DESCRIPTION (provided by applicant): The aim of this application is to enable the submission of IND applications for Oxy(Gly)4-dKLH, a vaccine directed against oxycodone and related prescription opioids, and M(Gly)4-dKLH, a vaccine directed against heroin and morphine. The long-term goal of this work (not included in this proposal but planned to immediately follow) is an IND submission for the co-administration of these two vaccines to treat abuse or addiction from a broad range of prescription or illicit opioids. Opioid addiction and associated deaths have increased markedly in the last 15 years due to increased abuse of prescription opioids and more recently heroin as well. Medications to treat opioid abuse are available but, because of real or perceived limitations, less than 1 in 5 who could benefit opt to use them. Opioid vaccines represent an additional treatment option that could circumvent these limitations. In contrast to agonist medications (methadone, buprenorphine), vaccines are not addictive, pose no diversion risk, and have proven free of significant side effects. In contrast to naltrexone, vaccines don't cause dysphoria, won't preclude the use of certain opioids for legitimate medical needs such as surgery, and would have a longer duration of action than even depot naltrexone. For both agonist and antagonist maintenance therapies, many addicts choose to skip or stop their medication entirely at some point and relapse rates are quite high. Vaccines could be used in addition to these medications and offer protection against relapse during medication noncompliance or discontinuation. Heroin vaccines elicit high titers of drug-specific antibodies in animals that can block a wide range of addiction- relevant behaviors including heroin self-administration and reinstatement. We have developed one such vaccine M(Gly)4-dKLH consisting of morphine conjugated to keyhole limpet hemocyanin subunit dimer (dKLH), a highly immunogenic carrier protein that is suitable for human use. We have also developed an analogous oxycodone vaccine Oxy(Gly)4-dKLH that blocks the effects of the most commonly abused prescription opioids: oxycodone, hydrocodone, and oxymorphone. When co-administered to rats, these two vaccines provide blockade of a wide variety of abused opioids. Specific Aims of the project are Aim 1: Optimization of vaccine formulation and dosing, and confirmation of key aspects of efficacy and safety of the vaccines in animal models, Aim 2: Optimize manufacturing processes, qualify product release assay methods for intermediates and final products, and transfer methods to Contract Manufacturing Organizations, Aim 3: Toxicology testing of cGMP vaccines, and Aim 4: Submission of IND application for Oxy(Gly)4-dKLH and completion of studies to support an IND application for M(Gly)4-dKLH. The main hypothesis of this project is that the M(Gly)4-dKLH and Oxy(Gly)4-dKLH vaccines can be manufactured in formulations suitable for human use, with preservation or enhancement of their efficacy over that previously demonstrated, and no toxicity.

PUBLIC HEALTH RELEVANCE The abuse of heroin and of prescription opioids such as oxycodone and hydrocodone have increased dramatically over the past 15 years in the U.S. Vaccines directed against these drugs have shown promise as potential treatment medications that could add to the available treatment options. We propose to develop two such vaccines which target the most commonly abused opioids, and to perform studies that would allow them to enter clinical trials.