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As the world wearies of trying to suppress the SARS-CoV-2 virus, many of us are wondering what the future will look like as we try to learn to live with it.

Will it always have the capacity to make us so sick? Will our immune systems learn — and remember — how to cope with the new threat? Will vaccines be protective and long-lasting?

These pressing questions gained even greater urgency Monday with the news that scientists in Hong Kong have confirmed a 33-year-old man was reinfected with Covid-19; his second infection as diagnosed — by airport screening — came 4.5 months after his first infection in March.

“I’ve been thinking about it a lot,” Malik Peiris, a coronavirus expert at the Hong Kong University who was one of the co-discoverers of SARS-1, said when asked about the question of immunity. 

Peiris isn’t alone. STAT asked a number of experts to map out scenarios of how we might come to coexist with this new threat. In a time of uncertainty, the scenarios they sketched were actually hopeful, even if the relief most envisage is not immediately around the corner.

“I don’t think we’ll be wearing masks in two to three years — for this virus,” said Vineet Menachery, a coronavirus researcher at the University of Texas Medical Branch in Galveston.

Menachery laid out four possible scenarios for how humans might interact with SARS-2 over time — in other words, what kind of immunity we might expect.

Some of the terms are of his own creation, so they may not be instantly recognizable to people who have studied immunology. They also cover a spectrum, and the lines between some of the scenarios can be blurry in spots. But they provide a useful discussion starter.

As Menachery sees it, the possibilities for the future when it comes to Covid-19 and human immunity break down as follows: sterilizing immunity, functional immunity, waning immunity, and lost immunity.

Please remember: These are educated guesses, based on what’s known about the way the immune system works in general, and how it responds to other coronaviruses.

Sterilizing immunity

Sterilizing immunity would be a best-case scenario. It describes an immune system that is armed against a foe, able to fend it off before infection can take hold.

Diseases that we think of as “one-and-done” infections induce such a robust and durable immune response in a single encounter that we cannot be reinfected. In general terms, measles fits into this category, although there are rare reports of people contracting measles more than once.

The bad news is that viruses that infect via the mucus membranes of the nose and throat, like SARS-2, typically don’t induce sterilizing immunity.

“Sterilizing [immunity] in my view is out of the question, as with any respiratory virus,” said Marion Koopmans, head of virology at Erasmus Medical Center in Rotterdam, the Netherlands. Stanley Perlman, a coronavirus researcher at the University of Iowa, called this option “not so likely.”

But Florian Krammer, a professor of vaccinology at the Icahn School of Medicine at Mount Sinai Hospital in New York, does believe some people will develop sterilizing immunity after a bout of Covid-19.

One last observation about sterilizing immunity: If infection doesn’t trigger it, there is reason to be concerned that vaccines may not either. Peiris noted that so far most of the experimental vaccines, when tested in primates, protect the lungs from severe disease but don’t block replication of virus in the upper airways.

If the primates predict how the vaccines will work in people, these studies would suggest that people may still be able to be infected and they may emit viruses that potentially could infect others, but the type of Covid-19 disease that lands people in ICUs and that sometimes kills them would be prevented.

“Of course, what we’d all like is immunity that protects the individual — protects from infection and protects from transmission. We may not achieve that,” Peiris said. “Because protecting from infection of the upper respiratory tract and then transmission is quite a challenge.”

Functional immunity

Functional immunity, on the other hand, may be within reach. In fact, it’s the scenario Menachery sees as most likely.

Under this scenario, people whose immune systems have been primed to recognize and fight the virus — whether through infection or vaccination — could contract it again in the future. But these infections would be cut short as the immune system’s defenses kick into gear. People infected might not develop symptoms or might have a mild, cold-like infection.

“I’m a believer that if you’ve gotten Covid-19, then your likelihood of dying from a second Covid-19 case is very low, if you maintain immunity,” Menachery said.

Peiris agreed. “It won’t have the impact it has now. … It becomes manageable.”

There’s been enormous amounts of debate — and concern — about how long-lasting or “durable” immune responses to this virus will be, based on a few scientific papers that suggest some people don’t develop many antibodies to the virus and others that report that those antibodies appear to decline quickly.

The experts who spoke with STAT all felt that the immune responses to this virus are exactly what you would expect to see. And the case of the Hong Kong man who appears to have been reinfected underscore that, several said.

“The fact that somebody may get reinfected is not surprising. But the reinfection didn’t cause disease,” said Peiris, who knows about the case but was not one of the authors reporting it.

Angela Rasmussen, a virologist at Columbia University in New York who studies human responses to viral infections, said it is hard to be definitive, given the limited human experience with this new coronavirus, but she said she could see no reason to believe the immune system would behave differently to this respiratory virus than to others.

“So far, anyway, the evidence supports functional immunity, but the only way to see how long that will last is to follow people over time and see if those responses diminish,” she said.

“The idea there is that, yes, your antibodies might wane, but your memory responses aren’t absent,” said Menachery, noting that when a primed immune system re-encounters the virus, production of antibodies would kick into gear.

Christian Drosten, who is another co-discoverer of SARS-1, describes a future that fits into this category.

“I clearly expect lasting and relevant immunity that is almost sterilizing immunity against SARS-2 in almost every person infected with SARS-2,” Drosten, director of the Institute of Virology at Berlin’s Charité University Hospital, said via email.

“It may be possible to become infected again, without any change in the virus. The resulting infection will be mild or asymptomatic, with significantly lower levels of virus replication and onward transmission.”

Drosten’s last point would be a big bonus. If people who are reinfected don’t generate high levels of SARS-2 viruses in their respiratory tracts and therefore don’t contribute much to the spread of the virus, Covid-19 may become, over time, not just less dangerous, but also less common.

“It may become a rare infection, although that is difficult to foresee given the size of the global population,” Koopmans said.

Another hopeful part of this scenario relates to young children, who are far less likely than adults to develop severe disease. Krammer expects that children who first encounter the virus when they are very young may end up being infected several times over their lifetimes, but those later infections won’t lead to severe illness, even when they are elderly.

“I think that’s kind of how, in the long run, it would play out without the intervention of vaccines,” Krammer said. “I think with vaccines, we just basically speed up that process.”

A big question mark here relates to people who were infected and developed no symptoms, or who had very mild infections. Perlman said it’s not clear if their immune systems were sufficiently “tickled” to induce a long-lasting response, though he said he would guess — and he stressed it was a guess — that they would have enough protection to ward off severe disease.

While this scenario sounds truly hopeful, Perlman sounded a note of caution. This type of protection, if it comes to pass, will exist on the individual level. There will likely remain pockets of people who have never been infected and who haven’t been vaccinated. If they contract the virus, “we should still see bad disease,” he said.

Waning immunity

Waning infection, the third scenario, is a variation of functional immunity. In this scenario, people who have been infected or vaccinated would lose their protection over time. But even if immunity wanes, reinfections would be less severe, Menachery said.

“You will never get as sick as you were the first time,” he said.

The man from Hong Kong may be an example of this phenomenon, though details of his immune responses to his first and second infections are not yet public.

This is the pattern seen with the four coronaviruses that cause about 15% of what we consider common colds — OC43, 229E, NL63, and HKU1. People can be reinfected with these viruses after a relatively short period of time.

Thirty years ago, British scientists reported that a year after deliberately infecting a small number of volunteers with 229E, two-thirds became reinfected when again exposed to the virus. “However, the period of virus shedding was shorter than before and none developed a cold,” they wrote.

In another ambitious study, Dutch researchers followed 10 healthy individuals for decades, measuring antibody levels to the four human coronaviruses at regular intervals. Rises in antibodies were interpreted as evidence of recent infections. Most of the subjects had multiple infections with each of the viruses.

The shortest period between infections was six months, though the median period between reinfections was 30 months. “We saw frequent reinfections at 12 months post‐infection and substantial reduction in antibody levels as soon as six months post‐infection,” they wrote. The paper is a preprint, meaning it has not yet undergone peer review.

The senior author of the paper, Lia van der Hoek of Amsterdam University Medical Center, said via email that she felt waning immunity was the most likely scenario for what will happen with SARS-2, but wouldn’t be drawn on what that would mean for people who are reinfected.

“It is completely unknown what the symptoms will be when reinfection occurs. This could be less, or worse, or equal. We scientists cannot make a prediction on that,” she said.

Krammer believes the overall picture will be mixed. Some people will have sterilizing immunity, but most will fit into either the functional or waning immunity categories. The net outcome: less of the type of disease that prompted most countries to take the extraordinary steps of locking down this spring.

“What I think is going to happen with the majority of people who have natural infections, but also the majority of vaccinees, is that they will be protected from disease and might have much less virus if they get infected. They might not know that they’re infected,” he said.

Lost immunity

Lost immunity describes a scenario in which people who have been infected would lose all their immune munitions against the virus within some time frame. A reinfection after that point would be like a first infection — carrying all the same risk of severe disease now seen with Covid-19.

None of the experts who spoke to STAT felt this was a possibility.

“I can’t imagine this being a situation where I get infected and then in 10 years, I get infected again and I have zero immunity,” Perlman said.

“If you generate a response to clear the virus, I think you will maintain that immunity long term,” Menachery added, though he raised a question about people who have had symptom-free or mildly symptomatic infections. “For people with mild or asymptomatic infection, it may not be lost immunity, but rather no immunity generated.”

If these experts are correct, and the worst-case scenario is off the table, humans can expect to see a waning of the threat SARS-2 poses to people over time. Our immune systems will know how to deal with it. It could become the fifth human coronavirus to cause common colds.

Dan Barouch, director of the Center for Virology and Vaccine Research at Boston’s Beth Israel Deaconess Medical Center, sounded a note of caution, though. The journey from where we are to that more manageable situation won’t be a quick one, he said. Most of the world’s population still has no experience with this virus and even if vaccines work, vaccinating billions of people around the world is the work of years, not months.

He didn’t agree that what might happen could fit neatly into one of four categories listed above, saying he sees immunity more in terms of shades of gray that shift depending on the person’s immune status and the nature of their exposure to the virus.

As Barouch sees it, some people’s immune responses might be able to ward off infection entirely in some circumstances, but other types of exposures might result in infection — for instance, if they were exposed to a large amount of the virus.

“The short answer is we don’t know. So, anyone who gives you a scenario is providing a hypothesis,” he said.

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