@article{73ee94fd6bb24079a54aded71afcf105,
title = "An adjuvant strategy enabled by modulation of the physical properties of microbial ligands expands antigen immunogenicity",
abstract = "Activation of the innate immune system via pattern recognition receptors (PRRs) is key to generate lasting adaptive immunity. PRRs detect unique chemical patterns associated with invading microorganisms, but whether and how the physical properties of PRR ligands influence the development of the immune response remains unknown. Through the study of fungal mannans, we show that the physical form of PRR ligands dictates the immune response. Soluble mannans are immunosilent in the periphery but elicit a potent pro-inflammatory response in the draining lymph node (dLN). By modulating the physical form of mannans, we developed a formulation that targets both the periphery and the dLN. When combined with viral glycoprotein antigens, this mannan formulation broadens epitope recognition, elicits potent antigen-specific neutralizing antibodies, and confers protection against viral infections of the lung. Thus, the physical properties of microbial ligands determine the outcome of the immune response and can be harnessed for vaccine development.",
keywords = "Dectin, PAMP, PRR, SARS-CoV-2, coronavirus, inflammation, influenza A virus, innate immunity, interferon, pathogen-associated molecular pattern, pattern recognition receptor, viral glycoprotein",
author = "Francesco Borriello and Valentina Poli and Ellen Shrock and Roberto Spreafico and Xin Liu and Novalia Pishesha and Claire Carpenet and Janet Chou and {Di Gioia}, Marco and McGrath, {Marisa E.} and Dillen, {Carly A.} and Barrett, {Nora A.} and Lucrezia Lacanfora and Franco, {Marcella E.} and Laura Marongiu and Yoichiro Iwakura and Ferdinando Pucci and Kruppa, {Michael D.} and Zuchao Ma and Lowman, {Douglas W.} and Ensley, {Harry E.} and Etsuro Nanishi and Yoshine Saito and O'Meara, {Timothy R.} and Seo, {Hyuk Soo} and Sirano Dhe-Paganon and Dowling, {David J.} and Matthew Frieman and Elledge, {Stephen J.} and Ofer Levy and Irvine, {Darrell J.} and Ploegh, {Hidde L.} and Williams, {David L.} and Ivan Zanoni",
note = "Funding Information: I.Z. is supported by NIH grants 1R01AI121066, 1R01DK115217, 1R01AI165505 and contract no. 75N93019C00044, Lloyd J. Old STAR Program CRI3888 and holds an Investigators in the Pathogenesis of Infectious Disease Award from the Burroughs Wellcome Fund. D.J.D. is supported by NIH grant 1R21AI137932-01A1 and contract nos. 75N93019C00044 and 75N93020C00038. S.J.E. is funded by grants from the Value of Vaccine Research Network and the MassCPR. M.D.K. is supported by NIH grant R21 1R21AI159877. D.L.W. is supported by NIH grants 1R01GM119197, 1R01GM083016, and C06RR0306551. E.S. is funded by the NSF Graduate Research Fellowship Program. S.J.E. is an investigator with the Howard Hughes Medical Institute. M.F. is supported by NIH grants R01 AI148166, R21AI153480, DARPA HR0011-20-2-0040, and DHS/BARDA ASPR-20-01495. We thank Drs. Barney S. Graham (NIH Vaccine Research Center) and Aaron G. Schmidt (Ragon Institute) for providing plasmids for pre-fusion stabilized SARS-CoV-2 Spike trimer and RBD, respectively. R.S. thanks the UCLA Institute for Quantitative and Computational Biosciences (QCBio) Collaboratory community directed by Matteo Pellegrini. F.B. conceived, designed, performed, analyzed the experiments, and wrote the manuscript; V.P. performed and designed in vitro and in vivo experiments; R.S. performed the analysis of the sequencing data; J.C. contributed to the design of the sequencing analysis; N.A.B. provided Clec4n mice and discussed experiments; M.D.G. L.L. M.E.F. and L.M. participated in the analysis of in vitro data; S.D.-P. and H.-S.S. provided SARS-CoV-2 Spike and RBD; E.N. Y.S. T.R.O. D.J.D. O.L. N.P. X.L. C.C. and H.L.P. participated in immunization experiments and edited the manuscript; Y.I. provided Clec4n mice; F.P. provided CD169-DTR mice; D.J.I. provided Lipo-CpG; M.E.M. C.A.D. and M.F. performed and analyzed the SARS-CoV-2 neutralization experiments and SARS-CoV-2 infections; E.S. and S.J.E. performed and analyzed VirScan experiments; M.D.K. Z.M. D.W.L. H.E.E. and D.L.W. provided fungal ligands, quantified the mannan formulation, and contributed to the design of the experiments; I.Z. conceived the project, designed the experiments, supervised the study, and wrote the paper. All authors reviewed and provided input to the manuscript. F.B. E.N. T.R.O. I.Z. D.J.D. and O.L. are named inventors on invention disclosures and patents involving vaccine adjuvants. S.J.E. is a founder of TSCAN Therapeutics, ImmuneID, MAZE Therapeutics, and Mirimus. S.J.E. serves on the scientific advisory board of Homology Medicines, TSCAN Therapeutics, MAZE Therapetics, and XChem, and is an advisor for MPM, none of which impact this work. S.J.E. is an inventor on a patent application issued to the Brigham and Women's Hospital (US20160320406A) that covers the use of the VirScan library to identify pathogen antibodies in blood. The other authors declare no commercial or financial conflict of interest. Funding Information: I.Z. is supported by NIH grants 1R01AI121066 , 1R01DK115217 , 1R01AI165505 and contract no. 75N93019C00044 , Lloyd J. Old STAR Program CRI3888 and holds an Investigators in the Pathogenesis of Infectious Disease Award from the Burroughs Wellcome Fund . D.J.D. is supported by NIH grant 1R21AI137932-01A1 and contract nos. 75N93019C00044 and 75N93020C00038 . S.J.E. is funded by grants from the Value of Vaccine Research Network and the MassCPR . M.D.K. is supported by NIH grant R21 1R21AI159877 . D.L.W. is supported by NIH grants 1R01GM119197 , 1R01GM083016 , and C06RR0306551 . E.S. is funded by the NSF Graduate Research Fellowship Program . S.J.E. is an investigator with the Howard Hughes Medical Institute. M.F. is supported by NIH grants R01 AI148166 , R21AI153480 , DARPA HR0011-20-2-0040 , and DHS/BARDA ASPR-20-01495 . We thank Drs. Barney S. Graham (NIH Vaccine Research Center) and Aaron G. Schmidt (Ragon Institute) for providing plasmids for pre-fusion stabilized SARS-CoV-2 Spike trimer and RBD, respectively. R.S. thanks the UCLA Institute for Quantitative and Computational Biosciences (QCBio) Collaboratory community directed by Matteo Pellegrini. Publisher Copyright: {\textcopyright} 2022 Elsevier Inc.",
year = "2022",
month = feb,
day = "17",
doi = "10.1016/j.cell.2022.01.009",
language = "English",
volume = "185",
pages = "614--629.e21",
journal = "Cell",
issn = "0092-8674",
publisher = "Cell Press",
number = "4",
}