Vaccines to treat opioid use disorders and to reduce opioid overdoses

As the incidence of opioid-related fatal overdoses continues to rise in the United States, new therapeutic strategies for opioid use disorders (OUD) are needed. One proposed solution is active immunization with anti-opioid conjugate vaccines, which selectively reduce the effects of their target opioid through production of drug-specific antibodies. As opposed to pharmacotherapies (e.g., methadone, buprenorphine, and naltrexone) targeting opioid receptors in the brain, opioid-specific antibodies operate through a pharmacokinetic mechanism by sequestering the target opioid in serum and reducing its distribution to the brain. Anti-opioid vaccines could provide safe and cost-effective interventions that offer several advantages over current small molecule medications: long-lasting protection that reduces the burden of compliance; no abuse liability or risk of diversion; and due to their selectivity, vaccines do not interfere with endogenous opioids, or with nontarget opioids prescribed for pain management or for treatment of OUD. To improve clinical outcome, vaccines could be used in combination with other medications for OUD.

Extensive preclinical studies have identified a series of lead vaccines selectively targeting heroin, oxycodone, hydrocodone, or fentanyl (e.g., [1,2,3]). Anti-opioid vaccines effectively reduce distribution of the target opioid to the brain, and reduce opioid-induced behavior, including drug self-administration, in mice, rats, or nonhuman primates. Notably, vaccine efficacy in reducing opioid distribution to the brain depends on the target opioid, its dose, and route of exposure [2], highlighting the need to consider variables such as patterns of drug use in study design of clinical trials. Supporting a role for vaccines in overdose prevention, vaccination reduces opioid-induced respiratory depression and bradycardia, two significant factors in overdose-related fatalities [4]. Additionally, anti-opioid vaccines do not interfere with naloxone reversal of opioid toxicity [4] and improve survival following a lethal heroin dose [5].

Clinical evaluation of first-generation nicotine and cocaine vaccines has shown that only a subset of immunized subjects produced levels of drug-specific antibodies sufficient for efficacy. Therefore, it is critical to optimize vaccine formulations to maximize efficacy, to understand the immunological mechanisms underlying effective immune responses, and to identify biomarkers predictive of individual variability. Multiple studies have focused on vaccine design, including optimization of hapten and linker chemistry, choice of carrier protein and adjuvant, and development of novel carriers and delivery platforms. Effective formulations of vaccines against heroin have included the TLR9 agonist CpG [5] and liposomes containing the TLR4 agonist monophosphoryl lipid A [3]. The efficacy of an oxycodone vaccine was enhanced by shifting IgG subclass distribution through inhibition of interleukin-4 signaling, both indicating a pharmacological target for vaccine development, and granting insight into mechanisms underlying vaccine efficacy [6]. Additionally, the pre-immunization frequency of hapten-specific B cell population subsets correlated with vaccine efficacy, suggesting that subjects likely to generate clinically effective opioid-specific antibody responses could be identified prior to vaccination [7]. Accelerating the translation of vaccines for OUD will benefit from rational design of more effective vaccine components, development of clinically viable formulations, and biomarkers supporting patient stratification.

Mounting preclinical data provide proof of selectivity and efficacy for anti-opioid vaccines, demonstrating their potential to treat OUD and reduce incidence of opioid overdoses. Testing these vaccines in clinical trials is warranted.

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Acknowledgements

This work is supported by a Hennepin Healthcare Research Institute award (M.P.), and by the NIH under grants U01 DA038876 (M.P.), R01 DA041730 (M.P.), and T32DA007097 (C.B.).

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Correspondence to Marco Pravetoni.

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M.P. is the inventor of “Cytokine Signaling Immunomodulators and Methods,” International Application No. PCT/US2017/031907 filed on May 10, 2017. C.B. declares no competing interests.

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Baehr, C., Pravetoni, M. Vaccines to treat opioid use disorders and to reduce opioid overdoses. Neuropsychopharmacol 44, 217–218 (2019). https://doi.org/10.1038/s41386-018-0197-3

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