If one thing is clear about this teeny tiny new coronavirus, it’s that it has changed the world. Its mark is massive. But SARS-CoV-2 is still clouded in mystery, and front and center in this puzzle is understanding immunity.
Why do some people get sick, and others don’t? What mechanisms in the body can successfully fight off the SARS-CoV-2, the virus that causes the disease COVID-19, and what backfires?
“One of the important questions that we were trying to figure out is what sort of immunity is protective for SARS-CoV-2?”
“One of the important questions that we were trying to figure out is what sort of immunity is protective for SARS-CoV-2?” said Dr. Sydney Ramirez, a doctor and virologist in the division of infectious diseases and global public health at the University of California San Diego and the nearby La Jolla Institute for Immunology.
Ramirez was already studying coronaviruses before the pandemic. Her inspiration came from her dad, a doctor, who cared for people who came down with the original SARS back in 2003. When the new coronavirus emerged in January, she was ready to jump in.
In the six months since then, she and other scientists around the globe have picked up more and more clues about immunity. Still, the answers are not so straightforward, at least not yet.
Immunity as warfare
In general, a virus is a lump of proteins that can’t do a thing on its own. It needs to get into a host cell to survive. One way to think about an immune response against a virus is to imagine a war within the body.
“There's always this arms race where the virus is trying to make better weapons, and then the body's trying to make better weapons,” Ramirez said. “And it's sort of a matter of like, who wins?”
Scientists have learned that SARS-Cov-2 has a particular way of invading our cells. The virus has a spike-shaped protein on its shell — it’s like a special key that can then unlock the doors to our cells, Ramirez explained.
“So, basically once it's inside the cell, it hijacks the factory and starts pumping out various pieces of itself and makes more virus and more virus and more virus,” Ramirez said. “And usually, what happens is it makes so much virus that it ends up killing the cell.”
Our bodies have different weapons and strategies on reserve to try and stop this takeover. Some act as general first responders to any kind of infection.
“It’s kind of a blunt instrument, and it doesn’t know the difference between different viruses.”
“It’s kind of a blunt instrument, and it doesn’t know the difference between different viruses,” she said, adding that a person might experience a rising temperature and fever with this response.
Other responses are more targeted and learn to adapt to a specific virus — similar to special forces units. They can include certain antibody proteins that can neutralize a virus or T cells. Different types of T cells can coordinate an attack on a virus or even kill it.
Immunity hints in T cells?
Ramirez began searching for clues to how these responses play out against SARS-Cov-2 in the blood samples of a handful of patients who had been infected and recovered from mild cases of COVID-19.
“Part of what we saw that was really great, is that we saw people made good immune responses, both antibody responses and T-cell responses to the spike protein,” Ramirez said. “And the reason I say this is good news is the fact that the spike protein is the main part of the virus that the vaccines out there are targeting.”
Looking at immune responses in the lab has limitations, and these are also small sample sizes.
“So, it gave us the first steps,” she said.
The winding road ahead
These first steps are launching scientists on a winding journey. For example, some people don’t generate a strong antibody response, but still seem to survive the coronavirus just fine. Ramirez saw in all of the samples she studied that the virus activated certain T-cell responses.
Could this be a hint that this branch of our body’s special forces leads the attack?
“I don’t think it’s black and white,” said Rory de Vries, a virologist focused on immunology at Erasmus Medical Center in the Netherlands.
De Vries has been following patients long term, and recently worked on a study of samples from patients who, unlike the samples Ramirez looked at, were really sick. Some died.
“It means these T cells can be protective, but it could also be some kind of clue that these T cells play a role in making the disease worse. We just don’t know yet and that is one of the topics we need to study further.”
“It means these T cells can be protective, but it could also be some kind of clue that these T cells play a role in making the disease worse," he said. "We just don’t know yet and that is one of the topics we need to study further.”
Sometimes, depending on the virus, these special forces can overreact and kill innocent bystanders, or rather, inadvertently attack our own body and organs. Sometimes, the effectiveness of these special forces units depends on timing, and how quickly and robustly they can mobilize as the virus takes hold. Sometimes, it’s the combination of the responses that is key.
De Vries, Ramirez and others are now pursuing these possibilities, as well as whether previous exposures to other types of coronaviruses, like the common cold, may help the body’s immune response to SARS-Cov-2.
Ramirez’s group, for example, found that some blood samples of patients who had never been infected with SARS-CoV-2 still had an immune response to the virus in the lab. She suspects that might be because those patients had already had other coronaviruses.
For Dr. Susanna Dunachie, who now co-runs an immunology lab on COVID-19 at the University of Oxford in the UK, the new coronavirus continues to surprise her.
“I have been humbled so many times about this virus,” said Dunachie, whose work is independent from Oxford’s vaccine trial.
Dunachie also thinks T cells could be important in building up a protective immunity, or an adaptive one, in which the body's special forces learn to successfully recognize and attack this particular virus in the future.
But why some people get sick and others don’t could depend on lots of other factors, like what’s happening in the immune responses and the cells at the site of the initial exposure to the virus, like in the nose.
“It might be that the other germs up your nose, the other bacteria and viruses that live harmlessly up there, they might have an impact on whether this particular virus takes a hold.”
“It might be that the other germs up your nose, the other bacteria and viruses that live harmlessly up there, they might have an impact on whether this particular virus takes a hold,” she said.
For Donna Farber, head of surgical sciences and a professor of microbiology and immunology at Columbia University, important clues to immunity may reside in what is happening at the specific site of infection, like the lung.
“What is going on in this immune response in the lung and why is it failing [for people who get very ill]? I think that's really key,” Farber said.
Researchers are also looking for immunity clues in age differences. What is different about kids’ immune responses compared to adults? In all of these efforts, the big looming question is when people do get COVID-19 and recover, how long will they stay immune to the disease?
“The next thing to find out is whether people get significant infection again,” said Dunachie. “And we need to wait and see.”
Dunachie and others hope that all these clues they’re learning about immunity right now will improve the world’s understanding of this virus, and with that, better shape treatments, vaccines and the overall response.