Immunity Is Redefining COVID-19
Boghuma Kabisen Titanji was just 8 years old when the hyper-contagious virus swept through her classroom. Days later, she started to feel feverish, and developed a sparse, rosy rash. Three years after being fully dosed with the measles vaccine, one of the most durably effective immunizations in our roster, Titanji fell ill with the very pathogen her shots were designed to prevent.
Her parents rushed her to a pediatrician, worried that her first inoculations had failed to take. But the doctor allayed their fears: “It happens. She’ll be fine.” And she was. Her fever and rash cleared up in just a couple days; she never sickened anyone else in her family. It was, says Titanji, now an infectious-disease physician and a researcher at Emory University, a textbook case of “modified” measles, a rare post-vaccination illness so mild and unthreatening that it doesn’t even deserve the full measles name.
The measles virus is ultra-infectious, much more so than SARS-CoV-2, and kills many of the uninoculated children it afflicts. But for those who have gotten all their shots, it’s a less formidable foe, which we’ve learned to live with long-term. That’s the direction that many experts hope we’re headed in with SARS-CoV-2 as it becomes endemic, as my colleague Sarah Zhang has written.
We’re not yet at the point where we can officially label post-vaccination COVID-19 cases as “modified”; maybe we never will be. Some immunized people are still getting dangerously sick. But the shots are softening COVID-19’s sharp edges: On average, breakthrough infections seem to be briefer, milder, and less contagious. Among the fully immunized, catching the coronavirus doesn’t mean the same thing it did last year. “It’s a very different kind of infection than in people who are immunologically naive,” Lindsey Baden, an infectious-disease physician and COVID-19 vaccine researcher at Brigham and Women’s Hospital in Boston, told me.
If this virus becomes as inescapable as the culprits behind the colds and flus that trouble us most years, we could all have to grapple with one of these infections, and learn that lesson on a personal level. That’s the social tax of a forever virus: Nearly everyone may eventually know what it is to get COVID-19—but a tamer, more domesticated version of its pre-inoculation self.
Since the start, COVID-19 has been tough to define.
Part of the problem is that COVID-19 is the disease, not the virus. Actual microbes, compared with the problems they cause, are arguably neater conceptual packages. SARS-CoV-2 is a knowable pathogen, a tangle of genetic material swaddled in a protein coat; COVID-19 has fuzzier boundaries, dependent on both the virus and how our bodies react to it. To understand that interaction, researchers had to, unfortunately, wait for a decent number of people to get sick—to observe the virus screwing with us in real time.
Next to other airway-loving viruses, such as the ones that cause the flu and common colds, SARS-CoV-2 can be a bit of an oddball. It lopes almost indiscriminately throughout the body, invading a plethora of tissues; it winds up certain immune responses, while dialing others down, sparking bouts of inflammation that can afflict everything from brain to toe. COVID symptom lists that at first focused on the virus’s ground zero—the respiratory tract—eventually ballooned to include nausea, vomiting, changes in mental status, and chest pain. Infection severity operates on a continuum, and SARS-CoV-2 occupies its spectrum fully. Many people never realize they’re infected; others might have a two-day tickle in their throat, while some weather the disability of long-haul COVID for months; a fraction end up ventilated in the ICU.
The experience of having COVID is now poised to splinter further, along immunological boundaries largely defined by vaccines. Inoculated bodies are less hospitable to SARS-CoV-2, making it harder for the pathogen to infect them; when it still manages to, it seems to be purged much faster, affording it less time to cause symptoms—especially the bad ones—and fewer opportunities to hop into other hosts. “I think about it as defanging the virus,” Natalie Dean, a biostatistician at Emory, told me.
A recent study from the United Kingdom illustrates this well. Researchers surveyed nearly 4.5 million people through a cellphone app, asking whether they’d tested positive for the virus, and if they were experiencing any of about two dozen symptoms. Roughly 1 million of them had received at least one vaccine dose. Among the fully immunized, nearly all the symptoms—including fever, nausea, and brain fog—were rarer. Many of the cases were totally asymptomatic. Even rates of long COVID, which can sprout from initially silent infections, seemed to be substantially slashed by shots.
These qualitative shifts aren’t easy to capture, especially with the studies coming out now that measure vaccine effectiveness in the real world. Most of them gravitate toward metrics at two opposite ends of the SARS-CoV-2 spectrum—how well the vaccines protect against all infections, or against severe disease, hospitalizations, and death—with less precision around the murky hinterlands of mid-level symptoms that exist in between. (The most serious outcomes are, to be fair, what vaccines are intended to prevent, and what inoculated immune systems are best at staving off, making that metric a pretty good one to concentrate on.)
Focusing on the extremes, though, blurs the texture in the middle. In studies of effectiveness against severe disease, anything too “mild” to be considered a serious illness—warranting hospitalization, for instance—ends up collapsed into a single category. At the other end of the spectrum, counting all infections equates every positive test to a case of concern, regardless of how gentle the viral encounter was. All of this makes it very difficult to characterize what post-vaccine COVID actually is—and to know whether immune responses are diluting the disease’s sting. “Just looking at the rate … loses that point,” Holly Janes, a biostatistician at the Fred Hutchinson Cancer Research Center in Seattle, told me. The experience of infection can be “considerably different for someone who was vaccinated.”
This isn’t an easy dilemma to solve. During the vaccine makers’ clinical trials, researchers were able to study participants closely enough to examine how well the shots were blocking any symptomatic cases of COVID-19. (Studying only the severest disease, which are relatively rare events, wouldn’t have been feasible without making the trials even larger, or stretching them out longer.) “Real-world studies are like the wild, wild West,” Dean told me. Researchers often have to wrestle evidence out of electronic medical records, which aren’t logged consistently, or they have to depend on people to seek out tests and accurately remember their symptoms. They might monitor only the worst infections, because they’re more likely to prompt people to seek clinical care and are easier to document and study. Milder cases, meanwhile, are squishier, more subjective; not everyone will interpret an ache or a pain in the same way, or follow up on it with a professional. The studies that have tackled the task of measuring real-world vaccine effectiveness against all symptomatic disease may not always count the same COVID-19 symptoms, experts told me, potentially inflating or deflating numbers. Thorniest of all may be the data investigating long COVID, which still lacks a universal case definition, after vaccination, Lekshmi Santhosh, a critical-care physician at UC San Francisco, told me. “Most studies aren’t even looking,” she said.
Important variations exist, even at SARS-CoV-2’s extremes. Some hospitalized patients might be admitted for just a couple days, while others need weeks of critical care or die. Early evidence hints that vaccines are batting away the worst blows here as well, another nuance lost when hospitalizations are lumped together. Positive test results, too, can be misleading. Tests, which hunt for precise pieces of the pathogen, can’t distinguish between viruses that are intact, or that have been blown to smithereens by a protective immune response; SARS-CoV-2 carnage, especially in a person who’s immunized and asymptomatic, doesn’t guarantee disease or transmission. “It doesn’t mean the same thing to test positive if you’re vaccinated,” Julie Downs, a health-communications expert at Carnegie Mellon University, told me.
Still, some infections among immunized people will pose a low-but-not-nonexistent transmission risk, especially to the vulnerable among us, and we can’t yet afford to tune the milder cases out. A much larger fraction of the global population will need protection before COVID-19 can truly be considered mellower than before. But the fates of the inoculated and the uninoculated are clearly already forking, a potential preview of what’s to come, Baden, the Boston physician, told me. “If I were a betting man, I’d say, years from now, this will be another common cold.” Titanji, of Emory, has already confronted the likelihood that her childhood bout of modified measles might foreshadow her experience with the coronavirus. When she sees patients in her clinic in Georgia, she tells them, “We’re all very likely going to have COVID, including myself. But it is okay. I have a vaccine that will prevent me from landing in the hospital.”
COVID-19’s march toward diminution won’t be linear or uniform. Immune cells forget; viruses shape-shift; our vaccines will need touch-ups or boosts. Behavioral slipups—vaccine refusals, spotty masking during outbreaks—will create cracks for the pathogen to wriggle through. But on a population level, our future could look quite good. Most people will end up getting COVID-19 in their lifetime. In most cases, it won’t be so bad. Eventually, silent or mild infections will feel less catastrophic, because many of us will have confidence that they are unlikely to progress. Outbreaks might be smaller and slower-spreading, and breakthroughs will no longer be headline-making news. Positive test results, in the absence of symptoms, could generally be shrugged off, and infection will no longer feel quite so synonymous with disease. Our bodies will come to see the virus as familiar—not necessarily a welcome guest, but not quite the intruder it was before.
Data alone won’t define our experience here; our understanding of post-vaccination infection will need to come firsthand, too. For me, the pandemic anxiety that dominated much of 2020 is slow to fade, and the idea of getting COVID-19 still feels far worse than getting the flu, even if the symptoms were identical. “It takes time to get over that,” Downs told me.
A small number of post-vaccination infections are now trickling into my social circles, and it’s actually been sort of comforting to hear some of the stories. A few days ago, I talked with Jayne Spector, who just became mother-in-law to one of my best friends. Spector tested positive for the coronavirus a couple weeks ago—shortly after attending her grandmother’s funeral, where she’d hugged and kissed dozens of family members. Among them was her daughter, who was, at the time Spector received her test result, about to have her wedding, just 11 days later.
“I was really worried I had infected my soon-to-be-married daughter,” Spector told me. And had Spector not been vaccinated, “I think it would have been a disaster.” But Spector was vaccinated. So were almost all the family members she mingled with at the funeral—her daughter included—and not a single one of her contacts has tested positive. (They also kept a lot of the interactions outdoors, and wore masks inside.) Spector isolated at home, where she dealt with what she compares to a nasty but relatively fast-resolving cold—a paltry echo, she suspects, of the sickness she would have had, if not for her shots. “The fact that I’m vaccinated means that it’s tolerable,” she told me. “I took the precautions; I stayed away from others. Now I’m going back to my life.” Her daughter’s wedding was this past Saturday. All 18 people in attendance were fully vaccinated, and tested negative before the ceremony. Spector was one of them.