Drug Addiction? Try an Addiction Vaccine (Section One)

The global drug problem has become increasingly serious in the past 20 years. Drug abuse of narcotic drugs and psychotropic substances has become one of the serious problems that threaten human health in peacetime. There are many types of drugs, of which narcotic drugs are divided into opioids (opium, morphine, heroin, etc.), cocaine, and cannabis; psychotropic drugs are divided into sedative hypnotics and anxiolytics, central stimulants (amphetamine category, caffeine, etc.), hallucinogens; and others (tobacco, alcohol, etc.).

Drug abuse, as a chronic recurrent encephalopathy, poses serious harm to families and society, causing dangerous problems like the spread of infectious diseases such as AIDS and hepatitis. Studies have reported that the rate of HIV infection among drug users is 60%, that of hepatitis B virus (HBV) is about 60% to 80%, and that of hepatitis C virus (HCV) is even higher. Crimes caused by drugs have become a social issue of global concern. Crimes caused by or related to drugs have accounted for a corresponding proportion (20% to 50%), which are increasing year by year, seriously affecting the social stability.

Drug vaccines induce the body to produce specific antibodies against drugs, and form drug-antibody complexes with drugs that enter the bloodstream. This macromolecular complex cannot pass the blood-brain barrier, thereby blocking peripherally, or reducing or slowing drug entry into the center nervous system. Addicts cannot experience the euphoria brought by drug use again, thereby reducing the probability of drug cravings and relapses. This therapy does not target at treating the mental dependence of drugs on the mechanism of addiction, but provides anti-relapse protection to addicts on the periphery. Most addicts are willing to quit drug treatment after detoxification treatment, but it is easy to lose their will after the occurrence of stress events, environmental clues, or exposure to a small amount of drugs, using drugs again, and eventually result in relapse. In this case, the antibodies produced by the drug vaccine can function as a final barrier. Even if the patient uses the drug again, the withdrawal treatment will not be interrupted and the previous work will not be abandoned. Compared with traditional therapies, vaccination has fewer side effects but more convenient medical maintenance, and can combine with existing therapies to provide a relatively simple auxiliary method for drug addicts to break the old drug habit. At the same time, this drug vaccine has potential application prospects for the prevention of drug addiction among high-risk groups, especially adolescents.

1. The addiction vaccine of anti-heroin

    Heroin is a global drug of abuse. There are approximately 32.4 million heroin and other opioid abusers worldwide, accounting for about 0.7% of the world's population. Heroin is extremely addictive and has the highest fatality rate among all drugs, which is the chief mode of transmitting serious infectious diseases such as AIDS, inflicting damage to drug users and society.

Existing anti-heroin addiction therapies include alternative therapies using long-acting opioid receptor agonist methadone and blockade therapies using opioid antagonist naloxone, etc. The relapse rate after intermittent clinical monitoring treatment is as high as 90%. Heroin addiction patients' physical and psychological effects will be devastating, and re-treatment with drugs becomes more difficult once relapsed. Patients often fall into the cycle of drug abuse and relapse-relapse, which is difficult to get rid of. At present, the world is urgently in need of a new anti-heroin addiction therapy to overcome the shortcomings of existing therapies, to help addicts maintain withdrawal and prevent relapse.

With the progress of life sciences, on the one hand, the research on the mechanism of drug addiction is getting deeper. On the other hand, the development of relative drugs is also more targeted, and the related pharmacology is also clearer, among which the immune drugs are playing a significant role in the treatment and prevention of various human diseases. With the rapid development of immunotherapy and the deepening of research mechanisms on drug addiction, scientists have linked the dopamine pathway to drug addiction. Therefore, for the treatment of drug addiction, especially for the drug itself, immunotherapy also emerges in the corresponding treatment.

Heroin and its metabolites are linked to immunogenic carriers to construct a vaccine because they are small molecular compounds that cannot directly stimulate the body to produce antibodies. The design of the haptens, the attachment manners of haptens and carriers, and the site of attachment and the choice of the carrier all affect the immune efficacy and specificity of the vaccine. Heroin is a prodrug, which is rapidly hydrolyzed into 6-acetylmorphine (6-AM) when it enters the body. 6-AM is further hydrolyzed to produce morphine, which is eventually metabolized to morphine-3-glucuronide and morphine-6- glucaldehyde. The rapid and intense euphoria comes from heroin and 6-AM. The effect of 6-AM is stronger and the delayed effect that lasts for several hours mainly comes from morphine. Common vaccines only produce antibodies against a specific molecular structure, but ideal heroin vaccines need to produce specific antibodies against heroin, 6-AM and morphine, which should not be related to other metabolites and similar structures reaction occurs, greatly increasing the difficulty of constructing satisfactory heroin vaccine. The structure of heroin is very similar to other opioids. Such substance is usually an important neurotransmitter-endogenous opioid peptide in the body, such as codeine, buprenorphine and detoxification drugs such as methadone, naloxone and others. If the antibodies produced by the vaccine cannot distinguish these similar opioids, it will bring a series of side effects and affect clinical medication.

The vaccine development of heroin began in the 1970s. Early vaccines took the mother ring of morphine as the focus of immune recognition, and they were coupled to macromolecular protein carriers through the morphine structure's 2-, 3-, or 6-hydroxy group. Because the structural difference between heroin and morphine is only at the 3 and 6 acetyl groups, while the vaccine used the 3, 6 coupling, or the 2 coupling to block the 3 characteristic structure, the antibodies produced lack specificity for heroin. Both morphine and opioid-like structures had certain affinity. Subsequent studies used bridgehead N-position coupled protein carrier in the morphine structure and found that the specificity of antibodies produced by such conjugates was enhanced, with affinity only for morphine, and decreased affinity for heroin and similar structures. The molecular structure of the vaccine hapten and its coupling site with the carrier affect the characteristic structure of the hapten, especially the presentation of the spatial conformation, and greatly influence the strength and specificity of the immune response.

The representative heroin vaccines are mainly divided into two categories according to the hapten and the connection site. One is the conjugate of morphine hapten at 6 position, which has strong immune efficacy because its hapten structure is mainly morphine. The produced antibodies possess a high affinity for morphine or similar affinity for morphine, heroin and its metabolites. These vaccines are generally developed to prevent morphine/heroin addiction. The other is a heroin hapten bridgehead N-position conjugate, which has high affinity and specificity for heroin and its main metabolite 6-AM specific vaccine against heroin.

Heroin is small molecule substance that requires conjugate vector to construct vaccine. Commonly used heroin vaccine carriers are bovine serum albumin (BSA), ovalbumin (OVA), keyhole limpet hemocyanin (KLH), and tetanus toxoid protein (TT). The premise of selecting a carrier is safety, availability, and controllable quality, and then its immunogenicity, solubility, and whether it can form a suitable coupling with the happen. KLH is highly immunogenic and has more groups that can be coupled, but it has a large molecular weight, poor solubility, and is more expensive. BSA has a small molecular weight and contains a large amount of lysine in the molecule. It can be used at different pH and ionic strength, which maintains a large solubility and is cheap. The artificial PLL has low autoimmunity, but it can increase the hapten's immunity and stimulate the body to produce more specific antibodies. Compared with BSA, it has more free amino groups, which can increase the coupling ratio of carrier to hapten. Bacterial toxins such as TT have good water solubility and are widely used in approved conjugate vaccines. The effect mechanism of carrier protein on vaccine efficacy is complex. The choice of carrier may not be most optimal, but it must adapt to the hapten and binding method.