According to the World Health Organization (WHO), smoking tobacco is responsible for more than 5m deaths/year, with around 50% of smokers dying prematurely. There are several strategies available to help people quit smoking, including drugs such as varenicline and bupropion that act on neural pathways; nicotine replacement therapies (NRT), such as nicotine patches; and electronic cigarettes, which deliver controlled levels of nicotine vapour without the additional carcinogens found in tobacco. But the overall success rates of these approaches are low. A 2009 meta-analysis of 20 UK studies of individuals who had sought the UK’s NHS Stop Smoking Services, which use primarily NRT and varenicline, showed only 15% managed to stop smoking long term. The quest for a definitive treatment continues.
With this in mind, the US government and others are investing millions into the design of a nicotine vaccine. The idea is to stimulate the production of antibodies that will grab nicotine molecules in the bloodstream and prevent them from reaching the brain. This would block the pleasurable effect of smoking, caused by the release of the neurotransmitter dopamine, and without this reward, the hope is that smokers will find it easier to quit.
Among the first vaccines produced was one by Nabi Biopharmaceuticals, US, in the early 2000s, consisting of a nicotine analogue, 3’-aminomethylnicotine, with a functionalised sidearm that could attach to bacterial or viral proteins. The nicotine molecule is too small to elicit an immune response on its own, but when attached to a larger carrier molecule, the body generates antibodies to which the small-molecule, or so-called ‘hapten’, will bind.
However, despite initial indications that the vaccine did trigger antibody production, in 2011 the company announced that clinical trials for their much anticipated vaccine NicVax had not been successful. This followed the announcement, in 2009, that another nicotine vaccine developed by Novartis, had also failed, and whole field of nicotine vaccines was starting to look like a dead end. Vaccine designer, Kim Janda, professor of chemistry at The Scripps Research Institute in California, US, says the failure of these trials ‘gave a black eye to the drug abuse vaccine field’.
Nevertheless, there were some positive findings from the failed clinical trials that have led other researchers to stay confident that the concept is viable.
Significantly, patients who had given up smoking on either trial tended to have higher nicotine antibody levels in their bloodstream, in comparison with those who did not stop. In the case of the NicVax trial,1 further analysis showed that when only the 30% of patients with the highest antibody levels were examined, a statistically significant number had stopped smoking in the trial, compared with a placebo. This suggested to the researchers that there was a relationship between high levels of nicotine antibodies and smoking cessation. Indeed, many heralded this as proof-of-concept – when antibody levels were high enough, the vaccines seemed to perform.
Kei Kishimoto, chief scientific officer of Selecta Biosciences in Massachusetts, US, one of the companies now designing the next-generation of nicotine vaccines, says: ‘The take-away message from these studies is that you have to have very high antibody levels to neutralise the nicotine inhaled by smoking... much higher thn that of a typical vaccine for an infectious disease.’ He explains that, typically, a vaccine conferring protection against an infectious disease delivers low or sub-microgram/ml antibody concentrations in the blood, but in the case of the nicotine vaccine, it would need to be 50–100µg/ml.
The question then became: can a vaccine be produced that induces a larger immune response in more patients? The clinical trials had shown a large individual variation of antibody concentrations. Kishimoto says: ‘It’s not atypical for a vaccine to give 100- or even 1000-fold differences in response from subject to subject.’
To compound the problem, smokers have reduced antibody responses to infectious disease vaccines, and so could turn out to be the group in which it’s most difficult to increase nicotine antibody levels.2
In addition, in the early vaccine designs, the chirality of the nicotine molecule was overlooked. The majority of nicotine molecules found in tobacco are the left-handed version, but vaccines were mixtures of right- and left-handed nicotine derivatives. This meant that a proportion of antibodies produced would not recognise tobacco nicotine.
Janda decided to tackle the issue and design a chiral vaccine. He separated a left- and right-handed mixture of 3’-aminomethylnicotine molecules using fluid chromatography and then attached each chiral molecule to a tetanus toxoid protein via a succinyl linker group. Both versions of the vaccine were tested on rats and the results, published in January 2015, showed that the left-hand version lead to four times as many antibodies as the right-handed molecule.3 Janda comments that using a chiral vaccine could have made a big difference to the previously unsuccessful clinical trials; ‘rather than 20% maybe it would have worked for 50 or 60%,’ he says.
Other innovation approaches
Meanwhile, other researchers are pursuing alternative approaches to vaccine design. Ronald Crystal, professor of medicine at Weill Cornell Medical College, New York, US, is taking his cue from gene-therapy; the idea being that delivery of a genetically-modified virus could continuously make nicotine antibodies from a pre-designed genetic blueprint.4
Crystal’s vaccine consists of the genetic sequence for an engineered nicotine antibody inserted into an adeno-associated virus (AAV) – a commonly used virus in gene therapies. The vaccine goes directly to liver cells where it produces high concentrations of the antibodies. A 2012 study of mice given the vaccine showed that subsequent injection with nicotine resulted in 85% lower nicotine levels in the brain.
Another approach uses synthetic ‘carrier’ nanoparticles to try and boost the immune response. Viral carrier proteins may be too small to elicit a big enough immune response and may be easily broken down by white blood cells before antibodies have a chance to be formed. Mike Zhang, professor of biological systems engineering at Virginia Tech, Blacksburg, Virginia, US, has designed a vaccine delivery system, made from a non-toxic biodegradable polymer.5
The 100-500nm polymer particles comprise a cationic lipid structure with up to 18 bovine serum albumin (BSA) proteins attached to nicotine molecules. The spherical double-layered lipid vesicle is called a liposome, or lipoplex. Zhang suggests the vaccine could be delivered by a patch or nasal spray and may only need to be given twice for long-term protection. ‘We are testing how effective the vaccine can be right now in an animal model and we hope it’s going to last at least six months, hopefully longer,’ he says.
Selecta Biosciences has also developed a synthetic vaccine, which is the first of its type to enter clinical trials. The company produced its vaccine using its synthetic vaccine particle (SVP) platform. Kishimoto explains the particles are made from the biodegradable polymer PLGA (poly(lactic-co-glycolic acid)) but no carrier proteins are used. ‘The immune system is basically a competitive system…by reducing everything to the essential components, we are focusing the immune response on exactly what we want to focus on – nicotine,’ says Kishimoto.
Selecta’s vaccine comprises nicotine attached to the nanoparticle surface, plus two types of agents that help stimulate a greater immune response inside the nanoparticles.6 One is a synthetic TLR (toll-like receptor) agonist, which serves as an adjuvant – a molecule that signals the presence of foreign material and can stimulate a greater immune response; adjuvants such as alum are commonly used with viral vaccines. The second is a universal T-cell helper peptide, which induces a response in immune T-cells that provide help to antibody-producing B-cells. Encapsulating these agents within the biodegradable nanoparticle provides a controlled release that minimises any extreme inflammatory reactions that could occur.
Results of animal and human trials have been promising so far. Immunisation of mice and monkeys led to the generation of high levels of nicotine antibodies that lasted for over six months. Initial human studies on 80 people found the vaccine to be safe and well tolerated, and in 2014, Selecta was awarded an $8.1m grant from the US National Institute on Drug Abuse to continue clinical trials, which the company expects to start in 2016.
Kishimoto says the strength of using synthetic vaccines is the ability for rational design. ‘Typically with most other vaccines you make your best shot and that’s your product. With our particle technology, we can make a dozen in a day. We can vary the density of nicotine on the surface and play with the amount of adjuvant and T-cell peptide in the particle; we can change a whole range of design parameters to optimise the response.’ The company uses combinatorial approaches to do this and being fully synthetic, the costs of production are lower than those of vaccines that use biological or viral material.
These next generation vaccine technologies have led to some optimism for the future of nicotine vaccines, but there are still questions as to whether the concept is really feasible. Peter Hajek, director of the Tobacco Dependence Research Unit at Queen Mary, University of London, UK, does not think the concept will prove successful. ‘I would predict the new vaccines again showing zero effect, as the old ones did,’ he says. Hajek argues that vaccines would be unable to prevent all nicotine molecules from reaching the brain because binding is reversible and small amounts could still be enough to cause addiction. Plus, there is always the danger that smokers will actually increase the number of cigarettes smoked to satisfy their cravings, although this has not been seen in clinical trials.
Social and ethical views
Meanwhile, Anna Wolters, a social scientist at Maastricht University in The Netherlands, has been looking at the social and behavioural factors that might affect vaccine success, such as the type of support people are given when using the vaccine. She says these factors have been neglected in investigations so far but play a part in the success or failure of interventions designed to help people stop smoking. Wolters thinks that ultimately a successful solution is going to need to consider these aspects as well as purely physiological effects.7
Wolters has also been looking at the interesting ethical and social issues that arise from nicotine vaccines. Such vaccines could be given to adolescents or children to prevent them from becoming addicted to nicotine in the first place. But, she says, some ethicists argue that giving nicotine vaccines to children would take away their ability to decide for themselves when they are older. Others do not see this as an ethical problem, reasoning that the prevention of nicotine addiction is in a child’s best interest and has no harmful consequences.7
In addition to nicotine vaccines, researchers are working on vaccines for other addictive substances, such as cocaine, heroin and methamphetamine. The future for all these vaccines is still uncertain, but if they do become a reality, society will need to consider carefully how and when they are used.
1 D K Hatsukami et al, Clinical Pharmacol. Therapeutics, 2011, 89, 392
2 A P Winter et al, Vaccine, 1994, 12(9), 771
3 J W Lockner et al, J. Med. Chem., 2015, 58(2), 1005
4 M J Hicks et al, Sci. Transl. Med., 2012, 4(140), 140
5 Y Hu et al, Human Vaccine Immunother, 2014, 10(1), 64
6 P O Ilyinskii et al, Vaccine, 2014, 32, 2882
7 A Wolters et al, Addiction, 2014, 109(8), 1221
Rachel Brazil is a science writer based in London, UK