Distinct single-component adjuvants steer human DC-mediated T-cell polarization via Toll-like receptor signaling toward a potent antiviral immune response

Abstract

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.

Toll-Like Receptor Signaling in Severe Acute Respiratory Syndrome Coronavirus 2-Induced Innate Immune Responses and the Potential Application Value of Toll-Like Receptor Immunomodulators in Patients With Coronavirus Disease 2019

“…An imiquimod analog, resiquimod (R848), was proven to be a dual TLR7 and TLR8 synthetic agonist that elicits prominent IFN-α/β and IL-6 responses and robust cytotoxic T-cell (CTL) and B-cell proliferation; thus, it is particularly suited for antiviral immune responses. Indeed, the cytokine profiles induced by R848, are almost identical to the profiles induced by the licensed mRNA vaccines against COVID-19 ( Rossmann et al, 2021 ). In a SARS-CoV-2 virus-mimetic nanoparticle vaccine, the SARS-CoV-2 spike protein S1 subunit and R848 were attached to erythrocytes and injected into mice, resulting in greater maturation and activation of APCs, production of specific IgG antibodies, and systemic antiviral T-cell responses than the nanoparticles alone ( Wang et al, 2021 ).…”

Shaping neonatal immunization by tuning delivery of synergistic adjuvants via nanocarriers

“…Dual STING and TLR7/8 stimulation drives IL-12 dependent Th1-Polarization in early life STING [13][14][15] and TLR7/8 12,16,17 agonists induce overlapping but distinct innate immunological profiles 18 , with both upstream activation pathways leading to the secretion of innate type 1 interferon and pro-inflammatory cytokine production. These cytokines are critical to APC priming of T cells and the initiation of adaptive immune responses.…”

An Overview of Recent Insights into the Response of TLR to SARS-CoV-2 Infection and the Potential of TLR Agonists as SARS-CoV-2 Vaccine Adjuvants

“…It has been reported that second-generation adjuvants that interact with TLRs, such as TLR ligand adjuvants, are superior to first-generation adjuvants, such as Al(OH) 3 . TLR agonist adjuvants may induce dendritic cell maturation, which is lacking in first-generation adjuvants, such as Al(OH) 3 [102]. TLR agonists are capable of stimulating innate immune responses, which also trigger adaptive immune responses, thereby improving vaccine efficacy.…”