Immunotherapy is a promising treatment for drug addiction. However, insufficient immune responses to vaccines in most subjects pose a challenge. In this study, we tested the efficacy of a new cocaine vaccine (dAd5GNE) in antagonizing cocaine addiction-related behaviors in rats. This vaccine used a disrupted serotype 5 adenovirus (Ad) gene transfer vector coupled to a third-generation cocaine hapten, termed GNE (6-(2R,3S)-3-(benzoyloxy)-8-methyl-8-azabicyclo [3.2.1] octane-2-carboxamido-hexanoic acid). Three groups of rats were immunized with dAd5GNE. One group was injected with 3 H-cocaine, and radioactivity in the blood and brain was determined. A second group was tested for cocaine-induced locomotor sensitization. A third group was examined for cocaine self-administration, extinction, and reinstatement of responding for cocaine. Antibody titers were determined at various time-points. In each experiment, we added a control group that was immunized with dAd5 without a hapten. The vaccination with dAd5GNE produced long-lasting high titers (410 5 ) of anti-cocaine antibodies in all of the rats. The vaccination inhibited cocaine-induced hyperlocomotor activity and sensitization. Vaccinated rats acquired cocaine self-administration, but they showed less motivation to self-administer cocaine under a progressive-ratio schedule than control rats. When cocaine was not available in a session, control rats exhibited 'extinction burst' responding, whereas vaccinated rats did not. Moreover, when primed with cocaine, vaccinated rats did not reinstate responding, suggesting a blockade of cocaine-seeking behavior. These data strongly suggest that our dAd5GNE vector-based vaccine may be effective in treating cocaine abuse and addiction.

Onchocerciasis, also known as “river blindness”, is a neglected tropical disease infecting millions of people mainly in Africa and the Middle East but also in South America and Central America. Disease infectivity initiates from the filarial parasitic nematode Onchocerca volvulus , which is transmitted by the blackfly vector Simulium sp. carrying infectious third-stage larvae. Ivermectin has controlled transmission of microfilariae, with an African Program elimination target date of 2025. However, there is currently no point-of-care diagnostic that can distinguish the burden of infection—including active and/or past infection—and enable the elimination program to be effectively monitored. Here, we describe how liquid chromatography-MS–based urine metabolome analysis can be exploited for the identification of a unique biomarker, N -acetyltyramine- O ,β-glucuronide (NATOG), a neurotransmitter-derived secretion metabolite from O. volvulus . The regulation of this tyramine neurotransmitter was found to be linked to patient disease infection, including the controversial antibiotic doxycycline treatment that has been shown to both sterilize and kill adult female worms. Further clues to its regulation have been elucidated through biosynthetic pathway determination within the nematode and its human host. Our results demonstrate that NATOG tracks O. volvulus metabolism in both worms and humans, and thus can be considered a host-specific biomarker for onchocerciasis progression. Liquid chromatography-MS–based urine metabolome analysis discovery of NATOG not only has broad implications for a noninvasive host-specific onchocerciasis diagnostic but provides a basis for the metabolome mining of other neglected tropical diseases for the discovery of distinct biomarkers and monitoring of disease progression.

Based on the concept that anticocaine antibodies could prevent inhaled cocaine from reaching its target receptors in the brain, an effective anticocaine vaccine could help reverse cocaine addiction. Leveraging the knowledge that E1(-)E3(-) adenovirus (Ad) gene transfer vectors are potent immunogens, we have developed a novel vaccine platform for addictive drugs by covalently linking a cocaine analog to the capsid proteins of noninfectious, disrupted Ad vector. The Ad-based anticocaine vaccine evokes high-titer anticocaine antibodies in mice sufficient to completely reverse, on a persistent basis, the hyperlocomotor activity induced by intravenous administration of cocaine.

(+)-Methamphetamine (METH) use and addiction has grown at alarming rates over the past two decades, while no approved pharmacotherapy exists for its treatment. Immunopharmacotherapy has the potential to offer relief through producing highly specific antibodies that prevent drug penetration across the blood-brain barrier thus decreasing reinforcement of the behavior. Current immunotherapy efforts against methamphetamine have focused on a single hapten structure, namely linker attachment at the aromatic ring of the METH molecule. Hapten design is largely responsible for immune recognition as it affects presentation of the target antigen and thus the quality of the response. In the current paper we report the systematic generation of a series of haptens designed to target the most stable conformations of methamphetamine as determined by molecular modeling. Based on our previous studies with nicotine, we show that introduction of strategic molecular constrain is able to maximize immune recognition of the target structure as evidenced by higher antibody affinity. Vaccination of GIX+ mice with six unique METH immunoconjugates, resulted in high antibody titers for three particularly promising formulations (45–108 μg/mL, after second immunization) and high affinity (82, 130 and 169 nM for MH2, MH6 and MH7 hapten-based vaccines, respectively). These findings represent a unique approach to the design of new vaccines against methamphetamine abuse.

Despite intensive efforts for its eradication, addiction to both legal and illicit drugs continues to be a major worldwide medical and social problem. Drug addiction is defined as a disease state in which the body relies on a substance for normal functioning and develops physical dependence leading to compulsive and repetitive use despite negative consequences to the user’s health, mental state or social life. Psychoactive substances such as cocaine, nicotine, alcohol, and amphetamines are able to cross the blood-brain barrier once ingested and temporarily alter the chemical balance of the brain. Current medications used for the treatment of dependence are typically agonists or antagonists of the drugs of abuse. The complex interrelations of the neuronal circuits have made it difficult to accurately predict the actions of potential agonist/antagonist drugs and have led to undesirable side effects within the central nervous system. Nearly forty years ago, a handful of groups began to explore the possibility of utilizing an individual’s own immune machinery to counteract the effects of drug exposure in an approach later termed by our laboratory, immunopharmacotherapy. Immunopharmacotherapy aims to use highly specific antibodies to sequester the drug of interest while the latter is still in the bloodstream. Thus, creation of the antibody-drug complex will blunt crossing of the blood brain barrier (BBB) not only counteracting the positive reinforcing effects of the drug but also preventing any detrimental side effects on the CNS. In the present mini-review we aim to present a focused summary, including relevant challenges and future directions, of the current state of cocaine and nicotine vaccines as these two programs have been the most successful to date.