3M-052, a synthetic TLR-7/8 agonist, induces durable HIV-1 envelope-specific plasma cells and humoral immunity in nonhuman primates.
Details
Serval ID
serval:BIB_DF43F44F88B5
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
3M-052, a synthetic TLR-7/8 agonist, induces durable HIV-1 envelope-specific plasma cells and humoral immunity in nonhuman primates.
Journal
Science immunology
ISSN
2470-9468 (Electronic)
ISSN-L
2470-9468
Publication state
Published
Issued date
19/06/2020
Peer-reviewed
Oui
Volume
5
Number
48
Language
english
Notes
Publication types: Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
Publication Status: ppublish
Publication Status: ppublish
Abstract
A fundamental challenge in vaccinology is learning how to induce durable antibody responses. Live viral vaccines induce antibody responses that last a lifetime, but those induced with subunit vaccines wane rapidly. Studies in mice and humans have established that long-lived plasma cells (LLPCs) in the bone marrow (BM) are critical mediators of durable antibody responses. Here, we present data that adjuvanting an HIV-1 clade C 1086.C-derived gp140 immunogen (Env) with a novel synthetic Toll-like receptor (TLR)-7/8 agonist named 3M-052 formulated in poly(lactic-co-glycolic)acid or PLGA nanoparticles (NPs) or with alum, either alone or in combination with a TLR-4 agonist GLA, induces notably high and persistent (up to ~1 year) frequencies of Env-specific LLPCs in the BM and serum antibody responses in rhesus macaques. Up to 36 and 18% of Env-specific cells among total IgG-secreting BM-resident plasma cells were detected at peak and termination, respectively. In contrast, adjuvanting Env with alum or GLA in NP induced significantly lower (~<100-fold) LLPC and antibody responses. Immune responses induced by 3M-052 were also significantly higher than those induced by a combination of TLR-7/8 (R848) and TLR-4 (MPL) agonists. Adjuvanting Env with 3M-052 also induced robust activation of blood monocytes, strong plasmablast responses in blood, germinal center B cells, T follicular helper (T <sub>FH</sub> ) cells, and persistent Env-specific plasma cells in draining lymph nodes. Overall, these results demonstrate efficacy of 3M-052 in promoting high magnitude and durability of antibody responses via robust stimulation of innate immunity and BM-resident LLPCs.
Keywords
Adjuvants, Immunologic, Animals, Female, Heterocyclic Compounds, 3-Ring/pharmacology, Immunity, Humoral/immunology, Macaca mulatta/immunology, Male, Membrane Glycoproteins/agonists, Membrane Glycoproteins/immunology, Plasma Cells/drug effects, Plasma Cells/immunology, Stearic Acids/pharmacology, Toll-Like Receptor 7/agonists, Toll-Like Receptor 7/immunology, Toll-Like Receptor 8/agonists, Toll-Like Receptor 8/immunology, env Gene Products, Human Immunodeficiency Virus/immunology
Pubmed
Web of science
Create date
28/02/2022 12:45
Last modification date
23/03/2024 8:24