Sep 2, 2020
Show Notes for Episode Fifteen of seX & whY: Sex
Differences in Immunology and Drug Therapy
Host: Jeannette Wolfe
Guests:
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
References:
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