s / Drug and Alcohol Dependence 156 (2015) e102–e182 e143 Hapten selection for heroin vaccines Gary R. Matyas2, Fuying Li1,3, Joshua Antoline1,3, Rashmi Jalah4, Oscar Torres4, Zoltan Beck4, Arthur Jacobson1,3, Carl Alving2, Kenner Rice1,3 1 Drug Design and Synthesis Section, National Institute on Drug Abuse, NIH, Bethesda, MD, United States 2 US Military HIV Research Program, Walter Reed Army Institute of Research, Silver Spring, MD, United States 3 National Institute on Alcohol Abuse and Alcoholism, NIH, Bethesda, MD, United States 4 US Military HIV Research Program, Herny M. Jackson Foundation for the Advancement of Military Medicine, Bethesda, MD, United States Aims: The aim of this study is to select a heroin hapten for a heroin vaccine. Heroin rapidly degrades to 6-acetylmophine and morphine after injection. We hypothesize that a heroin hapten can bedesigned that is chemically stable and can induce antibodies that bind to heroin and its metabolites. Methods: Seven different opioid haptens were synthesized. A mercaptopropanamide group was attached as the linker at the C3, C6or thebridgenitrogen. The acetyl groups of heroinwere replaced with acetamide or 2-oxypropyl groups. The haptens were attached to tetanus toxoid and mixed with liposomal lipid A. Mice were immunized with 3 doses every 3 weeks. The sera were assayed for hapten antibodies. The mice were challenged by the subcutaneous route with heroin (0.75–1mg/kg) and efficacy was assessed by nociception assays. Results: Anti-hapten titers ranged from 100,000 to 6,000,000. Mice immunizedwith haptens coupled at the bridge nitrogenwere only partially protected with a % maximal potential effect (%MPE) ≥50. Animals immunized with C3 position haptens were not challengeddue to lowantibody titers.Mice immunizedwith a C6 linked morphine hapten (MorHap) had a %MPE of 35. After optimization of the MorHap conjugation procedure, the %MPE was