Fentanyl has become one of the most deadly drugs in the United States. Each year, fentanyl and related synthetic opioids cause more deaths than car crashes and gun violence combined. In high doses, these drugs can disrupt normal brain function and suppress signals that control breathing, often leading to fatal overdose. Medications can reverse an overdose, but must be given quickly to be effective.
Researchers at Scripps Research are now exploring an entirely different strategy. They developed an experimental vaccine designed to stop fentanyl from reaching the brain in the first place, rather than treating it after an overdose has occurred.
The survey results are Medicinal Chemistry Journalindicating that the vaccine may offer protection not only against fentanyl itself, but also against a wide range of fentanyl-related “designer drugs.” These modified versions are often created to increase potency or to help manufacturers evade detection and regulation.
“What this study shows is that we don’t have to keep up with every new synthetic designer drug that comes along,” said lead author Kim Janda, Ely R. Calloway Jr. Professor of Chemistry at the Scripps Research Institute. “Training the immune system to recognize the entire class of fentanyl, not just individual structures, can help us stay ahead of illegal drug traffickers.”
A new approach to fentanyl prevention
Scientists have spent years researching vaccines that trigger the production of antibodies that can bind to fentanyl in the bloodstream before it affects the brain. Janda’s lab previously developed vaccine candidates for both fentanyl and heroin.
However, most vaccine designs rely on the drug itself, or molecules that closely resemble the drug, to train the immune system. There are two major challenges with this approach. First, the drugs involved are highly regulated, making research and development more difficult. Second, immune responses tend to be highly specific and may only recognize the exact drug used in the vaccine.
“As the fentanyl situation evolves, black market drug companies are constantly coming up with new versions to circumvent regulations and avoid detection by standard tests,” Janda says. “We need countermeasures that are effective against all of these future variants simultaneously, not just one at a time.”
Testing unconventional vaccine designs
In previous research, Janda’s team developed a modified form of fentanyl that maintains its analgesic effects while eliminating many of the drug’s harmful side effects. In the new study, researchers investigated whether related molecules could serve as the basis for a vaccine.
Although this molecule shared some characteristics with fentanyl, it had a fundamentally different core structure.
“When we started testing this molecule as a component of a vaccine, we honestly didn’t know if it would work,” said Alan Stewart, a research scientist in Janda’s lab and lead author of the study. “Common sense is that in order for the immune system to recognize fentanyl, you need to use something that looks like fentanyl. We were doing the opposite.”
To test this idea, the researchers attached the modified molecule to a carrier protein and administered the vaccine to mice four times over eight weeks.
The results surprised the researchers. Rather than requiring an exact match to fentanyl’s structure, the immune system has generated antibodies that recognize broader molecular features shared by many fentanyl-related compounds.
Broad protection against fentanyl variants
When scientists evaluated antibodies against multiple fentanyl designer drugs, the vaccine demonstrated the broad protection they had hoped to achieve.
The antibody strongly recognized fentanyl as well as several dangerous variants, including carfentanil, China white, acetylfentanyl, and furanylfentanyl. At the same time, they did not bind to commonly used medical opioids such as morphine, oxycodone, remifentanil, and alfentanil.
The protective effect was also evident in animal studies. The vaccinated mice maintained near-normal breathing even after administration of fentanyl, which normally causes severe respiratory depression.
The researchers also found that fentanyl levels in the brains of vaccinated mice were about 70% lower than in unvaccinated mice.
Possibilities for future applications
The vaccine still needs to undergo clinical trials to determine if it is safe and effective in humans. Still, Janda believes the platform could ultimately help protect individuals enrolled in substance abuse recovery programs and others who face a high risk of fentanyl exposure.
“The public health potential here is huge,” Janda says. “But so too is the lesson that we can design vaccines that recognize entire drug classes, not just single drugs.”
The study, titled “Redefining Drug Immune Recognition: A Fundamentally Rearranged Molecular Structure Enables Protection for a Broad Range of Fentanyl Classes,” was authored by Janda, Stewart, Lisa Eubanks, Bin Zhou, and Rachel Steinhardt of Scripps Research.
This research was supported by the Shadek Family Foundation.
