Nicotine vaccine

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Nicotine vaccine is a novel immunological strategy for treating nicotine addiction. [1] Nicotine vaccine uses active immunization as the methodology to create polyclonal antibodies to the antigens, which is then used to treat drug abuse. [2] The immune system is then able to identify nicotine as a foreign substance and initiate an immune reaction targeting the drug. As a result, the quantity of nicotine that enters the brain would decrease after receiving the vaccine. [3] In preclinical studies, nicotine vaccines have demonstrated the ability to combat the negative effects of nicotine abuse, but none of the developed vaccines has been authorized for use in clinical trials as a smoking cessation strategy. [4] Theoretically, the decrease of nicotine's rewarding effects should result in smoking cessation. Some companies have tested candidate vaccines in clinical trials, but evidence failed to show the adequate antibody responses or exhibit superior efficacy to factors concerning placebo. [5]

Contents

Addiction and withdrawal

Nicotine increases dopamine release in a synapse Nicotine increases dopamine release in a synapse.gif
Nicotine increases dopamine release in a synapse

The aim of Nicotine vaccines is to prevent smoking relapse. Past studies discovered that the region ventral tegmental area (VTA) in which the dopaminergic neurons are located, is where nicotine binds to and activates its nAChR receptor, resulting in the release of dopamine. [7] Aside from dopamine release, there are additional neurotransmitters released, which include norepinephrine, acetylcholine, serotonin, γ-aminobutyric acid (GABA), glutamate, and endorphins. [8]

Tobacco, the use of which is considered by the World Health Organization to be a global epidemic, contains the highly addictive substance nicotine. [9] The increased dopamine level increases which results in drug dependence, in which smokers often face difficulties during the process of nicotine withdrawal. [7]

The main neurotransmitter dopamine contributes strongly to the rewarding system [10] experienced and reported by smokers, such as arousal, improved performance, pleasure and improved moods, which are all desired psychological states. [11]

Nicotine withdrawal symptoms include anxiety, stress, irritability, depressed mood, difficulty concentrating, increased sense of hunger, increased eating, insomnia, and addiction to tobacco. [8] Smokers that encounter these negative withdrawal symptoms choose to avoid such negative experiences and smoke tobacco again for the relief of nicotine withdrawal symptoms, resulting in relapse. [8]

Formulation

The constitution of nicotine vaccines involves the addition of adjuvants to the conjugation between synthetic drug-derived haptens [7] which share structural similarities to nicotine, and the immunogenic carrier protein. Altogether, this formulation is known as a conjugate vaccine.

The linker is vital for linking the hapten to the carrier protein, providing the appropriate geometry for the binding of hapten to B cells. Linkers also ensure that the number of nicotine haptens available for binding to B cells is optimal. [12] The carrier proteins used are all able to produce an immune response. [12]

Mechanism of action

Nicotinic Acetylcholine receptor Nicotinic Acetylcholine receptor.png
Nicotinic Acetylcholine receptor

Nicotine, an addictive natural substance present in tobacco, works as an agonist for the nicotinic acetylcholine receptor (nAChR). Pharmaceutical vaccine haptens attempt to imitate the structure of nicotine since the metabolites of nicotine (half-life of nicotine = 1–2 hours) are less physiologically active than the parent compound. [2] Nicotine vaccines are immunogens made up of synthetic drug haptens connected to immunogenic carriers, which are then packaged in adjuvants to boost immunogenicity. [4] The conjugate vaccine produces a strong immunogenic response from the body by stimulating the production of antibodies, which is administered through a vaccination.

A drug molecule with its structural composition altered and a chemical linker connected is referred to as a hapten. The immunogenic portion of the vaccine is linked to the hapten by a conjugated protein/macromolecular carrier. The entire configuration is called a hapten-conjugated protein/macromolecular carrier. Adjuvants are substances with aluminum content that strengthen immunity by improving the immune reaction to the antigen. Vaccine adjuvants are frequently used to curb drug abuse. [14]

T-dependent B cell activation T-dependent B cell activation.png
T-dependent B cell activation

Conjugated immunogens are injected to deliver the vaccine, which activates B and T cells in a T cell-dependent manner to create polyclonal anti-nicotine antibodies. The conjugated vaccine is exposed to lymphocytes by antigen-presenting cells. There is recognition of the peptide antigen by T-cell receptors. [16] With the involvement of cytokines and B cells, a humoral response [16] is elicited, which result in the synthesis of antibodies. Plasmatic cells produce immunoglobulins, the anti-nicotine antibodies that bind to nicotine. The nicotine and nicotine-specific antibodies are bound together, forming a complex. The complex prevents nicotine from passing through the blood-brain barrier, consequently inhibiting it from reaching the brain's nAChRs. [4]

Blood Brain Barrier Blood Brain Barriere.jpg
Blood Brain Barrier

The explanation for this is that when anti-nicotine antibodies bind to the nicotine molecules there is an increase in the overall molecular size. [18] This blocks it from passing through the blood-brain barrier, and so nicotine is unable to generate the multiple neurotransmitters to exhibit its CNS effects.This prevents the synthesis of adrenaline and dopamine, [16] which are the associated rewarding CNS effects that cause addiction, thereby inhibiting the pharmacological effects of nicotine.

Alternatives for smoking cessation

Bupropion Bupropion-zyban.jpg
Bupropion

Only nicotine replacement (patches or gum), the antidepressant bupropion, and the nicotinic receptor agonist varenicline are available to help tobacco users reduce their smoking while managing their addiction. [20] However, less than one-third of the treatment receivers had quit, and only one-third of them succeeded in quitting for more than six months. [21] Furthermore, more than half of those who received smoking cessation medication returned. [22] New strategies are required to solve this significant health issue in the midst of these obstacles in order to promote smoking cessation.

Immunotherapy-based methods, such as the use of vaccines to treat addiction, have been documented in the literature since the 1960s and 1970s. [23] A number of researchers re-evaluated the immunizations as side effects linked to licensed nicotine replacement therapy use have arisen. [24] Due to their capacity to generate high-affinity anti-drug IgG antibodies, conjugate vaccines show potential as an alternative method of treating drug use disorders. [2]

The list of nicotine vaccines that have been developed and included in trials include Nic-QB (NIC002), NicVax, Niccine and TA-NIC. [10]

Developmental challenges

Despite substantial efforts that have been exerted to methodically examine the efficacy of nicotine-based haptens with various lengths, polarities, and flexibility, obtaining adequately high and stable immunogenicity over extended periods of time is a major challenge. [25]

Although the use of nicotine vaccines may produce high levels of anti-nicotine antibodies to bind to all nicotine molecules and reduce the nicotine's effects on the brain by inhibiting its distribution, the dissociation rate constant (Kd) will determine whether there is a possibility of reversing the binding. [12]

Dosage

A total of three priming injections spaced 2–4 weeks apart are typically used in the conjugate vaccination regimen. The function of antibodies is dependent on two factors. The first factor is “titer”, which refers to the number of antibodies present, and the second factor is the “affinity” of the anti-nicotine antibody to the nicotine. [11]

Peak titer levels are reached between 2–4 weeks after a single injection and then begin to drop until a booster injection is given for the maintenance of nicotine antibody levels, due to the degradation [2] of antibodies. The vaccine boosters are appropriate to use, usually 2–3 months after the last priming injection. [26] [27] Although infectious disease vaccines can be useful for many years without injecting boosters, drug vaccines are likely to require shorter booster intervals of one year or less. [2]

Rationale for booster

The small size of nicotine molecule makes up its relatively low molecular weight, and an individual's immune system is unable to respond with an immune response. Thus the methodology and practice behind nicotine vaccines are through repeated vaccine administration in order to maintain the vital serum levels of nicotine antibodies. This rationale is from the consideration of therapeutic antibody degradation. [16]

Secondary Immune Response Humeral Secondary Immune Response.png
Secondary Immune Response

The purpose of the use of a booster is different from the mechanism of the first vaccination of the nicotine-conjugate vaccine. The first vaccination marks the immune system’s initial contact with the antigen, which is how immunological memory functions. [29] The booster vaccines are for the production of antibodies which utilize the immune system’s memory regarding the encounter with antigens. This methodology will allow booster vaccines to generate a more rapid and efficient response to the antigen. [16]

Adverse effects

Clinical studies with cocaine and nicotine, which commonly used doses of 200 or 400 micrograms per dose, have shown convincing evidence that doses of immunobinding agents, even up to 2 mg per dose, are positively correlated with titer levels. [30] [31] Since there was no ceiling effect, these findings imply that the optimal dose was the highest dose of the vaccine that can be administered without causing adverse reactions. So far, no clinical conjugate vaccine studies have found any major adverse reactions to drug or vaccine conjugates. [31]

Pros and cons

The preferred technique for treating drug use disorders is active immunization because it is relatively safe and convenient in that the effect lasts even after several doses of the vaccine. [4] Compared to small molecule medications, vaccines have a much-extended duration of action because they generate IgG antibodies with a longer half-life. [2]

Conjugated vaccines act as immune antagonists that hinder the efficacy of the target substances. The anti-drug antibodies do not affect drug receptors in the brain or periphery, and therefore, the side effects are negligible. [2]

One additional advantage of conjugate vaccines is that they are universal and can be created to target any single drug or drug combinations in theory. [2]

Despite having long-lasting impacts, the vaccination strategy's antibody response is comparatively slow. [24]

The effectiveness of the active vaccination method in changing behavior has not been established. They do not lessen withdrawal signs or drug cravings. [2]

Efficacy

Animal trials

To produce antibodies to measure nicotine amounts in human blood and urine, a trans-3′-succinimidylmethyl nicotine conjugate was coupled to KLH and administered to rabbits. [24] Soon after, a 6-(p-aminobenzamide) nicotine conjugate-based BSA-conjugated vaccine was created, and it was once more shown to induce an animal model to generate an antibody response against nicotine. [24] The produced antibodies were found to have a high affinity for nicotine at various binding locations, which strongly supported their use. [24] After receiving a vaccination with a conjugate vaccine made of a 6-(carboxymethylurea)-()-nicotine conjugate conjugated with KLH, rats developed antibodies that significantly bound nicotine in the plasma but had no impact on nicotine levels in the brain, limiting the vaccine's potential efficacy. [24] Animal studies have been more successful when using more contemporary methods. [24] The nicotine levels in the rat brain and the rat's motor activity in reaction to a nicotine challenge were lowered by a vaccine using a non-nicotine conjugate linked to KLH via a novel linker protein (dubbed NIC). [3]

In non-human primates, a second-generation nicotine combination called NIC7 demonstrated potential in producing anti-nicotine antibodies, which may lower the drug's concentration in the brain. [25] [32] It has been demonstrated that a completely synthetic nicotine vaccine (SEL-068) that contains an unidentified hapten prevents nicotine discrimination in non-human primates. [33] [34]

Human clinical trials

The results of several vaccine candidates that have reached human trials have, generally speaking, been discouraging. [24]

In a Phase I trial involving 68 smokers, the 3′-AmNic-rEPA vaccine, also known as "NicVax," a 3'-aminomethyl nicotine conjugate conjugated to Pseudomonas aeruginosa exoprotein A, demonstrated a positive response. [24] Higher doses resulted in higher levels of abstinence, and the medication had a favorable safety profile. [35] Positive findings from phase II trials showed strong antibody outcomes and higher quit percentages in the treatment group in comparison to the placebo group. [30] The vaccine was advanced to a phase III trial, but it was unable to achieve its endpoints as a single intervention or in combination with varenicline and counseling. [36]

In trials, the Niccine tetanus toxoid conjugate vaccine, which had an acceptable safety profile, demonstrated a comparable impact without altering smokers' habits. [37] NIC-002 contained nicotine conjugated to virus-like particles, also failed to achieve major clinical endpoints in the trial. [38] It showed a marginally higher rate of smoking cessation at the two months but no change at the six months. [38] TA-NIC was withdrawn since it failed to reach its clinical endpoints. [24]

Despite many clinical trials, there is still a lack of evidence that supports vaccines as the effective solution to preventing drug abuse. Low antibody responses, short-lived antibody responses, individual differences in antibody responses, and continued substance use in the presence of an antibody response contribute to the undesired efficacy. [14]

Related Research Articles

<span class="mw-page-title-main">Nicotine</span> Chemical stimulant produced by some plants

Nicotine is a naturally produced alkaloid in the nightshade family of plants and is widely used recreationally as a stimulant and anxiolytic. As a pharmaceutical drug, it is used for smoking cessation to relieve withdrawal symptoms. Nicotine acts as a receptor agonist at most nicotinic acetylcholine receptors (nAChRs), except at two nicotinic receptor subunits where it acts as a receptor antagonist.

<span class="mw-page-title-main">Smoking cessation</span> Process of discontinuing tobacco smoking

Smoking cessation, usually called quitting smoking or stopping smoking, is the process of discontinuing tobacco smoking. Tobacco smoke contains nicotine, which is addictive and can cause dependence. As a result, nicotine withdrawal often makes the process of quitting difficult.

Haptens are small molecules that elicit an immune response only when attached to a large carrier such as a protein; the carrier may be one that also does not elicit an immune response by itself. The mechanisms of absence of immune response may vary and involve complex immunological interactions, but can include absent or insufficient co-stimulatory signals from antigen-presenting cells.

<span class="mw-page-title-main">Nicotine replacement therapy</span> Treatment for tobacco use disorder

Nicotine replacement therapy (NRT) is a medically approved way to treat people with tobacco use disorder by taking nicotine through means other than tobacco. It is used to help with quitting smoking or stopping chewing tobacco. It increases the chance of quitting tobacco smoking by about 55%. Often it is used along with other behavioral techniques. NRT has also been used to treat ulcerative colitis. Types of NRT include the adhesive patch, chewing gum, lozenges, nose spray, and inhaler. The use of multiple types of NRT at a time may increase effectiveness.

<span class="mw-page-title-main">Conjugate vaccine</span> Type of vaccine

A conjugate vaccine is a type of subunit vaccine which combines a weak antigen with a strong antigen as a carrier so that the immune system has a stronger response to the weak antigen.

An immunogen is any substance that generates B-cell (humoral/antibody) and/or T-cell (cellular) adaptive immune responses upon exposure to a host organism. Immunogens that generate antibodies are called antigens ("antibody-generating"). Immunogens that generate antibodies are directly bound by host antibodies and lead to the selective expansion of antigen-specific B-cells. Immunogens that generate T-cells are indirectly bound by host T-cells after processing and presentation by host antigen-presenting cells.

Immunogenicity is the ability of a foreign substance, such as an antigen, to provoke an immune response in the body of a human or other animal. It may be wanted or unwanted:

<span class="mw-page-title-main">Varenicline</span> Nicotinic receptor agonist

Varenicline, sold under the brand names Chantix and Champix among others, is a medication used for smoking cessation and for the treatment of dry eye disease. It is a nicotinic receptor partial agonist and a cholinergic agonist. When activated, this receptor releases dopamine in the nucleus accumbens, the brain's reward center, thereby reducing cravings and withdrawal symptoms associated with smoking cessation.

NicVAX is an experimental conjugate vaccine intended to reduce or eliminate physical dependence to nicotine. According to the U.S. National Institute of Drug Abuse, NicVAX can potentially be used to inoculate against nicotine addiction. This proprietary vaccine is being developed by Nabi Biopharmaceuticals of Rockville, MD. with the support from the U.S. National Institute on Drug Abuse. NicVAX consists of the hapten 3'-aminomethylnicotine which has been conjugated (attached) to Pseudomonas aeruginosa exotoxin A.

<span class="mw-page-title-main">Monoclonal antibody therapy</span> Form of immunotherapy

Monoclonal antibodies (mAbs) have varied therapeutic uses. It is possible to create a mAb that binds specifically to almost any extracellular target, such as cell surface proteins and cytokines. They can be used to render their target ineffective, to induce a specific cell signal, to cause the immune system to attack specific cells, or to bring a drug to a specific cell type.

<span class="mw-page-title-main">Lobeline</span> Chemical compound

Lobeline is a piperidine alkaloid found in a variety of plants, particularly those in the genus Lobelia, including Indian tobacco, Devil's tobacco, great lobelia, Lobelia chinensis, and Hippobroma longiflora. In its pure form, it is a white amorphous powder which is freely soluble in water.

<span class="mw-page-title-main">Nicotine dependence</span> Chronic disease

Nicotine dependence is a state of dependence upon nicotine. Nicotine dependence is a chronic, relapsing disease defined as a compulsive craving to use the drug, despite social consequences, loss of control over drug intake, and emergence of withdrawal symptoms. Tolerance is another component of drug dependence. Nicotine dependence develops over time as a person continues to use nicotine. The most commonly used tobacco product is cigarettes, but all forms of tobacco use and e-cigarette use can cause dependence. Nicotine dependence is a serious public health problem because it leads to continued tobacco use, which is one of the leading preventable causes of death worldwide, causing more than 8 million deaths per year.

TA-CD is a vaccine developed by the Xenova Group and designed to negate the effects of cocaine, making it suitable for use in treatment of addiction. It is created by combining norcocaine with inactivated cholera toxin.

A subunit vaccine is a vaccine that contains purified parts of the pathogen that are antigenic, or necessary to elicit a protective immune response. Subunit vaccine can be made from dissembled viral particles in cell culture or recombinant DNA expression, in which case it is a recombinant subunit vaccine.

TA-NIC is a proprietary vaccine in development similar to TA-CD but being used to create human anti-nicotine antibodies in a person to destroy nicotine in the human body so that it is no longer effective.

Schizophrenia and tobacco smoking have been historically associated. Smoking is known to harm the health of people with schizophrenia.

<span class="mw-page-title-main">Substance use disorder</span> Continual use of drugs (including alcohol) despite detrimental consequences

Substance use disorder (SUD) is the persistent use of drugs despite the substantial harm and adverse consequences to one's own self and others, as a result of their use. In perspective, the effects of the wrong use of substances that are capable of causing harm to the user or others, have been extensively described in different studies using a variety of terms such as substance use problems, problematic drugs or alcohol use, and substance use disorder. The National Institute of Mental Health (NIMH) states that "Substance use disorder (SUD) is a treatable mental disorder that affects a person's brain and behavior, leading to their inability to control their use of substances like legal or illegal drugs, alcohol, or medications. Symptoms can be moderate to severe, with addiction being the most severe form of SUD". Substance use disorders (SUD) are considered to be a serious mental illness that fluctuates with the age that symptoms first start appearing in an individual, the time during which it exists and the type of substance that is used. It is not uncommon for those who have SUD to also have other mental health disorders. Substance use disorders are characterized by an array of mental/emotional, physical, and behavioral problems such as chronic guilt; an inability to reduce or stop consuming the substance(s) despite repeated attempts; operating vehicles while intoxicated; and physiological withdrawal symptoms. Drug classes that are commonly involved in SUD include: alcohol (alcoholism); cannabis; opioids; stimulants such as nicotine, cocaine and amphetamines; benzodiazepines; barbiturates; and other substances.

<span class="mw-page-title-main">Addiction</span> Disorder resulting in compulsive behaviours

Addiction is a neuropsychological disorder characterized by a persistent and intense urge to use a drug or engage in a behaviour that produces natural reward, despite substantial harm and other negative consequences. Repetitive drug use often alters brain function in ways that perpetuate craving, and weakens self-control. This phenomenon – drugs reshaping brain function – has led to an understanding of addiction as a brain disorder with a complex variety of psychosocial as well as neurobiological factors that are implicated in addiction's development. Classic signs of addiction include compulsive engagement in rewarding stimuli, preoccupation with substances or behavior, and continued use despite negative consequences. Habits and patterns associated with addiction are typically characterized by immediate gratification, coupled with delayed deleterious effects.

Jed Eugene Rose is an American academic professor, inventor and researcher in the field of nicotine and smoking cessation. Rose is presently the President and CEO of the Rose Research Center, LLC in Raleigh, North Carolina. Additionally, he is the Director of the Duke Center for Smoking Cessation at Duke University Medical Center.

Exposure to nicotine, from conventional or electronic cigarettes during adolescence can impair the developing human brain. E-cigarette use is recognized as a substantial threat to adolescent behavioral health. The use of tobacco products, no matter what type, is almost always started and established during adolescence when the developing brain is most vulnerable to nicotine addiction. Young people's brains build synapses faster than adult brains. Because addiction is a form of learning, adolescents can get addicted more easily than adults. The nicotine in e-cigarettes can also prime the adolescent brain for addiction to other drugs such as cocaine. Exposure to nicotine and its great risk of developing an addiction, are areas of significant concern.

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