PT  - JOURNAL ARTICLE
AU  - Hamid, Fatima A.
AU  - Siram, Karthik
AU  - Burkhart, David
AU  - Evans, Jay T.
AU  - Pravetoni, Marco
TI  - Mechanistic insights into the cellular and molecular mechanisms of an anti-opioid vaccine formulated with a novel Toll-Like receptor (TLR) 7/8 agonist
AID  - 10.1124/jpet.480.933550
DP  - 2024 Jun 01
TA  - Journal of Pharmacology and Experimental Therapeutics
PG  - 480
VI  - 389
IP  - S3
4099  - http://jpet.aspetjournals.org/content/389/S3/480.short
4100  - http://jpet.aspetjournals.org/content/389/S3/480.full
SO  - J Pharmacol Exp Ther2024 Jun 01; 389
AB  - Abstract ID 93355Poster Board 480Synthetic opioids are driving the ongoing opioid epidemic in the United States, accounting for almost 88% of the >100,000 fatal overdoses annually. This public health crisis urges acceleration of the translation of more effective treatments for opioid use disorder (OUD) and overdose. Drug conjugate vaccine represent an innovative and promising treatment approach for OUD. Adjuvants are indispensable for drug conjugate vaccines to produce a robust and durable antigen-specific antibody (Ab) response. Our novel lipidated adjuvant INI-4001 which engages TLR 7/8 signaling on innate immune cells was shown to significantly enhance the immunogenicity and efficacy of an anti-fentanyl vaccine in blocking fentanyl induced-antinociception, respiratory and cardiovascular depression in rodents. To understand the mechanism of action(s) underlying TLR7/8 adjuvant properties in the context of anti-opioid vaccines, this study characterized the cellular and molecular mechanism of the INI-4001 adjuvant’s enhancement of humoral immunity. We applied in vivo and in vitro flow cytometry-based assays to decipher innate immune response and B cell responses associated with adjuvanted fentanyl vaccine formulation. Kinetics of innate immune response post vaccination at the site of injection (muscle) and draining lymph nodes were tracked, as well as the maturation and the activation status of multiple dendritic cell (DC) subsets and other cells, to identify early molecular signatures of vaccine efficacy.