"Nature" long article: What are the risks of reinfection of the new coronavirus?

Researchers differ on the risk of reinfection and whether COVID-19 will cause lasting changes to the immune system.

At the beginning of 2020, the new crown epidemic hit suddenly. Overnight, the coronavirus (SARS-CoV-2), a strange and terrifying enemy, threw the world into chaos. More than three years on, everyone is familiar with the symptoms of infection and is accustomed to COVID-19 coexisting with humans like other common diseases that infect humans. Experts estimate that most of the world's population has been infected at least once, and about 65% of people in the United States have been infected more than once [1]. And in the next 10 years, everyone may be infected a few more times.

In July 2022, passengers flocked to the ship in Toronto, Canada. The Omicron variant has caused a rise in infections locally. Source: Creative Touch Imaging Ltd./NurPhoto via Getty

The harm to the human body from reinfection has been controversial. Danny Altmann, an immunologist at Imperial College, said: "Pathology can be basically divided into two views. "One group believes that the new coronavirus is just an ordinary respiratory virus, no more terrible than the common cold, especially for those who have been vaccinated. Another group believes that reinfection is an adventure, and that each infection can hit the immune system or change it, with lasting health effects. Both views are well founded. So, what data is available on the risk of reinfection and the long-term problems COVID-19 can cause?

Is reinfection common? Is it risky?

First, reinfection appears to be rare in studies that conduct long-term COVID testing. The latest figures from different countries put the proportion between 5%[2] and 15%[3], but higher is expected in the future.

If a reinfection occurs, the good news is that the immune system should be able to respond quickly. In a preprint paper published in March [4], researchers analyzed reinfection of NBA basketball players, employees, and families. They found that reinfected people cleared the virus faster, averaging about 5 days, compared with about 7 days when they were first infected. People who were vaccinated during their first and second infections cleared the virus the fastest, said co-author Stephen Kissler, an infectious disease researcher at the Harvard T.H. Chan School of Public Health.

Other studies have also shown that people with mild initial infection may also have mild reinfection [5]. Two large studies showed that reinfection is less risky than primary infection. One study[6] compared two groups of unvaccinated infected people in Qatar, with about 6,000 people infected only once and 1,300 infected multiple times. The study found that the probability of severe, critical or fatal illness in reinfection was nearly 90% lower than when first infected.

Another study[7] analysed 3.8 million primary infections and 14,000 reinfections in the UK and found that participants had a 61% lower mortality rate one month after reinfection than the same period after the first infection, and a 76% lower chance of admission to the intensive care unit.

But reinfection is not risky. People most at risk of severe illness at the time of initial infection remain at risk, even if the probability of hospitalization or death has decreased. A January preprint paper[5] that analyzed the clinical data of more than 16 million people in the National COVID Cohort Collaborative found that most reinfected people — more than three-quarters — were mild both times. A small proportion of people who were not hospitalized at the time of initial infection need to be hospitalized if they are reinfected. However, secondary infection is more common in people with severe initial infection. Of those who had been on a ventilator at the time of initial infection, 30% would be readmitted to hospital after a second infection. Richard Moffitt, a biostatistician at Emory University School of Medicine, said: "These people may need to be worried. ”

A study on reinfection analyzed the U.S. Department of Veterans Affairs' electronic medical records [8] and attracted significant media attention. The researchers found that nearly 500,000 people in this database had been infected with the new coronavirus once, and about 41,000 people had been diagnosed with two or more infections. Instead of comparing symptoms of a single infection versus multiple infections, the paper compares the final results after a single infection and two or more infections. At that time, Ziyad Al-Aly, an epidemiologist at the University of Washington School of Medicine, saw many patients who had been vaccinated and infected again. They feel like they're out of reach. "The media says these patients are 'super immune.'" Al-Aly wondered if secondary infection had any effect on these individuals.

The study suggests that there is indeed an impact (see "Risk of reinfection"). Multiple infections with COVID-19 are more harmful than just once. Al-Aly said: "It's not surprising. "If you hit your head twice, he said, it's definitely more serious than hitting you once. People who are reinfected have twice the risk of dying and three times more likely to die from hospitalization, heart disease, or blood clots. Surprisingly, vaccination does not seem to have a small effect, although other studies have shown that vaccines do have a protective effect. Whether these results hold true for the general population remains to be verified. Because this Department of Veterans Affairs cohort is predominantly older white male, it is not representative of the larger general population.

Source: Reference 8

Preeti Malani, an infectious disease doctor at the University of Michigan-Ann Arbor, thinks it's probably unrealistic to stay completely uninfected. But she also said, "A second or third infection is no good for anyone." ”

Does reinfection increase the risk of growing a new crown?

Al-Aly's finding that every COVID-19 infection carries some risk. To his surprise, the risks associated with reinfection persisted beyond the acute phase. Even after 6 months of reinfection, the researchers were able to detect excess risks associated with heart disease, lung problems, diabetes, fatigue, neurological dysfunction, and more. Al-Aly said: "If you dodge the bullet for the first time and don't get the new crown, there is still the possibility of getting the new crown after being re-infected." ”

However, the latest data (go.nature.com/3h6vl67) from the Office for National Statistics in the UK show that the risk of prolonged new crown will gradually decrease in subsequent infections. The risk of developing a new crown after initial infection in adults is 4%, which drops to 2.4% after reinfection. For children and adolescents, the risk of prolonged COVID after initial infection is 1%, and the decline after that is modest.

For people who already have a long coronavirus, reinfection seems to worsen pre-existing symptoms. A survey (go.nature.com/3a0aadc) of nearly 600 people with COVID by British charity Long Covid Kids & Friends showed that 80% reported that reinfection worsened some of their symptoms. Only 15% reported that reinfection had no effect on pre-existing symptoms.

Can COVID-19 change the immune system?

Whether it is the first or fourth infection, there is another reason why some scientists advocate not to get the new coronavirus. There is a view that even mild COVID can cause lasting damage to the immune system, which may make people more susceptible to other viruses. The sudden increase in influenza and other respiratory illnesses in the northern hemisphere in early October last year was thought to be the cause. Such evidence "refutes the fallacy that superinfection is harmless," Rambod Rouhbakhsh, a doctor at Forrest General Hospital, said in a press release. ”

But many immunologists believe that this hypothesis lacks evidence. Long COVID is indeed accompanied by immune abnormalities that persist after severe COVID-19, but for most people who have recovered, there is no indication that COVID causes long-term immune deficiency. "We know what true immunodeficiency looks like." Sheena Cruickshank, an immunologist at the University of Manchester in the UK, said. Only a few common viruses suppress the immune system: HIV infects and kills immune cells such as T cells, making infected people more susceptible to other infections; The measles virus infects immune memory cells, making them the object of destruction, allowing the immune system to forget pathogens it has encountered before.

A COVID-19 testing station in New York, USA, June 2022. It is estimated that most people in the United States have contracted COVID-19 more than once. Credit: Stephen Shaver/Shutterstock

However, some studies have found immune changes that persist weeks or months after the initial infection with the new coronavirus, including some people with mild symptoms and people who appear to have fully recovered. Several studies analyzed different immune markers, such as inflammatory proteins and various immune cells, and persistent alterations were observed in these studies.

A worrying paper published earlier this year compared T cells in three populations: people who were infected with the new coronavirus but never vaccinated, people who were vaccinated but never infected, and people who were infected and then vaccinated [9]. The study found significant differences in the number and activity of killer T cells, which can find and destroy infected cells. The vaccine-induced killer T cell response was weaker in people who were vaccinated but never infected in people who were vaccinated and then vaccinated. The weaker response "deserves our concern," the authors write, because it could mean that these people are at risk of reinfection or other health problems even after being vaccinated.

However, the practical significance of these changes observed so far is not entirely clear. Altmann said: "We don't yet know how this affects people's lives. ”

Marc Veldhoen, an immunologist at the University of Lisbon, is unhappy with calling these changes immune dysfunction or immunomodulatory abnormalities. Most of these papers describe the final stages of the body's normal physiological response to a new infection, he said. In layman's terms, the coronavirus "behaves like all viruses we're familiar with," he said, "and we haven't found anything magical about this virus yet." ”

Some papers that found the absence of immune dysfunction have also been used as evidence to prove the presence of immune dysfunction. A study published by Immunologist Margarita Dominguez-Villar and her colleagues at Imperial College London [10] showed that monocytes – immune cells that are the "first line of defense" against pathogens – express genes associated with thrombosis after coronavirus infection. The study focused only on acute infection and did not give evidence of immune impairment. But the study went viral on Twitter; Some tweets said it proves that innate immunity recombines. "All of a sudden, I saw my paper being retweeted 1,000 times," she said, "and I thought the paper caused undeserved panic." ”

Are these immune changes specific to COVID infection?

It's hard to say. No other virus has been studied so deeply by researchers using a full suite of modern tools. Many of the observed alterations in immune function may also be after other viral infections, Dominguez-Villar said, "If we study influenza viruses like we study coronavirus, we may find some commonalities." ”

Perhaps scientists are wrong to think that everything will return to baseline after any viral infection. To test this, researchers analyzed whether COVID-19 alters the immune system in a small study published in January[11]. The study recruited 33 people who contracted the virus early in the outbreak and took blood samples in the months before and after they received the flu vaccine. When they compared these individuals to people who did not have COVID when they received the flu vaccine, they found unanticipated differences between male and female subjects. In general, women respond more strongly to the flu vaccine. "But we're seeing the opposite here," says John Tsang, a systematic immunologist at Yale School of Medicine. Tsang co-completed the study during his tenure at the National Institutes of Health.

"It's probably not that the situation is better or worse, it's just a little bit different." John Wherry, an immunologist at the University of Pennsylvania, said. He has not found any significant changes in his study of the subsequent effects of the new coronavirus on immune function. In a preprint paper in February[12], his team studied the immune response of people who were infected after vaccination. "We saw markers that showed high activation of T cells and B cells," he said. They all returned to baseline levels within 45-60 days. ”

Many of these questions may never have complete answers. Even with increasing reinfections, tracking this will be harder as COVID-19 testing rates decline. In addition, the immune profile for COVID-19 is becoming increasingly complex. The dose and type of vaccination people receive, whether they have been infected, which strain they infect, and the duration of each exposure can vary individually. Tsang said: "None of these aspects seem very clear. ”

Regardless of the risk, COVID-19 will continue to exist, continue to evolve, continue to infect and superinfect people, and will continue to reveal the mysteries of the immune system.

Originally written by Cassandra Willyard

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Are repeat COVID infections dangerous? The headline What the science says was published in the news feature section of Nature on April 26, 2023

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doi: 10.1038/d41586-023-01371-9

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