The potential role of opioid vaccines and monoclonal antibodies in the opioid overdose crisis

1. The need for continued development of medications to treat opioid overdose

Since the late 1990s, the U.S. has experienced an exponential increase in opioid-related overdose deaths and made substantial economic expenditures to address the harms associated with opioid use disorder (OUD) [1,2]. As the epidemic has evolved, we have observed a substantial increase in the detection of potent, illicitly manufactured fentanyls in opioid drug supplies as well as in cocaine and methamphetamine drug supplies, and within counterfeit pills sold as oxycodone, benzodiazepines, and other prescription drugs. This has led to increases in the rates of opioid-related overdose among those with OUD and among those who are not traditionally at risk such as psychostimulant users and recreational non-opioid drug users (i.e. individuals who may not meet criteria for a substance use disorder) [3].

The development of novel evidence-based treatments remains a key focus of the U.S. Food and Drug Administration (FDA)’s efforts to address the opioid epidemic [4]. Two strategies that are known to reduce the morbidity and mortality associated with opioid overdose are the use of naloxone (and nalmefene) to reverse an acute overdose and maintenance on FDA-approved medications, such as methadone, buprenorphine, and naltrexone [5]. The currently available FDA-approved medications for opioid overdose and OUD largely exact their therapeutic effects via the mu-opioid receptor [6]. However, rates of fatal opioid overdose remain high. Therefore, the development of novel therapeutics is a public health priority.

2. Using vaccines and monoclonal antibodies to target opioid overdose

A research area that is gaining traction for treating substance use disorders is the development of immunotherapies, which first began in the 1970s [7]. Opioid vaccines activate the immune system to create antibodies that selectively bind to a targeted opioid. By preventing the passage of drugs across the blood-brain barrier, or other target organs, opioid-specific antibodies attenuate the pharmacological effects of opioids [8]. Preclinical studies have demonstrated that opioid vaccines are highly specific to their target drug (i.e. oxycodone, morphine, fentanyl), and demonstrate the ability of vaccines to reduce the abuse potential of opioids in various models (e.g. conditioned place-preference, drug self-administration) [9–12]. Importantly, preclinical models have shown that opioid-specific antibodies can prevent opioid-induced respiratory depression, the primary means by which opioid over-intoxication becomes fatal [13,14]. Active immunization with vaccines, however, typically requires multiple injections over several weeks so this approach is not feasible for treating acute opioid overdose. However, if antibody production produced by vaccination is robust and long-lasting, vaccination could prevent an overdose from occurring or re-occurring in patients who relapse to illicit opioid use.

Another immunotherapeutic approach to treating opioid overdose is passive immunization with monoclonal antibodies (mAbs) that target specific opioids. Like the antibodies that are produced through active immunization with a vaccine, mAbs bind and sequester opioid drug molecules in the serum and other organs, which prevents them from entering the central nervous system [15]. Monoclonal antibodies are primarily produced from antigen-specific B cell lymphocytes via several techniques including hybridoma technology, phage display, and cloning and expression of antibody binding domains as recombinant monoclonal antibodies [15]. One of the potential advantages of mAbs is their rapid onset of action and ability to bind opioids after a single administration [16]. Therefore, mAbs could be useful for reversing an acute opioid overdose. If the mAb is long-lasting, this approach also could prevent an opioid overdose. One recent study in rodents found that the administration of mAbs successfully reversed fentanyl-induced respiratory depression, antinociception, and bradycardia for up to a week [17]. Other rodent studies from independent groups also show the preclinical efficacy of anti-opioid mAbs and the viability of chimeric or humanized mAbs against opioids [15,16,18,19]. In sum, preclinical findings in these rodent models suggest that opioid vaccines and monoclonal antibodies have significant potential in the treatment of opioid overdose.

3. Clinical considerations

3.1. Preclinical to clinical translation

The translation of robust preclinical findings into promising results in human trials is where most treatments fail in the medication development pipeline [20]. Similar to opioid vaccines, preclinical studies of nicotine and cocaine vaccines demonstrated the ability to attenuate the abuse potential of nicotine and cocaine [21–26]. Unfortunately, subsequent clinical trials yielded disappointing results. One of the issues was significant variability in antibody levels post-vaccination. In many of these studies, less than one-third of vaccinated participants developed sufficient antibody levels to produce a good clinical response [27]. Furthermore, it could take a month or longer and require repeated vaccine injections to establish a therapeutic immune response [22].

3.2. Key pharmacokinetic factors affecting clinical outcomes

Two clinical studies have been published to date on a morphine vaccine [28,29]. The investigators reported dose-dependent increases in antibody levels and no serious medication-related adverse effects [29]. However, no treatment-related outcomes were reported so questions remain regarding the efficacy of immunotherapy in humans with OUD. For example, the optimal schedule of inoculations, the needed frequency of boosters, the ideal range and onset/offset of antibody titers needed to produce a clinically meaningful medication effect, and the interindividual variability in antibody titers are critical but unanswered clinical questions.

3.3. Risk of attempts to override the effects of opioid vaccines/mAbs

An additional concern is the possibility of individuals attempting to override the vaccine’s therapeutic effect by taking larger doses of the target opioid, potentially exposing them to additional overdose risk. Data from other therapeutics, however, suggest that this is more a theoretical than an actual concern. Prior studies of the competitive opioid antagonist naltrexone found attempts to override the blockade occurred infrequently suggesting that the high cost of larger doses of the opioid of choice may serve as a sufficient barrier to continued opioid use [30]. This study, paired with clinical evidence supporting naltrexone’s efficacy, suggests that it is unlikely that individuals would frequently attempt to override the antagonist effects of naltrexone, which may extend to blockade induced by opioid vaccines.

3.4. Risk of ‘opioid-switching’

The risk of ‘opioid-switching’ by individuals who use opioids illicitly is also a clinical concern. For example, a primary oxycodone user may initiate heroin or fentanyl use if a vaccine or mAb targeting oxycodone blocks the pharmacological effects of oxycodone. Because vaccines/mAbs are so selective for the target opioid, a multivalent vaccine/mAb approach that targets multiple opioids makes the most sense clinically from the perspective of both safety and effectiveness for the treatment of both opioid overdose and OUD.

3.5. Implications for pain management

Whether and how opioid vaccines/mAbs could affect standard medical practices, such as pain management, is also an important consideration. For example, the introduction of an opioid vaccine/mAb would require clinicians to be aware of their patient’s opioid vaccination status in order to select the most efficacious opioids for pain management. This could become challenging if an individual is vaccinated against the same opioid selected by their clinician for pain management and alternatives are not readily available. Factors such as regional differences in the availability of certain opioids could worsen some of these issues and lead to unintended health disparities.

3.6. Stand-alone versus adjunctive treatment

One important issue with opioid vaccine treatments is the context and potential application of their use. The introduction of an opioid vaccine could be implemented as an adjunct to the current standards of care (e.g. vaccination + naltrexone, methadone, or buprenorphine). In this proposed approach, the vaccine would target the illicit opioid, like heroin, while not affecting the function of a maintenance opioid, like buprenorphine. As such, the potential benefits of the immunotherapy would be additive to that of the OUD medication. This approach is a departure from previous vaccine development attempts, especially the psychostimulant vaccines, where there are no FDA-approved medications. Opioid immunotherapies could also be used as stand-alone treatments for OUD, should clinical trials demonstrate robust effects on treatment outcomes. An immunotherapeutic treatment may be preferable in situations where pharmacotherapy is not ideal or desired by the patient, or for long-term stabilization after traditional pharmacotherapy is phased out.

3.7. Implications for medication compliance

One of the most promising advantages of opioid immunotherapy is the possibility of increased medication compliance, an issue that plagues all forms of OUD treatment [31]. The frequency of lapses, relapses, and discontinuation of pharmacotherapy presents a serious challenge for the successful management of OUD, as well as increasing the vulnerability to overdose [5]. Immunotherapy may provide individuals who are experiencing a relapse episode with an additional layer of protection against overdose while they reengage in traditional pharmacotherapy and psychotherapy.

3.8. Implications for treatment of users of non-opioid drugs

Finally, opioid immunotherapy could have novel indications related to overdose risk mitigation. Opioid vaccines could be offered to individuals who may not meet criteria for OUD but are at risk of opioid overdose. For example, vaccination against fentanyl could serve as an overdose risk mitigation strategy for individuals who use cocaine and methamphetamine, whose risk of unintentional fentanyl exposure has risen in recent years.

4. Expert opinion

To fully understand the clinical potential of opioid immunotherapy, additional clinical research is needed in several areas. In addition to safety and tolerability evaluations, data on the immunogenicity (e.g. heterogeneity in immune response) of opioid vaccines is crucial to assessing their efficacy, implementation, and planned indications for use. These issues have significantly stifled the development of vaccine therapies for other substance use disorders. Preclinical data suggest opioid vaccines and monoclonal antibodies may not only yield improved outcomes in the treatment of OUD but also provide a novel and innovative overdose mitigation strategy. However, these promising findings have yet to be replicated in clinical samples, which is not a given, as preclinical studies do not always predict effectiveness in clinical trials. Furthermore, a comprehensive treatment strategy for OUD would likely necessitate multivalent vaccines/mAbs targeting several opioids. Just as the opioid epidemic transitioned from prescription opioids to heroin and then fentanyl, new non-fentanyl opioids have already begun to emerge in the illicit market [32]. Multivalent vaccines or monoclonal antibodies could allow immunotherapies to adapt to a changing drug market. Yet more preclinical and clinical research is needed on efficacy and safety. Finally, given the concerns that individuals have expressed concerning other types of vaccines (e.g. COVID-19 vaccines), research is needed to understand the acceptability, appropriateness, and feasibility of this approach in different subgroups of people who use drugs to inform implementation strategies. It is critical to have these discussions not only with diverse samples of individuals with OUD but also clinicians to ensure all risks and viewpoints are understood.

Despite the promise of opioid vaccines and monoclonal antibodies, several scientific and ethical considerations warrant mentioning. The implementation of opioid vaccination therapy may lead to an ongoing ‘cat-and-mouse game’ between vaccine developers and illicit drug manufacturers. This may result in new, more dangerous opioids entering the illicit drug market. Finally, individuals with substance use disorders and their treatment historically have often been entrenched in punitive approaches in the U.S., particularly among individuals from minority backgrounds. Thus, concerning vaccine/mAb therapy, vigorous ethical debate should be conducted regarding the potential use of this therapeutic approach to safeguard the self-determination and autonomy of individuals who use drugs.

One of the main goals of the development of opioid immunotherapies is to provide an effective treatments for OUD and/or overdose prevention. These treatments may have the ability to serve as a stand-alone or adjunctive treatment to the currently available interventions. Although the development of immunotherapies may be promising, it is critical to remember that this research is still in its early stages. As such, it is difficult to predict exactly how the development of opioid immunotherapies evolve in the future with certainty or precision. However, if this research continues to show effectiveness in the progression from animal to human studies, there are novel and impactful real-world applications. For example, it may be possible to identify individuals who are at high risk of developing OUD and use immunotherapies to prevent the development or progression of severe addiction. Similarly, immunotherapies could be used as a overdose mitigation strategy to reduce overdose risk among those not interested in OUD treatment, or in cases of treatment-refractory OUD. Additionally, it is possible that the large-scale implementation of an efficacious immunotherapy could reduce the overall demand for opioids.

The availability of a opioid vaccine or monoclonal antibody therapy could become a standard of care, and could be included in evidence-based guidelines for OUD and overdose prevention. Nonetheless, it is important to note that many unanswered questions remain, and more research is needed to fully understand their potential indications and impact. More specifically, studies including clinical trials, are needed to determine the safety, efficacy, and long-term impact of these treatments, as well as their cost-effectiveness compared to current treatments. Moreover, any changes to treatment guidelines would need to consider barriers to the widespread adoption of these immunotherapies, including regulatory approval, reimbursement, and availability of the treatments.

There are also other challenges in the development of opioid immunotherapies worth mentioning, specifically variability in response to the intervention. Prior research with nicotine and cocaine vaccines, suggests some individuals may respond well to opioid immunotherapies, while others may not, which would complicate the implementation of this treatment approach. Taken together, the development of opioid immunotherapies has the potential to greatly impact the current and future opioid epidemic . As evidence is still emerging, the authors have exercised caution in making proclamations concerning the potential of opioid vaccines and monoclonal antibodies in the opioid overdose crisis. Although the development of opioid immunotherapies presents notable challenges, novel treatment approaches are needed given the now decades-long opioid crisis. Opioid immunotherapy may present a novel treatment and overdose risk mitigation strategy with a larger target audience, in comparison to currently available approaches.

Article highlights.

• Immunotherapies may present a novel approach to help address the evolving opioid overdose crisis

• Preclinical data suggest that opioid vaccines and monoclonal antibodies have therapeutic potential

• More research, specifically in humans, is needed to demonstrate the efficacy and safety of immunotherapies for opioid use disorder and better understand potential implementation barriers

List of Abbreviations

FDA

Food and Drug Administration

OUD

Opioid Use Disorder