Opioid Overdose: Are Vaccines the Answer?

SINCE THE 1990S, when the first wave of opioid overdose deaths began with an increase in prescribing opioids, the number of people with opioid use disorder (OUD) has increased at an alarming rate. The Centers for Disease Control and Prevention (CDC) reported that 806,000 lives were lost to opioid overdoses between 1999 and 2023 from prescription and non-prescription opioids.¹

Based on this shockingly high number of opioid overdose deaths, CDC and the U.S. Food and Drug Administration (FDA) recently launched a number of initiatives that aim to prevent, as well as treat, persons with OUD and help reduce the number of opioid overdose deaths.

Opioid Overdose Prevention

In May 2024, FDA launched Prescribe with Confidence, an educational campaign designed to provide primary care providers with resources, education and support when prescribing medication to treat patients with OUD. The goal is to increase the number of primary care providers who can recognize OUD and prescribe medication to treat it by helping them understand how to diagnose OUD and work with their patients to design an individualized treatment plan.²

FDA’s Overdose Prevention Frame-work, announced in 2021, contains four priorities: 1) support primary prevention by eliminating unnecessary initial prescription drug exposure and inappropriate prolonged prescribing; 2) encourage harm reduction through innovation and education; 3) advance development of evidence-based treatments for substance use disorders; and 4) protect the public from unapproved, diverted or counterfeit drugs presenting overdose risks.³

In 2023, CDC announced its Overdose Data to Action (OD2A), a cooperative agreement that provides funding to 90 health departments under state and local programs to reduce drug overdoses: “This cooperative agreement supports jurisdictions in implementing prevention activities and in collecting accurate, comprehensive and timely data on nonfatal and fatal overdoses and in using those data to enhance programmatic and surveillance efforts. OD2A focuses on understanding and tracking the complex and changing nature of the drug overdose crisis by seamlessly integrating data and prevention strategies.”

CDC also supports the Drug-Free Communities (DFC) program: “The DFC program has been a central component of our nation’s youth substance use prevention strategy, and it provides funding and support to community coalitions to prevent and reduce youth substance use.”⁴

However, even after FDA approved three opioid medications for medication-assisted treatment (buprenorphine, methadone and naltrexone) for OUD and two overdose reversal medications (naloxone and nalmefene) to reverse active overdoses, opioid overdose deaths still average in the tens of thousands of deaths per year.

And, although CDC reported opioid overdose deaths decreased almost 27 percent in 2024,⁵ the consensus among the population and in the medical community is that something more needs to be done to continue to dramatically reduce the number of opioid overdose deaths.

Therefore, in 2024, Elissa Weitzman, ScD, MSc, director of research for Boston Children’s Hospital’s Division of Addiction Medicine, conducted an interview study to explore the acceptability of a fentanyl vaccine to prevent opioid overdose deaths. The study showed many participants, including parents who had lost their children to overdose and adolescents at risk for overdose, were enthusiastic about a potential fentanyl vaccine. However, based on the interviews, Dr. Weitzman said, “One size is not going to fit all.”⁶

How Opioids and Opioid Vaccines Work

According to the Government Accountability Office’s (GAO) spotlight on opioid vaccines, the vaccines are designed to block opioids, specifically fentanyl and heroin, from crossing the blood-brain-barrier (BBB), thereby preventing addiction and other negative effects.

Specifically, opioid vaccines are designed to trigger an immune response to chemical structures in opioid molecules. Opioid-specific antibodies stick to opioid molecules in the bloodstream, forming a unit that is too large to enter the central nervous system. By not crossing the BBB, the opioid molecule is not able to cause addiction or overdose death and is eventually excreted from the body.

“Opioid vaccines could offer advantages over current treatment options,” said GAO. “[They] could be useful for at-risk individuals, patients in drug recovery programs and first responders who might accidentally come into contact with deadly opioids that can be absorbed through the skin.”⁷

Academic Research Institutions and Vaccine Manufacturers

For the past decade, several academic research institutions and vaccine manufacturers have partnered to develop an opioid vaccine. Yet, because adjuvants in opioid vaccines bind an opioid and select analogs in circulation, adjuvants are needed to increase the quantity and quality of the anti-drug antibody response in people with opioid addictions. As such, adjuvants, haptens, conjugates and delivery systems will need to be carefully evaluated in clinical trials.

University of Houston/ARMR Sciences, Inc. The University of Houston (UH), in collaboration with Tulane University School of Medicine (that developed the adjuvant), is conducting research for a potential fentanyl vaccine candidate. Having been funded by the Department of Defense since 2016, preclinical studies have been completed, and clinical trials are currently underway.

Colin N. Haile, MD, PhD, research associate professor in the Gibson Addiction Research Laboratory at UH, said, “The adjuvant in this vaccine is a genetically modified non-infectious enterotoxin derived from Escherichia coli and cholera toxin, named dmLT. This adjuvant has been in 15 human clinical trials in combination with other vaccines, one of which was conducted in infants, with minimal to no side effects across studies. As well, this vaccine uses the carrier protein CRM197, which is currently in vaccines on the market.”

In 2021, the results of a study to evaluate adjuvant and delivery strategies for conjugate antigen vaccination with fentanyl-based haptens showed “that dmLT or LTA1 adjuvant, as well as mucosal delivery, may be attractive strategies for improving the efficacy of vaccines against SUD [substance use disorder].”⁸

Although the oral version of this vaccine is still in development, Dr. Haile said, “The results of our 2021 study showed that the oral and intranasal formulations of our vaccine were more efficacious than administering the vaccine intramuscular.”

According to the results of a preclinical study conducted in 2022, the “anti-FEN (fentanyl) vaccine conjugate in combination with the adjuvant dmLT produced significant amounts of anti-FEN antibodies that were associated with complete blockade of FEN-induced analgesia in the tail flick and hotplate tests, rate-disrupting effects on schedule-controlled responding, and physiological effects. … Vaccination also significantly reduced FEN entry into the brain, and anti-FEN antibodies targeted FEN with no cross-reactions to other opioids.”⁹

According to Dr. Haile, the results of the efficacy study of this vaccine in rodents were also successful: “This vaccine did not cause any adverse side effects in the immunized rats in the preclinical trial. The results also showed the vaccine blocked 92 to 98 percent of fentanyl from entering the animal’s brain, and protection lasted 20 weeks, which might translate to up to a year of protection in humans.

“We have now tested our anti-fentanyl vaccine in hundreds, maybe thousands, of rodents in many different analgesic and behavioral paradigms. We recently finished experiments where we combined the vaccine with methadone and naltrexone, and it showed 100 percent blockage of fentanyl-induced analgesia and decreases in O₂ saturation and heart rate in our overdose model. We also showed the vaccine blocks fentanyl-induced reinstatement of drug-seeking behavior in animals self-administering fentanyl.”

The results of the toxicology testing that were conducted in April 2025 were also successful, said Dr. Haile: “The results of the toxicology testing were excellent. We administered 20 times the dose we’re going to administer to humans with no toxicity or adverse effects.”

ARMR Sciences, Inc. (formerly Ovax Inc.), a biodefense company that develops preventive countermeasures to protect against bioweapons, has partnered with UH to develop this fentanyl vaccine candidate. Named ARMR100, the vaccine is in development for military and first responders with potential application for OUD patients.

Collin Gage, founder and CEO of ARMR, said, “ARMR’s Phase I/II trial is scheduled to begin in the first quarter of 2026 and will enroll approximately 40 healthy adults at the Centre for Human Drug Research in the Netherlands. This will be the first time an anti-fentanyl vaccine has been tested in humans.

“The first part of the trial will evaluate the vaccine’s safety and determine the best dosage. Volunteers will receive a series of two administrations in varying doses, and researchers will measure their blood antibody levels. In the second part of the trial, a small group of participants will receive a medical dose of fentanyl so that investigators can study how well the vaccine blocks its effects. We anticipate results of this trial in the first half of 2027.”

Although the efficacy of this vaccine is currently unknown, it is anticipated that the two-shot regimen — potentially eventually a single dose — would protect humans for approximately a year, with the possibility of annual booster shots.

University of Montana (UM)/Inimmune Corp./University of Washington (UW)/Columbia University. With $33.4 million in funding from the National Institutes of Health’s Helping to End Addiction Long-term initiative, UM, in collaboration with Inimmune Corp., UW and Columbia University, began research in 2020 on a heroin and fentanyl vaccine that would protect persons with OUD and those at risk of accidental overdose.

“It [this funding] will allow us to advance lead opioid vaccine candidates to Phase I human clinical trials and better understand the safety and efficacy of our vaccine adjuvants, which early research has shown will be needed to increase the quantity and quality of the anti-drug antibody response in people with opioid addictions,” said Jay Evans, PhD, director of the Center for Translational Medicine at UW.¹⁰

Inimmune Corp. is a biotechnology company that develops innovative immunotherapeutics, vaccine adjuvants and vaccines. Its lead vaccine candidate uses its own adjuvant INI-4001 in combination with a fentanyl hapten conjugated to a carrier protein, CRM-197. The inclusion of INI-4001 increases critical antibody titers, increasing the likelihood of protection in humans.

“Inimmune is a proud supporter of this groundbreaking, anti-fentanyl vaccine to combat one of the worst human-created epidemics in history,” said David Burkhart, PhD, chief executive officer at Inimmune Corp. “This vaccine could save tens of thousands of lives every year and provide relief to families around the world who live in fear of fentanyl overdose of loved ones.”

The results of one preclinical study showed that “the addition of the synthetic TLR7/8 [adjuvant] agonist INI-4001 to our lead anti-fentanyl vaccine significantly increased antigen-specific antibody titers, which led to increases in vaccine efficacy after drug challenge in multiple animal species, drug doses and administration paradigms,” Dr. Burkhart added.¹¹

In addition, he noted that the results of another preclinical study showed “the use of a synthetic TLR7/8 adjuvant, INI-4001, in combination with alum significantly and preferentially increased F1-specific IgG2a antibody titers and significantly increased average polyclonal antibody avidity [the total, accumulated binding strength of a multivalent antibody to a multivalent antigen] for the fentanyl hapten compared to F1-CRM and F1-CRM plus alum.”¹²

“GLP toxicology studies have been completed for both the heroin and fentanyl vaccine candidates and are supportive for advancing these vaccine candidates to human clinical trials,” said Dr. Evans. “The IND for the heroin vaccine has been submitted to the FDA. All IND enabling studies — efficacy, toxicology and GMP manufacturing — are also complete to support the fentanyl vaccine.”

Inimmune and UW have completed the process development and scale-up manufacturing of GMP to produce the volumes and quality of vaccine products necessary for the Phase I clinical trials for both opioid vaccines. Inimmune will manufacture the vaccines for the clinical trials.

UM has also partnered with Marco Pravetoni, PhD, at UW whose research team designs haptens and drug conjugate vaccines that can elicit the production of antibodies against target opioids.

The Phase I clinical trial for the heroin vaccine is in the recruiting stage. This trial is being conducted at Columbia University and will include a drug challenge to evaluate its safety and efficacy. The trial will involve gradual dose escalation, and patients will be followed to evaluate how long the antibodies against the opioid will last.

However, Dr. Evans said, “The Phase I clinical trial for the fentanyl vaccine has been delayed due to recent HHS/NIH budget cuts and administration changes, but the team is hopeful this important vaccine program can secure the necessary funding in 2026 to advance the fentanyl vaccine to Phase I clinical trials.”

Boston Children’s Hospital’s (BCH) Precision Vaccines Program (PVP). Based in the Department of Pediatrics at BCH, the PVP is an academic research program developing the next generation of vaccines tailored to vulnerable populations.

BCH-PVP is working in collaboration with UH and Inimmune to develop a fentanyl vaccine. The goals of this five-year project, currently on extension until 2027, are to identify adjuvants that would boost immune responses to the vaccine in this age group and to explore how opioids themselves affect immune responses.

The PVP applies precision medicine principles to vaccinology, thereby optimizing vaccines specific to vulnerable populations. Since 2019, the PVP has received almost $15 million from The Heal Initiative to work on its vaccine, and by the end of contract, will have received approximately $20 million.

Specifically, BCH-PVP is developing a novel adjuvant — PVP-037 — and a novel antigen — Oxeth-2 — that comprise an adjuvanted fentanyl vaccine. This fentanyl vaccine is comprised of a fentanyl hapten, a fentanyl-like molecule linked to CRM protein (CRM-197) and PVP-037 small molecule (TLR7/8 agonist adjuvant). These formulations are being tested in humans in in vitro assays and in rodents. Inimmune will manufacture the vaccine for clinical trials.

Preclinical trials testing different adjuvants in animal models began in 2023 and are expected to be complete in 2026. To date, the results of these studies show the adjuvanted vaccine demonstrates robust induction of antibodies that can block fentanyl’s actions in animals. BCH-PVP hopes to publish data from this study soon.

“We believe youth and young adults — whether they have an OUD or not — will benefit from a fentanyl vaccine by reducing the risk of life-threatening overdose, which is currently a leading cause of death in this age group,” said Ofer Levy, MD, PhD, director of the PVP-BCH.

New York State Psychiatric Institute. The New York State Psychiatric Institute, in partnership with Columbia University and UW, is currently enrolling 45 participants who have an OUD for its first-in-human, multi-site, oxycodone clinical trial. This study will evaluate the safety, degree of antibody production and preliminary efficacy.

Headed by Sandra D. Comer, PhD, professor of clinical neurobiology in the division on SUD and the Department of Psychiatry at Columbia University, the proposed study is designed as a Phase Ia/Ib clinical trial for an oxycodone Oxy(Gly)4-sKLH conjugate vaccine, adsorbed, which has been developed by Dr. Pravetoni and his team.

Healthy adults, aged 18 to 59 years, who meet DSM-5 criteria for OUD but are not seeking treatment for their drug use and are physically dependent on opioids, are being recruited. This study employs a between-groups, placebo-controlled design: two active vaccine doses and one placebo.

The primary completion of the study (last patient-last visit) is estimated to be at the end of 2026 with the full study results estimated to be available at the end of the first quarter in 2027.¹⁴

CounterX Therapeutics, Inc. Founded in 2025, CounterX Therapeutics, Inc., is a biotechnology company that develops high-affinity monoclonal antibody therapies and vaccines to address OUD and opioid overdose. The company is currently researching two monoclonal antibodies (mAb) and two opioid vaccines.

CTRX-101, a mAb, was designed to bind fentanyl and its potent analogs in the circulation, block distribution to the brain and blunt its life-threatening effects. This mAb is differentiated because it binds directly to fentanyl and sequesters it in the bloodstream and does not interact with mu-opioid receptors in the brain like other available products that treat OUD.

CTRX-101 is a long-acting, once monthly, subcutaneous injectable therapeutic that is not an opioid or a controlled substance. It has been well-tolerated in preclinical models with no serious adverse events when used in combination with other OUD medications. And, it is not expected to cause opioid withdrawal and may be safe when used in combination with other OUD medications.

“Conducted in a translational preclinical model, the study demonstrates that administration of the CTRX-101 effectively restores normal breathing following fentanyl overdose,” a recent study reported.¹⁴ The company anticipates starting a Phase I clinical trial of CTRX-101 in 2026.

CTRX-201 is a next-generation mAb targeting fentanyl and its analogs that displays better safety, broader binding and a prolonged half-life, which will allow dosing every three months, thereby affording long-acting protection against overdose and active treatment of OUDs involving fentanyl and its analogs.

CounterX is also developing two opioid vaccines: CTRX-1001, a fentanyl vaccine for the prevention of accidental overdose in high-risk patients, and CTRX-2001, a heroin vaccine for OUD. These vaccines have reached IND (heroin vaccine) and a near IND completion (fentanyl vaccine).

In animal models, the vaccines provide protection against either fentanyl or heroin-induced pharmacological effects, including respiratory depression, bradycardia and drug self-administration, a preclinical model of OUD. They have also shown safety in various animal models.

“A fentanyl vaccine or mAb could provide a safety net for those patients diagnosed with an OUD, as well as those accidentally exposed to drug mixtures or counterfeit pills containing lethal doses of fentanyl or other related compounds. A vaccine or a mAb can really save lives,” said Dr. Pravetoni.

CounterX has recently completed a licensing agreement with UM and UW, which secured intellectual property rights related to anti-opioid vaccines, antibodies and the CounterXCL discovery platform. This deal will strengthen the company’s position on advancing its lead candidate into clinical trials.

What the Future Holds for Opioid Vaccines

Opioid vaccines are still in the experimental phase with some vaccines currently in the preclinical to early-stage clinical trial phase. Researchers hope an opioid vaccine might be available within the next three to five years, depending on the results of their clinical trials and FDA approvals. Most trials so far have shown very promising results in animals that an opioid vaccine can significantly reduce fentanyl-driven behaviors and blunt its addictive and lethal effects. However, once opioid vaccines become available on the market, they will still need to be used with current OUD treatments.