Antidrug Vaccines

Substance use disorders (SUD) are recognized worldwide as causes of negative medical, psychological, and social outcomes, and they result in significant personal consequences for affected persons, their families, and society at large. Treatment of SUD has focused on a combination of pharmacotherapy and behavioral therapies in an effort to improve patients’ chances of successfully entering and maintaining recovery.

Antidrug vaccines are a potentially important class of medications currently under investigation. They represent yet another frontier in the ongoing quest for novel pharmacological strategies that could be easily integrated into treatment plans to reduce substance use and establish abstinence. Ultimately, these vaccines reflect an important shift in our conceptualization of drugs of abuse, ie, that these substances are “foreign” and that the body’s own defenses can be used against them.

Mechanisms of action

Drugs of abuse act centrally on the reward and reinforcement pathways of the brain. After introduction into the body, via oral, intranasal, inhalation, or intravenous route, these substances rapidly enter the brain to activate target neurotransmitter systems. One factor of particular importance in addiction pharmacology relates to the size of the molecule, because substances of abuse must be small enough to traverse the blood-brain barrier. Once in the brain, the initial common pathway of the addictive process is through stimulation of dopamine release from the ventral tegmental area to the nucleus accumbens; this, in part, determines the addictive liability of a substance.

Although the use of a vaccine to treat chemical dependency-an illness characterized by its multifactorial etiology and biopsychosocial underpinnings-sounds like a concept from the pages of a science fiction novel, the field of addictions treatment is much closer than many may realize. Interestingly, the idea of treating SUD using immunological means was introduced almost 40 years ago.

In 1972, based on an animal study, Berkowitz and Spector¹ published their findings on the creation of a morphine vaccine. In rats, administration of a morphine hapten–bovine serum albumin (a carrier protein) was found to result in the creation of antimorphine antibodies. These antibodies were observed to reduce the plasma concentration of the drug in rats and to decrease self-administration of heroin in rhesus monkeys.²

In 1986, Owens and Mayersohn³ highlighted the ability of antibodies to sequester substances of abuse within the circulatory system. The researchers first characterized the pharmacokinetics and clearance of phencyclidine (PCP) in dogs.⁴ They followed this study by creating antigen-binding fragments through a process of passive immunization. Goats were immunized with PCP, which generated high-affinity antibody proteins that were then collected from the animal serum and purified. In their final experiment, they administered PCP to dogs and used the PCP-specific antigen-binding fragments to bind the drug, confining it to the plasma and limiting its distribution into tissue.³

What is already known about antidrug vaccines?
? They are medically safe and effective in reducing abuse of cocaine and nicotine in humans through a mechanism of competitive antagonism.

What new information does this article add?
? It provides a brief summary of the studies done with these vaccines over the past 15 years when they were first tested in humans and updates the status of their development in ongoing multisite randomized clinical trials.

What are the implications for psychiatric practice?
? Addictions, particularly nicotine dependence in psychotic patients, are the most common disorders in psychiatric practice. Nicotine has a few pharmacotherapies, but no blocking therapies, and the efficacy of existing treatments is relatively limited. Medical safety issues have also arisen with varenicline, the most effective agent, which is a partial blocker. Cocaine addiction has no FDA-approved therapies. For both these disorders, vaccines are significant additions to the treatment options and should be available commercially within a few years.

 

Since that time, additional studies of passive immunization for treatment of SUD have been conducted. Antibodies specific for methamphetamine, heroin, and morphine were shown to bind these drugs in the circulation, to reduce euphoric effects and symptoms of toxicity, and to protect against overdose. These agents are akin to other immunoglobulin treatments for a wide array of illnesses, including malignancies and infectious diseases.

Antidrug vaccines work via active immunization, where administration of the vaccine triggers an immunological response against the agent.⁵ Immunological memory is created, whereby re-exposure to the agent (ie, through booster injection) results in amplification of the initial response. Because the immune system has been primed by vaccination, later introduction of the agent produces an antigen-specific, IgG-mediated antibody response. These antibodies bind the substance of abuse and create immune complexes too large to cross the blood-brain barrier; as such, they trap the drug in the circulation and allow it to be cleared from the system. The individual’s subjective experience (ie, euphoria) and reward are reduced, which also affects the reinforcing nature of the drug.

Drugs of abuse do not typically cause the user to mount an immunological response with the creation of antibodies capable of binding and clearing the substance. Thus, in creating antidrug vaccines, the targeted substance of abuse (ie, drug hapten) must be conjugated to a molecule that carries immunogenicity-such as a foreign carrier protein (eg, inactivated cholera toxin, bovine serum albumin). The effectiveness of the vaccine is then measured by its ability to create antibodies with specificity and high binding affinity for the drug of abuse and the robustness of the antibody response, ie, the concentration of antibody produced.⁶

Clinical trials of substance abuse vaccines that target both cocaine and nicotine dependence are ongoing. Phase 1 and 2 clinical trials of these new medications are discussed below.

Cocaine vaccine

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