Opioid abuse is responsible for billions of dollars of additional healthcare expenditure, and more importantly, about 90 deaths every day in the US alone (1). In the treatment of addiction and eradication of the current opioid crisis, vaccination against street drugs has become a potential therapeutic option. Scientists from the Janda lab (Skaggs Institute) have developed a vaccine that exploits features from the immune system to prevent the adverse effects of opioids like heroin. Learning from a similar effort for a vaccine against cocaine (2) the team created a structure that could be injected into mice and sequester heroin by covalently conjugating a heroin analog (a hapten) to a carrier protein (3). The haptens tested were bound to proteins such as diphtheria toxoid or tetanus toxoid produced a strong immune response that resulted in a high blood antibody concentration; such concentration ultimately prevented the opioids from reaching the brain by antibody sequestration. The antibody’s specificity depends on what drug or metabolite it was meant to mimic structurally, giving high specificity control to the scientists. The vaccine, when administered in mice, was able to reduce heroin’s potency by over 3-fold initially (3), only to be made longer-lasting and more effective against high (even lethal) doses of heroin in subsequent work (4). In parallel, the Matyas lab (US Military HIV Research Program) optimized the hapten synthesis, making the process scalable and the vaccine protective against other abused opioids like oxycodone, hydrocodone and hydromorphone while not binding to endogenous opioid peptides or drugs used to treat overdoses and addiction such as naloxone or methadone (5).
If translated to the clinic, the vaccines combined with withdrawal-alleviating drugs could prove useful in the treatment of opioid addiction and the epidemic’s alleviation. However, if they are to become a therapeutic, and more generally if vaccination for drug addiction is to be the standard of care, the paradigm will need to face several questions. For instance, will patients and clinical trial volunteers be cooperative? Most likely not, as a failed clinical trial for a cocaine vaccine elucidated, or at least not without a proper psychosocial support network (6). At the same time, while efficient against multiple opioids, neither vaccine responds to fentanyl or sufentanil, both drugs abused by addicts, but also critical in severe pain management. Importantly: should they? If a vaccinated
patient is committed to relapse with heroin, they could easily (and inadvertently) overdose with high fentanyl doses present in laced street heroin believing they would
need a high dose after being vaccinated. On the other hand, if a vaccine is made effective against fentanyl, a patient in need for emergency pain management may be completely out of options having been vaccinated against them; the last resort in such a situation, a higher dose of opioids, could prove extremely dangerous, as the therapeutic dose varies in the population, making patients susceptible to an accidental overdose. On top of that,
how will a vaccination paradigm work against newer, more potent and elusive “designer drugs” (7)? Considering the radically different time scales of newer, more potent street drug production/commercialization and FDA-approved treatment development, there is a real possibility that science will never catch up to addiction. While promising, vaccines would do little to resolve the opioid crisis until other societal problems are solved first, and in fact may even result more dangerous than beneficial. In a situation as delicate as this one with thousands of lives at risk, the vaccination paradigm may prove ineffective –if not harmful– if not properly assessed by scientists and authorities. Vaccination is nevertheless an option worth considering in parallel with alternative paradigms in order to arrive at the most comprehensive solution.
Felipe Flores ’19 is a junior in Quincy House concentrating in Human Developmental and Regenerative Biology.
 Volkow, N. D. & Collins, F. S. The Role of Science in Addressing the Opioid Crisis. New England Journal of Medicine 377, 391–394 (2017).
 Kimishima, A., Wenthur, C. J., Eubanks, L. M., Sato, S. & Janda, K. D. Cocaine Vaccine Development: Evaluation of Carrier and Adjuvant Combinations That Activate Multiple Toll-Like Receptors. Molecular Pharmaceutics 13, 3884–3890 (2016).
 Bremer, P. T. et al. Development of a Clinically Viable Heroin Vaccine. Journal of the American Chemical Society 139, 8601–8611 (2017).
 Hwang, C. S. et al. Enhancing Efficacy and Stability of an Antiheroin Vaccine: Examination of Antinociception, Opioid Binding Profile, and Lethality. Molecular Pharmaceutics 15, 1062–1072 (2018).
 Sulima, A. et al. A Stable Heroin Analogue That Can Serve as a Vaccine Hapten to Induce Antibodies That Block the Effects of Heroin and Its Metabolites in Rodents and That Cross-React Immunologically with Related Drugs of Abuse. Journal of Medicinal Chemistry 61, 329–343 (2018).
 Kosten, T. R. et al. Vaccine for cocaine dependence: A randomized double-blind placebo-controlled efficacy trial. Drug and Alcohol Dependence 140, 42–47 (2014).
 Crews, B. O. & Petrie, M. S. Rent Trends in Designer Drug Abuse. Clinical Chemistry 61, 1000–1001