Throughout the Covid-19 pandemic, scientists have been saying that if the novel coronavirus, SARS-CoV-2, sticks around long enough, people are likely to catch it more than once. That’s based on what immunologists know about other members of the coronavirus family—the ones that have long survived their initial spillover events and now circulate seasonally, causing the common cold. People who get sick mount an immune response that protects them for months or years, depending on the person. But, at some point, that protection wanes and they become susceptible to infection again.
On Monday, researchers at Hong Kong University presented the first confirmation that this can, in fact, happen with SARS-CoV-2. Not a shock, say experts. But still a useful data point for understanding how immunity to the coronavirus works, both in individuals and in populations. At the molecular level of antibodies and T cells, the case provides reason to be hopeful. As for the odds of achieving herd immunity without a vaccine? It’s a cautionary example.
The report details how in March, a 33-year-old man living in Hong Kong came down with a sore throat, cough, fever, and headache. Tests confirmed he was positive for the virus. After two weeks in the hospital, his symptoms subsided and he was discharged. He resumed his life. And over the summer, he traveled to Spain. In August, on his way back, he was swabbed at the Hong Kong airport, as part of the nation’s strict traveler-screening process designed to catch any reimportations of the virus. He had no fever or cough, no symptoms at all. But the test came back positive again.
When Hong Kong University scientists compared the viral genomes extracted from each swab, they discovered significant differences between them. Both were SARS-CoV-2. But their genetic fingerprints didn’t match. The virus that infected the man in March was most closely related to strains collected in the USA and England during the spring. The one found inside his body in August bore the most resemblance to strains circulating around Europe in late summer. The only plausible explanation, the researchers concluded, was that four and half months after his first bout with Covid-19, he’d been infected a second time.
Sounds bad? Sure. But to those who study the immune system, a case of reinfection is not necessarily the same thing as a lack of protection. “This is actually good news, that this person was protected from illness,” says Donna Farber, an immunologist at Columbia University. It’s common for respiratory viruses to infect people more than once—and Farber was unsurprised to see it occur with SARS-CoV-2. That’s all part of the natural course of building immunity over time, akin to receiving a booster shot after a vaccination. But what’s important, she says, is that the second time around the immune system appears to have done its job and cleared the virus with little drama. That’s immunity at work. “Normally this wouldn’t even register, because this guy didn’t get sick. You wouldn’t even see it,” she says.
It’s difficult, however, to extrapolate from a single case. Scientists have been unsure what to make of the world-first, in part because of the way the news was disseminated. The study’s results were first publicized in a Hong Kong University press release Monday, and a subsequent story in the South China Morning Post. WIRED obtained a copy of the manuscript, which was later published online in the journal Clinical Infectious Diseases. Yuen Kwok-yung, one of the researchers who led the work, told WIRED in an email that the journal’s chief editor allowed the scientists to communicate with the media once the paper was accepted but ahead of publication, due to the public health significance of the finding that recovered people can be reinfected.
“It is unlikely that herd immunity can eliminate SARS-CoV-2,” he and his coauthors wrote in the report. “Although it is possible that subsequent infections may be milder than the first infection, as for this patient.”
Throughout the pandemic, doctors and researchers around the world have documented a handful of presumed Covid-19 reinfections. In the first case, a woman in Japan fully recovered before returning to the hospital three weeks later with a new round of symptoms. In other instances—in China, France and the US—patients went up to six weeks between negative tests and a new positive one. But those reports, which lacked systematic genetic analysis, were largely believed to be the result of flawed testing or unusually long-lived infections flaring up again. Some recovered patients can harbor the virus’s genetic material inside their nose and throats for months, long after their symptoms have subsided. That can lead to positive test results even in the absence of an active infection.
“People have assumed these reports were not true reinfections, but cases of prolonged viral shedding,” says Susan Kline, an infectious disease physician and epidemiologist at the University of Minnesota. This Hong Kong case, on the other hand, looks like the real deal to her. “The evidence here, with the sequences of the virus, is quite strong that this patient really was infected with a different strain the second time,” she says.
Reinfection is possible, yes. But just how common is it? That’s still unclear. Few swabs taken from patients are later used to extract a full viral sequence, enabling this kind of genetic detective work. And regular screening of people with no symptoms only happens in nations that have largely kicked Covid-19. In the US, where access to rapid testing is still hit-or-miss, such screening is often only conducted for health care workers and inside nursing homes and some prisons. “I suspect there are likely more patients like this out there,” says Kline.
For now, there’s just the one. That makes it impossible to say what reinfection will look like in other people. But at the time of his second infection, it appears this particular person lacked what immunologists call “sterilizing immunity,” says John Wherry, an immunologist at the University of Pennsylvania. That’s when a person’s immune system is able to completely stifle the virus’s ability to replicate, meaning no infection occurs at all.
In reality, Wherry says, “that is a very high bar to set.” The second time the body encounters a virus, it has a head-start against intruders: neutralizing antibodies, which glom onto specific proteins on the invading pathogen and prevent it from entering cells. Usually, those antibodies stick around at some level after an initial infection or shot of a vaccine. But it’s an imperfect defense system. Even the best vaccines protect only 90 to 95 percent of the population from reinfection, Wherry notes. Similarly, natural infections by respiratory viruses almost always leave some chance of reinfection. Maybe the second time around there aren’t enough antibodies on hand—they’ve waned, perhaps, or the body didn’t mount much of a response in the first place. Or maybe those antibodies are not perfectly adept at plugging up the proteins the virus uses to latch onto a cell. In that case, some virus winds up getting inside and begins to replicate. A new infection has begun.
What turns an infection into an illness largely depends on what comes next. During the primary infection, the body has never seen the virus before, so it’s stuck creating a customized immune response from scratch: an army of B cells that help create antibodies specific to the virus’s proteins, and T cells that help identify virus particles and eliminate infected cells. But while those forces are being mustered, the virus has an ample window of opportunity—perhaps a week to 10 days, Wherry estimates—to replicate and spread. “By then, the virus has spread around the lungs and outside the lungs, and when the troops show up you’ve got a big problem on their hands,” he says.
During subsequent infections, there’s typically a bit of a delay as those cells “wake up” and leap into action, Wherry says. But it’s a quicker process than before, meaning the virus has less time to spread and infect new cells. Perhaps the virus stays in the nose and the nasopharynx, where a swab sample can detect it, but hasn’t yet reached deeper into the respiratory tract, where it can cause more severe disease. “It’s not nearly the size of the wildfire you’d have in 10 days,” Wherry says. In other words, the immune response takes care of the virus before the person gets sick.
And, he adds, the immune system is often left readier than ever to fight off subsequent exposures. The effect is similar to a booster shot after a vaccine, to make sure an immune response really sticks.
At least, that’s how immunity should work, in theory. But this single patient’s story involves many unknowns. One limitation, Wherry points out, is that there appears to be little data on the patient’s response to his first infection—what kind of immune cell repertoire they developed, and what level of neutralizing antibodies were generated and maintained at the point of reinfection. All of those factors could bear on why this person lacked signs of disease the second time. In another person, due to differences in their bodies, or in the way their first bout of illness progressed, a second infection could wind up being more severe. Larger population studies that track people—and all the complexities of their immune responses—are necessary to truly understand how reinfection by SARS-CoV-2 might work, Wherry says.
To immunologists, it might be good news that this particular patient had no symptoms the second time. But for scientists who study how diseases spread, the revelation is more worrisome. Asymptomatic people have already proven to be a major challenge in containing Covid-19.
The researchers have not directly shown that this patient was able to spread the virus—that would require culturing live virus sampled from their respiratory tract. But it's safe to assume this person was infectious, based on the amount of virus the researchers detected, says Pedro Piedra, who studies respiratory infectious diseases at Baylor College of Medicine. But it’s unclear how long they might have been contagious. The Hong Kong team observed that the patient’s viral load began to drop significantly three days after hospitalization, as compared to the week or longer it takes most Covid-19 patients. “This time period may be shorter than the initial infection,” says Piedra. That’s common with so-called “breakthrough” infections that occur in spite of vaccination. But in the Hong Kong report, the researchers did not attempt to grow the virus from each day’s swab, to see if it could in fact infect living cells. Kwok-yung told WIRED in an email that his team is conducting those studies now.
That will shed some light on whether or not people experiencing reinfections can be infectious themselves. But it’s still unclear how effective they might be at disease transmission. If a person doesn’t experience virus-flinging coughing or sneezing fits, and only carries an infection-causing viral payload in his or her nose and lungs for a few days, are they going to be a significant driver of new infections? It’s hard to say. The report did not note if Hong Kong’s aggressive contact-tracing efforts turned up any individuals the patient went on to sicken during his second infection.
It’s a crucial outstanding question for understanding the future course of the pandemic, says Bill Hanage, an infectious disease epidemiologist at Harvard’s T. C. Chan School of Public Health. He recently joined a number of other scientists in suggesting that some pockets of hard-hit cities may be closer to herd immunity than traditional calculations would project.
That math starts out simple enough. Take the epidemic’s so-called reproductive number, R0—how many people, on average, one infected person will spread the virus to—and plug it into the following formula: 1 – (1/R0). That gives you the herd immunity threshold, or what percentage of the population has to become immune before the virus will stop spreading at an accelerating rate. But it gets tricky fast, because that formula assumes each individual is equally susceptible to the virus, and that each one behaves randomly—that is, that they have an equal chance of infecting every other individual in their community. Which of course, they don’t.
More complicated models try to capture how people behave in the real world. One such model predicts herd immunity could be achieved with only 43 percent of the population exposed to the virus, because the connective tissue of society—younger people and essential workers—will get infected earlier on and create a wall of immunity around the more isolated, more vulnerable groups. But those models bank on the idea that people who survive their first bout with the disease can no longer transmit the virus.
If it’s the norm for people to move from the protected group back to the susceptible category after just a few months, that could radically change the math. Now the number of times each member of the population can get infected isn’t 1. And if those people never feel sick, they might not take as many precautions to self-isolate. “If this leads to a large number of people who don’t know they are infected, that could present problems,” Hanage says.
Of course, that all depends on to what extent people who get reinfected are able to continue spreading the disease a second (or third, or fourth) time. And Hanage suspects that fewer symptoms means less viral load, which in turn means less transmission. That would allow something closer to the original herd immunity math to still hold. Even so, he says, relying on immunity from the spring is a dangerous game. “Any virus that spreads via the respiratory route from people who don’t know they are infected will be difficult to contain,” he says.
Wherry goes one step further. “This tells us we should be very cautious about last week’s fad of herd immunity protecting us all,” he says. To him, even if reinfection is uncommon, the possibility of repeat infections underlines the necessity of a vaccine as part of a realistic pandemic exit strategy. If people are going to need a boost to avoid reinfection and avoid infecting others, better to do it with a vaccine. The Hong Kong researchers point out that this means previously infected people should perhaps be included in vaccination plans, if and when an effective vaccine becomes available.
Still, it bears repeating that the Hong Kong patient was just one Covid-19 case out of tens of millions. And there’s only so much you should ever try to take away from a study with an N of 1. Only with more carefully observed cases and close genetic evaluation will scientists start to understand how frequently reinfection happens and how significant it is in fueling additional spread of the disease. But as the pandemic stretches into its eighth month, with more than 200,000 new infections still being recorded daily across the globe, the odds are good that they’ll get the opportunity to find out.