Adjuvants significantly enhance vaccine efficacy, however, their use is currently limited by inflammatory side-effects such as pyrexia. To address this, we investigated if combining adjuvants and thermoresponsive polymers could provide adjuvant-polymer bioconjugates with attenuated activity under pyrexic conditions. Thermoresponsive adjuvants consisted of trehalose glycolipid adjuvant and poly-N-isoporpylacrylamide (NIPAM) thermoresponsive subunits that self-assembled into nanoparticles with temperature-dependent sizes (90-270nm). Here we show that thermoresponsive glycolipid adjuvants attenuate inflammation in response to small (1-2 °C) changes in temperature about their Lower Critical Solution Temperatures. The thermoresponsive adjuvants activated HEK-mMINCLE, RAW-Blue, and JAWSII innate immune cell lines. In primary mouse Bone Marrow Derived Dendritic Cells (BMDCs) and Macrophages (BMDMs), cytokine production (TNF and IL-6) was attenuated at 39 °C relative to 35 °C. This correlated with decreased Rg measured by DLS and lipid-NIPAM interactions observed by NOESY-NMR indicating a molecular mechanism whereby isopropyl NIPAM side-chains shield beheinic acids critical for glycolipid activity. In-vivo, mice immunized using a PFA influenza vaccine with thermoresponsive adjuvant produced more potent hemagglutinin neutralizing sera and exhibited less weight loss on influenza re-challenge relative to unadjuvanted control vaccine. Enhanced production of CD4+/44+/62L+ lung central memory T Cells was also observed. Together, these results demonstrate the first adjuvants with activity explicitly regulated by temperature, an approach we envision that could be used to enhance vaccine safety while maintaining efficacy.

Thermophobic glycolipid bioconjugates as macrophage-inducible C-type lectin receptor vaccine adjuvants

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