Systems analysis of human responses to an aluminium hydroxide-adsorbed TLR7 agonist (AS37) adjuvanted vaccine reveals a dose-dependent and specific activation of the interferon-mediated antiviral response. Issue 3 (16th January 2023)

• Record Type: Journal Article
• Authors: Siena, Emilio; Schiavetti, Francesca; Borgogni, Erica; Taccone, Marianna; Faenzi, Elisa; Brazzoli, Michela; Aprea, Susanna; Bardelli, Monia; Volpini, Gianfranco; Buricchi, Francesca; Sammicheli, Chiara; Tavarini, Simona; Bechtold, Viviane; Blohmke, Christoph J.; Cardamone, Dario; De Intinis, Carlo; Gonzalez-Lopez, Antonio; O'Hagan, Derek T.; Nuti, Sandra; Seidl, Claudia; Didierlaurent, Arnaud M; Bertholet, Sylvie; D'Oro, Ugo; Medini, Duccio; Finco, Oretta
• Is Part Of: Vaccine. Volume 41:Issue 3(2023)
• Page Start: 724
• Page End: 734
• Publication Date: 2023-01-16
• Subjects: Adjuvant System -- Toll-like receptor 7 -- Immune response -- Vaccine -- Plasmacytoid dendritic cells -- Type I interferon; ANOVA analysis of variance -- APC antigen-presenting cell -- BTM blood transcriptional module -- cDNA complementary DNA -- D study day -- DC dendritic cells -- DEG differentially-expressed gene -- ELISpot enzyme-linked immunospot -- FACS fluorescence-activated cell sorting -- GCRMA GC Robust Multiarray Average -- GEO Gene Expression Omnibus -- GSEA Gene Set Enrichment Analysis -- HBV hepatitis B virus -- hSBA human complement serum bactericidal assay -- IFN interferon -- IgG immunoglobulin G -- IgM immunoglobulin M -- IL interleukin -- MBC memory B cells -- MenC Neisseria meningitidis serogroup C -- MFI median fluorescence intensity -- NHP non-human primate -- PBMC peripheral blood mononuclear cells -- PBS phosphate-buffered saline -- PCA principal component analysis -- pDC plasmacytoid dendritic cells -- SMIP small molecule immune potentiator -- Tfh T follicular helper cells -- TLR toll-like receptor -- TLRa toll-like receptor agonist; Vaccines -- Periodicals; 615.372
• DOI: 10.1016/j.vaccine.2022.12.006
• Languages: English
• ISSNs: 0264-410X

Abstract

Highlights: An AS37-adjuvanted vaccine induced immune responses which maintained for 6 months. Extensive immune profiling was conducted on a subset of participants. AS37 increased expression of interferon-inducible genes and serum CXCL10 (IP-10). AS37 upregulated specific innate immune cells and Ag-specific B and T lymphocytes. The immune signature is consistent with toll-like receptor 7 engagement. Abstract: The candidate Adjuvant System AS37 contains a synthetic toll-like receptor agonist (TLR7a) adsorbed to alum. In a phase I study (NCT02639351), healthy adults were randomised to receive one dose of licensed alum-adjuvanted meningococcal serogroup C (MenC-CRM197 ) conjugate vaccine (control) or MenC-CRM197 conjugate vaccine adjuvanted with AS37 (TLR7a dose 12.5, 25, 50 or 100 µg). A subset of 66 participants consented to characterisation of peripheral whole blood transcriptomic responses, systemic cytokine/chemokine responses and multiple myeloid and lymphoid cell responses as exploratory study endpoints. Blood samples were collected pre-vaccination, 6 and 24 h post-vaccination, and 3, 7, 28 and 180 days post-vaccination. The gene expression profile in whole blood showed an early, AS37-specific transcriptome response that peaked at 24 h, increased with TLR7a dose up to 50 µg and generally resolved within one week. Five clusters of differentially expressed genes were identified, including those involved in the interferon-mediated antiviral response. Evaluation of 30 cytokines/chemokines by multiplex assay showed an increased level of interferon-induced chemokine CXCL10 (IP-10) at 24 h and 3 days post-vaccination in the AS37-adjuvanted vaccine groups. Increases in activated plasmacytoid dendritic cells (pDC) and intermediate monocytes were detected 3 days post-vaccination in the AS37-adjuvanted vaccine groups. T follicular helper (Tfh) cells increased 7 days post-vaccination and were maintained at 28 days post-vaccination, particularly in the AS37-adjuvanted vaccine groups. Moreover, most of the subjects that received vaccine containing 25, 50 and 100 µg TLR7a showed an increased MenC-specific memory B cell responses versus baseline. These data show that the adsorption of TLR7a to alum promotes an immune signature consistent with TLR7 engagement, with up-regulation of interferon-inducible genes, cytokines and frequency of activated pDC, intermediate monocytes, MenC-specific memory B cells and Tfh cells. TLR7a 25–50 µg can be considered the optimal dose for AS37, particularly for the adjuvanted MenC-CRM197 conjugate vaccine.