NicVAX is an experimental

conjugate 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. Vaccines are used to prevent diseases by invoking an immune ...

intended to reduce or eliminate

physical dependence Physical dependence is a physical condition caused by chronic use of a tolerance-forming drug, in which abrupt or gradual drug withdrawal causes unpleasant physical symptoms. Physical dependence can develop from low-dose therapeutic use of certai ...

nicotine Nicotine is a natural product, naturally produced alkaloid in the nightshade family of plants (most predominantly in tobacco and ''Duboisia hopwoodii'') and is widely used recreational drug use, recreationally as a stimulant and anxiolytic. As ...

. 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 In immunology, 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 (in general, only large molecules, i ...

3'-aminomethylnicotine which has been conjugated (attached) to ''

Pseudomonas aeruginosa ''Pseudomonas aeruginosa'' is a common encapsulated, gram-negative, aerobic–facultatively anaerobic, rod-shaped bacterium that can cause disease in plants and animals, including humans. A species of considerable medical importance, ''P. aerugi ...

exotoxin A The Pseudomonas exotoxin (or exotoxin A) is an exotoxin produced by ''Pseudomonas aeruginosa''. ''Vibrio cholerae'' produces a similar protein called the Cholix toxin (). It inhibits elongation factor-2. It does so by ADP-ribosylation of EF2 u ...

. Early trials of NicVax were promising; two successive phase III trials showed results no better than placebo,http://phx.corporate-ir.net/phoenix.zhtml?c=100445&p=irol-newsArticle&ID=1586001&highlight=http://phx.corporate-ir.net/phoenix.zhtml?c=100445&p=irol-newsArticle&ID=1626882&highlight= and a more recent study showed that the drug decreased subjects' cravings for cigarettes.

Mechanism

Nicotine is a small

molecule A molecule is a group of two or more atoms held together by attractive forces known as chemical bonds; depending on context, the term may or may not include ions which satisfy this criterion. In quantum physics, organic chemistry, and bioch ...

that, after inhalation into the lungs, quickly passes into the

bloodstream The blood circulatory system is a system of organs that includes the heart, blood vessels, and blood which is circulated throughout the entire body of a human or other vertebrate. It includes the cardiovascular system, or vascular system, tha ...

, subsequently crossing the

blood–brain barrier The blood–brain barrier (BBB) is a highly selective semipermeable membrane, semipermeable border of endothelium, endothelial cells that prevents solutes in the circulating blood from ''non-selectively'' crossing into the extracellular fluid of ...

. Once in the brain, it binds to specific nicotine

receptors Receptor may refer to: *Sensory receptor, in physiology, any structure which, on receiving environmental stimuli, produces an informative nerve impulse *Receptor (biochemistry), in biochemistry, a protein molecule that receives and responds to a n ...

, resulting in the release of neurotransmitters, such as

dopamine Dopamine (DA, a contraction of 3,4-dihydroxyphenethylamine) is a neuromodulatory molecule that plays several important roles in cells. It is an organic compound, organic chemical of the catecholamine and phenethylamine families. Dopamine const ...

and

norepinephrine Norepinephrine (NE), also called noradrenaline (NA) or noradrenalin, is an organic chemical in the catecholamine family that functions in the brain and body as both a hormone and neurotransmitter. The name "noradrenaline" (from Latin '' ad'', ...

. NicVAX is a relapse prevention therapy designed to stimulate the

immune system The immune system is a network of biological processes that protects an organism from diseases. It detects and responds to a wide variety of pathogens, from viruses to parasitic worms, as well as cancer cells and objects such as wood splinte ...

to produce

antibodies An antibody (Ab), also known as an immunoglobulin (Ig), is a large, Y-shaped protein used by the immune system to identify and neutralize foreign objects such as pathogenic bacteria and viruses. The antibody recognizes a unique molecule of the ...

that bind to nicotine in the bloodstream and prevent and/or slow it from crossing the blood–brain barrier and entering the brain. With a reduced amount of nicotine reaching the brain, neurotransmitter release is greatly lessened and the pleasurable, positive-reinforcing effects of nicotine are diminished. Pre-clinical studies with the vaccine have shown that vaccination slows and decreases the amount of nicotine that reaches the brain and blocks the effects of nicotine, including effects that can reinforce and maintain addiction in animals. Therefore, if a recently quit tobacco smoker is vaccinated and has a tobacco cigarette after the immunization series is completed, the antibodies generated by the vaccine bind nicotine and alter its distribution into the brain. Because not enough nicotine enters the brain, addiction-relevant neural pathways are not activated. No pleasure is derived from the tobacco cigarette and the vaccinated subject does not relapse and begin smoking again. NicVAX is administered by

injection Injection or injected may refer to: Science and technology * Injective function, a mathematical function mapping distinct arguments to distinct values * Injection (medicine), insertion of liquid into the body with a syringe * Injection, in broadca ...

into the arm; the 3'-aminomethylnicotine molecule found in the vaccine instigates an

immune response An immune response is a reaction which occurs within an organism for the purpose of defending against foreign invaders. These invaders include a wide variety of different microorganisms including viruses, bacteria, parasites, and fungi which could ...

in which 'nicotine'

are created. The antibodies bind to nicotine molecules, causing the nicotine-antibody complexes to be too large to enter the brain; this prevents nicotine from being able to affect addiction-relevant pathways in the brain. The idea behind the drug is that since often even a single cigarette can deliver enough nicotine to the brain to reinstate the addiction, blocking the entry of nicotine into the brain might prevent this renewed dependence. This treatment works for nicotine addiction from any source. ''

Clinical Pharmacology & Therapeutics ''Clinical Pharmacology & Therapeutics'' is a monthly peer-reviewed medical journal which covers research on the nature, action, efficacy, and evaluation of therapeutics. The editor-in-chief is Piet van der GraafCetara. The journal was establishe ...

'' considers this method "attractive," since the antibody does not enter the brain; as a result, side effects on the

central nervous system The central nervous system (CNS) is the part of the nervous system consisting primarily of the brain and spinal cord. The CNS is so named because the brain integrates the received information and coordinates and influences the activity of all par ...

are minimal, if any. Additionally, the antibodies produced bind only to nicotine and not to nicotine metabolites or any similar endogenous structures such as acetylcholine. However, while this drug may curtail addiction, it does not prevent psychological cravings; a user could potentially smoke heavily to compensate for the nullifying effects of NicVAX. However, a study performed indicated that this did not happen among the test subjects.

Studies

Initial tests, involving injections of nicotine-specific

immunoglobulin An antibody (Ab), also known as an immunoglobulin (Ig), is a large, Y-shaped protein used by the immune system to identify and neutralize foreign objects such as pathogenic bacteria and viruses. The antibody recognizes a unique molecule of the ...

G into laboratory rats in the early 2000s, resulted in nicotine levels in the brain cut by up to 65%.

Phase II trials

An early study in 2005 for 38 weeks by the University of Minnesota Cancer Center's Transdisciplinary Tobacco Use Research Center and published in ''Clinical Pharmacology & Therapeutics'', involved 68 smokers, none of whom had known health problems or intended to quit smoking in the next month. Subjects were not instructed to quit smoking during the study. The test subjects were injected four times throughout the trial: when it began, and after four, eight and 26 weeks with either one of three dosages of NicVAX or a

placebo A placebo ( ) is a substance or treatment which is designed to have no therapeutic value. Common placebos include inert tablets (like sugar pills), inert injections (like Saline (medicine), saline), sham surgery, and other procedures. In general ...

. At the conclusion of the study, it was concluded that NicVAX was "safe and well tolerated", with side effects including

headache Headache is the symptom of pain in the face, head, or neck. It can occur as a migraine, tension-type headache, or cluster headache. There is an increased risk of depression in those with severe headaches. Headaches can occur as a result ...

colds The common cold or the cold is a viral infectious disease of the upper respiratory tract that primarily affects the respiratory mucosa of the nose, throat, sinuses, and larynx. Signs and symptoms may appear fewer than two days after exposu ...

, and

upper respiratory tract The respiratory tract is the subdivision of the respiratory system involved with the process of respiration in mammals. The respiratory tract is lined with respiratory epithelium as respiratory mucosa. Air is breathed in through the nose to th ...

infections. While most of the test subjects continued to smoke, six people from the high dosage group, one person from the medium dosage group, no one from the low dosage group, and two people from the placebo group quit smoking. They did not start again for at least thirty days. In a further Phase IIb trial, a statistically significant number of patients with a high anti-nicotine

antibody An antibody (Ab), also known as an immunoglobulin (Ig), is a large, Y-shaped protein used by the immune system to identify and neutralize foreign objects such as pathogenic bacteria and viruses. The antibody recognizes a unique molecule of the ...

response met the primary endpoint of eight weeks of continuous abstinence between weeks 19–26. The top 30% of antibody responders (61 of the total 201 patients receiving drug) were examined in detail. A statistically significant number of these patients, (24.6%; p=0.04) showed continuous abstinence between weeks 19-26 compared to only 13.0% for the 100 patients receiving placebo. The quit rate of those patients who did not have a high antibody response was not statistically significant from placebo. The trial enrolled a total of 301 heavy smokers who smoked an average of 24 cigarettes per day prior to enrollment. Nabi issued a press release indicating that phase IIB testing was a success, showing statistically significant rates of

smoking cessation 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 m ...

and continuous long-term smoking abstinence during the trial period.

Phase III trials

Nabi Biopharmaceuticals conducted two Phase III trials of the drug. The first started in November 2009 and the second in March 2010. Nabi issued press releases announcing the start of these trials. In July 2011 it was announced that the first of two planned phase III trials for NicVAX failed, sending the market capitalization of NABI Biopharmaceuticals to below the value of its cash holdings. In November 2011, NABI announced that NicVAX had failed the second phase III clinical trial, performing no better than a placebo.

References

{{Vaccines Vaccines against drugs Smoking