PMID- 37002787 OWN - NLM STAT- MEDLINE DCOM- 20230728 LR - 20230730 IS - 2192-2659 (Electronic) IS - 2192-2640 (Linking) VI - 12 IP - 19 DP - 2023 Jul TI - Thermophobic Trehalose Glycopolymers as Smart C-Type Lectin Receptor Vaccine Adjuvants. PG - e2202918 LID - 10.1002/adhm.202202918 [doi] AB - Herein, this work reports the first synthetic vaccine adjuvants that attenuate potency in response to small, 1-2 degrees C changes in temperature about their lower critical solution temperature (LCST). Adjuvant additives significantly increase vaccine efficacy. However, adjuvants also cause inflammatory side effects, such as pyrexia, which currently limits their use. To address this, a thermophobic vaccine adjuvant engineered to attenuate potency at temperatures correlating to pyrexia is created. Thermophobic adjuvants are synthesized by combining a rationally designed trehalose glycolipid vaccine adjuvant with thermoresponsive poly-N-isoporpylacrylamide (NIPAM) via reversible addition fragmentation chain transfer (RAFT) polymerization. The resulting thermophobic adjuvants exhibit LCSTs near 37 degrees C, and self-assembled into nanoparticles with temperature-dependent sizes (90-270 nm). Thermophobic adjuvants activate HEK-mMINCLE and other innate immune cell lines as well as primary mouse bone marrow derived dendritic cells (BMDCs) and bone marrow derived macrophages (BMDMs). Inflammatory cytokine production is attenuated under conditions mimicking pyrexia (above the LCST) relative to homeostasis (37 degrees C) or below the LCST. This thermophobic behavior correlated with decreased adjuvant R(g) is observed by DLS, as well as glycolipid-NIPAM shielding interactions are observed by NOESY-NMR. In vivo, thermophobic adjuvants enhance efficacy of a whole inactivated influenza A/California/04/2009 virus vaccine, by increasing neutralizing antibody titers and CD4(+) /44(+) /62L(+) lung and lymph node central memory T cells, as well as providing better protection from morbidity after viral challenge relative to unadjuvanted control vaccine. Together, these results demonstrate the first adjuvants with potency regulated by temperature. This work envisions that with further investigation, this approach can enhance vaccine efficacy while maintaining safety. CI - (c) 2023 The Authors. Advanced Healthcare Materials published by Wiley-VCH GmbH. FAU - Hendricksen, Aaron T AU - Hendricksen AT AD - Department of Chemistry, Washington State University, 1470 NE College Ave, Pullman, WA, 99164, USA. FAU - Ezzatpour, Shahrzad AU - Ezzatpour S AD - Department of Microbiology and Immunology, Cornell University, 618 Tower Road, Ithaca, NY, 14850, USA. FAU - Pulukuri, Anunay J AU - Pulukuri AJ AD - Department of Chemistry, Washington State University, 1470 NE College Ave, Pullman, WA, 99164, USA. FAU - Ryan, Austin T AU - Ryan AT AD - Department of Chemistry, Washington State University, 1470 NE College Ave, Pullman, WA, 99164, USA. FAU - Flanagan, Tatum J AU - Flanagan TJ AD - Department of Chemistry, Washington State University, 1470 NE College Ave, Pullman, WA, 99164, USA. FAU - Frantz, William AU - Frantz W AD - Department of Chemistry, Washington State University, 1470 NE College Ave, Pullman, WA, 99164, USA. FAU - Buchholz, David W AU - Buchholz DW AD - Department of Microbiology and Immunology, Cornell University, 618 Tower Road, Ithaca, NY, 14850, USA. FAU - Ortega, Victoria AU - Ortega V AD - Department of Microbiology and Immunology, Cornell University, 618 Tower Road, Ithaca, NY, 14850, USA. FAU - Monreal, Isaac A AU - Monreal IA AD - Department of Microbiology and Immunology, Cornell University, 618 Tower Road, Ithaca, NY, 14850, USA. FAU - Sahler, Julie M AU - Sahler JM AD - Department of Microbiology and Immunology, Cornell University, 618 Tower Road, Ithaca, NY, 14850, USA. FAU - Nielsen, Amy E AU - Nielsen AE AUID- ORCID: 0000-0002-7393-4846 AD - Astante Therapeutics Inc., 120 N Pine Street, Suite 270A, Spokane, WA, 99202, USA. FAU - Aguilar, Hector C AU - Aguilar HC AUID- ORCID: 0000-0001-6879-8360 AD - Department of Microbiology and Immunology, Cornell University, 618 Tower Road, Ithaca, NY, 14850, USA. FAU - Mancini, Rock J AU - Mancini RJ AUID- ORCID: 0000-0002-3557-8123 AD - Department of Chemistry, Washington State University, 1470 NE College Ave, Pullman, WA, 99164, USA. AD - Department of Chemistry and Biochemistry, Miami University, 651 E. High Street, Oxford, OH, 45056, USA. LA - eng GR - R01 CA234115/CA/NCI NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't PT - Research Support, U.S. Gov't, Non-P.H.S. DEP - 20230425 PL - Germany TA - Adv Healthc Mater JT - Advanced healthcare materials JID - 101581613 RN - 0 (Adjuvants, Vaccine) RN - B8WCK70T7I (Trehalose) RN - 0 (Lectins, C-Type) RN - 0 (Adjuvants, Immunologic) RN - 0 (Vaccines) RN - 0 (Glycolipids) RN - 0 (Antibodies, Viral) SB - IM MH - Animals MH - Mice MH - *Adjuvants, Vaccine MH - Trehalose/pharmacology/chemistry MH - Lectins, C-Type/metabolism MH - Adjuvants, Immunologic/pharmacology/chemistry MH - *Vaccines MH - Glycolipids/pharmacology/chemistry MH - Antibodies, Viral OTO - NOTNLM OT - C-type lectin receptors OT - MINCLE OT - adjuvants OT - cord factors OT - glycopolymers OT - thermoresponsive polymers EDAT- 2023/04/02 06:00 MHDA- 2023/07/28 06:43 CRDT- 2023/04/01 05:02 PHST- 2023/02/06 00:00 [revised] PHST- 2022/11/21 00:00 [received] PHST- 2023/07/28 06:43 [medline] PHST- 2023/04/02 06:00 [pubmed] PHST- 2023/04/01 05:02 [entrez] AID - 10.1002/adhm.202202918 [doi] PST - ppublish SO - Adv Healthc Mater. 2023 Jul;12(19):e2202918. doi: 10.1002/adhm.202202918. Epub 2023 Apr 25.