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
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
Author(s)
Kasturi S.P., Rasheed MAU, Havenar-Daughton C., Pham M., Legere T., Sher Z.J., Kovalenkov Y., Gumber S., Huang J.Y., Gottardo R., Fulp W., Sato A., Sawant S., Stanfield-Oakley S., Yates N., LaBranche C., Alam S.M., Tomaras G., Ferrari G., Montefiori D., Wrammert J., Villinger F., Tomai M., Vasilakos J., Fox C.B., Reed S.G., Haynes B.F., Crotty S., Ahmed R., Pulendran B.
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
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
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