文章基本信息

标题：Distinct single-component adjuvants steer human DC-mediated T-cell polarization via Toll-like receptor signaling toward a potent antiviral immune response
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作者：Laura Roßmann ; Katrin Bagola ; Tharshana Stephen 等
期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2021
卷号：118
期号：39
DOI：10.1073/pnas.2103651118
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：Significance Vaccines profit from the addition of adjuvants to better and more specifically initiate, amplify, and shape immune responses. Although the number of adjuvant candidates has steadily increased, peaking in the current SARS-CoV-2 pandemic, little is known about their inherent mode of action. Using human blood immune cells, we established a multilayer method to systematically assess the adjuvants’ effects on innate and adaptive immune cells. By employing a multiplex analysis with cells from 30 different donors, we determined important patterns of adjuvant function. Moreover, we demonstrate correlates of an antiviral immune response using a Toll-like receptor 7/8 ligand adjuvant and single-stranded RNA. This knowledge about adjuvants’ distinct immune signatures supports the selection of safe and effective adjuvants for future vaccines. The COVID-19 pandemic highlights the importance of efficient and safe vaccine development. Vaccine adjuvants are essential to boost and tailor the immune response to the corresponding pathogen. To allow for an educated selection, we assessed the effect of different adjuvants on human monocyte-derived dendritic cells (DCs) and their ability to polarize innate and adaptive immune responses. In contrast to commonly used adjuvants, such as aluminum hydroxide, Toll-like receptor (TLR) agonists induced robust phenotypic and functional DC maturation. In a DC-lymphocyte coculture system, we investigated the ensuing immune reactions. While monophosphoryl lipid A synthetic, a TLR4 ligand, induced checkpoint inhibitors indicative for immune exhaustion, the TLR7/8 agonist Resiquimod (R848) induced prominent type-1 interferon and interleukin 6 responses and robust CTL, B-cell, and NK-cell proliferation, which is particularly suited for antiviral immune responses. The recently licensed COVID-19 vaccines, BNT162b and mRNA-1273, are both based on single-stranded RNA. Indeed, we could confirm that the cytokine profile induced by lipid-complexed RNA was almost identical to the pattern induced by R848. Although this awaits further investigation, our results suggest that their efficacy involves the highly efficient antiviral response pattern stimulated by the RNAs’ TLR7/8 activation.
关键词：enadjuvants;mRNA vaccines;TLR;primary human cells