Gonadal androgens are associated with decreased type I interferon production by plasmacytoid dendritic cells and increased IgG titres to BNT162b2 following co-vaccination with live attenuated influenza vaccine in adolescents
File(s)
Published version
Author(s)
Type
Journal Article
Abstract
mRNA vaccine technologies introduced following the SARS-CoV-2 pandemic have highlighted the need to better understand the interaction of adjuvants and the early innate immune response. Type I interferon (IFN-I) is an integral part of this early innate response that primes several components of the adaptive immune response. Women are widely reported to respond better than men to tri- and quadrivalent influenza vaccines. Plasmacytoid dendritic cells (pDCs) are the primary cell type responsible for IFN-I production, and female pDCs produce more IFN-I than male pDCs since the upstream pattern recognition receptor Toll-like receptor 7 (TLR7) is encoded by X chromosome and is biallelically expressed by up to 30% of female immune cells. Additionally, the TLR7 promoter contains several putative androgen response elements, and androgens have been reported to suppress pDC IFN-I in vitro. Unexpectedly, therefore, we recently observed that male adolescents mount stronger antibody responses to the Pfizer BNT162b2 mRNA vaccine than female adolescents after controlling for natural SARS-CoV-2 infection. We here examined pDC behaviour in this same cohort to determine the impact of IFN-I on anti-spike and anti-receptor-binding domain IgG titres to BNT162b2. Through flow cytometry and least absolute shrinkage and selection operator (LASSO) modelling, we determined that serum-free testosterone was associated with reduced pDC IFN-I, but contrary to the well-described immunosuppressive role for androgens, the most bioactive androgen dihydrotestosterone was associated with increased IgG titres to BNT162b2. Also unexpectedly, we observed that co-vaccination with live attenuated influenza vaccine boosted the magnitude of IgG responses to BNT162b2. Together, these data support a model where systemic IFN-I increases vaccine-mediated immune responses, yet for vaccines with intracellular stages, modulation of the local IFN-I response may alter antigen longevity and consequently improve vaccine-driven immunity.
Date Issued
2024-02-28
Date Acceptance
2024-02-13
Citation
Frontiers in Immunology, 2024, 15
ISSN
1664-3224
Publisher
Frontiers Media S.A.
Journal / Book Title
Frontiers in Immunology
Volume
15
Copyright Statement
Copyright © 2024 Sampson, Jay, Adland, Csala, Lim, Ebbrecht, Gilligan, Taylor, George, Longet, Jones, Barnes, Frater, Klenerman, Dunachie, Carrol, Hawley, Arlt, Groll and Goulder. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
License URL
Identifier
https://www.ncbi.nlm.nih.gov/pubmed/38481993
Subjects
Adolescent
Androgens
BNT162 Vaccine
Dendritic Cells
Female
Humans
Immunoglobulin G
Influenza Vaccines
Interferon Type I
Interferon-alpha
Male
mRNA Vaccines
Toll-Like Receptor 7
Vaccination
adolescent vaccination
androgen
immune sex difference
plasmacytoid dendritic cell
type I interferon
Publication Status
Published
Coverage Spatial
Switzerland
Article Number
1329805
Date Publish Online
2024-02-28