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A potential vaccine against cocaine abuse

Research is underway to develop an immunizing agent for treating addiction to the drug

Cocaine base: cocaine is the second most consumed illicit substance in Brazil

Foca Lisboa / UFMG

Addiction to cocaine, including derivatives like crack, remains a global public-health concern for which the medical community has yet to find an effective treatment. A team of researchers at the Federal University of Minas Gerais (UFMG) is turning to immunology to find a solution. The group is developing a novel vaccine against cocaine addiction and is currently seeking funding for its first human trials. Initial experiments on animals have demonstrated the vaccine’s ability to stimulate the production of antibodies targeting the cocaine molecule, but they have yet to produce scientific evidence confirming its effectiveness in reducing drug dependency. The researchers plan to conduct further testing in animals before proceeding to clinical trials involving human volunteers, on a yet-to-be-determined date.

“In testing on rodents and nonhuman primates — specifically marmosets of the species Callithrix penicillata — our vaccine, called Calixcoca, produced no significant side effects. We only observed a mild reaction at the injection site, which did not affect the overall health of the animals,” says Frederico Duarte Garcia, a professor in the Mental Health Department at the UFMG School of Medicine, and the lead author of the study.

The name Calixcoca, he says, is inspired by the chemical structure of the immunizing agent, known as calixarene, so named because it resembles a chalice. This molecule serves as the carrier for the antigen, a hapten that is an analogue of cocaine — antigens are high-molecular-weight substances capable of eliciting an immune response.

Pharmacist Paulo Sérgio de Almeida Augusto, a member of the UFMG research group, explains that haptens are tiny molecules that, due to their diminutive size, are typically not recognized by the immune system as invaders, and need to be combined with a larger carrier macromolecule to prompt an immune response within the body. This is the case with cocaine. “Cocaine,” Augusto explains, “represents a foreign molecule within the human body. However, it often lacks the required molecular weight and chemical complexity to elicit a substantial immune response. Although such a response may occur with individuals who use high doses of the drug frequently, it does not occur with every individual.”

The researchers developed their immunizing agent by deriving a hapten from a cocaine molecule specifically modified to bind to the carrier. When coupled with calixarene, this hapten has a higher molecular weight and is able to elicit an immune response. If a vaccinated individual consumes cocaine or crack, the antibodies will bind to the drug molecules in the bloodstream, preventing — or at least reducing — their passage through the blood-brain barrier. This barrier lines the blood vessels that vascularize the central nervous system, acting as a selective gatekeeper that controls the transport of substances into the brain.

UFMGRadiochemical essay images showing a lower concentration of a radiolabeled cocaine analog in the brains of rodents immunized with the UFMG vaccine (pink dots in the center of the image) compared to the control groupUFMG

Radiochemical assays in mice administered the synthesized molecule showed that the vaccine successfully reduced drug transport across the blood-brain barrier in tested animals. “Immunized animals were treated with a radiolabeled analogue of cocaine. Immunosorbent assays detected a lower concentration of this compound in the brain and a higher concentration in the bloodstream compared to animals that received only the placebo,” explains Augusto. The study results were published in the Journal of Advanced Research.

The UFMG researchers hypothesize that if the vaccine is able to prevent cocaine molecules from crossing the blood-brain barrier, individuals will no longer feel the same pleasurable sensations that previously triggered the brain’s reward circuitry, driving compulsive behavior. This, however, has yet to be demonstrated in clinical trials. “Without the compulsion, patients gain the opportunity to reclaim their family life, professional pursuits, and rediscover the other pleasures and interests that were once overshadowed by addiction,” explains Garcia.

A long-standing challenge
The new therapeutic approach is viewed with guarded optimism by drug addiction experts. “Medicine has yet to develop an approved drug for fighting addiction. Current treatments primarily focus on managing the symptoms of withdrawal and related disorders, coupled with behavioral therapy,” explains Fábio Cardoso Cruz, a professor of biochemistry in the Department of Pharmacology at the Federal University of São Paulo (UNIFESP) who was not involved in the UFMG study.

Cruz is currently researching the neurobiological mechanisms underlying relapse to cocaine use, in a FAPESP-funded project. His study aims to answer the question of why 70% to 80% of individuals relapse during treatment. “This shows the urgent need to develop new therapeutic strategies. Vaccines are now emerging as a promising pharmacological approach,” he says.

Calixcoca is not the first immunology-based therapeutic formulation to tackle substance dependence. “The therapeutic potential of vaccines against drug addiction was first demonstrated in the mid-1970s when a conjugate of morphine and bovine serum albumin was found to mildly reduce self-administration of heroin in a rhesus monkey. The 1990s saw the first papers describing attempts to develop vaccines against cocaine and nicotine,” says Cruz. The experiment with the rhesus monkey was reported in Molecular Psychiatry in 1974.

UFMGRaissa Pereira, a PhD student at UFMG, holding a vial containing the Calixcoca vaccine formulationUFMG

Despite the promising results in preclinical trials and some early clinical trials, no antidrug vaccines have yet been approved. “Several hurdles remain on the path to clinical success. Notably, not all individuals respond uniformly to these vaccines, and some may fail to produce the levels of antibodies necessary for achieving the desired clinical efficacy,” says Cruz from UNIFESP.

“In general, vaccines are shown to be efficient in animal models. However, when they progress to the clinical trial phase, results often fall short of expectations,” says Denise Morais da Fonseca, an immunologist affiliated with the Institute of Biomedical Sciences at the University of São Paulo (ICB-USP). In March, she collaborated in developing an ICB course on pharmacological treatments for addiction. In preparation, she delved into literature reviews concerning drug vaccines — with rather disappointing results. “A 2022 review documented 23 clinical trials involving antidrug vaccines, with six targeting cocaine addiction — most were focused on nicotine,” notes Fonseca. “Every single one of them failed.”

Some vaccines, she elaborates, failed to elicit a sufficient quantity of antibodies, or the immune response waned far too quickly. The precise reasons behind these results remain unclear, although they might be attributed to genetic variability among the individuals tested — a factor absent in animal models. “In most studies, researchers use isogenic mice, meaning they are genetically identical,” Fonseca explains.

Another possible explanation could lie in the behavior of the vaccine recipients themselves. “In some unsuccessful trials, individuals struggling with addiction consumed larger drug doses to achieve the desired effect,” she remarks.

The UFMG researchers recognize the theoretical risk of individuals attempting to overcome the vaccine’s effects by consuming larger doses of cocaine to reactivate the brain’s reward circuitry. According to Augusto, this concern will be addressed in subsequent studies using experimental models that can estimate the quantity of drug that the vaccine is capable of blocking. “Our primary goal is to roadblock the compulsion mechanism,” notes Garcia. “Beyond a certain point, increased consumption would significantly raise the cost for the user, to a point where it becomes financially prohibitive.”

The UFMG group is confident that Calixcoca will outperform the efficacy of previous candidates. Their confidence stems from the vaccine’s unique chemical composition. “The key distinction in our proposition is that the vaccine has no protein base. Calixarene is a synthetic organic substance,” summarizes Ângelo de Fátima, a professor at the UFMG Department of Chemistry who developed the vaccine’s immunogenic platform.

Prior antidrug vaccine programs relied on proteins as carriers, some of which had been employed in other commercially available vaccines. This raised concerns about potential sensitization issues. “Patients reacted not only against the drug but also against these proteins. Our vaccine induces a better response because it introduces an entirely new molecule to the body,” says Garcia.

Another significant advantage of the new formulation, say its developers, lies in its production process. “Calixarene is a more stable substance and doesn’t require a cold chain for production and storage. This makes the process more cost-effective,” explains Garcia. A cold chain refers to the logistics of handling, storing, distributing, and transporting temperature-sensitive medications.

Even if Calixcoca proves effective in generating antibodies against cocaine in humans during future clinical studies, it will need additional therapeutic support, notes Cruz, drawing on his research into the biological mechanisms of addiction. He notes that patients’ associative memory related to drug use can be triggered by various cues, such as stress or exposure to environments and settings associated with drug use.

Alexandre Affonso / Revista Pesquisa FAPESP

When a person has chronically used a particular substance, the brain associates the drug’s effects with the location where it was typically consumed, the objects used to consume it, the people around, and even clothing worn during these occasions. Exposure to these elements can ignite an uncontrollable craving for the substance. “Vaccines can be used as part of an integrated approach combining behavioral therapy, psychosocial support, and other interventions to assist individuals in overcoming addiction,” says Cruz.

“Antidrug vaccines need to be thought of as a component of broader public programs,” adds Fonseca from ICB-USP. She sees several ethical issues surrounding the use of vaccines. “Will we employ them as therapeutic or prophylactic vaccines? Will we screen high-risk groups for vaccination?” she asks. One potential use of the new pharmaceutical, according to Cruz, could be in protecting expecting mothers and their infants from the harm caused by prenatal drug exposure. This is another facet of the UFMG group’s research, and a subject of Paulo Augusto’s doctoral thesis in molecular medicine, which he defended in 2020.

Cruz notes that cocaine exposure during pregnancy poses risks not only to mothers, who may experience miscarriages or complications during delivery, but also to fetuses and infants, with long-term implications throughput the child’s lifetime. Prematurity, low birth weight, impaired neurobiological development, malformations, and an increased risk of developing psychiatric disorders in adolescence are among the deleterious effects associated with cocaine use during pregnancy. “The best approach to prevent prenatal cocaine exposure is to cease consumption. However, only 25% of cocaine users manage to quit while pregnant,” notes Augusto.

His doctoral research served as a proof of concept for administering the anticocaine vaccine during pregnancy, based on testing on pregnant rats. Published in Molecular Psychiatry in 2021, his paper was the first study to report the efficacy of an immunizing agent during gestation. This project ran when Calixcoca was still being developed, so Augusto chose to use a vaccine created by American researcher Kim Janda, known as GNE-KLH. This vaccine, the culmination of studies dating back to the 1990s, demonstrated promising results in preclinical testing but failed to yield the anticipated effects in clinical trials.

In animal testing, however, the outcomes were positive. “Compared to mothers treated with a placebo, those vaccinated during pregnancy exhibited higher gestational weight gain and larger litters,” the researcher reports. “Anticocaine antibodies were detected in fetuses, newborns, and even in breast milk.”

These antibodies also helped to mitigate the hyperactivity and hyperlocomotion effects induced by cocaine in newly weaned offspring, he adds. To validate this hypothesis, the rodents received doses of cocaine and were subsequently placed inside boxes for observation. “The typical behavior of the pups is to huddle in a corner of the box. Under the influence of cocaine, they became more uninhibited, moving throughout the box’s space. However, those administered antibodies exhibited their normal behavior.” The UFMG group plans to replicate the same experiment using Calixcoca.

For Cruz, scientists must seek to gain an understanding of the mechanisms of addiction in order to find novel approaches to treatment. “Addiction has not yet been treated with the compassion it deserves. It’s not a character flaw or lack of willpower; it’s a lifelong illness.”

The UFMG group has been in discussions with potential funders for clinical trials. In June, the municipal government of São Paulo announced a R$4 million grant for the project and its intention to evaluate administration of the vaccine among eligible groups, including recovering drug addicts, in the next phase of trials. Conversations are also underway with the São Paulo state government and the Butantan Institute. “We’ll require R$30 million for the Phase I and II clinical studies, which are expected to take between two and three years to complete,” says Cruz.

The researchers have already filed a patent for the vaccine candidate on behalf of UFMG and the Minas Gerais State Research Foundation (FAPEMIG), which is funding the project. In May, the UFMG study was selected as a finalist for the 2nd Euro Innovation in Health Award, an international initiative recognizing medical innovations, sponsored by Brazilian pharmaceutical company Eurofarma.

Neurobiological study of cocaine and crack abuse relapse: Identification of plasticities in neuronal ensembles that store memories related to drug addiction (nº 18/15505-4); Grant Mechanism Young Investigator Award; Principal Investigator Fabio Cardoso Cruz (UNIFESP); Investment R$3,237,915.96.

Scientific articles
SABATO, B. et al. Safety and immunogenicity of the anti-cocaine vaccine UFMG-VAC-V4N2 in a non-human primate model. Vaccine. mar. 24, 2023.
ASSIS, B. R. D. et al. Low doses of pharmaceutical formulations loaded with UFMG-V4N2 immunogen induce the production of IgG anti-cocaine antibodies and provide evidence of cerebral protection in the preclinical model. Journal of Colloid and Interface Science (JCIS) Open. vol. 9, apr. 2023.
NETO, L. S. et al. Calix[n]arene-based immunogens: A new non-proteic strategy for anti-cocaine vaccine. Journal of Advanced Research. vol. 38, pp. 285–98. may 2022.
AUGUSTO, P. S. A. et al. The GNE-KLH anti-cocaine vaccine protects dams and offspring from cocaine-induced effects during the prenatal and lactating periods. Molecular Psychiatry. aug. 11, 2021.
BLOOM, B. T. et al. Vaccines against Drug Abuse ‒ Are we there yet? Vaccines. may 27, 2022.