Abstract The United States is experiencing an opioid crisis, which is a public health emergency. In 2016, opioid overdose deaths exceeded 40,000. Heroin overdose was responsible for 15,000 of the opioid deaths and prescription opioid-related deaths were 17,000. A novel approach to address this crisis is through the development of a heroin/opioid vaccine. We have developed a candidate vaccine which induces antibodies that bind heroin/opioid upon injection and, subsequently, prevent the drug from crossing the blood-brain barrier and interacting with the brain's µ-opioid receptor. Under a 2012, NIDA Avant Garde Award, we completed pre-clinical testing of the vaccine candidate in mice and rats demonstrating they were protected from subcutaneous and intravenous heroin challenge. Our ongoing durability studies have demonstrated that antibody titer and protective efficacy were maintained 6 months after the last vaccination. The binding affinities of the antibodies to heroin and other abused prescription opioids were very tight (<0.1-15 nM). We propose to advance the development of our vaccine candidate by conducting a Phase I/IIa human clinical trial. Under the UG3 mechanism, vaccine synthesis and nonclinical studies will be conducted. We will manufacture the heroin hapten, 6-AmHap, under cGMP, and purchase clinical grade tetanus toxoid and linker. Army Liposome Formulation (ALF43) and Alhydrogel® adjuvants have been manufactured and vialed under cGMP and are available for use. Vaccine components will be tested in rodents for immunogenicity and efficacy from heroin challenge. A vaccine potency assay will be developed. An IND dossier will be assembled and pre-IND meeting will be completed. A GLP rabbit pharmacology-toxicology study will be conducted. Under the UH3 mechanism, the clinical trial will be conducted at the SUNY Upstate Medical University. The trial will have 4 components. Component 1 will enroll healthy volunteers 18-49 years old without history of heroin use disorder; 22 vaccine recipients and 12 placebo recipients. They will be vaccinated by the intramuscular route at weeks 0, 3, 6, and 14. Exploring the vaccine's safety will be the primary objective. Immunogenicity will be assessed at multiple time points through antibody determinations. Saliva for microRNA determinations will be collected at the same time points. Component 2 will enroll 44 (22 vaccine and 22 placebo) healthy adults 18-49 with a history of heroin use disorder and documented abstinence for no less than 6 months. Component 3 will include a subset of volunteers from Component 1 to undergo plasma and leukopharesis and then participate in a low dose morphine challenge and protection assessment. Component 4 will take products from plasma and leukopharesis and conduct passive transfer and heroin challenge experiments in mice and rat models. The vaccine proof of principle will be established.

Narrative The outcome of this research will demonstrate, in a Phase I/IIa clinical trial, the safety, immunogenicity, and efficacy against morphine challenge of a novel candidate heroin/opioid vaccine consisting of 6- AmHap conjugated to tetanus toxoid and adjuvanted with Army Liposome Formulation (liposomes contain monophosphoryl lipid A) and aluminum hydroxide (ALFA). Serum samples from the clinical trial participants will be assessed to determine the vaccine performance as measured by both polyclonal antibody and IgG subclass titers to 6-AmHap, antibody persistence, cross-reactivity with other opioids, antibody affinities, and antibody efficacy in a mouse passive transfer heroin challenge model; leukopharesis samples will be collected and banked to support future passive transfer studies; and saliva samples will be used to explore microRNA gene signatures correlating with vaccine efficacy against morphine challenge and abstinence and relapse in volunteers with a history of heroin use disorder currently in treatment. The overall outcome the clinical trial will be to demonstrate vaccine safety in those with and without a history of heroin abuse, assess immunogenicity patterns and kinetics, explore the potential for clinical benefit using morphine challenge, and establish the rationale for proceeding to advanced clinical testing in larger trials and moving towards licensure.