The US opioid crisis may seem like a near-unsolvable problem. With 115 people dying from opioid overdoses every day (be that prescription opioids like oxycodone or street equivalents like heroin), opioids are now responsible for more fatalities than car accidents and guns. According to the Centers for Disease Control and Prevention (CDC), the total economic burden of prescription opioid abuse alone amounts to $78.5bn a year.

The issue, which was last year declared a ‘public health emergency’, shows no signs of dying down. Following the alarming rise of fentanyl, a synthetic opioid 50 times more potent than heroin, the fatality rates have been climbing year on year. A staggering 2.1 million Americans had an opioid use disorder in 2016.

While this problem has many dimensions, one of the key sticking points is treatment. At present, opioid addiction is treated via a range of medical and behavioural strategies, with the available medications including methadone and naltrexone.

A ‘cold turkey’ approach is often used, in which patients are told to abstain from the drug altogether. However, this can sometimes do more harm than good, insofar as it can reduce the person’s tolerance without diminishing their craving. If they relapse a few months down the line, the risk of overdose is very high.

These difficulties have led some to wonder whether there might be a better way. One suggestion that is generating some buzz is the idea of opioid vaccines. Unlike abstinence-based strategies (which hinge on a moralistic view of drug addiction), the vaccine idea treats opioid abuse as a strictly medical issue, which can be treated through pharmacological means.

“Vaccines might be used not only for abuse per se but also some of the consequences, such as fatal overdoses,” says Marco Pravetoni, associate professor of medicine at the University of Minnesota Medical School and Minneapolis Medical Research Foundation senior investigator.

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How the vaccines work: Neutralising the addictive potential of opioids

Since the late 2000s, Pravetoni’s lab has been at the forefront of these efforts. The team is working to develop vaccines against heroin and prescription opioids such as oxycodone, and has now reached a late stage of preclinical research.

“Once the opioids bind to the antibody they are no longer active.”

“The vaccines consist of a modified form of the target opioid, chemically conjugated to a protein,” says Pravetoni. “Like any vaccine, this is an injectable product that is mixed in an adjunct, and once injected will stimulate the patient’s immune system to develop antibodies that will be selective for the target opioid.”

In essence, if the patient does ingest opioids after taking the vaccine, the antibodies will bind to the opioids and neutralise them, so that there is no effect. Without the possibility of getting high, the drugs lose their addictive potential. What’s more, the risk of fatal overdose is minimised.

“Once the opioids bind to the antibody they are no longer active, and since they’re too big to cross the blood-brain barrier, the opioids won’t get to the brain,” says Pravetoni. “We have also found that our vaccines are pretty effective in blocking opioid-induced respiratory depression, which is one of the causes of people dying of overdose.”

Obstacles to success: the challenges of developing an addiction vaccine

Unfortunately, although the basic concept is intuitive, the actual execution of the idea is tricky. The first attempts to develop an opioid vaccine occurred as early as the 1970s, with several animal studies confirming it was possible to immunise against heroin. However, research stalled, and the idea was not reprised until the late 2000s.

“One of the major pitfalls is that the vaccines are not 100% effective.”

“Some of the early studies were interesting, but research efforts were abandoned when methadone was approved by Congress,” says Pravetoni. “I got started in 2008, and over the last five to ten years there’s been a lot of interest, with a few groups working on vaccines for opioid abuse. However, no commercial vaccines have been approved against opioids or any other kind of drug.”

One of the major pitfalls is that the vaccines are not 100% effective. In clinical trials for nicotine and cocaine vaccines, only around a third of patients developed the appropriate antibodies. Pravetoni thinks that opioid vaccines will be similar, and may end up being prescribed only to a particular subset of the population.

“Vaccine responses are built into our genetic makeup, and there must be other things going on as well,” he says. “In our lab, we study how B lymphocytes respond to vaccines, and we find that the frequency of B-cells that are specific to our opioid vaccines vary across the population in mice and rats. That seems to be a predictor of which subjects will respond.”

Another issue is funding, which, depending on the political climate, can be difficult to obtain. (Pravetoni’s own work is supported by grants from the National Institute on Drug Abuse at the National Institutes of Health.)

“Any vaccine requires an enormous amount of funding to move it forward to the various preclinical and clinical stages,” he says. “As you probably can imagine, it’s easier to convince people to go to a clinical trial for, say, an HIV vaccine than for an addiction vaccine – the message comes across more clearly. So that’s probably a limitation as well.”

Potential implications and combination treatment methods

These kinds of challenges notwithstanding, Pravetoni and his colleagues have produced some very positive preclinical results, with recent papers in the Journal of Pharmacology and Experimental Therapeutics, Scientifics Reports, and PLOS ONE.

“Patients could benefit from the vaccine and standard pharmacotherapy.”

They found, for instance, that heroin and oxycodone vaccines are highly immunogenic in rodents, and that novel immunomodulators may help improve the vaccine efficacy.

“We believe we have biomarkers that can predict vaccine efficacy and help us select individuals who will benefit from this therapy,” he says. “We have also found that we can combine immunomodulators with these vaccines to get over the issue of individual variability.”

Encouragingly, these vaccines can be combined with other medications. This opens up the possibility that a patient could take methadone or naltrexone in conjunction with the vaccine, attacking the problem from all sides.

“We don’t see the vaccine as a single line of intervention – patients could benefit from the vaccine and standard pharmacotherapy, and it would provide an additional line of protection against death from opioids,” says Pravetoni.

At present, the researchers are working hard to move the research into clinical trials – manufacturing the pharmaceutical grade version of the vaccines, fine-honing the formulations and sourcing funding for clinical testing. They are also working on vaccines for other opioid targets, such as fentanyl.

Pravetoni expects they could receive funding next year, or the year after that, and describes himself as ‘conservatively optimistic’. If all goes according to plan, and the vaccines do reach the clinic, the implications could be huge.

“We are hoping to reach a lot of people with opioid abuse,” he explains. “When people stop using for three to four months and then have a life stress that triggers a relapse, it’s a risky scenario. But if you vaccinate somebody, realistically you could have antibodies around for six months to a year. Hopefully having the vaccine will provide protection for a longer time so people won’t overdose.”