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Have You Already Had a Breakthrough COVID Infection?

Despite breakthroughs, it's important to remember that most vaccinated people no longer need to fear dying #COVID19. They are also much less likely to be hospitalized.

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.)

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.

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