Developing a vaccine against multiple psychoactive targets: a case study of heroin

Abstract

Heroin addiction is a wide-reaching problem with a spectrum of damaging social consequences. Currently approved heroin addiction medications include drugs that bind at the same receptors (e.g. opioid receptors) occupied by heroin and/or its metabolites in the brain, but undesired side effects of these treatments, maintenance dependence and relapse to drug taking remains problematic. A vaccine capable of blocking heroin's effects could provide an economical, long-lasting and sustainable adjunct to heroin addiction therapy without the side effects associated with available treatment options. Heroin, however, presents a particularly challenging vaccine target as it is metabolized to multiple psychoactive molecules of differing lipophilicity, with differing abilities to cross the blood brain barrier. In this review, we discuss the opiate scaffolding and hapten design considerations to confer immunogenicity as well as the specificity of the immune response towards structurally similar opiates. In addition, we detail different strategies employed in the design of immunoconjugates for a vaccine-based therapy for heroin addiction treatment.

Figure 1

Heroin metabolic pathway in humans. All half-lives units are minutes, C_max units are μmol/L, AUC units are hour · μmol/L. Adapted from Rook et al. 2006.[32]

Figure 2

Numbering system for the 1′ to 6′ positions of the opiate scaffold.

Figure 3

Linker attachment points for previous haptens.

Figure 4

Immunoconjugates synthesized by Bonese and Anton and Leff.

Figure 5

Bridgehead nitrogen linked heroin like hapten 14 and immunoconjugates 15-17.

Figure 6

Usage of Alum to create a selective immune response for opiates of interest. Her-KLH = Heroin-KLH, 6AM-KLH = 6-acetylmorphine-KLH, Mor-KLH = Morphine-KLH.

Figure 7

Vaccine titer levels over the course of 165 days. Vertical arrows represent booster injections at t = 14, 28, 53, 108 and 151 days. Data represented are the pooled mean value ± SEM.

Figure 8

Heroin vaccination selectively blocks the thermal and mechanical antinociceptive effects of heroin. Systemic injection of heroin (1 mg/kg, s.c.) produced robust decreases in both thermal (A) nociceptive sensitivity as measured by hot plate, and mechanical sensitivity (B) as measured by von Frey filament testing. This was fully reversed in the heroin-like 15 vaccine group. Morphine-like vaccine 16 significantly blunted the thermal nociceptive effects of heroin compared to control, but was still significantly elevated from baseline, while able to fully block mechanical effects of heroin. The combined vaccine 17 produced a partial blockade of heroin’s thermal antinociception, while fully blocking the any changes in mechanical sensitivity due to heroin. N = 7-8 per group, *p < 0.05, ***p < 0.001, 30 min post-drug versus baseline; ^#p < 0.05, ^##p < 0.01, ^###p < 0.001, versus KLH response post-drug. Portions of this figure were adapted from Stowe et al. 2011.[87]

Figure 9

Acquisition of heroin self-administration is prevented in a subset of rats vaccinated with heroin-like immunoconjugate 15, but not morphine-like 16 or immunoconjugate mixture 17. The percentage of animals that obtain the acquisition criteria, maintaining at least 3 consecutive sessions of 3 infusions (60 μg/kg/infusion) or more, is presented in the survival analysis graphs below. (A) The number of animals that acquired heroin self-administration was significantly lower in a group of rats receiving heroin-like vaccine 15 compared to KLH controls (p < 0.05). Only 3 of 7 rats receiving heroin-like vaccine 15 achieved criteria. (B) Conversely, the morphine-like vaccine 16 did not alter acquisition of heroin self-administration (p = 0.96). (C) Simultaneous vaccination 17 produced a delayed, but insignificant effect on heroin acquisition (p = 0.25). N = 7-8 per group. Portions of this figure were adapted from Stowe et al. 2011.[87]

Figure 10

A) Proposed conversion of heroin to stabilized amide derivative. B) Conversion of cocaine to stabilized amide derivative.