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When a healthy individual suffers from an acute infection, there is an expectation that their immune system will ramp up to fight the invading pathogens and then return to its baseline state. The truth is not so simple, as people have diverse immune responses that can change throughout their lifetimes, including after surviving infection.

John Tsang, currently a professor at Yale University, has spent his research career determining why people respond to infection differently. “One of the questions we've been trying to understand is, ‘How are [baseline immune] states set?” said Tsang. “If you look at certain immune cells and their states before they get a perturbation, like a vaccine, that can predict their responses independent of things like age, sex, [and] pre-existing immunity.”

While in his previous position at the National Institutes of Health (NIH), Tsang and a research team assembled by clinical immunologist Rachel Sparks sought to learn if people’s baseline immune statuses changed in response to mild COVID-19. Their results were recently published in Nature.

The early days of the COVID-19 pandemic presented an unprecedented scenario where many people were infected with a pathogen that their immune systems had never experienced. Tsang and Sparks’s team compared the immune statuses of people who had recovered from mild COVID-19 during the first wave of the pandemic to those never exposed to SARS-CoV-2.

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After performing multiomic analyses on cells, proteins, RNA, and DNA in the blood to determine each person’s baseline state, the researchers activated the participants’ immune systems by administering flu vaccines. The team then compared the innate and adaptive immune responses over time of males and females who had or had not experienced COVID-19.

Females tend to mount stronger immune responses in general and to the flu shot, but Tsang’s team saw the opposite in the COVID-19 recovered population. “We saw that the males had higher antibody responses and corresponding B cell responses to the flu vaccine than females,” said Tsang.

These findings were in line with what other researchers had noticed about COVID-19—male patients tended to have stronger inflammatory responses to SARS-CoV-2 infection and greater mortality rates than females. Tsang hypothesized that the robust reaction in males may leave lasting effects in multiple immune cell types.

The researchers found that males recovered from COVID-19 had elevated numbers of long-lived virtual memory T cells at baseline. These cells have not been exposed to their target antigen, yet respond vigorously to cytokine stimuli, similarly to true memory T cells. After vaccination, COVID-19 recovered males exhibited monocyte populations that highly expressed the inflammatory cytokine interleukin 15 (IL-15), which induced virtual memory T cells to produce another cytokine, interferon gamma (IFN-γ). These elevated cell numbers and cytokine levels may be what caused greater antibody production against influenza.

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“There're so many possible biomarkers that have been proposed in the literature, but at the end of the day, we always struggle with a question of association and causation. I think one of the nice things about this paper is that we are getting closer to trying to look at this mechanistically,” said Grace Lam, assistant professor at the University of Alberta, who was not involved in the study. “That suggests that there is an avenue for intervention.”

Tsang hopes that his team’s findings will help researchers build better vaccines. By adding IL-15 as a vaccine adjuvant, individuals—whether they be male or female—could mount stronger immune responses with increased antibody production in response to vaccination.