Abstract. Cocaine addiction is a major problem for which there is no effective therapy. Because addiction is a chronic relapsing illness, characterized by cycles of drug use and abstinence, vaccination against cocaine could be an effective therapeutic. The challenge in developing an anti- cocaine vaccine is that cocaine is a small molecule, invisible to the immune system. Attempts to link cocaine as a hapten to a protein carrier has had limited success, likely because the protein carrier has not been sufficiently immunogenic to evoke high affinity, high titer antibodies sufficient to block cocaine from reaching its receptors in the brain. We have developed a novel strategy leveraging the knowledge that adenovirus (Ad) capsid proteins are highly immunogenic in humans. We hypothesized that linking a cocaine analog to Ad capsid proteins would elicit high-affinity, high-titer antibodies against cocaine, sufficient to sequester systemically administered drug from access to the brain, with consequent reduction in cocaine-induced behavior. We strategized that we could avoid any risk of the infectious virus by disrupting the Ad, with the concept that a vaccine comprised of the cocaine analog coupled to disrupted capsid proteins would retain the immunologic adjuvant properties of intact Ad. Based on these concepts, we developed dAd5GNE, a disrupted E1‾E3‾ serotype 5 Ad with GNE, a stable cocaine analog, covalently linked to the Ad capsid. In mice, rats and nonhuman primates, dAd5GNE evoked persistent, high titer, high affinity IgG anti-cocaine antibodies. dAd5GNE vaccination was highly effective in: abrogating cocaine-induced hyperactivity in mice; limiting both hyperactivity and cocaine self-administration behavior in rats; and blocking cocaine access to its cognate CNS receptors and suppressing cocaine self-administration in nonhuman primates. With NIDA grant U01 DA033835, we developed methods to manufacture dAd5GNE vaccine in our GMP facility, produced clinical-grade dAd5GNE for a clinical study, executed IND-enabling preclinical efficacy and safety testing of the dAd5GNE product, submitted an IND package, gained approval from the FDA and other regulatory groups to initiate a phase I clinical trial, and carried out an initial clinical trial of the low dose cohort (100 μg, 6 monthly doses) in cocaine addicts. The data from this cohort demonstrated that at this low dose, the dAd5GNE vaccine is safe and elicits persistent serum cocaine-specific antibodies in the range approaching that which should be efficacious. The focus of the present proposal is to complete the FDA and IRB approved clinical trial with 2 higher doses (cohort 2: 316 µg/dose and cohort 3: 1,000 µg/dose; each for 6 monthly doses). Specific aim. Initiate and complete cohorts 2 and 3 of the clinical trial to assess the safety and preliminary measure of efficacy of the dAd5GNE vaccine in cocaine addicts.

Narrative. We developed an anti-cocaine vaccine dAd5GNE, a highly immunogenic disrupted serotype 5 human adenovirus to which a cocaine analog is coupled. Studies in mice, rats and nonhuman primates demonstrated dAd5GNE is highly effective in evoking anti-cocaine antibodies that prevent cocaine from reaching the brain and with NIDA grant U01 DA033835, we carried out a clinical trial in cocaine addicts (cohort 1, 100 μg, 6 monthly doses), demonstrating that at this low dose, the vaccine is safe and evokes serum anti-cocaine specific antibodies. The goal of the present proposal is to extend the clinical study to cohorts 2 and 3, with increasing doses (316 or 1000 μg, 6 monthly doses) to evaluate safety and preliminary assessment of efficacy at these higher doses.