Opiate and opioid drugs killed 70,000 Americans1 in 2017, according to statistics from the Centers for Disease Control and Prevention, the latest grim note in a still growing addiction crisis and demanding a wide public health response. In May 2017, National Institutes of Health Director Francis Collins, MD, PhD, wrote that it was time for “all scientific hands on deck,” and highlighted the need to invest in new technologies beyond the standard toolset for reversing opioid drug overdoses and treating addiction.2

NIH has now announced new resources for research into one such alternate approach to combatting the opioid epidemic, immunotherapy.

A March 20 solicitation from the National Institute of Allergy and Infectious Diseases3 (NIAID), announced the division’s search for outside researchers interested in developing vaccines to protect against heroin and the powerful synthetic opioid fentanyl, with goal of awarding multiple groups contracts, according to Kentner Singleton, PhD, program officer in the basic immunology branch of NIAID. He expects to announce the awards by August 2020. “Once we make the awards, we can facilitate collaborations between all the different groups so we can leverage the strength of one group to minimize the weakness of another group, so that we can have a cohesive consortium of investigators all working towards the same goal in unison and in parallel,” he says. “At the end of the day, the goal is to have a product that is brought into clinical trials.”

That independent but collaborative spirit is mirrored in the way NIH divisions are approaching Collins’s all hands on deck call more generally, according to Singleton. “I am leading an NIH Helping End Addiction Long Term (HEAL) initiative,” he says, an across NIH program to support solutions to the opioid crisis. “That includes sharing expertise between NIAID researchers, who have had great success in creating potent vaccines against infectious disease, and researchers at the National Institute on Drug Abuse (NIDA), who have the substance use and behavioral health experience.”

Immunological Approach

An immunological approach to treating substance use disorders, using vaccines or even monoclonal antibodies is not an entirely new idea. NIDA began funding research in that direction in the 1990s, according to Ivan Montoya, MD, director of the division of therapeutics and medical consequences. “It’s what’s called a pharmacokinetic antagonism, that means that it’s sequestering the drug of abuse in the blood system and avoiding going into the brain,” he says. Antibodies targeting the drug protects against overdose, prevents the user from getting high, and given repeated attempts to use without reward, Montoya says, “eventually the desire to use the drug is extinguished by behavioral processes.”

A vaccine for people in treatment for opioid-use disorders, Singleton says, would have a number of advantages. They can be opioid specific, protecting against heroin or fentanyl use but leaving meperidine available for use in a medical emergency, he says, while offering longer lasting protection than opioid receptor antagonists such as naltrexone, which requires monthly injections.

At the same time, notes Marco Pravetoni, PhD, an associate professor of pharmacology and medicine at University of Minnesota Medical School whose lab is developing opioid vaccines, such vaccines do not bind opioid receptors, so should have fewer side effects than mu receptor antagonists, such as naltrexone, nor will they interfere with agonists used in treatment, such as buprenorphine. “Ideally you could have someone who is on the heroin vaccine plus buprenorphine, or methadone plus the fentanyl vaccine.”

That’s the way experts would like an opioid vaccine to work. But past NIDA research into vaccines for several different drugs of abuse failed to reach approval for use in humans. The most advanced candidate, a nicotine vaccine, made it to Phase III clinical trials, but ultimately failed to consistently produce enough antibody titers in patients to fully sequester the target drug, Montoya says. “Something was still getting through the blood brain barrier and getting into the brain.” No opioid vaccine has yet been tested in humans, he says.

This is exactly the sort of problem researchers at NIAID have developed tools to combat, Singleton says, “such as an adjuvant pool that we can leverage,” adjuvants being a vaccine component that can amplify the innate immune system response to an antigen, he says. “They had low antibody titers, we have tools that can help elevate antibody titers, and this is something that we’re an expert in that not necessarily an opioid expert would be familiar with.”

Pravetoni currently has a number of vaccine candidates in development, including oxycodone and heroin vaccines4 headed for Phase I clinical trials, and says he plans to apply to the solicitation and hopes to become an awardee. Not only is the marriage of NIDA and NIAID approaches a good idea, Pravetoni says, a key advantage of from his point of view as an academic researcher would be access to resources that are otherwise cost prohibitive to him or else limited to proprietary use in industry. “We are going to have access to adjuvants that are perhaps cutting edge or have been in used humans that otherwise would be hard to access,” he says. “The technology is not necessarily the hurdle to vaccine development, sometimes it’s access to components that are suitable for FDA guidelines and approval.”

There’s no guarantee than Pravetoni will be awarded a contract, of course, and conversely, there’s no guarantee that other researchers not associated with the solicitation will develop a working opioid vaccine first. But that, Singleton says, would be a welcome embarrassment of riches, and his collaborators would have plenty to work on improving the next generation of vaccines.

“Opioid vaccines have really a strong potential to help with minimizing the opioid crisis. They won’t, in and of themselves solve it, they will be just one tool out of many tools for solving the opioid crisis,” he says. “I think the more players that are out there the better it would be for the community, for all of us together.”


1. www.cdc.gov/opioids/strategy.html
2. directorsblog.nih.gov/2017/05/31/all-scientific-hands-on-deck-to-end-the-opioid-crisis/
3. www.fbo.gov/index?s=opportunity&mode=form&id=fa488317362c6180f48d7b9bffd91dfc&tab=core&_cview=1
4. www.ncbi.nlm.nih.gov/pubmed/29535156

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