in and usually has a fairly trivial infection that was picked up serendipitously because they were exposed to a friend or family member. A month later, they come back; they’re not shedding virus, they’re antigen negative; PCR negative, but they have high fever, they have evidence of pulmonary disease, kidney disease, heart disease, liver disease. It is a frightening illness and they will occasionally die. That is a post-infectious inflammatory disease that is caused by a respiratory virus, and I haven’t seen anything like that before. That to me is the most compelling reason to get vaccinated, actually, because it’s just so different from what you normally see.
But, you know, this virus can cause severe illness. Yes, it’s relatively rare, but it certainly compares to the other viruses for which we have vaccines. I mean, if you’re willing to get a polio vaccine or a flu vaccine or a chickenpox vaccine or measles vaccine, this virus compares to those in terms of how likely it is to kill you.
Faust: We’re running out of time, but I can’t resist, why is it that MIS-C, this multisystem inflammatory syndrome in children, seems to have gone down in incidents in the Delta and Omicron period? This is a tremendous relief, but why do we think that happened?
Offit: It has. I mean, I think it was the data out of South Africa regarding Omicron and subvariants that [said] that MIS-C is definitely less common. You would have to argue that the price that the virus is paying to be more contagious, which is to say the mutations that are associated with immune evasiveness, are also associated with a lesser virulence…
Faust: Which favors spread of the virus, actually.
Offit: Right, In theory, if you anthropomorphize the virus, it’s never to the virus’ advantage to kill you. I mean, if it wants to live, and presumably it does, then it’s easier to spread from person to person if you’re not dead.
Faust: Right. At the extremes, the symptomatology has some impact on the reproductive number, but only at the extremes. Other than that, a little bit more virulent, a little bit less; it doesn’t matter.
I think you are the perfect person to ask this, what I think will be my final question: That is that whenever we are looking at a therapeutic or a vaccine or any intervention in a pandemic environment, you have to balance the need to act with incomplete information in an emergency setting versus waiting until you have enough data that says this is a safe, effective, and even cost-effective approach. How do you balance that?
I sense that your balance is a little bit more towards the second one when you sense it is safe to wait, but how do you tell people to make that balance? Because most people are saying, ‘Oh, we’ve got to act. We’ve got to act, forget it, no time for data.’
Offit: Right. Good question. We on the FDA vaccine advisory committee have continued to face that ever since December of 2020, especially for the childhood vaccines; for the vaccine for less than 5-year-olds. Because the question is never ‘When do you know everything?,’ because you never know everything. The question is, ‘When do you know enough?’ When do you cross that line where you feel comfortable that you know enough [while] knowing there’s always a human price to pay for knowledge.
I mean, if you go back to December 2020, there was a death in that placebo group associated with that. I give a lot of credit to these parents who volunteer for these trials knowing their child may be injected with a placebo, knowing that their child may suffer the disease because of that decision. And it’s the same for us, because the decision not to get a vaccine is not a risk-free choice. It’s just a choice to take a different risk. Our goal is to try and figure out how to advise parents or others to take the lesser risk.
I’ll just add one story because I’m an old person, as you can see since this is a video. I’m a child of the fifties. If you look at the polio vaccine story. So we always hail Jonas Salk, rightfully, as a critical researcher in the development of the polio vaccine. Well, when we did that trial — when Thomas Francis ran that so-called Francis Field Trial of the polio vaccine between 1954 and 1955 — you had 1.2 million children who were vaccinated, ultimately. It was about 400,000 children that were vaccinated with the inactivated vaccine, 200,000 received the placebo shot, and you had another 1.2 million children who were observed on inactivated controls. It was like a 1.8-million child study; a huge study.
Jonas Salk didn’t want to do that study. He didn’t. He felt he’d vaccinated 700 children in the Pittsburgh area, he thought that the immune response was excellent, it was an inactivated vaccine, he could not imagine that anyone should ever do a trial with a placebo. He couldn’t conscience that trial.
The 1.2 million children who were observed uninoculated were really a nod to him. He did not want to inoculate children with placebo in the mid-1950s, knowing that every year 20,000 to 30,000 children suffered paralysis, and about 1,500 children died of polio.
So when Thomas Francis gets up and he makes the announcement that the vaccine was safe, potent, and effective — three words that appeared on the headline of every newspaper in this country — how did he know it was effective? He knew it was effective because 16 children died of polio in that study, all in the placebo group. He knew it was effective because there were 36 children who were paralyzed in that study, 34 in the placebo group.
Those were first and second graders in the 1950s; I was a first and second grader in the 1950s. Those children could have lived long, productive lives but for the flip of a coin. There is always a human price to pay for knowledge, and that’s the hardest part of all of this.
Faust: And yet if they don’t do that study, or they don’t do the study today, how many people will die or have bad outcomes because they say, ‘Well, I’m not going to do it just because some fancy doctor said it works’? People will be convinced, ultimately, by a combination of education through their pediatricians or through the press, or even through experience where they say, ‘Look, every kid I know who had this bad outcome didn’t have a vaccine.’ Eventually, the anecdotal evidence kind of piles up in a way that’s meaningful. Is that fair?
Offit: I mean, you’re certainly right. You don’t convince people without doing those kinds of studies. And in fact, if you look at these two mRNA vaccines, as big as those studies were that were presented back in December 2020 — 40,000 for Pfizer and 30,000 for Moderna, those are the size of any typical pediatric or adult vaccine trial — still, we didn’t know about myocarditis or pericarditis as a consequence of that vaccine. You knew that only when millions of children were vaccinated.
Maurice Hilleman, who I consider to be the father of modern vaccines in many ways because he did the primary research development on nine of the 14 vaccines that we give children, said it best. He said, ‘I never breathe a sigh of relief until the first 3 million doses are out there.” But that’s never going to be done pre-licensure or preapproval. So that’s how you learn.
Medical innovation invariably comes with a human cost either way, either because you do get the vaccine or because you don’t get the vaccine.
Faust: Dr. Paul Offit, thank you so much for joining us. Your analysis has been almost singular in the public conversation in terms of balancing what I would call an exceedingly pro-vaccine stance while insisting on excellent science so that we eventually reach the most people. So thank you for doing that and for joining us here today.
Offit: My pleasure. Thank you.