Worldwide this year, over 80 million people have been diagnosed with COVID-19 and over 1.7 million have died. Despite this devastating level, scientists have taken significant steps in understanding one of the pandemic’s greatest mysteries: Why some people recover quickly, while others develop severe cases of coronavirus.
Twelve months of study have shown that our body, in many cases, develops a robust and persistent immune response to SARS-CoV-2, but for some people with severe cases, it can cope and hurt more than it helps.
Our fundamental understanding of coronavirus immune responses has grown significantly, but several questions – such as the longevity of immunity – are still to be answered, especially amid concerns that mutations may help SARS-CoV-2 evade our immune defenses. With vaccination on the horizon for many individuals at risk, the complexity of the immune response is even more critical to understand.
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Immune responses fall into a spectrum. Our bodies develop lifelong immunity to viruses such as hepatitis A or measles, while HIV, at the other end, can steal our body’s defenses as long as we live.
“Fortunately, SARS-CoV-2 is closer to the end of hepatitis A in the spectrum,” said Andrea Cox, a viral immunologist at Johns Hopkins University. “It’s not the easiest virus, but it’s far from HIV.”
In a key paper in June, researchers showed for the first time that recovered patients produced not only coronavirus-specific antibodies – proteins designed to glomerulate and often neutralize an invader – but also supported strong T cell levels. killers and helper T cells. Killer T cells recognize and destroy your own infected cells, a deliberate attack of collateral damage designed to prevent the spread of a virus. Meanwhile, helper T cells process and coordinate the maturation of antibodies.
“If you go back in time, there was a lot of concern about whether the virus would actually induce a good immune response,” says Alessandro Sette, an immunologist at the La Jolla Institute of Immunology who co-authored the study. Through a partnership with another immunologist at the institute, Shane Crotty, the project designed a crucial cocktail of laboratory chemicals that could detect various aspects of the immune response in biological samples collected from patients with recovered COVID-19.
These were encouraging results and more were on the way. Although there has been much talk about how recovered patients developed antibodies, no one actually demonstrated the presence of these proteins protected against infection until the University of Washington virologist Alex Greninger and colleagues designed a natural experiment.
As part of their COVID-19 testing program, they screened a commercial fishing boat, collecting blood samples before and after the trip to look for antibodies. Most of the 122 people on the fishing boat tested positive for coronavirus on their return to shore – but none of the three crew members whose blood had antibodies to SARS-CoV-2 before departure were infected on the voyage. Due to a bit of luck and a clever design, the published study was the first to show that having antibodies probably protects against infection.
“It was a spectacular discovery,” said Akiko Iwasaki, an immunologist at Yale University and an investigator at the Howard Hughes Medical Institute. She also highlights the positive news in a November 16 pre-print of the Crotty and Sette partnership, which showed continuous and multiple immune responses to SARS-CoV-2 more than six months after infection.
“It’s very good. We will probably be protected from reinfection much longer than we thought, maybe a year, ”says Iwasaki. “But there is variability in a person’s response to this infection.”
The river
Not everyone has a mild case of COVID-19 with a long-lasting immune response – as evidenced by the grim numbers of hospitalizations and deaths around the world. The United States is now facing twice as many hospitalizations as at any other time during the pandemic. In severe cases, the immune system often manages and causes more problems than it solves.
“Any virus that can cause disease in humans must have at least one good immune evasion mechanism,” says Crotty. He believes that an important tactic that SARS-CoV-2 uses is to avoid the innate immune response, the first line of defense before the development of specific immunity – antibodies and T cells -. In particular, this coronavirus is particularly good at avoiding type I interferons, signaling proteins that promote antiviral activity in nearby cells and prioritize the innate immune system. This process is often associated with severe cases.
But scientists also see the variability of immune responses between people, so they proposed different models for harder-to-explain cases of severe COVID-19.
For example, Shiv Pillai, an immunologist at Harvard Medical School, studies the lymph nodes and their germ centers, where B cells refine antibodies to a specific pathogen. In August, his laboratory found that these centers were not present in patients with COVID-19, his team autopsied.
“It’s because the virus cheated on the type I interferon system,” says Pillai. “So now you don’t get proper germ centers, and those who do are kind of wimpy germ centers. So, at the end of the day, you don’t get the best response with the longest-lived antibodies. “
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Regardless of the method that the coronavirus uses to evade innate immunity, when the immune system finally wakes up to the invasion, it can overreact and do its own damage – such as creating a cytokine storm. Cox compares it to calling a thousand fire trucks to your house.
“The problem is that in some cases, these alarm bells go off, but they’re not turned off properly,” says Cox. “Finally, you will have practically a lot of material damage, because you received a thousand firefighters walking on the grass, and the fire was extinguished six hours ago.”
If germ centers do not form in the first place, B cells will sometimes throw the kitchen sink over the problem instead of selecting the best type of antibody against a particular invader.
“You will benefit from short-term protection, but it can also be at the price of short-term autoimmunity, because there are not too many regulations there. Everything works, ”says Iñaki Sanz, an immunologist at Emory University who studies autoimmune diseases. Sanz showed in a study that some severe cases have exactly this response, turning the immune system against one’s own body, similar to what happens with autoimmune diseases such as lupus.
Reports of carriers with long-term COVID – patients who have prolonged problems even after coronavirus clearance – are also worrying and may be linked to an immune response in adults and a small number of children.
“We don’t know exactly what causes it, but my presence is that there is some kind of autoimmune or auto-inflammatory disease that occurs or that there may be an infection of a critical part of the brain that induces this,” says Iwasaki. In children, this widespread inflammation has been linked to intestinal infections.
Solving the unknowns
Questions about the duration of immunity – and, with it, concerns about the low but growing number of reported reinfections – are likely to persist, especially with the variability of immune responses. Although a recent study by Sette and Crotty showed that about 90% of patients had multiple responses six months after infection, Sette says there are still concerns.
“The flip side is that you don’t see [persistent immunity] in 10 percent of people, ”says Sette. “So, as a word of caution, people should not assume, because they were infected, that they are now protected and invincible.”
The bright side: vaccines generally create a narrower immune response than natural coronavirus infections, which produce more varied immune responses, Iwasaki notes. This could limit reinfection rates as more people become immunized.
“People will develop very strong antibodies that last longer,” says Iwasaki. So that’s why I think vaccines are superior to natural infections to give resistance in the future. “
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Vaccines produce better responses because they focus your body’s attention, Pillai adds. Rather than the extension of SARS-CoV-2 and its 26 separate proteins, a vaccinated person’s immune system can improve on a single, spike protein that the coronavirus uses to bind to and enter cells. . The open question now focuses on sustainability.
The number of people vaccinated at this time is small, but it will increase – as will the appetite for responses to their immune responses. We hope that vaccination limits transmission quickly enough so that the virus is less likely to move, which could affect long-term protection. Scientists do not expect the two new variants reported in the UK and South Africa to bypass vaccines, and Sette says a mutant is unlikely to block all immune defenses observed by researchers.
“We’ve never been able to anticipate evolution better than we can now,” says Greninger. “We can see those mutations that appear in a vessel that escapes immunity and we can monitor them because we have never sequenced more in the history of time.”
Whether it is mutations, reinfections or long-term durability, the answers will be different for the vaccine-derived immunity compared to how the body responds after the natural infection.
“To some extent, we are in the same position we were in March for natural immunity, where we saw good responses and said, ‘Well, we have to wait six to eight months to see if they are sustainable.’ Say Seven. “At the moment, we are seeing good results for vaccines. But will it give you good and lasting immune protection? We will have to get the data. “
To facilitate research into the coronavirus’s immune response, the National Cancer Institute is leading a $ 300 million government-backed initiative called SeroNet. This includes a network of eight specially funded centers of excellence in serological sciences; Cox and Sanz participate.
SeroNet will also provide standardized reagents and controls for assessing immune responses, which Cox compares to passing from each scientific group that knits its own sweaters to everyone who follows a pattern.
“This will allow us to compare what we see in our tests,” says Cox. “This will really allow us to realize how immunity develops in the population.”