When COVID-19 began spreading like wildfire in the Northeast United States this spring, critical care doctor Nuala Meyer could barely believe what she was seeing.
“The number of patients who were presenting with critical illness all at the same time was staggering,” remembers Meyer, a professor of medicine at the Hospital of the University of Pennsylvania. But it wasn’t just that these patients were really sick—it was that they were sick in a startling variety of ways. Some had cardiac issues. Others had blood clots in their legs. Then there were those who developed pneumonia and related respiratory problems. Organ failure affected some. The list went on and on.
When Meyer and colleagues profiled the ways in which hospitalized patients’ bodies had tried to combat the virus, they found a variety of different immune responses. T and B cells were highly activated in some but not others, for instance. Their work joins a swath of recent publications aiming to decipher the role of these crucial cells in fending off SARS-CoV-2. To understand how vaccines and long-term immunity function, scientists say, they’ll need to uncover how T and B cells fight this most challenging of infections.
In pursuit of this goal, Meyer and her colleagues examined immune responses in a sample of 125 patients. Their findings were published in Science July 15.
The fact that antibody levels are falling doesn’t mean we haven’t got a memory response.—Sheena Cruickshank, University of Manchester
The researchers found that some patients had very unbalanced immune cell activity and that this imbalance could manifest in multiple ways. For instance, some produced lots of CD4+ T cells—helper cells that assist other parts of the immune system to block or destroy the virus—but very few CD8+ T “killer” cells, which destroy infected cells in the body. Meanwhile, some patients generated lots of B cells, which churn out antibodies, but not in concert with the two main types of T cell. Getting these cells to work together is important, explains coauthor Michael Betts, an immunologist at the Penn Institute for Immunology, because it helps fight infection on several fronts at once. Some T cells, for instance, help B cells to produce antibodies—it’s a joint effort. In some patients studied by the group, there was a worrying lack of T and B cells in general.
Severely ill patients, notably, experienced “the spectrum” of responses, says Betts—from hardly any T and B cell activation to excessive amounts. He says it’s still not clear what drives severe illness in many patients. Scientists also don’t yet know precisely what kind of T and B cell response occurs in patients who have mild or no symptoms.
“It’s a very nice paper,” says Akiko Iwasaki, an immunologist at Yale University. She says that while antibodies have been much talked about, it’s important to recognize that for people to retain immunity to the virus over time, good T and B cell responses are necessary.
There are indeed signs that people won’t gain long-term immunity through having neutralizing antibodies circulate in their blood for years. Rather, it will likely be provided by those T and B cells. A study published June 18 in Nature Medicine showed how, in a cohort of 74 symptomatic and asymptomatic COVID-19 patients, antibodies waned dramatically in most of these people after just a few months. Those individuals may well be able to produce antibodies quickly again if they get infected, however, thanks to their T and B cells. It’s a bit like having a fire department available to call on—that way, you don’t need the firemen always hanging around on site just in case a blaze breaks out.
Role of T cells in COVID-19 vaccines
“The fact that antibody levels are falling doesn’t mean we haven’t got a memory response,” says Sheena Cruickshank, an immunologist at the University of Manchester in the UK who was not involved in the study.
This is why, when multiple groups working on vaccines announced the results of early phase clinical trials lately, there was excitement over the fact that they reported T and B cell responses in trial participants.
Among those reporting results was the team at the University of Oxford that has developed a vaccine based on a chimpanzee adenovirus. The adenovirus is modified to harbor the gene that encodes the SARS-CoV-2 spike (S) protein.
The group’s results, published July 20 in The Lancet, show that the vaccine did not provoke serious side effects in a sample of around 1,000 healthy adults aged 18–55 and it also produced what appears to be a desirable immune response involving both antibodies and T and B cells.
Another group at biotech firm Moderna reported results from a Phase 1 trial of its vaccine in the New England Journal of Medicine on July 14. In 45 healthy adults aged 18–55, neutralizing antibodies and T cells were stimulated, including CD8+ killer T cells.
“Those T cell responses reported from the vaccine trials looked pretty impressive,” says Iwasaki.
Scientists are uncovering a string of immunological mysteries associated with the disease.
All vaccines currently in development still need to undergo further tests to show that they are safe in a broader group of people and that they do indeed prevent SARS-CoV-2 infection.
Betts points out that there will be differences between the immune response to a natural infection and the response provoked by a successful vaccine. As of yet, scientists are still not sure what the ideal response in either case looks like. But one thing vaccine researchers will look for, Betts notes, is a T and B cell response that can maintain some degree of immunity over a significant period of time.
“As with other vaccines, it is possible, even likely, that the vaccine won’t prevent you from catching COVID but may greatly reduce severity,” he says in an email.
“Puzzling” immune responses to SARS-CoV-2
It is possible that some people have gained T cell–based immunity to the SARS-CoV-2 virus from other previous infections.
On July 15, a study in Nature described evidence of immunity to SARS-CoV-2 in 23 patients who had previously contracted the original SARS virus 17 years ago.
This was based on the fact that those individuals retained long-lasting CD4+ and CD8+ T cells that the authors showed produced a protein called interferon-gamma when exposed to the SARS-CoV-2 virus’s nucleocapsid (N) protein. This suggests that those people’s T cells were primed to help fend off SARS-CoV-2.
The authors even found SARS-CoV-2–specific T cells in 37 other patients who had no history of SARS, COVID-19, or contact with people who had had those diseases. While it’s difficult to be certain about those individuals’ medical histories, based on the study’s results, cross-reactivity—when the immune system is able to fend off one type of infection thanks to immunity acquired after another—has possibly been at work in people who have experienced mild or no symptoms following SARS-CoV-2 infection, the authors speculate.
The list of things to investigate about COVID-19 doesn’t stop at T and B cells. In fact, scientists are uncovering a string of immunological mysteries associated with the disease.
Iwasaki says that two key types of antibody seem to be generated in an unusual order after infection. With COVID-19, IgG antibodies are often generated very quickly and then followed by a rise in IgM antibodies—the wrong way round.
“That’s kind of puzzling because that’s not a typical textbook way in which the antibodies are generated,” says Iwasaki. And in some patients, B cells begin reacting as though the person were experiencing an allergic reaction, producing IgE antibodies. This too is, so far, unexplained.
Betts and Meyer also noticed that some patients in their study produced high volumes of plasmablasts—B cells converted into immature plasma cells that produce antibodies.
“We normally think of something like Ebola infection being pretty awful,” says Betts. “These plasmablast responses that we see in severe COVID are actually larger than the ones we see in Ebola.”
It’s unusual to see such a strong plasmablast response that lasts for days, confirms Meyer.
Eventually, answers to the many questions around COVID-19 immunity may emerge. Scientists already know far more than they did just a few months ago. But as Meyer says, “We have a lot of work to do.”