What Breakthrough Infections Can Tell Us

Post-vaccination infections reveal how effective vaccines are—and which variants are sneaking past our defenses.

A nurse inserts a swab into a person's nose to test them for a virus.
Lisa Maree Williams / Getty

With 165 million people and counting inoculated in the United States, vaccines have, at long last, tamped the pandemic’s blaze down to a relative smolder in this part of the world. But the protection that vaccines offer is more like a coat of flame retardant than an impenetrable firewall. SARS-CoV-2 can, very rarely, still set up shop in people who are more than two weeks out from their last COVID-19 shot.

These rare breakthroughs, as I’ve written before, are no cause for alarm. For starters, they’re fundamentally different from the infections we dealt with during the pre-mass-vaccination era. The people who experience them are getting less sick, for shorter periods of time; they are harboring less of the coronavirus, and spreading fewer particles to others. Breakthroughs are also expected, even unextraordinary. They will be with us for as long as the coronavirus is—and experts are now grappling with questions about when and how often these cases should be tracked.

Breakthroughs can offer a unique wellspring of data. Ferreting them out will help researchers confirm the effectiveness of COVID-19 vaccines, detect coronavirus variants that could evade our immune defenses, and estimate when we might need our next round of shots—if we do at all. “The more complete and precise data we have about the pathogen and how it spreads through the community, the better off we’re always going to be,” Jay Varma, the senior adviser for public health in the New York City mayor’s office, told me.

But testing too often can sometimes cause as much damage as testing too little. The nation has yet to settle into its late-pandemic testing patterns, and decide which types of breakthroughs warrant the most attention. On May 1, after weeks of reporting all post-vaccination infections, regardless of whether they were linked to symptoms, the CDC narrowed its focus to cases involving hospitalization or death—a move that prioritizes investigations of “cases that have the most public-health significance,” Tom Clark, who leads the agency’s vaccine-evaluation unit, told me.

The decision sparked controversy. Although hospitalization and death are among the most serious consequences of a coronavirus infection—and reasonable priorities for a public-health system with limited resources—the agency’s decision may have been premature, experts told me. Most of the world remains unvaccinated, and will for a while yet; our knowledge of SARS-CoV-2 and its capacity to shapeshift is still growing by the day. One of the best hopes for staying ahead of the pathogen is to watch it closely, in its many iterations, across a diverse set of hosts. Stopping a small fire from spreading is far easier than erasing the damage a conflagration has left—but we’re still figuring out how many stray sparks we’ll need to track.

This early in our relationship with SARS-CoV-2, the perks of testing for breakthrough cases are clear.

The trio of authorized vaccines in the United States, made by Pfizer, Moderna, and Johnson & Johnson, proved spectacular at staving off symptomatic cases of COVID-19, especially in its severest forms, during clinical trials. In the real world, the protective punch of immunizations can take a slight dip, particularly in people who weren’t well represented in the vaccine makers’ studies. Certain people have naturally different susceptibility to infection, in the same way that certain types of bark catch fire more easily. The first round of vaccine vetting also didn’t formally look into the shots’ potential to curb asymptomatic infections, or transmission—data that are now being gathered in real time.

It’s because of breakthroughs—and how few of them we’re finding—that we know that the vaccines are performing well in a broad range of people, knocking back both disease and infection, even as the number of coronavirus variants carrying antibody-dodging mutations continues to rise. By the end of April, when more than 100 million Americans had finished their shots, the CDC had received documentation of 10,262 post-vaccination infections of all severities, according to a report published this week. (That’s a definite undercount of the true number, but breakthroughs are still a tiny fraction of the millions of SARS-CoV-2 infections that have been reported to the agency since the vaccine rollout began.) Breakthroughs could also eventually clue researchers in to how well the vaccines thwart very rare or late-appearing consequences of infection, including long COVID. And the future of COVID-19 booster shots hinges on carefully archiving breakthroughs. Clusters of these post-vaccination infections compelled public-health officials to alter the dosing schedules for measles and chicken-pox vaccines, for example.

A subset of the test samples collected from breakthrough cases can also be sequenced, as part of the search for unusual mutations in a pathogen’s genome. Genetic surveillance has, for months, been the pandemic’s bellwether for variants; more than 1.6 million SARS-CoV-2 genomes from around the world have been cataloged in an ever-growing database. Of those 10,000 breakthrough cases, 555—roughly 5 percent—came with sequencing data. Although that’s not a highly representative sample, dozens of those sequences turned up as coronavirus variants that can bypass certain immune defenders.

Across the country, the news on variants and vaccines seems mixed, experts told me. One recent study, out of Washington State, found that variants—including several known to stump certain antibodies in the lab—were dominating sequenced breakthroughs. But in Minnesota, post-vaccination infections “just reflect what’s circulating in the community,” Stephanie Meyer, the COVID-19 Epidemiology and Data Unit Supervisor at the Minnesota Department of Health, told me.

If a variant were to consistently pop up among the vaccinated, researchers would need to understand why. A new version of the virus might be more efficient at infecting people, or have a new way of eluding the immune system. To tease out those possibilities, researchers need data, the more comprehensive, the better. “Asymptomatic, mild symptoms, hospitalized, passed away—all that information is important,” says Ryan McNamara, a virologist at the University of North Carolina at Chapel Hill, where he and his colleagues are sequencing samples from breakthrough cases across the spectrum of severity. “If you’re asking what variant is driving worse clinical outcomes, you need both ends of the data,” he told me.

Many public-health laboratories at the state and local level have been diligently tracking breakthroughs of all kinds for months, and are unsure of whether to mirror the CDC’s shifting priorities. “Previously, labs were sequencing all the breakthrough cases we could get our hands on,” Kelly Wroblewski, the director of infectious disease at the Association of Public Health Laboratories (APHL), told me. “Now states are scrambling, trying to sort it out.” Some states, such as Illinois and Tennessee, quickly followed the CDC’s lead. Others are hesitant. For now, “we’re not changing what we’ll be sequencing,” Myra Kunas, the director of Minnesota’s state public-health laboratory, told me.

Some of the same vaccine attributes that make breakthroughs rare also make them difficult to unearth and sequence. When sparks of virus do take hold in a vaccinated person, their fire still seems to burn extremely low—though infected, these people simply don’t carry much virus. That’s great news from a clinical standpoint, but not for someone hoping to identify a virus variant. Proper sequencing requires rounds of shredding and scanning pieces of the coronavirus’s genome, then cobbling them back together into a readable format. Sometimes, the samples from vaccinated people are barely enough to prompt a positive from a test, let alone yield a decent sequence.

Other barriers stand in the way of comprehensive sequencing. Antigen tests can catch breakthrough infections, but aren’t usually compatible with sequencing. And many of the labs that process coronavirus tests don’t have sequencing infrastructure, or enough storage to keep hundreds of samples on standby. In many parts of the country, researchers are having trouble tying vaccination records to test results, making it difficult to prioritize specimens for further genetic analysis. Sequencing only 5 percent of breakthroughs is low, experts told me. Minnesota’s lab, for instance, has been able to sequence about a fifth of its 2,500 or so breakthrough specimens. But processing all post-vaccination infections in this way isn’t a reasonable expectation.

Fervor for testing has also waned nationwide since the vaccine rollout began. Most vaccinated people don’t need to regularly seek out tests, especially if they’re not feeling sick. The CDC has loosened guidelines about quarantine and associated testing for fully vaccinated people, even after known exposures, and has also recommended that the immunized be “exempted from routine screening testing programs, if feasible.” In recent weeks, several college and professional sports organizations that had for months implemented routine testing for athletes and staffers announced that they were cutting back on screening for the immunized.

Programs like these might have otherwise revealed some breakthroughs. But hunting for these cases has other drawbacks. Earlier this month, the New York Yankees, a team that continued to regularly test its fully vaccinated personnel, recently reported nine positive tests—most connected to asymptomatic cases. Many experts framed the detection of mostly symptomless infections as proof that the shots were doing their job, but worried about rote reliance on testing as a security blanket, and wondered about the possibility of false positives. Vaccinated people are so unlikely to catch the virus that administering a bunch of tests wastes resources and increases the likelihood for errors, says Omai Garner, a clinical microbiologist at UCLA Health. Chasing constant reassurance about infections after vaccination could also send the wrong message, Saskia Popescu, an infection-prevention expert at George Mason University, told me. “If we’re telling people they can be unmasked and we’re still [frequently] testing them, what’s the signal we’re sending?”

Vaccinated people in high-risk settings, such as health-care workers and long-term-care-facility residents, might have more reason to test going forward, especially in areas where caseloads are high. Collecting data from these populations will lend itself to studies of real-world vaccine effectiveness—an endeavor the CDC is still engaged in. But “there’s no recommendation that you get tested randomly” if you’re vaccinated, says Kristen Ehresmann, the director of infectious-disease epidemiology, prevention, and control at Minnesota’s Department of Health.

This creates a strange bind for public-health officials who depend on the data that testing programs yield. As collective immunity around the nation builds, finding its weak spots is becoming harder. “We’re running into this potential of losing our pipeline for studying variants in the population,” Wroblewski, of APHL, told me.

The CDC’s revised guidelines on monitoring post-vaccination infections could, in some ways, be seen as pragmatic. More severe sickness is relatively straightforward to tabulate, and hospitalizations and deaths lend themselves to a more comprehensive census. (One big caveat is that the agency is including in its counts cases of hospitalization or death that weren’t necessarily caused by COVID-19, but simply involved a positive post-vaccination test.)

“With viruses, and with any infectious disease, there’s no end to how much work you can do,” Robin Patel, the director of the Infectious Diseases Research Laboratory at Mayo Clinic, told me. “You have to stop somewhere.”

The agency’s decision to shunt attention away from quieter breakthroughs could also help normalize mild or silent coronavirus infections—ones that have been effectively tamed by our suite of lifesaving shots—as a typical experience in the era of COVID-19 vaccines. Though the pandemic will eventually be declared over, SARS-CoV-2 is not exiting the human population anytime soon. Periodic liaisons with the virus will remain a part of everyday life; they might even remind our dormant immune cells to stay on guard.

In Minnesota, Meyer and Ehresmann, of the state’s health department, are continuing to collect data on breakthroughs and variants “at perhaps a more detailed level than what CDC is asking for,” Ehresmann told me. That’ll be the case, she added, “as long as that information is helping us in our decision making.” There’s no clear milestone for their team to meet—the virus, if anything, has proved unpredictable—but maybe they’ll change their criteria once caseloads are lower, and more information on vaccine effectiveness is available.

I asked Meyer when she thinks her job will get easier. She laughed. “If you figure that out,” she said, “can you let us know?”

A total moratorium on SARS-CoV-2 diagnostics isn’t in the cards. Pandemic or no, “we will always have to test for this virus,” Garner, of UCLA Health, told me. But “it is not sustainable to track and trace the way we have for over a year now,” Meyer said. Eventually, the nation will hit upon a more sustainable approach to testing that both helps individuals in clinical settings and serves public-health objectives en masse. The coronavirus will become, perhaps, another seasonal respiratory pathogen that flares up each winter, joining the rotating cast of usual suspects. Surveillance of the virus, in its many iterations, will be modeled on what’s done for the flu, with labs regularly soliciting specimens from around the nation and sequencing them. We will approach a reality in which our relationship with the virus settles into a tense but sustainable truce, in which small fires flare up every once in a while. We’ll be able to see many of them coming, because we’ll know where to look.