Immune Memory to COVID-19 Vaccination Is Stored Throughout the Body

After people are vaccinated against COVID-19 with mRNA vaccines, the immune system stockpiles memory T and B cells—essential for long-term immunity—in tissues around the body, including the lung, spleen, and bone marrow, researchers at Columbia University Vagelos College of Physicians and Surgeons have found.

The new study suggests that even if evidence of vaccine-induced immune memory is not detected in blood, it may still persist in lymphoid organs and sites of infection.

“Our study suggests that many people who seem to have no immunological memory of COVID-19 vaccination in their blood, may have more protection than we think,” says study leader Donna Farber, PhD, professor of microbiology & immunology.

In blood, memory cells and antibodies that neutralize the virus decline rapidly after vaccination, particularly in older people. “But our results suggest that many people, including seniors, have the right memory cells—they’re just hidden in their tissues,” Farber says.

The findings of the study may help researchers develop vaccines and vaccination strategies that maximize protection against current and emerging pathogens.

Blood does not tell the full story

Researchers have long thought that vaccine-induced immune cells largely circulate in the blood and quickly migrate to tissues whenever and wherever needed. But recent research—including pivotal studies by Farber—has shown that some memory cells find long-term homes in various tissues.

Farber was among the first researchers to show, in mice infected with influenza virus, that these cells are integral in the defense against pathogens. Her team found that full protection against subsequent exposure to influenza was only achieved if memory T cells established long-term residence in the animals’ lungs after the initial exposure. These non-circulating immune cells were subsequently called tissue-resident memory T cells, or TRMs.

Evidence of the importance of TRMs in people came early in the pandemic, when Farber’s team found that immune cells from the lungs of COVID-19 patients were different from the immune cells found in their blood. “COVID has shown we must study immunity in the whole body,” wrote Farber in a 2021 Nature comment.

Accessing tissues

The problem with studying immunity in the whole human body is that most tissues are only accessible with invasive procedures. Working with LiveOnNY, a nonprofit organization that facilitates organ donation and transplantation in the greater New York City area, Farber set up a novel system for procuring tissue samples from organ donors. In addition to obtaining organs for transplantation, the transplant team also collects other tissue samples for immunological research.

In the current study, Farber’s team examined the blood and tissues of 63 organ donors (ages 23 to 86) for immunological memory to the COVID-19 mRNA vaccine.

The study employed new single-cell RNA and protein techniques, which allowed the researchers to determine the types of immune cells present in each tissue and the cells’ functional capacities.

Long-lasting memory to COVID vaccination in tissues

In most people, fully functional and long-lasting TRMs specific to COVID vaccination were found throughout the body. In contrast, memory cells were not detected in the blood of many individuals, especially older people. “This shows that immune memory to vaccines can be maintained even when it is not detected in blood,” Farber says.

The study also found that memory cells that circulate in the bloodstream have different functions than memory cells that reside in tissues.

“In circulating blood, immune memory is more inflammatory and geared toward killing and clearing infected cells, while in tissues, T cell memory has more regulatory functions, possibly to limit tissue damage,” says Peter Sims, associate professor of systems biology and a co-author of the study.

In mouse models, T cell memory in tissues is sufficient for protection even when T cell memory is not present in blood, “but we don’t know if this also applies to humans,” Farber says.

Other viruses

The researchers also found evidence that immune memory to influenza infection and vaccination has a similar profile and response in tissues, suggesting that this phenomenon may apply to many other vaccines and viruses.

The team is currently looking at the immune response in tissues to other viruses, including Epstein-Barr virus and cytomegalovirus, and to other vaccines, including standard childhood immunizations.