PROJECT SUMMARY Opioid use disorder (OUD) and associated opioid overdoses are public health crises of increasing severity, reflected by a staggering 80,000 opioid overdose associated deaths in the United States alone in 2021. Despite the availability of current treatment strategies including medications for opioid use disorder and medication assisted treatment (MOUD and MAT), opioid overdoses continue to skyrocket at an alarming rate. Recently, vaccines targeting opioids were proposed as a novel intervention to combat the growing crisis. Vaccines targeting opioids have been developed using traditional protein carrier approaches and are entering human clinical trials. The overall goal of this fellowship is to investigate the efficacy of a Qβ bacteriophage virus-like particle (VLP) based vaccine targeting oxycodone as a novel treatment to prevent oxycodone overdose. Bacteriophage VLPs are highly immunogenic vaccine platforms that are well-established to be safe and effective in humans. This project will be conducted under the central hypothesis that a Qβ VLP conjugated vaccine targeting oxycodone will offer protection upon cognate drug challenge with limited cross-reactivity. This hypothesis will be investigated by the following specific aims: Specific Aim 1: Determine the impact of immunization on drug distribution across the blood-brain barrier. Using high-performance liquid chromatography mass spectrometry (HPLC-MS), drug concentrations will be determined in the blood and brain compartments of immunized animals. Specific Aim 2: Investigate protection elicited by Qβ-oxycodone upon intravenous drug challenge. Utilizing whole-body plethysmography (WBP), I will investigate Qβ-oxycodone mediated protection from opioid induced respiratory depression upon intravenous drug challenge. Specific Aim 3: Examine the impact of immunization on naloxone efficacy. Using in-vitro and in-vivo approaches, the cross-reactivity of vaccine elicited antibodies with the opioid receptor antagonist naloxone will be determined. Together, these aims are focused on the long-term goal to inform effective vaccine design and offer new treatment options for OUD patients.