Vaccines in the Treatment of Substance Abuse

Substances of abuse exert their initial central effects by stimulation of reward and reinforcement pathways in the brain. Typically, this requires rapid entrance into the circulation, crossing the blood-brain barrier, and activation of one or more neurotransmitter systems (1). It is important to recognize that the addictive liability of a drug is, in part, related to the speed with which it is able to traverse the blood-brain barrier as well as its ability to stimulate certain (i.e., dopaminergic) neurotransmitter systems. Volkow et al. (2) demonstrated that route of administration determines intensity of subjective euphoria, because those substances of abuse that are delivered to the brain more rapidly are associated with increased levels of “high” experienced by the user, independent of levels of brain receptor occupancy or transporter blockade (2). Consequently, slowing the entry of drugs of abuse into the brain may be as effective as reducing the amount of substance in the brain, because it would allow for concurrent reductions in (behaviorally) reinforcing properties (1). Conceptually, immunotherapy for SUDs involves both active and passive immunization. With active immunization, vaccines are administered to an individual, who subsequently mounts an immunological response against the agent. An immunological memory, in which reexposure to the vaccine (through booster injection) results in amplified response of the immune system, is also created. Once the immune system has been primed by administration of the vaccine, upon reintroduction of the substance of abuse into the system, the body will then produce an IgG-mediated antibody response and clear the toxin while it is in the periphery, thereby reducing the action of the drug in the CNS. Drugs of abuse, because of their small size (molecular mass <1000 Da), do not typically result in the activation of the immune cascade. Thus, it is necessary to attach the drug hapten to a foreign carrier protein with immunogenicity, such as inactivated cholera vaccine or bovine albumin. Structurally, then, substance abuse vaccines are composed of the chemical structure of the drug along with another agent that is present in widely used (and available) vaccines. The extent of the response to the vaccine can be measured by 1) receptor binding affinity and 2) concentration of antibody produced (3). Receptor binding affinity references the quality of the antibody produced, whereas the amount/concentration related to quantity. It is necessary to have a certain threshold amount of antibody produced, and to have a clinical benefit, these antibodies must have an affinity for the drug sufficient to bind the drug and reduce the amount of free drug available in the circulation. Under ideal circumstances, drug is bound by antibodies, and the resulting immune complexes are cleared before the central activation by the substance. Drugs of abuse readily cross the blood-brain barrier, whereas antibodies, which are comparatively larger molecules (molecular mass ~150,000 Da), are unable to do so. This is an important factor, because it means that antibodies bound to substances of abuse cannot act centrally or stimulate target neurotransmitter systems. However, it is also important to note that simply slowing the progression of these substances across the blood-brain barrier can result in decreased activation of the CNS and limit the reward experienced by the user. Thus, even antibodies with weak affinity for the drug may be helpful, because they would transiently bind the substance and impede the rapid stimulation of the reward system. Passive immunization involves the administration of exogenously produced antibodies to specific substances of abuse. Two general classes of antibodies exist, polyclonal and monoclonal. After immunization of an animal (i.e., rat, mouse, or goat), polyclonal antibodies are generated by multiple cell lines within the animal. The IgG molecules created as a result of the immune response are collected from the animal serum. Of note, polyclonal antibodies are used primarily within the context of animal studies, and there are no current approved uses in humans. Monoclonal antibodies originate from a single cell line, typically a hybrid of human and mouse (i.e., hybridoma). These cell lines are created within the laboratory and exposed to an antigen so that they might express IgG antibodies, which are then harvested for treatment. At present, monoclonal antibodies are being used for treatment of a wide variety of illnesses including malignancies and infectious diseases.