A particulate saponin/TLR agonist vaccine adjuvant alters lymph flow and modulates adaptive immunity

• Type of Material: Article
• Authors: Murillo Silva, Massachusetts Institute of Technology; Yu Kato, Scripps Research Institute; Mariane B Melo, Massachusetts Institute of Technology; Ivy Phung, Scripps Research Institute; Brian L Freeman, La Jolla Inst Immunol; Zhongming Li, Massachusetts Institute of Technology; Kangsan Roh, Massachusetts General Hospital; Jan W Van Wijnbergen, Massachusetts General Hospital; Hannah Watkins, Massachusetts Institute of Technology; Chiamaka A Enemuo, Emory University; Brittany L Hartwell, Massachusetts Institute of Technology; Jason YH Chang, Massachusetts Institute of Technology; Shuhao Xiao, Massachusetts Institute of Technology; Kristen A Rodrigues, Massachusetts Institute of Technology; Kimberly M Cirelli, Scripps Research Institute; Na Li, Massachusetts Institute of Technology; Sonya Haupt, La Jolla Institute for Immunology; Aereas Aung, Massachusetts Institute of Technology; Benjamin Cossette, Massachusetts Institute of Technology; Wuhbet Abraham, Massachusetts Institute of Technology; Swati Kataria, Massachusetts Institute of Technology; Raiza Bastidas, Scripps Research Institute; Jinal Bhiman, Scripps Research Institute; Caitlyn Linde, Ragon Inst Massachusetts Gen Hosp Massachusetts I; Nathaniel I Bloom, La Jolla Institute for Immunology; Bettina Groschel, Scripps Research Institute; Erik Georgeson, Scripps Research Institute; Nicole Phelps, Scripps Research Institute; Ayush Thomas, Massachusetts Institute of Technology; Julia Bals, Ragon Inst Massachusetts Gen Hosp Massachusetts I; Diane G Carnathan, Scripps Research Institute; Daniel Lingwood, Ragon Inst Massachusetts Gen Hosp Massachusetts I; Dennis R Burton, Scripps Research Institute; Galit Alter, Ragon Inst Massachusetts Gen Hosp Massachusetts I; Timothy P Padera, Massachusetts General Hospital; Angela M Belcher, Massachusetts Institute of Technology; William R Schlef, Scripps Research Institute; Guido Silvestri, Emory University; Ruth M Ruprecht, Texas Biomedical Research Institute; Shane Crotty, Scripps Research Institute; Darrell J Irvine, Massachusetts Institute of Technology
• Language: English
• Date: 2021-12-01
• Publisher: AMER ASSOC ADVANCEMENT SCIENCE
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2021 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1126/sciimmunol.abf1152
• Title of Journal or Parent Work: SCIENCE IMMUNOLOGY
• Volume: 6
• Issue: 66
• Start Page: eabf1152
• End Page: eabf1152
• Grant/Funding Information: This work was supported in part by the National Institute of Allergy and Infectious Diseases of the NIH under award numbers UM1AI100663 (D.R.B., W.R.S., G.S., S.C., and D.J.I.), UM1AI144462 (D.R.B., W.R.S., G.S., S.C., and D.J.I.), R01CA214913 (T.P.P.), R01AI125068 (S.C. and D.J.I.), R01AI137057 (D.L.), R01AI153098 (D.L.), P01AI104715 (D.J.I.), and P01AI048240 (R.M.R. and D.J.I.), the Marble Center for Cancer Nanomedicine (A.M.B. and D.J.I.), the U. S. Army Research Office through the Institute for Soldier Nanotechnologies at MIT under Cooperative Agreement Number W911NF-18-2-0048 (D.J.I.), the Koch Institute Support (core) Grant P30-CA14051 from the National Cancer Institute (A.M.B. and D.J.I.), the IAVI Neutralizing Antibody Center (NAC) (W.R.S. and D.R.B.), the Bill and Melinda Gates Foundation Collaboration for AIDS Vaccine Discovery funding for the IAVI NAC (W.R.S. and D.R.B.), and the Ragon Institute of MGH, MIT, and Harvard (G.A., D.L., D.R.B., W.R.S., and D.J.I.). Yerkes National Primate Research Center is supported by the base grant P51 OD011132. M.S. is an NRSA Fellow (T32 AI07386). D.J.I. is an investigator of the Howard Hughes Medical Institute.
• Keywords: TLR AGONISTS; NEUTRALIZING ANTIBODY-RESPONSES; MATRIX M(TM) ADJUVANT; FOLLICULAR HELPER-CELLS; Immunology; Science & Technology; NONHUMAN-PRIMATES; Life Sciences & Biomedicine; DENDRITIC CELLS; ISCOMATRIX ADJUVANT; T-CELLS; SUBCAPSULAR SINUS MACROPHAGES; HIV-1 ENVELOPE PROTEIN

Abstract

Saponins are potent and safe vaccine adjuvants, but their mechanisms of action remain incompletely understood. Here, we explored the properties of several saponin formulations, including immune-stimulatory complexes (ISCOMs) formed by the self-assembly of saponin and phospholipids in the absence or presence of the Toll-like receptor 4 agonist monophosphoryl lipid A (MPLA). We found that MPLA self-assembles with saponins to form particles physically resembling ISCOMs, which we termed saponin/MPLA nanoparticles (SMNP). Saponin-containing adjuvants exhibited distinctive mechanisms of action, altering lymph flow in a mast cell-dependent manner and promoting antigen entry into draining lymph nodes. SMNP was particularly effective, exhibiting even greater potency than the compositionally related adjuvant AS01B in mice, and primed robust germinal center B cell, TFH, and HIV tier 2 neutralizing antibodies in nonhuman primates. Together, these findings shed new light on mechanisms by which saponin adjuvants act to promote the immune response and suggest that SMNP may be a promising adjuvant in the setting of HIV, SARS-CoV-2, and other pathogens.