Around the world this year, more than 80 million people have been diagnosed with COVID-19, and more than 1.7 million have died. Despite that devastating toll, scientists have made significant strides in understanding one of the pandemic’s biggest mysteries: Why some people recover quickly while others develop severe cases of the coronavirus.
Twelve months of study have shown that our bodies, in many cases, develop a robust and persistent immune response to SARS-CoV-2, but for some people with severe cases, it can go haywire and hurts more than helps.
Our fundamental comprehension of immune responses to the coronavirus has grown significantly, but more questions—like the longevity of immunity—are still to be answered, especially amid concerns that mutations may help SARS-CoV-2 evade our immunological defenses. With vaccination on the horizon for many at-risk individuals, the immune response’s intricacies are even more critical to understand.
Immune responses fall on a spectrum. Our bodies develop lifelong immunity to viruses like hepatitis A or measles, while HIV, on the other end, can evade our bodies’ defenses for as long as we live.
“Fortunately, SARS-CoV-2 is closer to the hepatitis A end of the spectrum,” says Andrea Cox, a viral immunologist at Johns Hopkins University. “It's not the easiest virus, but it's nowhere near HIV.”
In a pivotal paper in June, researchers showed for the first time that recovered patients made not only coronavirus-specific antibodies—proteins designed to glom on and often neutralize an invader—but also elicited strong levels of killer T cells and helper T cells. Killer T cells recognize and destroy your own infected cells, an intentional bout of collateral damage intended to prevent a virus’s spread. Meanwhile, helper T cells aid that process and coordinate the maturation of antibodies.
“If you go back in time, there was a lot of apprehension whether the virus would actually induce a good immune response,” says Alessandro Sette, an immunologist at the La Jolla Institute for Immunology who co-authored the study. Through a partnership with another institute immunologist, Shane Crotty, the project designed a crucial cocktail of lab chemicals that could detect different aspects of the immune response in biological samples collected from recovered COVID-19 patients.
These were encouraging results, and more were on the way. Though there was much talk of how recovered patients developed antibodies, nobody had actually shown that the presence of these proteins protected against infection until University of Washington virologist Alex Greninger and colleagues devised a natural experiment.
As part of their ongoing COVID-19 testing program, they performed screening for a commercial fishing boat, collecting blood samples before and after the voyage to track antibodies. Most of the 122 people on the fishing boat tested positive for the coronavirus on the return to shore—but none of the three crew members whose blood had antibodies against SARS-CoV-2 before departure were infected on the trip. Thanks to a bit of luck and clever design, the published study was the first to show that having antibodies likely protects from infection.
“That was a spectacular finding,” says Akiko Iwasaki, an immunologist at Yale University and an investigator with Howard Hughes Medical Institute. She also highlights the positive news in a November 16 preprint by the Crotty and Sette partnership, which showed continuing, multipronged immune responses to SARS-CoV-2 more than six months after infection.
“That's really good. We're likely going to be protected from reinfection for much longer than we thought, perhaps a year,” says Iwasaki. “But, there is a variability in a person's response to this infection.”
Not everyone has a light case of COVID-19 with a lasting immune response—as evidenced by the grim figures of hospitalizations and deaths worldwide. The United States is experiencing twice as many hospitalizations now than at any other time in the pandemic. In severe cases, the immune system often goes haywire and causes more problems than it solves.
“Any virus that can cause disease in people has to have at least one good immune evasion mechanism,” Crotty says. He thinks an important tactic SARS-CoV-2 employs is evading the innate immune response, the first line of defense before specific immunity—antibodies and T cells—is developed. In particular, this coronavirus is particularly good at evading type I interferons, signaling proteins that promote antiviral activity in nearby cells and prime the innate immune system. This process is often associated with severe cases.
But scientists also see variability in immune responses between people, so they’ve proposed different models for harder-to-explain cases of severe COVID-19.
For example, Shiv Pillai, an immunologist at Harvard Medical School, studies lymph nodes and their germinal centers, where B cells refine antibodies to a specific pathogen. In August, his lab found these centers were not present in COVID-19 patients his team autopsied.
“It's happening because the virus screwed up the type I interferon system,” Pillai says. “So, now you don't get proper germinal centers, and those who do, it’s kind of wimpy germinal centers. So then at the end of the day, you don't get the best, longest-lived antibody response.”
Whatever method the coronavirus uses to evade innate immunity, when the immune system does finally wake 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 get set off, but they're not being turned off properly,” Cox says. “You end up with basically a lot of property damage because you got a thousand firemen stepping all over the grass, and the fire was put out six hours ago.”
If the germinal centers don’t form in the first place, B cells will sometimes throw the kitchen sink at the problem instead of selecting the best kind of antibody against a particular invader.
“You get short-term protection, but it may be at the price of some short-term autoimmunity as well because there's not a lot of regulation there. Everything goes,” says Iñaki Sanz, an immunologist at Emory University who studies autoimmune diseases. Sanz has shown in a study that some severe cases have exactly this response, turning the immune system against its own body, akin to what happens with autoimmune diseases such as lupus.
Reports of COVID long haulers—patients who have prolonged issues even after clearing the coronavirus—are also concerning and may be linked to a haywire immune response in adults and a small number of children.
“We don't know exactly what's driving it, but my hunch is that there is some sort of autoimmune or autoinflammatory disease that's occurring or that there may be infection of a critical part of the brain that's inducing this,” Iwasaki says. In kids, this widespread inflammation has been tied to gut infections.
Solving the unknowns
Questions about the length of immunity—and along with them, worries about the low but rising number of reported reinfections—will likely linger, especially with the variability in immune responses. Though that recent study from Sette and Crotty showed that about 90 percent of patients had multiple responses going on six months post-infection, Sette says there are still concerns.
“The flip side is that you don't see [persistent immunity] in 10 percent of the people,” Sette says. “So, as a word of caution, people should not assume because they have been infected that they now are protected and invincible.”
The bright side: Vaccines create a narrower immune response in general than natural coronavirus infections, which produce more varied immune responses, Iwasaki notes. That could limit reinfection rates as more people get immunized.
“People are going to develop very strong antibodies that are longer-lasting,” Iwasaki says. “So that's why I think vaccines are more superior than natural infection in conferring resistance going forward.”
Vaccines produce better responses because they focus your body’s attention, Pillai adds. Rather than scope out SARS-CoV-2 and its 26 separate proteins, a vaccinated person’s immune system can hone in on just one, the spike protein that the coronavirus uses to bind to and enter cells. The open question now centers on durability.
The number of people vaccinated right now is small but will increase—as will the appetite for answers on their immune responses. Hopefully, vaccination curbs transmission fast enough that the virus doesn’t have as many chances to mutate, which might affect long-term protection. Scientists don’t expect the two new variants reported in Britain and South Africa to bypass the vaccines, and Sette says it is unlikely that a mutant could thwart all of the immune defenses being observed by researchers.
“We've never been able to anticipate evolution better than we can now,” Greninger says. “We can see those mutations that occur in a dish that escape immunity, and we can monitor for them because we've never been sequencing more in the history of time.”
Whether it’s questions of mutations, reinfections, or long-term durability, the answers will likely be different for vaccine-derived immunity as compared to how the body responds after natural infection.
“To a certain extent, we are in the same position we were at in March for natural immunity, where we saw good responses, and we said, Well, we need to wait six to eight months to see if they're durable,” Sette says. “Right now, we see good results for the vaccines. But will it give you good, lasting immune protection? We'll have to get the data.”
To facilitate research on the coronavirus’s immune response, the National Cancer Institute is leading a more than $300 million, government-backed initiative called SeroNet. This includes a network of eight specially funded Serological Sciences Centers of Excellence; Cox and Sanz are participating.
SeroNet will also provide standardized reagents and controls for assessing immune responses, which Cox likens to shifting from every scientific group knitting their own sweaters to everyone following one pattern.
“That will allow us to compare what we’re seeing in our assays,” says Cox. “That will really allow us to get a sense of how immunity is developing in the population.”