Does Gender Determine the Body’s Reaction to COVID-19

Long-term effects of infection on the immune system have long piqued the interest of Yale immunobiologist John Tsang. Does the immune system revert to its former baseline after the body has dealt with a pathogen? Or does a single infection modify its response not only to a familiar virus but also to the next novel viral or bacterial threat it faces?

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How does a Viral Infection Affect the Body

Tsang, a Yale professor of immunobiology and biomedical engineering, has long thought that after a viral infection, the immune system returns to its former stable baseline.

The onset of the COVID-19 pandemic in 2020 provided an opportunity for him and others to put that notion to the test. According to a study published in the journal Nature, the response depends on the individual’s sex.

Tsang, who was at the time at the National Institute of Allergy and Infectious Diseases (NIAID), and colleagues, including main author Rachel Sparks, also from NIAID, evaluated the immune responses of healthy persons who had received the flu vaccine for the study. They next compared the responses of those who had never been infected with SARS-CoV-2, the virus that produces COVID-19, and those who had mild instances but recovered.

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Gender Disparity in Immune Responses

Surprisingly, they discovered that the immune systems of males who had recovered from minor instances of COVID-19 responded more strongly to flu vaccines than the immune systems of women who had recovered from light cases or men and women who had never been infected.

The baseline immunological statuses of men previously infected with SARS-CoV-2 were altered in ways that impacted the response to exposure other than SARS-CoV-2, according to the authors.

“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.”

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COVID-19 Induces Stronger Inflammatory Responses in Men than Women

The findings could potentially be linked to an earlier observation made during the pandemic: men were much more likely than women to die from a hyperactive immune response after getting the COVID-19 virus. The current findings imply that even mild cases of COVID-19 may induce larger inflammatory responses in males than females, resulting in more significant functional alterations to the male immune system even after recovery.

Their unbiased examination of immune system status down to the individual cell level found many disparities between COVID-19 recovered males and healthy controls, as well as between COVID-19 recovered females and healthy controls, both before and after flu vaccines. For example, previously infected males produced more influenza antibodies as well as higher levels of interferons, which are produced by cells in response to infections or vaccines. In general, healthy females have greater interferon responses than healthy males.

Understanding the long-term consequences of COVID-19 on the immune system is critical, according to the authors, because over 600 million individuals have been infected so far, and the emergence of ‘long-COVID-19’ symptoms in some people remains 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,” said Sparks. “The immune status of an individual is likely shaped by a multitude of prior exposures and perturbations.”

Tsang believes that these discoveries could help scientists develop better vaccines against a variety of dangers by replicating how moderate COVID-19 alters the male immunological baseline.