For most of the year, Provincetown, Massachusetts, on the northern tip of Cape Cod, has around three thousand residents.In summertime, however, it becomes a vacation destination and gay mecca.Thousands of visitors typically descend for festivals, concerts, parades, comedy shows, and parties organized around themed weeks.Almost all of this has been suspended during the pandemic; in June, Provincetown didn’t record a single coronavirus case.
Then, in early July, thousands of gay men arrived for Circuit Party week.
The crowds thrummed with a sense of post-pandemic exuberance.The weather was rainy, and people squeezed into indoor venues “to the point you could hardly move,” one reveller, from Ohio, told the Washington Post .Another, speaking with NPR, recalled that it would “get so incredibly hot in these clubs that you would just be wet with sweat, so you’d have to step outside for a moment just to get a breath of fresh air.”
Not long afterward, dozens of attendees developed symptoms of COVID -19.Investigators from the Centers for Disease Control and Prevention quickly identified four hundred and sixty-nine new cases among Massachusetts residents.Almost all of the infections were due to the highly contagious Delta variant , and nearly three-quarters occurred in vaccinated people.
By mid-July, the test-positivity rate in Provincetown had soared to over fifteen per cent .Perhaps the most concerning finding about the outbreak was that, judging by their nasal swabs, vaccinated and unvaccinated people were harboring similar levels of the virus.
To some, this discovery suggested that immunized individuals might spread Delta more readily than previously thought; it prompted the C.D.C.to recommend that all Americans, regardless of vaccination status, resume wearing masks in public, indoor spaces when in locales with “substantial” or “high” COVID transmission.
(According to the agency’s definition, those designations apply to more than ninety per cent of counties in the U.S.)
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Many people heard about these findings late last month, when they appeared on slide seventeen of an internal document from the C.D.C., which was widely published in newspapers.The deck contained a few other concerning messages—that some thirty-five thousand vaccinated people experience symptomatic coronavirus infections each week; that the proportion of vaccinated individuals hospitalized with COVID -19 has increased; that the Delta variant likely inflicts more severe disease than its predecessors.A single phrase in the deck was quoted in headlines: “The war has changed.”
Even before Americans learned of the Provincetown outbreak, nearly two-thirds said that they were worried about the rise of Delta.
Vaccinated people were much more likely to express concern—a sign that fear of breakthrough infection was starting to puncture the promise of post-pandemic life.Since then, American optimism has cratered, with a forty-nine-point drop in the number of survey respondents who say that our situation is getting better.
We’re now more pessimistic about COVID -19 than at any point since January, when we were in the midst of the nation’s deadliest weeks.
But to what degree has the war really changed? How much do we actually know about breakthrough infections and their possible dangers? Understanding the risks is not easy.The lockdown mind-set, despite its obvious drawbacks, was cognitively simple; life in the liminal state asks us to carry a heavier mental load.This is especially true because the term “breakthrough infection” is vague.A breakthrough infection could be an illness that knocks you flat, a tickle in your nose, or nothing.
Regular reports of breakthroughs suggest that we should be scared.
But what exactly should we be scared of?
In one sense, defining a breakthrough infection is straightforward: you have one if you test positive two or more weeks after completing all recommended doses of a COVID vaccine.But, in another sense, the meaning of the term is unclear.A highly sensitive P.C.R.test has detected some of the virus’s genetic code inside your nose.So what?
“Your body doesn’t produce infinite amounts of antibodies,” Angela Rasmussen, a virologist at the Vaccine and Infectious Disease Organization who studies the push and pull between hosts and pathogens, told me.“Your lymph nodes are not, like, the horn of plenty.” It’s possible to be exposed to more virus than the antibodies in your nose can handle.Still, Rasmussen said, “When you’ve been immunized and get an ‘infection’ ”—she raised her hands in scare quotes—“or, I should say, when you test positive by P.C.R.—that doesn’t mean there’s a robust viral infection raging in your body.
Even if some cells do get infected, other parts of the immune system spring into action and stop it from spreading.” She went on, “Is that an infection? That’s a philosophical question.Technically, some cells got infected and the virus started to replicate.But the immune system prevented you from getting sick and shedding copious amounts of virus that can go on to infect someone else.”
Rasmussen thinks that, when it comes to asymptomatic or mildly symptomatic cases, the term “breakthrough infection” is somewhat misleading.
“It doesn’t describe how vaccines work very well,” she said.In such cases, the vaccines have actually succeeded, and there’s no meaningful sense in which the virus has broken through.Instead of using the breakthrough metaphor, Rasmussen suggests imagining an encounter between two armies.“The immune system has multiple specialized units that can be deployed strategically and dynamically,” she said.“The virus has some tricks up its sleeve, but, compared to the human immune system, it doesn’t have as much at its disposal.
It’s like ‘Lord of the Rings’ or ‘Troy’: one army usually kicks the other’s ass.If you’re vaccinated, your immune system is ready, it’s better equipped, and it usually kicks the virus’s ass.”
But not always.
In some cases, the virus gains a foothold, multiplies, and challenges even a primed immune system, inflicting real disease—a true breakthrough.Michel Nussenzweig, a molecular immunologist at Rockefeller University, told me that three main factors influence the course of events.First, there are your antibody levels; second, there’s your antibodies’ affinity for a particular variant; and, third, there’s the amount of virus to which you’ve been exposed.Whether a small viral incursion escalates into a major battle depends on how those factors combine.
Antibody levels rise and fall: right after infection or vaccination, B cells in our blood produce huge numbers of them, but, as the months pass, antibody levels decline.The key question is how these declines affect the course of a coronavirus infection.Declines might make it easier for the virus to establish a foothold in your body, but not necessarily translate into a substantial weakening of your immunity.Nussenzweig pointed me to a recent study done in Australia.
The researchers found that, when a vaccinated person’s antibody levels fall to around twenty per cent of the typical post-infection level, protection against symptomatic infection drops to fifty per cent.Protection against severe disease, however, doesn’t fall to fifty per cent until antibodies wane to just three per cent of post-infection levels.
Many factors could account for the persistence of immune protection despite declines in antibodies.Part of the story may have to do with memory B cells—immune cells that hang around, sometimes for decades, for the specific purpose of quickly restarting our antibody response when a familiar pathogen reappears.T cells, which also continue to circulate long after an infection, also play a role, by hunting for infected cells.These and other systems come online quickly upon reinfection: like a computer coming out of sleep mode, the immune system snaps to life.
All this means that lower antibody levels aren’t as bad as they sound.A little protection goes a long way.
Viruses and vaccines are all different.Immunity against any given virus may or may not wane; the timeline for SARS -CoV-2 immunity is not yet clear.But, even when resistance stays robust, viruses can mutate.The data used by the Australian researchers predates the global spread of the Delta variant, which seems to have some “immune-evasive” properties.Research so far indicates that antibodies developed for the original strain of the coronavirus may be only half or a third as effective against Delta.
And Delta is different in another way: compared with the original virus, it generates a thousand-fold-higher viral load.Infected people are shedding a lot more of it.If you’re on the receiving end of that shedding, this could affect your “viral dose”—the amount of virus you’re exposed to.“The probability of getting infected with any virus is related to the number of infectious units that are going into you,” Nussenzweig said.
Antibody levels, antibody affinity, and viral dose—these three factors form the bedrock of the breakthrough-infection story.
They can combine in various ways.Our behavior affects the doses to which we’re exposed.We don’t know how much immunity is waning, and we are still learning about Delta’s properties.In the worst case, all three factors are at work.
As Nussenzweig told me, “If, instead of getting x particles of the Wuhan strain, you get a thousand times x of Delta, and your antibody response is two or three times diminished because the vaccine was based on a prior version of the virus, and it’s been a number of months since you got your shot—well, that’s a problem.”
But what exactly is the problem? Most vaccinated people no longer need to fear dying of a coronavirus infection.They are also much less likely to have to go to the hospital.
But they do want to avoid getting seriously sick with an illness that, even if not life-threatening, could be profoundly unpleasant; they worry about giving the virus to others who are vulnerable; and they fear developing long COVID —a syndrome of fatigue, shortness of breath, cognitive problems, and loss of taste or smell—after even a mild breakthrough infection.Studies, unhelpfully, have placed the risk of developing long COVID at somewhere between one and eighty-seven per cent.
There are no precise estimates of how many Americans have it, and such estimates, if they existed, would vary depending on how the syndrome is defined.Still, if even a small fraction of the tens of millions of infected Americans develop a post- COVID syndrome, their ranks could number in the tens of thousands.
To estimate any of these risks, we need to know how many breakthroughs there are.But that number is hard to fix, for both conceptual and practical reasons.In May, the C.D.C.stopped tracking infections among vaccinated people that didn’t cause hospitalization or death, a decision it described as intended to “help maximize the quality of the data collected on cases of greatest clinical and public health importance.” The move was widely criticized by patient advocacy groups, lawmakers, and public-health experts.
But, in truth, studying all breakthrough infections presents serious data-collection challenges.The C.D.C.relies on passive and voluntary reporting of infections, but many cases, especially those that are mild or asymptomatic, are never reported.
Meanwhile, when the agency tried to study people with asymptomatic breakthrough infections, it often found that there was “inadequate virus to even do so,” Rochelle Walensky, the C.D.C.director, said .
As an alternative to trying to track every breakthrough infection, researchers can use so-called cohort studies, which follow a defined group of people over time.This approach has an obvious advantage, in that you can test everyone—even those without symptoms.But it also has a critical limitation: you can never be quite certain how applicable the study’s findings are to other people, in other settings, at other times.
A new cohort study from Israel—conducted during the reign of Alpha, not Delta—provides perhaps the most rigorous evidence on the frequency and severity of breakthrough infections.Researchers examined what happened after Sheba Medical Center, Israel’s largest hospital, vaccinated more than eleven thousand health-care workers between December, 2020, and April, 2021.
During that period, around fifteen hundred workers experienced either a known coronavirus exposure or developed suspicious symptoms; of that number, thirty-nine—less than three per cent—tested positive for the coronavirus.Those who got infected tended to have lower antibody levels.Most had mild symptoms; a third were asymptomatic; no one had to be hospitalized; and no one passed the virus on to others.At the same time, nineteen per cent of those who experienced a breakthrough infection—seven people—continued to have symptoms, such as cough, fatigue, or loss of smell, six weeks later.These findings were widely publicized, sometimes in ways that focussed on this final, alarming statistic.“Study: 20% of vaccinated health workers who test positive suffer from long COVID ,” one headline read.
“One in five breakthrough cases among health care workers in Israel resulted in long COVID ,” announced another .
Such headlines, of course, fail to take account of the whole picture.In statistical terms, they neglect the “ base rates ” of infection.Take nineteen per cent of three per cent, and you’ll find that the people tested in the study had about a one-in-two-hundred chance of developing long COVID .Even this number is too high: of the more than eleven thousand vaccinated people in the hospital, the researchers tested only those who had symptoms or a known coronavirus exposure.
Widen the lens to take in all the vaccinated employees, and the long- COVID rate drops to less than one tenth of one per cent—something like one in fifteen hundred people.
Moreover, the study focussed on health-care workers, who have a higher than usual risk of contracting the virus and falling ill.In the pre-vaccine era, some studies estimated that they were nearly twenty times as likely to get infected, and more than seven times as likely to develop severe COVID .
The nineteen-per-cent figure itself may be higher than it should be.Farzad Mostashari, a former epidemic intelligence service officer at the C.D.C., has argued that a form of recall bias—a phenomenon in which people may attribute current symptoms to salient but unrelated prior events—could inflate the apparent prevalence of long COVID .Suppose that you provide someone who’s been sick with a questionnaire, asking him to indicate which of a list of symptoms he has continued to suffer over the past few months.
Faced with such a list, Mostashari wrote , on Twitter, “respondents often feel like they’re supposed to say ‘yes’ ” to some of the symptoms.In his view, this approach, which was taken in the Israeli study, could have led people to highlight symptoms needlessly.
A better strategy would be to randomly select a group of people with no documented history of the coronavirus, ask them about any symptoms they’re experiencing, and only then check their blood for antibodies to see if they’ve previously been infected.A recent study from Germany, not yet peer-reviewed, took such an approach; it found that adolescents who reported long- COVID -like symptoms were no more likely to have coronavirus antibodies than those who didn’t.
Millions of Americans have been infected but never tested, and so conducting such a study in the U.S.would be feasible, theoretically.
Until it’s done, the public conversation about breakthroughs and long COVID will be driven by data that’s outdated or incomplete.The same is true for breakthroughs generally.As it stands, we don’t know, with nearly enough specificity, how frequently they occur—or who’s most at risk, under what circumstances, and with what implications.
With so little conclusive data to go on, our reactions to what we learn about breakthroughs are heavily shaped by our expectations.When I first encountered the Provincetown findings, I felt discouraged.I hadn’t expected nearly three-quarters of the infections to register in fully vaccinated people—it was an outcome that seemed to strike at the heart of vaccine efficacy.
But, with time, I’ve come to think that there are reasons that the Provincetown outbreak, like the Israeli study, might not be as bad as its most alarming statistic.
Three-quarters sounds like a lot.But we need to revise our statistical expectations for a post-vaccine world.
Consider some basic math: if no one is vaccinated, then there can be no breakthrough infections; if we’re all vaccinated, then every infection will be a breakthrough.Our understanding of the Provincetown outbreak, therefore, depends in part on the area’s vaccination rate.According to official tallies, nearly seventy per cent of the eligible people in Massachusetts were vaccinated prior to the outbreak.
Assuming that’s true, there was virtually no difference in the chances of infection by vaccination status.But, according to the Provincetown town manager, the vaccination rate among town citizens may have been as high as ninety-five per cent.
A twenty-five-per-cent shift in the vaccination rate dramatically alters the import of the Provincetown numbers.If only five per cent of people were unvaccinated, and they accounted for a quarter of infections, then an unvaccinated person was actually seven times more likely to get infected—and this in a town that was full of packed clubs, sweaty dance floors, maskless parties, and crowded restaurants.“This was a level of exposure that few vaccines could overcome,” Jennifer Nuzzo, an epidemiologist at the Johns Hopkins Center for Health Security, told me.Given the role that viral dose plays in infections, it’s hard to imagine an environment more conducive to transmission.
From this perspective, the size of the outbreak might actually be reassuring.
Of course, we don’t know how likely out-of-town partiers were to have been vaccinated.We also don’t know how many people were infected in the outbreak but not identified, or whether they were vaccinated.“We don’t have denominators,” Nuzzo said.“We don’t know how many people were actually exposed.” By some estimates, there were as many as sixty thousand people in Provincetown during the first week of July.If this is the case, Nuzzo said, it could make breakthrough infections “really anomalous events.”
Even the finding that vaccinated and unvaccinated people carry similar viral loads may not be as alarming as it sounds.Some have taken it to mean that the two groups are equally likely to pass the virus to others.
But, once infected, vaccinated people tend to have fewer symptoms, reducing the chances that they’ll transmit the virus.Their antibodies may also move faster to coat it in ways that hamper its infectiousness and ability to replicate.One study , from Singapore, found that, while vaccinated and unvaccinated people have similar viral loads at first, the amount of circulating virus declines much faster in those who’ve been immunized.
Perhaps the most important fact about the Provincetown outbreak is that the vaccines worked marvellously when it came to the most concerning consequences of infection.In recent weeks, the number of cases linked to the outbreak has climbed to more than a thousand.Still, there have been just seven hospitalizations and no deaths.As German Lopez has pointed out, at Vox, a similar cluster of cases before the vaccines might have led to around ninety hospitalizations and nine deaths.
(The C.D.C.estimates that, across the nation, vaccinated people remain twenty-five times less likely to be hospitalized or die of COVID -19.) “From that perspective,” Nuzzo told me, “we might say, ‘Wow, these vaccines actually worked really well.’ ”
Our greatest fear is that, in the face of variants or time, vaccine efficacy might decline.Israel is one of the most vaccinated countries in the world, and yet it’s experiencing another COVID surge.As with Provincetown, the headline numbers are concerning: some sixty per cent of Israelis currently hospitalized with COVID -19 have been fully vaccinated.
“I believe we are at war,” Salman Zarka, Israel’s coronavirus czar, told a parliamentary committee last week.If the vaccines are effective against Delta, how can this be?
Here, too, it’s important to proceed slowly.One plausible answer is that, earlier this summer, as the pandemic’s toll lessened, Israel relaxed almost all social-distancing measures; even in a highly protected society, more contact almost always means more infection.But another answer has to do with how we analyze the numbers.
Israel has an extremely high rate of vaccination: nearly eighty per cent of the over-twelve population is immunized.If we take the underlying immunization rate into account, the vaccines appear to be nearly seventy per cent effective at preventing hospitalization.And Jeffrey Morris, a biostatistician at the University of Pennsylvania, argues that the vaccines are probably even more effective.Morris points out that older people are more likely to be vaccinated: in Israel, ninety per cent of people older than fifty have gotten a vaccine, compared with seventy-three per cent under fifty.They are also, because of their age, more likely to suffer severe illness.The most vaccinated group also has the highest risk.These two factors combine—a disparity on top of a disparity—to create the impression of lowered efficacy.
When we correct for these imbalances, Morris writes, the vaccines turn out to be eighty-five per cent effective at preventing severe disease in people over fifty, and more than ninety per cent effective for younger people.They still work.
Denominators, definitions, Delta: these are the challenges we face in understanding breakthrough risk.Without knowing how many vaccinated people have actually been exposed to the virus, it’s hard to calculate the true risk of breakthrough infection.Meanwhile, the significance of each positive test in a vaccinated person is not clear: as Nuzzo put it, “We may just be catching people’s bodies going through the motions of containing the virus, exactly how vaccines trained the body to do.” And the Delta variant has rendered once sharp data foggy.A single worker in the Israeli hospital study couldn’t go back to work after six weeks; that puts the odds of serious breakthrough long COVID somewhere close to the odds of getting struck by lightning.And yet the Israeli study was done before Delta.The Provincetown outbreak suggests that the likelihood of breakthrough illness with Delta could be meaningfully higher than in the past.
How much higher? It’s hard to draw conclusions from just one, atypical instance.
It’s possible that we’ll never have a satisfactory understanding of breakthrough infections.We may eventually arrive at a closer approximation of the breakthrough risk posed by Delta—but, by then, we could be contending with new variants, old vaccines, or waning immunity.
Each time we try to map the risk landscape, the sand will move beneath our feet.What does this mean for the pandemic’s future? Nuzzo told me that, in her view, that’s an impossible question to answer without a clearer idea of what we’re trying to accomplish.“The stated public-health goals have shifted so many times,” she told me.“Laypeople are saying, ‘Wait, I thought we were worried about hospitals being overwhelmed?’ Then it was, ‘Oh, we need to close schools because we’re worried about children giving the virus to their grandparents.’ Now grandparents are vaccinated, but we still need masks? We still need distance? The vaccines aren’t good enough?” Speaking about public-health officials, Nuzzo said that “they haven’t yet defined for the public what their current rationale and exit ramps are.If you lead people to believe the vaccines are not sufficiently protective, then they’ll wonder, ‘When does this end?’ ”
For the pandemic to resoundingly conclude, two trends must intersect.
The virus must cease to inflict overwhelming harm, and the risks that remain must be judged low enough for society to proceed with normal life.
On the first front, most vaccinated Americans should feel safe.But, on the second, we need data and we need a plan.“The public deserves a coherent strategy with end goals that define what we’re working toward, and then a research agenda aimed at answering the questions we need in order to make decisions,” Nuzzo told me.“That’s how we put ourselves in a position to decide when the pandemic is over.”
To navigate uncertainty, we need nuanced thinking.Right now, we speak of breakthrough infections as binary events: the virus either breached the gates, or it didn’t.But the course of an infection and the circumstances around it are more important than the mere fact of a positive test.
Are our immune systems still fighting off typical, predictable viral incursions? Or are small invasions more frequently escalating into pitched battles? The former suggests that we’re mostly safe most of the time; the latter is reason to pause business as usual.An all-or-nothing conceptualization of breakthroughs—one that overlooks the context and implications of P.C.R.positivity—coarsens the pandemic discourse and clouds our view of the future.
It’s possible to see reports of breakthrough infections not as disheartening setbacks but as expected developments in the pandemic story.We’ve been talking about boosters since the first COVID vaccines became available; all along, the implicit rationale—one that’s often gone unsaid—was that either our immunity would wane, or the virus’s genetic code would change, such that we would end up somewhat less protected.
We’re now witnessing something like what we predicted.We’ve already read the script, but we’re still surprised by the plot twist.
At the same time, it’s worth acknowledging to ourselves that, in the absence of definitive data, we are guessing about how we think the story will go.The Biden Administration is now recommending booster shots for most Americans, some as soon as September—about eight months after the first nursing-home residents and health-care workers were immunized.Its recommendation is based, in part, on three new studies, released by the C.D.C., which fail to present a slam-dunk case.
One study , of thousands of nursing-home residents across the country, found that, in recent months, the vaccines’ effectiveness against infection had declined from about seventy-five to fifty-three per cent; it’s not entirely clear what to make of the findings, however, because we don’t know when the residents were vaccinated or whether they went on to have symptoms.A second study , focussed on New York State during the period that Delta came to dominate, found that the vaccines were still nearly eighty per cent effective at preventing infection—down from about ninety-two per cent—and that there was no change in how reliably they prevented hospitalization.The third study , which analyzed data from eighteen states, supported the latter finding: six months after being vaccinated, people were just as protected against a COVID hospitalization as they were just after they got their shots.Over all, the evidence that vaccines prevent severe COVID -19—even with Delta, even half a year after immunization—remains both clear and encouraging.By contrast, the data that breakthrough infections present a major concern for the average American is much murkier.
In his “ Pensées ,” Blaise Pascal, the seventeenth-century French philosopher and mathematician, advanced an argument: Every rational person should believe in God.Pascal’s wager, as it’s come to be known, begins with the indisputable supposition that either God exists, or he doesn’t.If you believe in God, and he doesn’t exist, then you’ve lost very little—perhaps a chance at some risqué behavior that’s better avoided anyway.But if you don’t believe in God, and he does exist, you’re damned.
Better to believe in God.We might not call this “belief,” exactly—it’s too calculated for that—but it does have a certain logical appeal.
When it comes to breakthrough infections, we are not compelled to believe that they are seriously risky.The data are too inconclusive for that.But we may still choose, rationally, to make a wager.
For vaccinated people, the coronavirus threat is massively, undeniably smaller than it was last year; at the same time, we are taking more risks—visiting family, attending weddings, going to church, returning to the office.We have to make decisions about what’s worth it, what isn’t, what we should do now, and what can wait.
Like many Americans, I have started to scale back.I’ve cancelled trips, avoided gatherings, stopped dining indoors.
In my work as a physician, I’m again wearing an N95 respirator with every patient, not just those who’ve tested positive for the virus.I’ve concluded that the risk of Delta causing a significant breakthrough illness for me—a reasonably healthy man in his thirties—is low, but also that it’s a better bet to assume that the risk is real.
As a society, we are also making bets.We are now planning third shots for healthy Americans, even as billions of people around the world have yet to receive a single dose; in all likelihood, there will be college students in the U.S.who get boosters before nursing-home residents in Africa receive their first shots.Meanwhile, we don’t know, with any certainty, the true risks of waning immunity, of breakthrough infections, of long COVID , or of Delta-inflicted breakthrough disease.Still, we are deciding that the costs of waiting to find out may exceed the costs of acting today.
There are differences—morally, practically, emotionally—between being forced to feel afraid and choosing to be cautious.
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