Co-adjuvants of IFN-γ and a TLR agonist delivered by lipid-PLGA hybrid nanoparticles enhanced the efficacy of an oxycodone vaccine 2308279

Abstract Introduction Oxycodone misuse contributes to opioid use disorder and overdose. Immunopharmacotherapy offers a promising strategy by eliciting oxycodone-specific antibodies that sequester the drug in the bloodstream and reduce its entry into the central nervous system. Enhancing vaccine efficacy through optimized adjuvant selection and delivery platforms is key to achieving robust and protective immune responses. Methods Oxycodone hapten—sKLH vaccines were formulated as conventional conjugates or as lipid—PLGA hybrid nanoparticles (hNPs) incorporating IFN-γ alone or with TLR agonists (poly I:C or R848). The OXY—sKLH antigen was conjugated to hNPs via thiol—maleimide chemistry. Female BALB/c mice (n = 8/group) received subcutaneous immunizations on Days 0, 14, and 28. Anti-oxycodone IgG titers, subclasses, and affinity were assessed. On Day 42, mice received 2.5 mg/kg oxycodone subcutaneously. Serum and brain samples were collected 30 minutes later for pharmacokinetic analysis. Antinociception was evaluated using a 55 ± 1 °C hot plate test. Results All adjuvanted vaccines elicited strong anti-oxycodone IgG. hNP-based vaccines co-adjuvanted with IFN-γ and poly I:C or R848 generated the highest anti-oxycodone titers and strongest affinity (lowest IC50) compared to conjugate vaccines. Immune responses toward hNP-based vaccines were IgG1-dominant, with modest IgG2a in dual-adjuvant groups. Post-challenge, vaccinated mice showed higher serum and lower brain oxycodone levels, with the IFN-γ+R848 hNP-based vaccine group showing the lowest brain concentrations. All vaccines reduced oxycodone-induced antinociception, with the IFN-γ+poly I:C hNP-based vaccine yielding the greatest effect. Conclusion Co-delivery of IFN-γ with a TLR agonist in a lipid—PLGA hNP-based vaccine platform enhances both the magnitude and functional quality of anti-oxycodone antibodies, supporting this co-adjuvant nanovaccine strategy for opioid use disorder. Funding Source National Institutes of Health (NIH) / National Institute on Drug Abuse (NIDA) award 5UG3DA048775-02, PIs: C. Zhang and M. Pravetoni Topic Categories Vaccines and Immunotherapy (VAC)