That Other Deadly Epidemic
In Pursuit of Vaccines Against Opioids
Decades before the worldwide quest for a Covid-19 vaccine, longtime NIH grantee Dr. Thomas Kosten and collaborators were pursuing effective inoculation against another growing epidemic—opioid addiction. In a recent virtual lecture at Clinical Center Grand Rounds, he discussed the effects one widespread crisis is having on another and his quarter century of research on “Treating the Hidden Epidemic: Anti-Opioid Vaccines.”
Kosten began by acknowledging the impact of the coronavirus pandemic on fentanyl overdoses and abuse in the U.S. He said one might guess that during covid, substance abuse would decrease. After all, with a great many folks on lockdown, largely confined to home and operating under so many restrictions, the drug overdose rate should decline, right?
“But in fact,” Kosten said, “there’s been a marked increase in the percentage of overdoses, when you compare 2020 during covid with 2019.” There has been a steady rise in ODs every month since February. May 2020 saw a 42 percent increase in overdoses compared to May 2019.
“The covid epidemic has not cut back on overdoses,” he said. “Covid has accelerated the escalation of this overdose epidemic.”
The Waggoner professor in psychiatry, pharmacology, neuroscience, immunology and epidemiology at Baylor College of Medicine and MD Anderson Cancer Center, Kosten has a long history of support from and collaboration with NIH. He also closely collaborates with his wife, Dr. Therese Kosten, who works at the University of Houston and has NIDA support, and most recently with Dr. Elizabeth Norton of Tulane University, who has NIAID support.
Kosten gave the recent Contemporary Clinical Medicine: Great Teachers Lecture, sharing lessons his group has learned from 25 years of clinical trials of stimulant vaccine efficacy.
“Beginning in 2014, the [fentanyl] epidemic really took off in a very profound way,” he said, tracing the most recent—and deadliest—surge in opioid addiction history.
Why have we seen so many opioid deaths?
“Fentanyl is substantially more potent than natural opioids or semi-synthetics,” Kosten explained, describing how drug products and their ill-advised cocktails have grown deadlier in just the last decade. “It’s about 50 to 100 times more potent than morphine. It’s very rapidly acting, and carfentanil [an opioid prescribed by veterinarians and not approved for humans, but now being mixed with other illicit opioids and stimulants] is about 10,000 times more potent than morphine and 100 times more potent than fentanyl. Carfentanil causes almost instant death in people.”
Adding to reasons for increased mortality rates, the anti-OD medication naloxone provides only a short-term reversal of opioid overdose with fentanyl. Even then, the usual amount of naloxone is insufficient and OD reversal requires multiple doses at naloxone’s usual strength.
In addition, there seems to be low community awareness in the marketplace. Kosten said that “drug users seeking heroin seem largely unaware that they are using fentanyl,” and street dealers seem not to realize that their products contain fentanyl.
“We need to educate users on harm-reduction measures,” he said. Such measures include using less of the drug, not using alone and taking turns when using, avoiding mixing drugs and having the overdose-reversing naloxone on hand. “We’ve made some progress in our educational efforts in all those areas, but not enough.”
In the covid era, Kosten said, overdose clusters have shifted from centralized urban sites to nearby suburban and rural areas where there are many more people to affect who are less educated about drug abuse. The stress and isolation of social distancing also reduces community support. Finally, there are the physiological aspects: Drug abuse damages the lungs, cardiovascular system and metabolic system, which makes individuals more vulnerable to Covid-19.
“Those are some of the many reasons we think overdoses are going up with covid,” he said.
Could the pandemic help reduce substance abuse in any way?
While there has been a disruption of sorts to opioid markets, Kosten observed, the illicit drug trade is “a lot like the stock market—largely resilient.” The coronavirus crisis has made it harder for users to get illicit drugs. The covid pandemic also offers users better access to care with telemedicine outreach into abusers’ homes. And virtual support meetings have proliferated with more hotlines emerging for immediate help.
Kosten described how opioid vaccines coax production of antibodies to the drug and how these antibodies work like a sponge in an overdose victim’s blood, absorbing and reducing brain concentrations of the drug and preventing activation of the brain’s mu opioid target receptors.
“This first prevents the drug from getting into the brain,” he explained, “and because the affinity of these antibodies is much higher than the affinity of the opiate receptor for fentanyl, the antibodies will—in effect—pull the fentanyl out of the brain.”
Slowed brain entry also is a very important aspect of vaccine effectiveness, Kosten emphasized, because “abuse potential depends upon speed of brain entry.”
Kosten then shared data from studies of vaccines for oxycodone and smoked cocaine. One trial, conducted in collaboration with Columbia University, showed an “almost 80 percent reduction in the high from smoking 25 milligrams of cocaine—which is a quite reinforcing dose—so that was a pretty nice blockade…This study was a very nice proof-of-concept that these antibodies were doing what we hoped they would.”
He described a candidate fentanyl vaccine that works in a similar way and with comparable results in animal trials. His group hopes to move that vaccine into human studies soon.
Looking at the amount of antibody that vaccinated individuals produced in a multisite cocaine study, titers ranged from 250-plus (terrific) to under 40 (disappointing). Kosten acknowledged, “That is the problem with this vaccine approach—how much variation in antibody levels you get across individuals to these vaccines.” The more antibody produced, the greater an individual’s blockade of the drug will be and the more likely that he or she will attain sustained abstinence.
Still, Kosten concluded, arguments in favor of anti-opioid vaccines are strong: Medical risks are minimal because vaccines employ safe carrier proteins and only tiny quantities of the abused drug. Vaccines also provide a sustained but reversible drug blockade, introduce no direct brain effects or side effects and require minimal compliance after the patient is vaccinated.
Research on opioid vaccine development is as fast and furious as efforts toward a covid vaccine, Kosten said. See his full presentation at https://videocast.nih.gov/watch=38348.