More than 130 people in the U.S. die every day after overdosing on opioids, according to the National Institute on Drug Abuse (NIDA). Fatal overdoses may occur from illicit use of oxycodone, heroin, fentanyl or use of prescription opioids without following medical guidelines. People have also died from recreational use of street mixtures of heroin or cocaine laced with fentanyl or its potent analogs, such as sufentanil or carfentanil. 

Marco Pravetoni, PhD, an associate professor in the Departments of Pharmacology and Medicine at the University of Minnesota Medical School, and his laboratory are taking steps to combat the opioid epidemic both in the U.S. and globally. 

Dr. Pravetoni, a member of the Medical Discovery Team on Addiction, is driven to discover new therapies to fight the opioid crisis. Dr. Pravetoni’s current projects are focused on developing vaccines and other novel antibody-based strategies to treat opioid use disorders and prevent fatal overdose. To support this work, NIH awarded Dr. Pravetoni with several multi-million dollar grants. 

“These NIDA-funded grants open up all sorts of avenues for researchers and students as well as the community,” Dr. Pravetoni said. “It is a privilege to be able to conduct translational research aimed at closing the gap between bench and bedside and helping to improve or save the lives of those affected by opioid use disorders.” 

This funding will support multiple projects in Dr. Pravetoni’s laboratory as well as ongoing collaborations with colleagues across the country, all centered around translation of vaccines treating opioid use disorders and fatal overdose. 

“There are many components to developing vaccines, from basic science to manufacturing safe and effective formulations suitable for human testing. These grants are helping in many different steps along the way,” he said.  

The grants fund the discovery and development of vaccines against oxycodone, heroin, fentanyl and the potent analogs of fentanyl. In addition, the funding supports manufacturing and other key activities to seek approval from the Food and Drug Administration (FDA) and to initiate clinical evaluation.

One of the Phase I clinical trials is expected to start this year. The first in-human clinical trial of a vaccine against opioid use disorders will focus on oxycodone, which according to the Center for Disease Control and Prevention, is one of the most common drugs involved in prescription opioid overdose deaths. The other planned clinical trial will focus on a vaccine to prevent overdose from heroin. The long-term goal of Dr. Pravetoni and his colleagues is to develop a multivalent vaccine formulation that will target most of the illicitly abused opioids.

“We hope that vaccines will prevent accidental overdoses from happening in the first place,” Dr. Pravetoni said. “After vaccination, the patient's own body will generate antibodies that will bind the target opioid, reducing or preventing its effects on the body. We envision these vaccines working like a sponge to soak up opioids, inactivating their pharmacological effects and preventing their unwanted effects. Because of their selectivity, these vaccines can be combined with standard FDA-approved medications, such as methadone, buprenorphine, naltrexone and naloxone.”

Other FDA-approved medications involve administering substances that have the potential of causing severe withdrawal symptoms or a risk for misuse. Instead, vaccines are expected to create a biological response against the opioid without any risk of withdrawal or liability of misuse.

“Current FDA-approved medications are small molecules that target opioid receptors in the brain and have to be taken every day or once a month. A vaccine would offer longer protection. Patients could go six months to a year before needing to be revaccinated,” Dr. Pravetoni said. 

While anti-opioid vaccines are primarily targeted at individuals who have been diagnosed with an opioid use disorder, this medical intervention may also benefit people at-risk of accidental overdose resulting from occasional use of street mixtures of cocaine or counterfeit prescription drugs laced with fentanyl or its analogs. Beyond that, vaccines against fentanyl and its analogs may be used as occupational prophylaxis in people at risk of accidental or deliberate exposure through their jobs such as emergency medical staff, law enforcement, military and airport or customs personnel. 

In addition to prophylactic vaccines against fentanyl, the Pravetoni lab is developing monoclonal antibodies that can be used to treat fentanyl overdose after it happens. Similar to the FDA-approved drug naloxone, the monoclonal antibodies would counter the effects of fentanyl overdose, but unlike naloxone which lasts for 90 minutes, antibodies would last for days. The extended protection would minimize the risk of dying from recirculating fentanyl, otherwise known as re-narcotization. 

“Ideally, the monoclonal antibodies would be given in addition to naloxone, creating a dual attack on the drug to help patients surviving an overdose,” Dr. Pravetoni said. 

Dr. Pravetoni explained that the vaccines and the monoclonal antibodies are very safe and do not interfere with existing medications for treatment of pain or management of substance use disorders. 

Dr. Pravetoni is also studying novel ways to improve and to predict the efficacy of vaccines and tailor them to individuals, navigating towards the innovative concept of precision medicine. 

The goal of Dr. Pravetoni’s research program fits the mission of the NIH Helping to End Addiction Long-term (HEAL) Initiative, which supports science-based research to provide lasting, scientific solutions to the national opioid crisis. These projects are supported by DA047711, DA041730, DA038876, DA048386 and DA048775 awards from NIDA.