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. 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.
Subject(s)
COVID-19ABSTRACT
The adaptive immune system protects against infection via selection of specific antigen receptors on B-cells and T-cells. We studied the prevalent CD8 killer T-cell response mounted against SARS-CoV-2 Spike269-277 epitope YLQPRTFLL via the most frequent Human Leukocyte Antigen (HLA) class I worldwide, HLA A*02. The widespread Spike P272L mutation has arisen in five different SARS-CoV-2 lineages to date and was common in the B.1.177 lineage associated with establishing the second wave in Europe. The large CD8 T-cell response seen across a cohort of HLA A*02+ convalescent patients, comprising of over 120 different TCRs, failed to respond to the P272L variant suggesting that proline 272 dominates TCR contacts with this epitope. Additionally, sizable populations (0.01%-0.2%) of total CD8 T-cells from individuals vaccinated against SARS-CoV-2 stained with HLA A*02-YLQPRTFLL multimers but failed to bind to the P272L reagent. Viral escape at prevalent T-cell epitopes restricted by high frequency HLA may be particularly problematic when vaccine immunity is focussed on a single protein such as SARS-CoV-2 Spike and provides a strong argument for inclusion of multiple viral proteins in next generation vaccines and highlights the urgent need for monitoring T-cell escape in new SARS-CoV-2 variants.