seX & whY Episode 15: Sex Differences in Immunology and Drug Therapy

Jeannette WolfePodcast Episodes

Show Notes for Episode Fifteen of seX & whY: Sex Differences in Immunology and Drug Therapy

Host: Jeannette Wolfe


Evelyne Bischof MD, Associate Professor of Medicine at Shanghai University of Medicine and Health Sciences and internist at University Hospital of Basel Switzerland

Sabra Klein, PhD, Professor of Molecular Microbiology and Immunology at Johns Hopkins Bloomberg School of Public Health

This podcast focused on sex differences in immunology and pharmacology and its relevance to the Covid-19 pandemic.

Key points

  • Males are more likely to be admitted to the ICU and die from COVID-19 compared to females
  • Males and females have differences in both innate and adaptive immunity (which likely are a combo of chromosomal, hormonal and epigentic differences)
  • One difference in Innate immunity (the initial non-specific reaction to a foreign pathogen) is Toll-like receptor 7 (TLR7) This is a major player in the initial physiological response to a foreign pathogen and the gene for it is on the X chromosome. X-lined genes (like Ace-2 which is the receptor which SARS-Cov-2 initially binds to in the body) are interesting because they immediately bring up two considerations.  First, if someone has a specific variant of that gene, it could change their susceptibility to certain pathogens. Males, as they have an XY pair of sex chromosomes, only have one X chromosome and thus could be more adversely impacted than females (XX) who have a second copy of the gene (which may or may not express the same variant)  from their other X chromosome. The second consideration is that in the cells of most females, one of the X chromosomes is automatically turned off (X inactivation). It appears however, that some X-linked immune cells- like TLR7- don’t do this, leading to the possibility of increased expression of the gene like getting an “extra dose”.
  • In adaptive immunity (which involved B and T cells), females generally have a greater immunological response to most pathogens.
  • As such, females generally exhibit a more robust immune response to natural infections and vaccinations. The flip side, however, is compared to men, women are also at greater risk for autoimmune diseases and are more likely to get local and systemic reactions after a vaccination.
    • When testing the effectiveness and side effects of SARS-CoV-2 vaccines it would be ideal to consider the variables of biological sex and age.
    • In an influenza study, when women were given a ½ dose of the flu vaccine, they mounted a similar immune response to males who got full dose. If the same held true for developing SARS-Cov2 vaccinations, it could potentially increase the amount of vaccine available (though it is unclear if this is even being considered in early vaccine trials).
    • Aging can also impair the immune response and older adults may require higher doses of booster doses of some vaccines to optimize their immune response
  • The use of Artificial Intelligence in drug development may revolutionize the pharmaceutical research industry by allowing more predictive drug modeling leading to more successful drug development.
  • This could also be used to better identify potentially important biological sex- based pharmacodynamic and pharmacokinetic differences earlier in drug development.

Two unexpected findings associated with COVID-19

  • Males appear to be more vulnerable to cytokine storm (mechanism still not entirely clear may be differences in ACE-2 receptors, or chromosomal/hormonal differences in innate/adaptive immune system)
  • Elderly sick males who survived COVID-19 appear to have significant protective antibody production against SARS-Cov2


Bischof E, Wolfe J, Klein S: Clinical trials for Covid-19 should include Sex as a Variable. JCI 2020

Engler R, Nelson M, Klote M, et al. Half- vs Full-Dose Trivalent Inactivated Influenza Vaccine (2004-2005) Age, Dose, and Sex Effects on Immune Responses, JAMA Internal Medicine 2008

Gender and COVID-19 Working Group website

Global Health 50/50  global deaths disaggregated by sex

Klein S, Pekosz A, Park H. et al.  Sex, age and hospitalization drive antibody responses in a Covid-19 convalescent plasma donor population. JCI 2020

Roberts M, Genway S How Artificial Intelligence is transforming drug design. DDW

Souyris M, Cenac C, Azar P, et al. TLR7 Escapes X Chromosome Inactivation in Immune Cells. Autoimmune Disease 2018

Takehiro T, Ellingson M, Wong P et al. Sex Differences in Immune Responses that underlie COVID-19 disease outcomes. Nature 2020

Zucker I, Prendergast B.  Sex differences in pharmacokinetics predict adverse drug reactions in women. Biology of Sex Differences 2020

Special thanks to Doug Deems for help with editing.