The Perfect Vaccine Might Simply Be Impossible
In 1846, the Danish physician Peter Ludvig Panum traveled to the Faroe Islands in search of measles. The rocky archipelago, which sits some 200 miles north of Scotland, had been slammed with an outbreak, and Panum was dispatched by his government to investigate. The trip predated the formal discovery of viruses and antibodies by several decades, but Panum still stumbled upon a beguiling immunological trend: Dozens of the islands’ eldest residents, who had survived another measles epidemic in 1781—65 years earlier—weren’t getting sick this time around. “Not one, as far as I could find out by careful inquiry,” he wrote in a treatise, “was attacked the second time.”
Panum probably didn’t realize it then, but his observations helped spark the inklings of a notion that would survive his century, into the next, and the next: the promise of perfect immunity, a protection so comprehensive and absolute that it might even stave off measles for a lifetime. After measles vaccines were licensed in the 1960s, that expectation ballooned even further. Experts eventually came to describe the shot’s defenses as so strong and swift that the virus could be immediately purged from the body in nearly everyone who received it—stomping out not only the symptoms of measles, but the very possibility of the pathogen’s proliferation at all. To modern immunologists, the phenomenon is known as sterilizing immunity, the ability to “totally prevent infection,” Taia Wang, an immunologist at Stanford University, told me. The measles vaccine is still often held up as its paragon.
No infection means no disease, no death, and no transmission, the absolute immunological trifecta. It’s why sterilizing immunity has often been framed as a “holy grail,” what researchers aim for when they’re designing their shots, says David Martinez, a vaccinologist at the University of North Carolina at Chapel Hill. But sterilizing immunity also has been a source of trouble. Some people hoped the COVID-19 vaccines could achieve sterilizing immunity, especially after reports in the winter and spring trumpeted the jabs’ surprising power at preventing infections—enough that the CDC told vaccinated people they could shed their masks in May. Then sterilizing immunity came back to bite us, when breakthrough infections began to pop up among the immunized, prompting fear and confusion among those who’d been certain that the vaccines alone could quash the coronavirus’s spread.
COVID-19 vaccines were never going to give us sterilizing immunity; it’s possible they never will. But the reason isn’t just their design, or the wily nature of the virus, or heavy and frequent exposures, though those factors all play a role. It’s that sterilizing immunity itself might be a biological myth.
The classic tale of sterilizing immunity unfolds something like this: A pathogen attempts to infiltrate a body; antibodies, lurking in the vicinity thanks to vaccination or a previous infection, instantly zap it out of existence, so speedily that the microbe can’t even reproduce. No symptoms manifest, and most of the body’s immune cells never get involved, a bit like an intruder smacking up against an electric fence around a building, leaving the security guards inside none the wiser.
This is a very neat story. And it is “almost impossible to prove,” Mark Slifka, an immunologist and vaccine expert at Oregon Health & Science University, told me. To show sterilizing immunity, researchers have to demonstrate that an infection never occurred—a big ask, considering that microbiologists can’t even agree on what an infection actually is. An onslaught of pathogens ravaging the airway or gut certainly counts. But according to some experts, so does a single viral particle commencing the process of copying itself inside a cell. This is further muddled by the fact that many pathogens, including SARS-CoV-2, can set up shop inside their hosts without causing a single symptom. There is, and always has been, a disconnect between infection and disease.
One way to check for infection is to look for the pathogen itself, by, say, trying to extract it from a human or animal sample and getting it to grow in a lab, or scouring swabs for its genetic material. But not all bugs are amenable to replicating in a dish, and the genetic approach has sensitivity limits. Scientists also have the option of using bodily reactions to a microbe as a readout—if a person’s immune cells, for example, produce more antibodies, secrete alarm molecules, or rush to the site of infection. But many types of immune responses exist, and a lot of them are transient or extremely difficult to measure without invasive procedures. Even the most precise methods could miss the mark if deployed at the wrong time or in the wrong place.
That technical coarseness might help explain why several historical vaccines have been assumed to be sterilizing. With measles, for instance, scientists initially lacked the tests needed to show them otherwise, Diane Griffin, an immunologist at Johns Hopkins University, told me. When virtually no one fell ill after an inoculation campaign, researchers figured that infections had evaporated as well. Now, however, techniques are far more powerful, giving researchers the ability to zero in on even tiny blips of infection. Post-vaccination measles infections, though still uncommon, are much more “regularly observed” than they were once believed to be, Griffin said.
As detection tools improve, each data point further erodes the mythos of sterilization. With enough scrutiny, the experts I spoke with told me that similar illusions can probably be shattered against supposedly “sterilizing” shots that guard against other pathogens, including poxviruses such as smallpox, the bacteria that cause meningitis, and the parasites that cause malaria. “I think it’s literally chasing rainbows,” Slifka said. “The closer you get, the sooner you realize it’s not there.”
To be clear, many pathogens do regularly get knocked out by the immune system. Some isolated incidents may even be “sterilizing”—for example, when just a couple viral particles bop into someone’s nose, and immediately get clobbered by a glut of antibodies, or even the fast-acting cells of the innate immune system, which are always on patrol. With the right ratio of pathogen to antibody, “it’s achievable,” Stephanie Langel, an immunologist at Duke University, told me. But that’s not the same thing as observing long-term immunity that consistently obliterates the same bug over and over, across populations of people—the way that the term sterilizing immunity is often leveraged.
Perhaps it’s more useful, Yonatan Grad, an epidemiologist at Harvard, told me, to understand the ideal of sterilizing immunity as just that—an ideal, rather than a practical goal, like the unattainable end of an asymptote. Some vaccines certainly sit very far along this curve, including the HPV vaccine, which prevents infectious cervical cancer “essentially 100 percent” of the time, Bryce Chackerian, a vaccinologist at the University of New Mexico, told me. John Schiller, who helped invent the HPV vaccine, points out that even very low antibody levels are enough to obliterate the virus past detection, and vaccinated people seem to maintain these defenses for years. But he and Chackerian still admit that confirming the strictest case of sterilization may not be possible. “Have we absolutely shown sterilizing immunity?” Chackerian said. “We haven’t.”
Eventually, all discussions about sterilizing immunity become nerdy quibbles over semantics. Clearly, not every infection is clinically meaningful, or even logistically detectable, given the limits of our technology—nor do they need to be, if there’s no sickness or transmission. (A koan for pandemic times: If a microbe silently and inconsequentially copies itself in a tissue, and the body doesn’t notice, did it actually infect?) There is, for every pathogen, a threshold at which an infection becomes problematic; all the immune system has to do is suppress its rise below this line to keep someone safe.
But that might be exactly the point. Say that sterilizing immunity is impossible, that our immune systems cannot, in fact, be trained to achieve perfection. Then it’s neither a surprise nor a shortcoming that COVID-19 vaccines, or other vaccines, don’t manage it: An inoculation that guards marvelously well against disease—offering as much protection as it can—can still end an outbreak. Life would certainly be easier if vaccines offered invincible armor, with pathogens simply ricocheting off. But they don’t, and assuming or expecting them to manage that can be dangerous. The dubiousness of sterilizing immunity is a reminder that just about any immune response can be overwhelmed, if exposures are heavy and frequent enough, Grad told me. The best we can all hope for is functional immunity, more like a flame retardant than a firewall, that still keeps bad burns at bay.
That’s the effect our COVID-19 vaccines are delivering in spades. Yes, immunized people can get sick; a few of them might even end up in the hospital, or die from their viral encounter. But vaccines substantially slash those chances by making hosts inhospitable. Breakthroughs of any severity remain uncommon, and when they do happen, they tend to be milder and shorter; people carry less of the virus, and seem less likely to pass it on to others. Even silent infections seem to be rarer among the inoculated—a sign that immunized bodies are meeting the virus in near-full force. (Langel points out that there’s even a potential silver lining to non-sterilizing immunity: Low-level infections, suppressed by vaccination, might occasionally remind the immune system of an ongoing threat, like a crude booster.)
For most of vaccination history, humans have been guided by stopping sickness, and that’s been enough. The smallpox vaccine wasn’t sterilizing; it still helped us eradicate a pathogen. Even measles, a virus that’s much more contagious than SARS-CoV-2, can offer an optimistic example. Some people do end up getting infected after vaccination. But the vaccine has, in the decades since its premiere, largely driven measles into the ground in the United States, apart from recent outbreaks largely linked to low immunization rates. And the few immunized people who do fall ill tend to get what’s called “modified” measles, which isn’t “as bad as usual,” Griffin told me.
“Measles vaccine is not perfect,” Elena Conis, a measles historian at UC Berkeley, told me. No vaccine is. But that doesn’t make a shot “useless,” Conis said. “The truth is somewhere in between.”
Our future with SARS-CoV-2, then, will be more about domesticating the virus than eliminating it. With widespread vaccination, many of us will still be exposed, maybe even temporarily colonized, but it won’t often be a big deal. Most of the time, we might not even notice. Positive tests, too, may be less alarming: In the absence of symptoms, detecting hunks of virus might simply indicate that immune cells have squashed the pathogen, leaving only debris behind. The virus will become less of a pathogen, and more of a passenger—one that keeps the defensive wheels turning, for the short time that it’s there.