April 30, 2020

Is Coronavirus Reinfection Possible?

It’s one of the top questions on experts’ minds.

Coronavirus Reinfection Is It Possible — Getty / Carol Yepes

We’ve learned an incredible amount about the new coronavirus disease (COVID-19), but many uncertainties still linger. One key unanswered question: If you recover from the new coronavirus, is reinfection possible? Or does getting it once make you immune to getting the disease again? These questions are buzzing after recent news reports out of South Korea suggested that people who appear to have recovered from this infection are now once again testing positive for the virus. Does this mean there is little hope of beating this thing that has completely upended our lives? Since individual immunity is a critical part of creating herd immunity that could protect entire societies from becoming sick again if a community was exposed to someone with the illness, it’s a pressing question.

To figure out what might be happening here, I reached out to virologists Angela Rasmussen, Ph.D., at Columbia University, and Vineet Menachery, Ph.D., at the University of Texas Medical Branch. Both virologists have experience working on coronaviruses (which are a family of viruses that can cause illnesses like the common cold, not just this news-making disease).

Neither expert thinks that the situation here is as simple as people who have recovered from the disease getting the infection a second time—that is, sick people recovering from their symptoms, clearing the virus from their bodies, being exposed to another ill individual, and becoming sick again. “There is no evidence that reinfection has ever occurred in a person,” Rasmussen says. Instead, there are a number of other alternatives that could explain what we’re seeing.

It may involve a false positive or negative.

Tests that are used to determine viral presence are very sensitive, but they're also susceptible to variation for a number of reasons, which can lead to false positives and negatives in some cases.

The main kind of COVID-19 test experts have been using in the U.S. analyzes swabs or specimen samples for the ribonucleic acid (RNA) the SARS-CoV-2 virus uses to replicate and cause the new coronavirus disease. They don’t necessarily look for the live virus itself. There’s a variety of RNA tests for COVID-19 out there, and there aren’t yet solid numbers for how often false positives and negatives happen with these tests. However, the Centers for Disease Control and Prevention (CDC) has been clear that both are a possibility.

For instance, if your nose still contains viral RNA that your immune system already killed off (which you could then clear from your body by sneezing, blowing your nose, etc.), an RNA test could still pick it up, giving you a “positive” result even if your immune system has actually killed the virus already and can’t spread it to other people. If you’d previously gotten a negative result, this could be confusing.

Beyond that, small differences in sample collection technique could make it seem like someone got “reinfected” even when that’s not the case. “The quality of the data is based on the quality of the sample,” Menachery says.

For example, if one person collects a sample from a person who seems recovered from the new coronavirus, then later a different person collects a new sample from the same person, different sampling techniques can affect the results. One person may be better at getting the necessary material (like by making sure to swab far enough into the person’s nose to collect a sample from where the nasal cavity and throat intersect). Or maybe someone moves around a lot while getting the first swab to see whether they’re still infected (the collection process isn’t particularly comfortable), so there’s not adequate material and they test negative, then they tolerate it better the second time, allowing for better sampling that could lead to a more accurate result.

Another example is if the sampler happens to swab a location where there typically isn’t much RNA present, like deep in the nose after a person’s symptoms have resolved, which could result in a false negative. If the amount of viral RNA is very low, as is likely when a person is late in the illness, it could be right around the threshold where the test cuts the reporting off from positive to negative—so what might have been a negative test one day becomes a positive sample the next with a different swab and slightly more RNA.

“It’s plausible to me that recovering patients might be more likely to have false-negative tests, given that data so far suggests that viral loads are very low after symptoms have resolved, so these patients are likely to have very low levels of viral RNA in their swabs anyways,” Rasmussen says.

In this scenario, if the viral RNA is at very low levels, it doesn’t seem likely that a person is shedding the virus significantly enough to infect others, Menachery explains, although more research is necessary to know for sure.

Experts are considering if the virus can hide out in the body, then reactivate.

Another possibility experts are investigating is the idea that SARS-CoV-2 could simply linger in the body, then begin to replicate again at a later time. It’s a valid thought since this is known to happen with some other viruses.

“Some viruses can exist in a latent state in a host…quietly in a host cell without actively replicating,” Rasmussen explains. But viruses that do this are generally DNA viruses while SARS-CoV-2 is an RNA virus. DNA viruses include the herpes viruses that can cause sores on your mouth or genitalia as well as the chickenpox virus. Let’s take that last one as an example to explore how this mechanism really works.

With the chickenpox, caused by the varicella-zoster virus (also known as VZV), some of the viruses produced during infection hide out in a location called the dorsal root ganglia, which is nerve cell clusters near the spinal cord. Sequestered in these cells, viral replication stops. The viruses “turn off most viral gene expression and effectively hide out from the immune system,” says Rasmussen. “VZV can remain latent in the neurons for years until it is reactivated, turns everything back on, starts making new [viruses], and causes shingles.” Rasmussen also notes that we don’t know exactly what causes reactivation. According to the Mayo Clinic, shingles risk factors can include being older than 50 and immune deficiency. As NPR reported, some experts do believe having a weakened immune system could make it possible for SARS-CoV-2 to “rebound” in someone who has “recovered” and gotten down to an undetectable level of the virus.

The catch is that this mechanism of latency and reactivation has never previously been observed in coronaviruses, the experts say. “It is not clear what cell type they would go latent in and what machinery they would use to facilitate this. I am skeptical it would happen,” says Menachery.

Further, Rasmussen notes that both reinfection and such rapid reactivation seem biologically unlikely. “That would depend on people developing no protective immunity whatsoever,” she says, “and from all the data that’s come out so far, it looks like most recovered COVID patients are at least mounting antibody responses.” Still, she acknowledges we have much to learn about immunity for this infection.

Experts aren’t sure “chronic infection” is possible.

Chronic infection is similar to latency, but the virus isn’t necessarily dormant within a host cell. “There are other mechanisms by which RNA viruses establish chronic infections,” Rasmussen says. Think more along the lines of HIV, which can replicate in the body for an extended period of time. HIV turns its viral RNA into DNA that it then integrates into the host’s DNA so it can create copies of HIV RNA, according to the National Institute of Allergy and Infectious Diseases. Symptoms often appear two to four weeks after exposure, the CDC says, then the virus goes into a “clinical latency” stage and reproduces at low levels for years without causing symptoms. It’s a similar story with hepatitis C, another RNA virus, which can cause either acute or chronic infection. “Hepatitis C virus can just hang around, replicating at low levels and manipulating the host response to [be] infectious just enough to fly under the immune system’s radar,” Rasmussen says. It can take up to 12 weeks to develop hepatitis C symptoms, if ever.

Since SARS-CoV-2 is also an RNA virus like hepatitis C, chronic infection may be a bit more plausible than latency and reactivation, but both virologists still think it is unlikely to be responsible for the “reinfection” phenomenon we’re seeing in reports. From what we know so far, COVID-19 is an acute infection that can cause illness within 14 days of exposure, not one that causes a chronic infection.

“It’s not possible to completely eliminate some other previously unknown mechanism of coronavirus reactivation or chronic infection,” Rasmussen explains. “However, there’s no evidence that SARS-CoV-2 does either of those things, so while we can’t rule a novel mechanism for reactivation, my opinion is that it’s not very likely.” Menachery suggests that instead of chronic infection with SARS-CoV-2, “it may just take a longer time [for the immune system] to root out all the infected cells producing virus.”

Experts aren’t sure about the odds of getting reinfected after a longer period of recovery.

Most of the current discussion has focused on the possibility of reinfection shortly after recovery. But what about months or more? As the World Health Organization (WHO) recently noted, “We expect that most people who are infected with COVID-19 will develop an antibody response that will provide some level of protection. What we don't yet know is the level of protection or how long it will last. We are working with scientists around the world to better understand the body's response to COVID-19 infection. So far, no studies have answered these important questions.”

This is a key question that can only be answered by carrying out long-term studies of COVID-19 survivors to analyze their antibody response over time and see whether they develop new infections with SARS-CoV-2. Long-term studies are needed to confirm this.

How can we eventually figure this out?

Right now we’re missing data that would allow scientists to determine what is really going on when a person tests negative, believes their infection has resolved, and then tests positive at a later date. Rasmussen notes that the Korean Centers for Disease Control and Prevention (KCDC) has already stated that it will be conducting an epidemiological investigation into this. She anticipates this may start to answer some lingering questions, like if there’s evidence that anyone in this situation develops symptoms or actually transmits the virus to someone else. For instance, if these epidemiological studies fail to find additional new cases linked to “reinfection,” “that indicates that these ‘reactivations’ are probably just fluctuations in viral RNA or false negatives,” Rasmussen says, adding, “I’d worry if these negative-then-positive cases were associated with new clusters of cases, or if they were actually shedding infectious virus and not viral RNA.”

Menachery adds, “As more data comes out, we'll have a better picture. With the health care system in triage mode, it is difficult to really get a good handle on this.” He also notes that experimental models may help to resolve some of this confusion: “I think an animal model for SARS-CoV-2 would also help test these questions.”

What does this mean for you if you have or have had the coronavirus?

If you’ve tested positive or are otherwise certain you had it even without a test, what does all of the above mean for you and the people you know? Likely little beyond what you’ve been told already: to be careful, to isolate for at least 14 days while the illness runs its course, and to avoid contact with others as much as possible during that time. Rasmussen recommends following the guidelines for isolation, quarantine, and social distancing outlined by the CDC—which means that even if you’ve recovered, you should still practice social distancing until experts say it’s safe for all of us to ease off those recommendations. Besides that? “I wouldn’t be concerned about this, beyond the normal concern we all have now to stop viral spread,” Rasmussen says.

Update, July 20, 2020: This article has been updated to reflect that herpes is not a DNA virus.

The situation with coronavirus is evolving rapidly. The advice and information in this story is accurate as of press time, but it’s possible that some data points and recommendations have changed since publication. We encourage readers to stay up to date on news and recommendations for their community by checking with their local public health department.

Related: