We Should Have Known So Much About Covid from the Start

America has begun to treat Covid-19 like just any other disease — boosters are now arriving on an annual fall cycle, on the flu model, with large portions of the country not bothering with them, also on the flu model.

But, objectively, Covid is not just another disease — not yet. Last year, it was the only infectious disease among the country’s top 10 causes of death. We are obviously on an off-ramp from the pandemic emergency, since even though many more Americans have gotten Covid over the last year, many fewer are dying than did in the first two years of Covid-19. But while the worst is behind us, it’s also not quite right to see the disease as epidemiological wallpaper.

This is precisely the long transition from emergency to normality that the immunologist and epidemiologist Michael Mina has predicted since almost the beginning of the pandemic. Beginning in 2020, Mina took pains to describe Covid-19 as a “textbook virus,” with features that may have startled lay people — long Covid and post-acute sequelae, waning immunity and reinfection — but were, in his view, simply what could be expected from a new pathogen spreading through a global population with no immunity.

I spoke to Mina about what seeing Covid as a textbook virus tells us about the nature of the pandemic off-ramp — and about everything else we should’ve known about the disease from the outset. I’ve edited and condensed our conversation for clarity, and added some material from a follow-up interview.

Let’s start with the present. Where are we with this virus, heading toward year four?

I think we’re like toddlers. Maybe we’re four years old, maybe five. I’ve always said we’re going to have to grow out of this virus, to grow out of the pandemic, by gradually building our immune system up.

The vaccines can accelerate that process. But those gains will be marginally less powerful over time, especially because the spike protein of the virus, which is the focus of most vaccines, keeps mutating.

It’s so hard to talk about this in public because people think by talking about immunity, I’m saying people need to get exposed. Well, you can get exposed or you can get vaccinated. But either way, we have to keep building our immune system up, as babies do. That takes years to do. And I think it’s going to be a few more years at least.

And in the meantime?

We’ve seen a dramatic reduction in mortality. We’ve even seen, I’d say, a dramatic decline in rates of serious long Covid per infection.

But I do think it’s going to be a while before this virus becomes completely normal. And I’ve never been convinced that this current generation of elderly people will ever get to a place where it is completely normal. If you’re 65 or 75 or even older — it’s really hard to teach an immune system new tricks if you’re that age. And so while we may see excess mortality in the elderly decline somewhat, I don’t think we’ll see it ever disappear for this generation who was already old when the pandemic hit. Many will never develop that robust, long-term immunological memory we would want to see — and which happens naturally to someone who’s been exposed hundreds of times since they were a little baby.

For babies born today, though, I really think they’re not going to view Covid as any different than other viruses. By the time they are 20, it will be like any other virus to them. Because their immune systems will have grown up with it.

When you say “hundreds of times,” that’s striking. The way most people think about a virus like, say, RSV, or chickenpox, is that a single exposure, while potentially worrisome, does deliver lifelong protection. Is it really the case that, as babies, we are fighting off those viruses hundreds of times?

The short answer is yeah. We start seeing viruses when we’re 2 months old, when we’re a month old. And a lot of these viruses we’ve seen literally tens, if not hundreds of times for some people by the time we’re adults. People tend to think that immunity is binary — you’re either immune or you’re not. That couldn’t be farther from the truth. It’s a gradient, and your protection gets stronger the more times you see a virus.

Take chickenpox. As you say, people used to think that if you got chickenpox, you were good, you’d never get the virus again. But you can get shingles —

Which is caused by the same virus, though in older people.

It used to only happen when your immune system fell below a certain level: as you age, you lose your immunological memory and you can get shingles. But in recent years we’ve seen a massive shift in the age of people getting shingles. It used to be mostly people in their 70s or older. Now it’s hitting people in their 30s. And people started to say, well, that’s weird, what’s going on?

Yeah — what is going on?

We used to think we just had this spectacular immune response when we first encountered the virus at, say, age 6, and that the immune response lasted until we were 70. But actually what we were seeing was the effect of an immune system being retrained every time it came into contact with the virus after the initial infection — at 6, and 7, and 8, and so on. Every time your friend got chickenpox, or your neighbor, you got a massive boost. You were re-upping your immune response and diversifying your immunological tools — potentially multiple times a year, a kind of natural booster.

But now, in America, kids get chickenpox vaccines. So you don’t have kids in America getting chickenpox today, and never will. But that means that older Americans, who did get it as kids, are not being exposed again — certainly not multiple times each year. And it turns out that, in the absence of routine re-exposures, that first exposure alone isn’t nearly as good at driving lifelong immunity and warding off shingles until you immune system begins to fall apart in old age — it can last until you’re in your 30s, for example but not until your 70s.

There’s a similar story with measles. There is no routine later-life sequelae, like shingles, for measles. But what we do see is that, in measles outbreaks today, there are some people who were vaccinated who get it anyway. Maybe 5 to 15 percent of cases are not immunologically naïve people, but vaccinated people. So — what’s up with that? We thought we had lifelong protection from childhood vaccination, but because there’s no more natural boosting of measles anymore, that protection wanes to some degree over time.

But to think about that in the context of Covid, for a minute — all of those subsequent exposures to chickenpox were basically invisible. You didn’t get sick the second or fifth or ninth time you encountered the virus. Covid is still making some people sick, on reinfection, if typically less sick.

And with Covid, we’re getting infected frequently. But there is also a very basic difference between a disease like Covid and a disease like measles or chickenpox. For measles or chickenpox to cause a symptomatic infection, it has to be brought into the body, through the upper respiratory tract and the lungs, into the bloodstream and the lymph. It doesn’t really even start replicating until it gets that deep into the body. And if it doesn’t get that deep, it doesn’t replicate. With a disease like that, our T-cells and B-cells, which were created during past exposure or by vaccination, typically stop the virus early enough that no replication happens and we don’t even notice it.

With Covid, when it infects you, it can land in your upper respiratory tract and it just start replicating right there. Immediately, it’s present and replicating in your lungs and in your nose. And that alone elicits enough of an immune response to cause us to feel really crappy and even cause us to feel disease. But it’s why we don’t see the severe disease as much, with a second exposure or an exposure after vaccination: For most people, it’s not getting into the heart and the liver and stuff nearly as easily. But it doesn’t have to. It’s still causing symptomatic disease. And maybe mucosal vaccines could stop this, but without them we’re likely to continue seeing infections and even symptomatic infections.

This is a very different story about immunity than we were told through most of 2020 and into 2021, though. Back then, I think the conventional wisdom was that a single exposure — through infection or vaccination — would be the end of the pandemic for you. If this is basic virology and immunology, how did we get that so wrong?

The short answer is that epidemiologists are not immunologists and immunologists are not virologists and virologists are not epidemiologists. And, in general, physicians don’t know anything about the details. And the world has never before been forced to so directly grapple with these nuances.

But this failure had some pretty concrete impacts. When reinfections first began popping up, people were surprised, they were scared, and then, to some degree, they lost trust in vaccines. And the people they were turning to for guidance — not only did they not warn us about that, they were slow to acknowledge it, as well.

It had dramatic impacts and ripple effects that will last for years to limit our ability to get populations properly vaccinated. I know from pretty firsthand experience that both White Houses at different points were not making their decisions purely by the book.

And as I’ve argued elsewhere, if we know that the elderly are going to continue to be vulnerable, you really kind of need to tell them that they’re still vulnerable.

That was just not politically palatable. And frankly, it was scientific group think.

We really did imagine that there was an end game around the corner, not, what’s it going to be like living with this disease forever after?

That’s absolutely right. And the worst thing we can do during a pandemic is set inappropriately high expectations. These vaccines are incredible, they’ve had an enormously positive impact on mortality, but they were never going to end the pandemic.

And now, there’s a huge number of people questioning, do these vaccines even do anything? But we could have just set the narrative better at the beginning: look, you might get sick again, but your risk of landing in the hospital if going to be really low, and if you get a booster, you might still get sick again, but your risk of landing in the hospital is going to be even lower. That’s something I think humans can deal with, and I think the public could have understood it.

Instead, we set society up for failure, since people feel like the government failed everyone, that biology failed us, and that this was a crazy virus that has broken all the rules of our immune system, when it’s just doing what we’ve always known it would do.

How do you wish we had messaged things differently? What would it have meant to communicate early and clearly that Covid was a textbook virus, as you say?

I think the biggest thing would have been just to say, we understand the enemy.

To say that this is a textbook virus, it doesn’t mean that it’s not killing people. Objectively, it’s still killing more people than any other infectious disease. What it means is that we could’ve taken action based on what we knew, rather than waiting around to prove everything and publish papers in Nature and Science talking about things we already knew.

What action do you mean?

The first thing that really pushed me to start talking about it was seasonality. We could have prepared for November and December of 2020 and then for November and December of 2021. But everyone kept saying, we don’t know if it’s going to come back. We knew it was going to come back and it makes me want to cry to think about it. We did nothing and hundreds of thousands of people died. We didn’t prepare nursing homes because we all got to the summer of 2020 and we said, cross our fingers.

And then when the cases dropped in January and February, we were told it was because of human behavior modification. No People didn’t change their behavior that much between January and March. We had a lot of epidemiologists saying that. But if you just sat back and said, what do we know about these kinds of viruses, one of the first things you would say would be, well, they peak in January in countries like ours, in climates like ours, and usually by the third week of January, they’re really falling fast.

But it’s not just seasonality. Aerosol spread, age skew …

We knew how tests worked. We knew about serial testing and why it was important for a public health approach. We knew that vaccines could have really good impacts once they were around. And if you were looking through the correct lens, we even knew that they weren’t going to stop transmission.

We didn’t have to live in a world where we were flying blind. We could have lived in a world where we’re knowledgeable. But instead, we chose almost across the board to will ourselves into this state of fear and anxiety.

And that really started in the earliest days. Almost the first experience I had was a lot like that movie with Jennifer Lawrence —

Don’t Look Up.

I was watching the virus transmit in China wearing my epidemiology hat, and I remember going to the Brigham Hospital at Harvard, where I was the associate director of molecular virology, and saying, I need some resources. We’ve got to build a Covid test. This is going to be at our doorstep any day. And I’m like, oh my God, how do you guys not see this? It’s following every pattern we would expect for a virus that of course is going to circulate the globe. You should not be surprised in February, in March when it’s killing people in Boston.

I remember telling a friend in early March that a million Americans might die and having him freeze in disbelief.

But none of this was complicated. You just had to ask a simple question: what would happen if you took away all immunity from an adult? Well, once you control for no immunity, adults are going to get very, very sick.

Of course, by and large, babies didn’t get very sick from this disease.

Babies are immunologically naïve, but they are also resilient. A virus can tear up a baby, but a baby can repair its tissue so fast. Adults don’t have that. It’s just like a baby getting a cut. They’ll heal really quick. An adult getting a cut — you go by age, and every decade of age that you are, it’s going to take exponentially longer for that wound to heal. Eventually get to 80 or 90 and the wound can’t even heal. In the immunology world, this is called “tolerance.” Adults don’t have it as much. What they have instead is a well-trained immune system. And so, taking that view, you have to say, what would happen to an adult who doesn’t have that tolerance but also lacks all immunity?

I wanted to ask about some of the rarer outcomes, which struck most Americans as quite disconcerting. Pretty early on we saw it affecting the heart, for instance, or the brain.

Right — why are all these organ systems getting damaged when other viruses don’t seem to do that? It’s natural to think, it’s Covid — this is a weird disease. But it’s much more a story about immunity and how it develops than about the virus or the disease. None of our organ systems had any immune defenses around to help them out. And I think that the majority of post-acute sequelae and multi-organ complications and long Covid — they are not the result of the virus being a crazy different virus, but are a result of this virus replicating in an environment where there were such absent or exceedingly low defenses.

Is it the same whenever we encounter a virus for the first time?

Think about travelers. Travelers get way more sick from a local disease than people who grew up with that virus. If you get malaria as a traveler, you’re much more likely to get really sick. You don’t see everyone in Nicaragua taking chloroquine every day. But you definitely see travelers taking it, because malaria can be deadly for adults.

What about, not severity, but post-acute complications — do we have long malaria? Do we have liver complications from dengue?

The really hard part of answering that question is there’s just not enough data on the frequency of long-term effects, because nothing like this has ever happened at such scale. It’s like everyone in Europe and North America suddenly traveled to a country where malaria was endemic.

We see something similar with kids. I used to work with some pediatricians at Boston Children’s Hospital who would get all these weird cases — kids with random new heart problems, for instance. It’s called idiopathic, but idiopathic just means we don’t know what just happened. And my bet is that it is almost always a virus. It really is. We’re just seeing it with Covid now on a much different scale.

There was a good example that happened recently, with an enterovirus that’s infecting kids and causing acute flaccid myelitis — polio-like symptoms. There’s a new version of hand, foot and mouth disease. It entered into the North American populace around 2011. It’s causing much more atypical and severe disease in adults.

I think I had that.

Or measles. When you have a really bad measles case, it can get into your brain. We don’t normally think about it, but it can. And there’s people who get long-term effects and die 10 years after they get measles. It’s called subacute sclerosing panencephalitis.

Or think about H.I.V. It essentially kills your immune system, and once the immune barriers are down, other viruses that used to infect humans would get into tissues that we didn’t like them to get into. If there wasn’t such a clear signal of a loss of CD-4 T cells to explain it, people might still be scratching their heads and going, man, I wonder why all these patients are getting fungal infections. Well, there’s a virus there that’s depleting their immune system.

In general it feels like we’re learning a lot more about these interactions lately — for instance, your research links between Epstein Barr and multiple sclerosis.

Covid is absolutely waking the world up to this — to the fact that there are really weird long-term sequelae to viruses when they infect organ systems that would normally be protected. And I think we’re going to find that more and more cancers are being attributed to viral infections.

It wasn’t that long ago that we first learned that most cases of cervical cancer were caused by H.P.V. — I think the 1980s. And now we have a vaccine for H.P.V. and rates of cervical cancer have fallen by two-thirds.

We’ve always seen these problems associated with viruses or these problems that bring people into the hospital that are usually just not diagnosed. But I think Covid is raising massive awareness.

And what about incidence? We’ve talked at a few points about how important it’s to think about all of these questions in terms of the scale. What is the right scale for thinking about future long Covid, for instance, or other post-acute sequelae?

I think the absolute risk, per infection, is going down and down and down. That’s just true.

My understanding is that the best data on long Covid prevalence comes from the U.K.’s Office of National Statistics, which shows a much lower risk of developing long Covid now, from reinfection, than from an initial infection earlier in the pandemic.

I think the worst is behind us. By far. But I know multiple people, very close to me, who are dealing with really severe long Covid. Some of them have amorphous symptoms, but haven’t been able to work for a few years. Some have very significant heart disease. One person is in surgery right now today, from an infection a few years ago. But the worst is definitely behind us, which is a good thing, especially for people who worry that the problems will keep building and a lot of people — or even everyone — will get long Covid symptoms. I don’t think there’s a world where we’re looking at the babies of today dealing with long Covid at any meaningful scale.

My understanding is that, for long Covid at least, the large majority are relatively well recovered within a year.

Yes, that’s right. But a lot of the fear right now comes from the worst cases, and there’s a lot of worst cases. Even one of the people that I know well, I know in their mind they’re worried that they’ll never recover, but I think objectively they are recovering slowly. It might not be an eight month course. It might be a year and a half. But they will get better. Most of us will.

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