A key piece of the body’s immune response to COVID-19 looks to have been damaged in people who caught the disease before they were vaccinated, a study published this month found, resulting in a “major reduction” to part of the defense the body typically musters to fight off the virus.
“You have damage that, even in recovery from the infection, you haven’t really recovered your ability to make those CD8+ cells. So something happened in the course of infection to prevent that, to damage your response,” said Stanford Professor Mark Davis, head of the university’s Institute for Immunity, Transplantation and Infection. Davis is lead author of the paper, which was published this month in the journal Immunity.
CD4+ T cells, often dubbed “helper T cells” for their role in marshaling other parts of the immune response, appeared to be undamaged.
But Davis and his team found the response of CD8+ T cells, known as “killer T cells” for their role in destroying infected cells, was substantially worse in people who had survived an infection, with both the quantity and quality of the cells diminished. A disparity remained even after those people got vaccinated with the Pfizer-BioNTech vaccine.
“Looking at the broader swath of data, we came up with a seven-fold average reduction. But it was much larger in several of the cases. So that’s a big deal,” Davis said.
While researchers often look to antibodies first to measure the body’s initial protection against an infection, an array of T cells also make up an essential part of the body’s defenses. Davis and his team engineered a unique approach to measuring this response, leveraging a reagent they developed to essentially label a detailed picture of the T cells.
“Technology-wise, looking at the T cell response and quantitatively measuring it is harder than antibody detection. That’s why there’s a need to improve that technology and also relate it to vaccine development,” said Chao Jiang, a program officer for the National Institutes of Health. Jiang oversaw the research, which was funded by the agency.
Davis thinks the dropoff could result in the immune system taking longer to root out infected cells. Compared to others without the damage, it could also potentially make it harder to gain the full benefit from the vaccine they got and fend off new variants.
“I think it would be probably too much of a speculation to say that this could impair responses to other viruses. But SARS-CoV-2 variants have not gone away. They’re out there,” he said.
The study’s authors likened the dysfunction to that seen in their previous work with viruses like hepatitis C or HIV, lingering even after infections were quelled.
“So there are probably, after these years of study, we know that SARS-CoV-2 actually did alter our host immune response. And this CD8 T cell dysfunction may be just one aspect of it,” said Jiang.
Not every infectious disease has been linked to this kind of lasting dysfunction, Jiang said. But she cautioned that this does not mean SARS-CoV-2 inflicts the same kind of devastation that HIV can wreak on the immune system.
“This dysfunction may have some long-term immune consequences. It may be possibly related to long COVID, but we don’t know. And there is a lot of work ongoing, and I think we will understand more about the mechanism,” said Jiang.
It will also be important to study how this damage squares with other parts of the body’s complex immune response. Jiang noted research elsewhere has turned up signs of superior antibody protection from people who were both infected and vaccinated.
“That’s why, in my mind, it’s very important to follow up a study like this, especially when our clinical cohort is getting more years down the road, so that we could be able to correlate that with some more clinical symptoms,” Jiang said.
One limitation of this paper from Davis is that they relied on “peripheral” T cells in the blood. Gathering samples from elsewhere in the body — for example the lungs, where the immune response might look strongest — cannot be done with living humans.
However, Davis pointed out their measurements turned up other kinds of T cells for the virus in the blood at levels that looked fine.
“This question has been raised like a million times. And basically, what I would say is that everything ends up in the circulation eventually,” said Davis.
Some of the phenomenon they discovered may also be unique to the population scientists tested: people who got an mRNA vaccine for COVID-19 after they were infected.
Davis suggested it was possible people may see different results more years after their initial infection, especially in people who mix-and-matched with other vaccines for their booster.
“Maybe, as we go further along to look at some of those damaged CD8 responses, can we bring them back? Or do people recover after?” he said.