Gonadal androgens are associated with decreased type I interferon production by pDCs and increased IgG titres to BNT162b2 following co-vaccination with live attenuated influenza vaccine in adolescents

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. Interferon type I (IFN-I) is an integral part of this early innate response and can prime several components of the adaptive immune response. Females are widely reported to respond better than males to seasonal tri- and quad-valent 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 receptor TLR7 is encoded by the X-chromosome and is biallelically expressed by up to 30% of female immune cells. Additionally, the TLR7 promoter contains 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 cohort to determine the impact of IFN-I on anti-Spike and anti-receptor-binding domain titres to BNT162b2. Through 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 more potent 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 increased vaccine-mediated immune responses, but for vaccines with intracellular stages, modulation of the local IFN-I response may alter antigen longevity and consequently vaccine-driven immunity. Author SummaryType I interferons (IFN-I) are potent antiviral proteins which play a central role in activating the immune response and driving inflammation. IFN-I is predominantly produced by plasmacytoid dendritic cells (pDCs) and female pDCs produce more IFN-I than male pDCs. Consequently, females typically generate stronger antibody responses to vaccines such as seasonal influenza vaccines. In addition, females typically suffer more serious adverse events from vaccines. However, we recently reported in a study of adolescents that males generate stronger antibody responses to the SARS-CoV-2 mRNA vaccine BNT162b2 than females. Here we examine the IFN-I response of pDCs in adolescents co-/vaccinated with BNT162b2 and live-attenuated influenza vaccine (LAIV). We find that male sex hormones reduce pDC IFN-I but are associated with increased BNT162b2 antibody titres. We also observe that LAIV boosts BNT162b2 antibody titres through possible bystander activation of immune cells. These findings are consistent with a reportedly higher incidence of adverse events among males associated with this vaccine. Together these data suggest that IFN-I production typically enhances vaccine-specific immune responses but for new mRNA vaccines such as BNT162b2, that are modified to reduce innate immunogenicity, localised dampening of the IFN-I response in vaccinated tissue by male sex hormones may further delay the clearance of the vaccine, increasing vaccine antigen exposure and allowing time for a stronger antibody response.