Editor's Choice in Immunology

When healthy individuals suffer from an acute infection, they expect that their immune systems will ramp up to fight the invading pathogens and then return to their baseline states. The truth is not so simple since people have diverse immune responses that can change throughout their lifetimes, including after surviving infection.1

John Tsang from 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, 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.2

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. 

We saw that the males had higher antibody responses and corresponding B cell responses to the flu vaccine than females.

—John Tsang, Yale University

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 male and female volunteers who had or had not experienced COVID-19.

Female participants tend to mount stronger immune responses than male participants 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 female patients.3 Tsang hypothesized that the robust reaction in male volunteers may leave lasting effects on multiple immune cell types.

The researchers found that male patients who 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, similar to true memory T cells. After vaccination, COVID-19 recovered male individuals 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 vaccines. 

“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 at the University of Alberta, who was not involved in the study. “That suggests that there is an avenue for intervention.”

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


  1. M.J. Mina et al., “Measles virus infection diminishes preexisting antibodies that offer protection from other pathogens,” Science, 366:599-606, 2019.
  2. R. Sparks et al., “Influenza vaccination reveals sex dimorphic imprints of prior mild COVID-19,” Nature, 1–10, 2023.
  3. T. Takahashi et al., “Sex differences in immune responses that underlie COVID-19 disease outcomes,” Nature, 588:315-20, 2020.