Development of Methamphetamine Conjugated Vaccine through Hapten Design: In Vitro and In Vivo Characterization

Abstract

Background: Methamphetamine (METH) substance-use disorder is an ever-growing global health issue with no effective treatment. Anti-METH vaccines are under investigation as an alternative to existing psychological interventions. This platform has made significant progress over past decades mainly in preclinical stages, and efforts to develop an anti-METH vaccine with a high antibody response are of utmost importance. Methodology: A novel conjugated anti-METH vaccine was developed using METH HCl as the starting material for the design of hapten, a peptide linker consisting of five lysines and five glycines, and finally immunogenic carrier mannan, which is novel to this platform. All the chemical reaction steps were confirmed by several analytical techniques, and the immunogenicity of the developed vaccine was investigated in a mouse model. Results: Thin-layer chromatography and gas chromatography confirmed the reaction between METH and peptide linker. UV, NMR and color tests were used to confirm the presence of the aldehyde groups in oxidized mannan (OM). The final conjugated vaccine was confirmed by UV and LC-MS. The stability of mannan, the METH hapten, and the final vaccine was evaluated by UV and LC-MS and demonstrated satisfactory stability over 3 months in various storage conditions. Animal studies supported the immunogenicity of the novel vaccine. Conclusions: We successfully developed and characterized a novel METH vaccine in vitro and in vivo. The present study findings are encouraging and will form the basis of further exploration to assess its effectiveness to prevent METH addiction in preclinical models.

Vaccines to Treat Substance Use Disorders: Current Status and Future Directions

“…Recent advancements in anti-drug vaccine design have shown promising results, raising hopes that these vaccines may eventually prove successful in clinical settings. By improving various aspects of the design, such as hapten selection, carrier protein optimization, and adjuvant formulation, researchers have increased the likelihood of generating a robust and specific immune response against the drug of interest [ 42 , 43 , 104 , 105 ]. As with any medical development, further research and clinical trials will be crucial to establish the safety, efficacy, and applicability of drug conjugate vaccines as a viable strategy in the treatment of SUDs.…”

“…Here are some potential strategies to enhance the development of anti-drug vaccines: Focus on antibody function: Place greater emphasis on assessing the function of antibodies, particularly their affinity or avidity. The antigen’s structure, including the hapten, plays a crucial role in determining antibody function [ 42 ]; Explore novel adjuvants: consider using new adjuvants that have shown promise in boosting both antibody quantity and affinity [ 104 ]; Alternative administration routes: explore alternative administration methods beyond intramuscular injection, such as intranasal immunization, which could play a vital role in preventing cocaine’s direct entry into the brain through the olfactory bulb [ 106 ]; Combination: Recognizing the multifaceted complexity of SUDs is essential, as they result from the interplay of various environmental and individual factors. This understanding implies that a multidisciplinary approach should be adopted in their treatment, involving the combination of vaccines with other addiction interventions (such as medications, monitoring, behavioral therapy, and peer support), or the use of multiple vaccines.…”

“…Focus on antibody function: Place greater emphasis on assessing the function of antibodies, particularly their affinity or avidity. The antigen’s structure, including the hapten, plays a crucial role in determining antibody function [ 42 ];…”

“…Haptens are altered forms of the addictive substance capable of triggering an immune reaction. It is essential to design haptens that preserve the substance’s vital structural characteristics while also facilitating robust antibody attachment, a vital step in developing both antibody efficacy and specificity [ 41 , 42 ]. Haptens need to be structurally distinct from endogenous molecules to avoid cross-reactivity with normal cellular components.…”

Immunotherapies for the Treatment of Drug Addiction

“…This hapten density has a direct link to the efficient presentation of the antigen to the APC and subsequently antibody production. Bovine serum albumin (BSA), diphtheria toxoid (DT), tetanus toxoid (TT), and keyhole limpet hemocyanin (KLH) have been widely investigated as a protein carrier for antidrug vaccine development [26]. The development of antibody response using these protein carriers varied greatly based on the hapten density on its surface.…”