After facing down a pathogen, does the immune system return to its baseline, or does a single infection change how it will respond – not only to a familiar virus, but to the next new viral or bacterial threat it faces as well?
The long-term effects of infection on the immune system have long intrigued Prof. John Tsang, a Yale University immunobiologist and biomedical engineer who believes the immune system reverts to its previous stable baseline after viral infection.
The emergence of the pandemic in 2020 allowed him and colleagues to test that theory. The answer, he and his colleagues found, depends on the individual’s sex, according to a study in the journal Nature.
For the study, titled “Influenza vaccination reveals sex dimorphic imprints of prior mild COVID-19,” Tsang and lead author Dr. Rachel Sparks systematically analyzed immune responses of healthy people who had received the flu vaccine. They then compared the responses from those who had never been infected by SARS-CoV-2, the virus that causes COVID-19, and those who experienced mild cases but recovered.
They found that immune systems of men who had recovered from mild cases of COVID responded more robustly to flu vaccines than women who recovered from mild cases or men and women who had never been infected.
Thus, the baseline immune status in men previously infected with SARS-CoV-2 was altered in ways that changed the response to an exposure different from SARS-CoV-2, the authors said.
“This was a total surprise,” Tsang said. “Women usually mount a stronger overall immune response to pathogens and vaccines, but are also more likely to suffer from autoimmune diseases.”
“Women usually mount a stronger overall immune response to pathogens and vaccines, but are also more likely to suffer from autoimmune diseases.”
Dr. John Tsang
Why did COVID change men's immune responses to vaccines?
The findings may also be linked to an observation made early in the pandemic that after contracting the virus, men were much more likely to die from a runaway immune response than women were.
Even mild cases of COVID-19, the findings suggest, might trigger stronger inflammatory responses in males than females, resulting in more pronounced functional changes to the male immune system, even long after recovery.
Their analysis of immune-system status down to the individual cell level revealed several differences between COVID-recovered men and healthy controls, and COVID-recovered women, both before and after receiving flu vaccinations.
For instance, previously infected males produced more antibodies to influenza and increased levels of interferons, which are produced by cells in response to infections or vaccines. Generally, healthy females have stronger interferon responses than their male counterparts.
Understanding the lingering effects of COVID-19 on the immune system is crucial, wrote the authors, since more than 600 million people worldwide have been infected so far, and the emergence of “long-COVID” symptoms in some people continues to be a major health concern.
“Our findings point to the possibility that any infection or immune challenge may change the immune status to establish new set points,” Sparks said. “The immune status of an individual is likely shaped by a multitude of prior exposures and perturbations.”
Tsang believes these findings could also help scientists create better vaccines against diverse threats by, for instance, mimicking how mild COVID-19 changes the male immune baseline.