Following the news this week of what appears to have been the first confirmed case of a Covid-19 reinfection, other researchers have been coming forward with their own reports. One in Belgium, another in the Netherlands. And now, one in Nevada.

What caught experts’ attention about the case of the 25-year-old Reno man was not that he appears to have contracted SARS-CoV-2 (the name of the virus that causes Covid-19) a second time. Rather, it’s that his second bout was more serious than his first.

Immunologists had expected that if the immune response generated after an initial infection could not prevent a second case, then it should at least stave off more severe illness. That’s what occurred with the first known reinfection case, in a 33-year-old Hong Kong man.

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Still, despite what happened to the man in Nevada, researchers are stressing this is not a sky-is-falling situation or one that should result in firm conclusions. They always presumed people would become vulnerable to Covid-19 again some time after recovering from an initial case, based on how our immune systems respond to other respiratory viruses, including other coronaviruses. It’s possible that these early cases of reinfection are outliers and have features that won’t apply to the tens of millions of other people who have already shaken off Covid-19.

“There are millions and millions of cases,” said Michael Mina, an epidemiologist at Harvard’s T.H. Chan School of Public Health. The real question that should get the most focus, Mina said, is, “What happens to most people?”

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But with more reinfection reports likely to make it into the scientific literature soon, and from there into the mainstream press, here are some things to look for in assessing them.

What’s the deal with the Nevada case?

The Reno resident in question first tested positive for SARS-CoV-2 in April after coming down with a sore throat, cough, and headache, as well as nausea and diarrhea. He got better over time and later tested negative twice.

But then, some 48 days later, the man started experiencing headaches, cough, and other symptoms again. Eventually, he became so sick that he had to be hospitalized and was found to have pneumonia.

Researchers sequenced virus samples from both of his infections and found they were different, providing evidence that this was a new infection distinct from the first.

What happens when we get Covid-19 in the first case?

Researchers are finding that, generally, people who get Covid-19 develop a healthy immune response replete with both antibodies (molecules that can block pathogens from infecting cells) and T cells (which help wipe out the virus). This is what happens after other viral infections.

In addition to fending off the virus the first time, that immune response also creates memories of the virus, should it try to invade a second time. It’s thought, then, that people who recover from Covid-19 will typically be protected from another case for some amount of time. With other coronaviruses, protection is thought to last for perhaps a little less than a year to about three years.

But researchers can’t tell how long immunity will last with a new pathogen (like SARS-CoV-2) until people start getting reinfected. They also don’t know exactly what mechanisms provide protection against Covid-19, nor do they know what levels of antibodies or T cells are required to signal that someone is protected through a blood test. (These are called the “correlates of protection.”)

Why do experts expect second cases to be milder?

With other viruses, protective immunity doesn’t just vanish one day. Instead, it wanes over time. Researchers have then hypothesized that with SARS-CoV-2, perhaps our immune systems might not always be able to prevent it from getting a toehold in our cells — to halt infection entirely — but that it could still put up enough of a fight to guard us from getting really sick. Again, this is what happens with other respiratory pathogens.

And it’s why some researchers actually looked at the Hong Kong case with relief. The man had mild to moderate Covid-19 symptoms during the first case, but was asymptomatic the second time. It was a demonstration, experts said, of what you would want your immune system to do. (The case was only detected because the man’s sample was taken at the airport when he arrived back in Hong Kong after traveling in Europe.)

“The fact that somebody may get reinfected is not surprising,” Malik Peiris, a virologist at the University of Hong Kong, told STAT earlier this week about the first reinfection. “But the reinfection didn’t cause disease, so that’s the first point.”

The Nevada case, then, provides a counterexample to that.

What kind of immune response did the person who was reinfected generate initially?

Earlier, we described the robust immune response that most people who have Covid-19 seem to mount. But that was a generalization. Infections and the immune responses they induce in different people are “heterogeneous,” said Sarah Cobey, an epidemiologist and evolutionary biologist at the University of Chicago.

Older people often generate weaker immune responses than younger people. Some studies have also indicated that milder cases of Covid-19 induce tamer immune responses that might not provide as lasting or as thorough of a defense as stronger immune responses. The man in Hong Kong, for example, did not generate antibodies to the virus after his first infection, at least to the level that could be detected by blood tests. Perhaps that explains why he contracted the virus again just about 4 1/2 months after recovering from his initial infection.

In the Nevada case, researchers did not test what kind of immune response the man generated after the first case.

“Infection is not some binary event,” Cobey said. And with reinfection, “there’s going to be some viral replication, but the question is how much is the immune system getting engaged?”

What might be broadly meaningful is when people who mounted robust immune responses start getting reinfected, and how severe their second cases are.

Are people who have Covid-19 a second time infectious?

As discussed, immune memory can prevent reinfection. If it can’t, it might stave off serious illness. But there’s a third aspect of this, too.

“The most important question for reinfection, with the most serious implications for controlling the pandemic, is whether reinfected people can transmit the virus to others,” Columbia University virologist Angela Rasmussen wrote in Slate this week.

Unfortunately, neither the Hong Kong nor the Reno studies looked at this question. But if most people who get reinfected don’t spread the virus, that’s obviously good news.

What happens when people broadly become susceptible again?

Whether it’s six months after the first infection or nine months or a year or longer, at some point, protection for most people who recover from Covid-19 is expected to wane. And without the arrival of a vaccine and broad uptake of it, that could change the dynamics of local outbreaks.

In some communities, it’s thought that more than 20% of residents have experienced an initial Covid-19 case, and are thus theoretically protected from another case for some time. That is still below the point of herd immunity — when enough people are immune that transmission doesn’t occur — but still, the fewer vulnerable people there are, the less likely spread is to occur.

On the flip side though, if more people become susceptible to the virus again, that could increase the risk of transmission. Modelers are starting to factor that possibility into their forecasts.

A crucial question for which there is not an answer yet is whether what happened to the man in Reno, where the second case was more severe than the first, remains a rare occurrence, as researchers expect and hope. As the Nevada researchers wrote, “the generalizability of this finding is unknown.”

  • Perspective-
    1. Covid-19 has been mutating for some months – now effecting CNS (Central Nervous System), heart, kidneys etc…
    2.The body’s immune response, the ‘cytokine storm’, has generally come to be considered the biggest problem.
    3. The studies and science around Covid-19 continue to have data with no standard of criteria or interpretation – meaning I say tomato you say toe-ma-toe- ie; problem in California State numbers.

  • I just wanna say there’s an antimask dude that’s been emailing me for a week now asking for my address to come an teach me a lesson why masks are bad for my health especially my teeth. I mean SARS-CoV-2 are just trying to survive, but what in hell is wrong with people?

  • A few random thoughts. First, a mild case of Covid-19 may, in fact, indicate a *strong* immune response (which is why the case was mild), so the degree of the initial case may, in fact, be irrelevant. Second, the RNA test used for covid-19 is extremely sensitive, so while it may show the presence of the virus, that presence does not imply disease (where the virus has established and is creating lots of new virus). Human beings harbor lots of nasty bugs that never develop into disease. For that reason, our testing regime may, in fact, be leading to a severe over reaction to the presence of the virus in the community. It also means we must be careful to distinguish between “asymptomatic” cases (where the test has found virus, but there is no evidence of disease) and “pre-symptomatic” cases where there is no evidence of disease, but there will be shortly. During a pre-symptomatic phase, the virus has captured enough cells to be manufacturing lots of virus.

    “Reinfection” (or more precisely, testing positive for coronavirus twice) relative to asymptomatic cases must be dealt with very, very carefully given that the presence of coronavirus does not imply the presence of covid-19 (the disease where virus is being manufactured within the body in quantity).

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