Investigational Fentanyl Vaccine Could Block the Opioid from the Brain

A new vaccine targeting the synthetic opioid fentanyl has the ability to block the drug from crossing the blood-brain barrier, eliminating it’s rapid-onset, highly-reinforcing euphoria. The discovery, say the researchers from the University of Houston (UH), has the potential to become a relapse-prevention agent for people with chronic opioid use disorder (OUD).

The investigators, who published their recent findings in the journal Pharmaceutics, write that even with maintenance therapy, OUD has relapse rates of nearly 90%, “largely due to poor medication compliance with current agents.” Those who do relapse are at increasingly higher risk of an opioid overdose, they continue, as fentanyl and its derivatives have become ubiquitous adulterants of other abused substances. Moreover, fentanyl is now found in counterfeit formulations of commonly prescribed medications including benzodiazepines, oxycodone, and hydrocodone/acetaminophen, putting individuals who do not ordinarily use opioids at risk of overdose and/or death.

More than 150 people continue to die every day in the US from overdoses of synthetic opioids, including fentanyl. Fentanyl is 100 times more potent than morphine and 50 times more potent than heroin, according to a UH statement. Consumption of about 2 milligrams of fentanyl (the size of two grains of rice) is likely to be fatal depending on a person’s size.

“We believe these findings could have a significant impact on a very serious problem plaguing society for years – opioid misuse. Our vaccine is able to generate antifentanyl antibodies that bind to the consumed fentanyl and prevent it from entering the brain, allowing it to be eliminated out of the body via the kidneys. Thus, the individual will not feel the euphoric effects and can ‘get back on the wagon’ to sobriety,” said the study’s lead author Colin Haile, MD, PhD, a research associate professor of psychology at UH and the Texas Institute for Measurement, Evaluation and Statistics (TIMES), and a founding member of the UH Drug Discovery Institute.

"Our vaccine is able to generate antifentanyl antibodies that bind to the consumed fentanyl and prevent it from entering the brain, allowing it to be eliminated out of the body via the kidneys. Thus, the individual will not feel the euphoric effects and can ‘get back on the wagon’ to sobriety.”

In addition to demonstrating the vaccine’s ability to block fentanyl from entering the brain, Haile and colleagues’ findings show that it blocked fentanyl-induced depression of physiologic measures associated with overdose, such as oxygen saturation and heart rate. The research team also observed no adverse side effects in the immunized rats involved in lab studies. They state that they expect minimal side effects in humans as 2 of the components of the vaccine formulation are found in commercial vaccines or have been assessed in multiple clinical trials and found to be safe and effective.

The antifentanyl antibodies produced were specific to fentanyl and a fentanyl derivative and they observed no cross reaction to other opioids, ie, morphine. Vaccination, said Haile, thus will not preclude use of other opioids for pain management.

The vaccine evaluated contains dmLT, an adjuvant derived from E. coli that has been combined with other vaccines in human clinical trials. The ability of adjuvants to enhance a vaccine’s immunogenicity is particularly desirable in one targeting OUD.

The effectiveness of treatments currently available for OUD, ie, methadone, buprenorphine, and naltrexone, the authors stress, is dependent on formulation (eg, extended release, depot, implantable), compliance, access to medications as well as to the specific misused opioid.

"Game changer..."

Therese Kosten, PhD, senior author of the study and professor of psychology and director of the Developmental, Cognitive & Behavioral Neuroscience program at UH, calls the new vaccine a potential “game changer.”

“Fentanyl use and overdose is a particular treatment challenge that is not adequately addressed with current medications because of its pharmacodynamics and managing acute overdose with the short-acting naloxone is not appropriately effective as multiple doses of naloxone are often needed to reverse fentanyl’s fatal effects,” said Kosten. “This pharmacodynamic efficacy challenge can be addressed using immunotherapies that prevent fentanyl’s entry into the brain,” authors write in the study, “preemptively circumventing its reinforcing and overdose effects.

In the coming months, the team will begin manufacturing clinical-grade vaccine and plans clinical trials in humans in the near future.

The study was funded by the Department of Defense through the Alcohol and Substance Abuse Disorders Program managed by RTI International’s Pharmacotherapies for Alcohol and Substance Use Disorders Alliance, which has funded Haile’s lab for several years to develop the anti-fentanyl vaccine.

Reference: Haile CN, Baker MD, Sanchez SA, et al. An immunoconjugate vaccine alters distribution and reduces the antinociceptive, behavioral, and physiological effects of fentanyl in male and female rats. Pharmaceutics. 2022;14. doi:10.3390/pharmaceutics14112290