The vaccine stimulates the immune system to identify nicotine as a foreign antigen. This elicits antibodies that alter nicotine’s pharmacokinetics, reducing nicotine levels in the blood and ultimately entry into the central nervous system.
It consists of a large carrier protein, needed because nicotine particles alone are too small to trigger the immune system, conjugated to haptens – molecular mimics of nicotine which provoke an immune response.
The team improved on an anti-smoking vaccine trialled by Nabi BioPharmaceuticals (now Biota) that failed in Phase III clinical trials in 2011.
Nabi’s nicotine conjugate vaccine was effective only for “one-third of clinical trial participants,” said the Scripps scientists, “likely due in part to its use of racemic nicotine hapten, (±)-3’-AmNic.”
Scripps’s study on rats found better binding to nicotine and a greater antibody response is achieved with enantiopure (−)-3′-AmNic haptens – that is, “left-handed” chiral haptens.
“Our vaccine work demonstrates that careful consideration must be made in hapten design,” co-author Jonathan Lockner told BioPharma-Reporter.com.
“A previous nicotine vaccine clinical candidate may have failed partly due to the fact that it contained a mixture of “left-handed” and “right-handed” nicotine haptens.
“Our improved version, which contains only “left-handed” nicotine haptens, is superior to that failed vaccine, which was a mixture. Our vaccine is better optimized for eliciting antibodies that can recognize “left-handed” nicotine molecules, which are the prevalent version of nicotine in tobacco smoke.”
Companies taking nicotine vaccine candidates to clinical trial should incorporate these enantiopure haptens into their design, he said. “There might even be more effective haptens out there.”
Vaccine make-up
The Scripps team created an adjuvant vaccine, using a combination of Alhydrogel (a type of alum common in vaccines) and CpG ODN (oligodeoxynucleotide), a short single-stranded DNA molecule newer to vaccine use.
“CpG ODN stimulates innate immunity and stimulates B cells, monocytes, and dendritic cells. In essence, the combination of Alhydrogel and CpG ODN stimulates the immune system to respond more robustly to whatever is co-formulated with it,” said Lockner.
The antibody therapy is a departure from small molecule-based smoking cessation methods currently on the market. These use synthetic agonists or antagonists to target brain receptors – but “do not help much” and have side effects, said the Scripps researchers.
Lockner told us the team has “been in conversations with various suitors” to license and commercialise the vaccine.
The research was funded by the Tobacco-Related Disease Research Program.
Source: A Conjugate Vaccine Using Enantiopure Hapten Imparts Superior Nicotine-Binding Capacity, Journal of Medicinal Chemistry, December 10, 2014.