Sex and age differences in antibody responses to seasonal influenza vaccination are mediated by estrogenic upregulation of NF-κB and TNF signaling in B cells
6 affiliations
- 1W. Harry Feinstone Department of Molecular Microbiology and Immunology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, USA
- 2Department of Biostatistics, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, USA
- 3Department of Clinical Chemistry, Erasmus Medical Center, Rotterdam, the Netherlands
- 4Department of Emergency Medicine, The Johns Hopkins School of Medicine, Baltimore, Maryland, USA
- 5Division of Geriatric Medicine and Gerontology, Center on Aging and Immune Remodeling, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
- 6Laboratory of Molecular Biology and Immunology, National Institute on Aging, NIH, Baltimore, Maryland, USA
Abstract
Sex differences in the humoral immune responses to the seasonal quadrivalent influenza vaccine (QIV) in young adults (YA; 18–49 years old) or high-dose QIV in old adults (OA; 75+ years old) were analyzed to determine how age-related changes, including in steroids, impact sex differences in B cells. Among YAs, females had greater H3N2, but not H1N1, neutralizing antibody titers, and greater proportions of hemagglutinin (HA)+ CD19+ B cells and HA+ memory B cells than males through 28 days post-vaccination (DPV), that was not observed among OAs. Machine learning algorithms illustrated that baseline (0 DPV) steroids, including 17-hydroxyprogesterone, estrogens, and testosterone, as well as HA+ CD19+ B cells and HA+ antibody-secreting B cells (ASCs), were major predictors of seroconversion at 28 DPV, particularly in YA. Single-cell RNA sequencing demonstrated that CD19+ B cells from YA females had greater transcriptional activity at 7 DPV than YA males, with upregulation of genes with estrogen-response elements (EREs) along NF-κB-mediated TNF signaling pathways in B-cell subsets, which was mitigated in OA. Estradiol treatment of ASCs from YA females, but not males, increased the number and size of HA+ IgG+ cells and expression of ERE genes along the NF-κB-mediated TNF signaling pathway,that was inhibited by an estrogen receptor antagonist. Pharmacological inhibition of either NF-κB or TNF signaling blocked the ability of E2 to upregulate antibody secretion in cells from YA females. This study provides mechanistic insights into estrogen-mediated increases in influenza vaccine-induced antibody responses among reproductive-aged females and suggests a role for estrogen signaling in the reduction of sex differences in vaccine-induced immunity with old age.
IMPORTANCE: Sex differences in influenza vaccine-induced immune responses become less pronounced with old age, which we hypothesize could be related to changes in circulating gonadal steroids. Our study shows that after receipt of the seasonal influenza vaccine, young adult females, who have elevated estrogenic activity, have more B cells that recognize influenza hemagglutinin; their B cells have greater activity along estrogen signaling and inflammatory pathways, and mount stronger antibody responses than young adult males, with these sex differences being mitigated in old adults. We identify estrogen as a key driver of sex differences in influenza immunity by showing that ex vivo estradiol increases antibody production by B cells through the estrogen receptor and engagement with NF-κB. These findings help explain the biological basis for sex differences in vaccine immunity and suggest that the hormonal environment, not just chronological age, shapes how well a person responds to vaccination.
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BibTeX
@article{park2026differences,
title = {{Sex and age differences in antibody responses to seasonal influenza vaccination are mediated by estrogenic upregulation of NF-κB and TNF signaling in B cells}},
author = {Han-Sol Park and Anna Yin and Weiqiang Zhou and Eliane F. E. Wenstedt and Anne Jedlicka and Amanda Dziedzic and Annie Werner and Katherine Z. J. Fenstermacher and Huifen Li and Patrick J. Shea and John S. Lee and Patricia Gearhart and Robert W. Maul and Sjoerd A. A. Van Den Berg and Richard E. Rothman and Hongkai Ji and Sean X. Leng and Andrew Pekosz and Sabra L. Klein},
journal = {mBio},
year = {2026},
month = sep,
doi = {10.1128/mbio.01435-26},
url = {https://doi.org/10.1128/mbio.01435-26},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Sex and age differences in antibody responses to seasonal influenza vaccination are mediated by estrogenic upregulation of NF-κB and TNF signaling in B cells
AU - Han-Sol Park
AU - Anna Yin
AU - Weiqiang Zhou
AU - Eliane F. E. Wenstedt
AU - Anne Jedlicka
AU - Amanda Dziedzic
AU - Annie Werner
AU - Katherine Z. J. Fenstermacher
AU - Huifen Li
AU - Patrick J. Shea
AU - John S. Lee
AU - Patricia Gearhart
AU - Robert W. Maul
AU - Sjoerd A. A. Van Den Berg
AU - Richard E. Rothman
AU - Hongkai Ji
AU - Sean X. Leng
AU - Andrew Pekosz
AU - Sabra L. Klein
PY - 2026
DA - 2026/09/10
JO - mBio
DO - 10.1128/mbio.01435-26
UR - https://doi.org/10.1128/mbio.01435-26
AB - Sex differences in the humoral immune responses to the seasonal quadrivalent influenza vaccine (QIV) in young adults (YA; 18–49 years old) or high-dose QIV in old adults (OA; 75+ years old) were analyzed to determine how age-related changes, including in steroids, impact sex differences in B cells. Among YAs, females had greater H3N2, but not H1N1, neutralizing antibody titers, and greater proportions of hemagglutinin (HA)+ CD19+ B cells and HA+ memory B cells than males through 28 days post-vaccination (DPV), that was not observed among OAs. Machine learning algorithms illustrated that baseline (0 DPV) steroids, including 17-hydroxyprogesterone, estrogens, and testosterone, as well as HA+ CD19+ B cells and HA+ antibody-secreting B cells (ASCs), were major predictors of seroconversion at 28 DPV, particularly in YA. Single-cell RNA sequencing demonstrated that CD19+ B cells from YA females had greater transcriptional activity at 7 DPV than YA males, with upregulation of genes with estrogen-response elements (EREs) along NF-κB-mediated TNF signaling pathways in B-cell subsets, which was mitigated in OA. Estradiol treatment of ASCs from YA females, but not males, increased the number and size of HA+ IgG+ cells and expression of ERE genes along the NF-κB-mediated TNF signaling pathway,that was inhibited by an estrogen receptor antagonist. Pharmacological inhibition of either NF-κB or TNF signaling blocked the ability of E2 to upregulate antibody secretion in cells from YA females. This study provides mechanistic insights into estrogen-mediated increases in influenza vaccine-induced antibody responses among reproductive-aged females and suggests a role for estrogen signaling in the reduction of sex differences in vaccine-induced immunity with old age. IMPORTANCE: Sex differences in influenza vaccine-induced immune responses become less pronounced with old age, which we hypothesize could be related to changes in circulating gonadal steroids. Our study shows that after receipt of the seasonal influenza vaccine, young adult females, who have elevated estrogenic activity, have more B cells that recognize influenza hemagglutinin; their B cells have greater activity along estrogen signaling and inflammatory pathways, and mount stronger antibody responses than young adult males, with these sex differences being mitigated in old adults. We identify estrogen as a key driver of sex differences in influenza immunity by showing that ex vivo estradiol increases antibody production by B cells through the estrogen receptor and engagement with NF-κB. These findings help explain the biological basis for sex differences in vaccine immunity and suggest that the hormonal environment, not just chronological age, shapes how well a person responds to vaccination.
SN - 2150-7511
ER -