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Is it possible to design a clinically viable heroin vaccine? The progress and pitfalls

The opioid epidemic in the United States continues to escalate, with heroin (1) abuse significantly contributing to this crisis (Figure 1(a)). From 2005 to 2015, the number of individuals who had used heroin doubled from 379,000 to 828,000 [1]. Moreover, heroin-related fatal overdoses increased by 400% between 2010 to 2017 [2], which was due in part to the clandestine presence of synthetic designer drugs like fentanyl and its analogues [3]. The COVID-19 pandemic has only exacerbated the opioid epidemic, as evidenced by the 81,000 fatal drug overdoses reported in May 2020, the highest number ever recorded in a 12-month period, with opioids being the primary contributor [4]. Social isolation, anxiety and depression caused by uncertainty, lack of access to services, and disrupted treatments due to stay-at-home orders have likely contributed to increased rates of relapse and opioid abuse [5]. Given this epidemic within a pandemic, there is a dire need for effective treatments for opioid use disorder, especially for heroin abuse. Food and Drug Administration (FDA)-approved medications to treat heroin abuse (e.g. methadone (2), buprenorphine (3), and naltrexone (4), Figure 1(b)) work by interacting with opioid receptors in the brain, but are often underutilized clinically and have several limitations (e.g. abuse liability, patient compliance) [6–8]. Vaccines targeting opioids or immunopharmacotherapies are promising treatment options because they offer long-term protection, lack abuse liability, are generally free from drug-drug interactions, and are largely compatible with other opioid therapies [9]. Immunopharmacotherapies meet ideal criteria as new treatments, since they would not require detoxification from heroin, unlike 4, and would also not interfere with endogenous opioids and neuropeptides or their receptors in the central nervous system (CNS) [8,9]. In addition, vaccine development should extend beyond heroin to target the rise of fentanyl use and contamination through dual or multivalent vaccines [3]. The first proof-of-concept anti-heroin vaccine was developed in 1974 and produced a modest decrease in heroin selfadministration in monkeys [10]. A heroin vaccine is comprised of three primary components: a hapten, an immunogenic carrier protein, and adjuvants. Haptens are structurally similar to heroin and are chemically linked to an immunogenic carrier protein to stimulate an immune response. This immunoconjugate is then paired with various adjuvants (i.e. additives that function as delivery vehicles or further stimulate the adaptive immune response) to enhance the vaccine profile [1]. During vaccination, the immune system generates polyclonal antibodies with specificity to heroin. If a subject uses heroin, these antibodies bind to the drug and form an antibody-drug complex which cannot pass through the blood-brain barrier (BBB), thus preventing a psychoactive high [11]. Given the vaccine’s inherent high-affinity and selectivity for heroin and the fact that antibodies do not directly interact with opioid receptors, a heroin vaccine could be administered with opioid medications. Significant advances have been made in preclinical heroin vaccine development, involving multiple iterations of haptens, carrier proteins, and adjuvants. These studies have conducted testing in both sexes of mice, rats, and monkeys on a manifold of characterization and behavioral experiments including: antibody titers, binding, concentration, antinociception, selfadministration, lethality, blood-brain distribution, and drug discrimination [1,8,9,12]. Comprehensive reviews assessing vaccine effectiveness and preclinical behavioral metrics are available [8,9]. One challenge unique to heroin (relative to other opioids) is that heroin rapidly metabolizes to 6-monoacetylmorphine (6-AM (5)), the primary mediator of heroin reinforcement, which is then further metabolized to morphine (6, Figure 1(a)). To address this issue, researchers designed a ‘dynamic’ heroin hapten (8, Figure 2) [13][1,12], which stimulates antibodies for all three psychoactive metabolites. Other approaches include modifying the hydrolysable acetyl groups of 1 with amides (10) [14,15] or sulfonates (9) [16] to closely mimic 1 or 5 directly, or use a morphine-based hapten (11) to mimic 6 (Figure 2) [17,18]. These haptens can be further differentiated by conjugation method and linker attachment. Another notable trend with heroin vaccines is increasing investigations of bivalent and multivalent vaccines for structurally different opioids. The efficacy of the vaccine could potentially be undermined if an individual is using multiple opioids concurrently or if heroin is contaminated, most commonly with fentanyl [8]. A bivalent or multivalent vaccine would provide protection against the multiple drugs, thus, reducing the risk of overdose from different opioids.