Medication treatments for opiate addiction or abuse are available and effective, but each has real or perceived drawback that result in low acceptability. As a result, the vast majority of opiate addicts or abusers are not receiving pharmacotherapy for this disorder. Additional treatment options might increase the number of opiate users interested in treatment. The overall aim of this study is to develop and evaluate an opiate vaccine in rats as a potential treatment for opiate addiction or abuse. Vaccines which alter drug pharmacokinetics have shown substantial preclinical and preliminary clinical evidence of efficacy for nicotine and cocaine addiction, and several heroin vaccines have shown promise in animal models. Challenges for translating this approach to clinical use for opiate addiction include 1) providing efficacy against the wide range of commonly abused opiates, 2) avoiding blockade of key opiates needed for potential medical use, and 3) providing sufficient antibody titers to block the effects of the large doses of opiates used by addicts. We hypothesize that a multivalent opiate vaccine (MOpV) consisting of 3 immunogens, each targeting a specific group of structurally related opiates, can be designed which will attenuate the effects of a broad range of opiates yet avoid blocking non-targeted opiates. Potential advantages of an opiate vaccine, as an additional treatment option, include a long duration of action, lack of agonist effects (for those with real or perceived objections to taking an addictive medication), a novel mechanism of action and the possibility of being combined with existing medications to augment compliance or efficacy, and use in developing countries which lack the infrastructure needed to deliver agonist or partial agonist treatment. Immunogens will undergo an iterative, integrated series of developmental steps to identify and evaluate the efficacy of candidate MOpVs.
Aim 1 will design appropriate haptens and optimize efficacy through the use of a variety of linkers, carrier proteins and adjuvants.
Aim 2 will characterize the immunogenicity of individual immunogens and select the most effective for formulation into a single MOpV.
Aim 3 will provide rapid-throughput screening of pharmacokinetic and behavioral (hot plate analgesia) efficacy in mice, identify a lead MOpV, and test the hypothesis that immunogens can be combined into a single MOpV without loss of activity.
Aim 4 will characterize the effects of MOpV on opiate pharmacokinetics in a second species (rats) over a range of opiate doses and during both acute and repeated drug dosing.
Aim 5 will test MOpV efficacy in blocking opiate self-administration in rats, a key behavioral model.
Aim 6 will evaluate MOpV safety. These data will provide a comprehensive test of opiate vaccine feasibility, and the novel strategy of using a multivalent vaccine.
Heroin addiction has profound adverse effects on public health. In addition to disrupting the lives of the addict, family and friends, it is associated with crime, increased health care expenditures, and intravenous drug abuse contributes substantially to the spread of HIV/AIDS, hepatitis C and other infections. Abuse of prescription opiates has also emerged as a major public health concern, with more use of these opiates currently in the U.S. than heroin, and a substantial number of users becoming addicted. Medication treatments for opiate addiction or abuse are available and effective, but each has real or perceived drawback that result in low acceptability. As a result, the vast majority of opiate addicts or abusers are not receiving medication treatment for this disorder. Alternative medications, which could provide a greater choice of therapeutic options, might increase the number of addicts electing and staying in treatment. Vaccines have been developed for nicotine or cocaine addiction whereby vaccination stimulates the production of antibodies that can bind the addictive drug and reduce the amount that reaches brain. This reduces the drug's rewarding or pleasurable effects. Three nicotine vaccines (for smokers) and one cocaine vaccine are currently in clinical trials as addiction treatments. Initial work in animals suggests that a heroin vaccine could be similarly effective. One challenge in developing an opiate vaccine is that there are many different opiates that can substitute for each other, so that a vaccine would need to block each of these. We propose to develop an opiate vaccine which can block the effects of most of the opiates that are commonly abused. This will be accomplished by taking 3 or more individual vaccines, each of which blocks certain opiates, and combining them into a single "multivalent" vaccine. Our hypothesis is that this approach will provide safe and effective blockade of opiate effects in mice or rats, and provide a vaccine that is suitable for potential clinical development. This could provide an additional type of medication for those opiate addicts or abusers who find the currently available options unacceptable, or possibly for use in addition to existing medications to enhance their efficacy.
|Pravetoni, Marco; Pentel, Paul R; Potter, David N et al. (2014) Effects of an oxycodone conjugate vaccine on oxycodone self-administration and oxycodone-induced brain gene expression in rats. PLoS One 9:e101807|
|Pravetoni, Marco; Vervacke, Jeffrey S; Distefano, Mark D et al. (2014) Effect of currently approved carriers and adjuvants on the pre-clinical efficacy of a conjugate vaccine against oxycodone in mice and rats. PLoS One 9:e96547|
|Raleigh, M D; Pravetoni, M; Harris, A C et al. (2013) Selective effects of a morphine conjugate vaccine on heroin and metabolite distribution and heroin-induced behaviors in rats. J Pharmacol Exp Ther 344:397-406|
|Jones, Jessica M; Raleigh, Michael D; Pentel, Paul R et al. (2013) Stability of heroin, 6-monoacetylmorphine, and morphine in biological samples and validation of an LC-MS assay for delayed analyses of pharmacokinetic samples in rats. J Pharm Biomed Anal 74:291-7|
|Pravetoni, Marco; Le Naour, Morgan; Tucker, Ashli M et al. (2013) Reduced antinociception of opioids in rats and mice by vaccination with immunogens containing oxycodone and hydrocodone haptens. J Med Chem 56:915-23|
|Pravetoni, M; Le Naour, M; Harmon, T M et al. (2012) An oxycodone conjugate vaccine elicits drug-specific antibodies that reduce oxycodone distribution to brain and hot-plate analgesia. J Pharmacol Exp Ther 341:225-32|