Mechanisms of interleukin 4 mediated increase in efficacy of vaccines against opioid use disorders

Abstract

Opioid use disorders (OUD) affect over 27 million people worldwide. Anti-opioid vaccines offer a promising strategy to treat OUD and prevent overdose. Using immunomodulation of cytokine signaling to increase vaccine efficacy, this study found that blocking IL-4 improved the efficacy of vaccines targeting oxycodone and fentanyl in male and female mice. Genetic deletion of the IL-4 receptor, STAT6, or antibody-based depletion of IL-13, did not increase vaccine efficacy against opioids, suggesting the involvement of type I IL-4 receptors. Enhancement of vaccine efficacy with blockade of IL-4 was associated with improved germinal center formation in secondary lymphoid organs and selective transcriptome signatures in the activated CD4+ T cell population subset. These data suggest that IL-4 is both a pharmacological target and a potential biomarker of vaccine efficacy against OUD.

An Epitope-Focused Trypanosome-Derived Vaccine Platform Elicits High-Affinity Antibodies and Immunity Against Fentanyl Effects

“…Importantly, there was also a recognizable isotype-switched memory B cell population (switched-MBC) identified with this analysis. These data further support earlier pre-clinical evidence that opioid-carrier conjugate vaccines induce CD4+ T cell-dependent B cell processes to elicit opioid-specific IgG antibodies, including germinal center formation as assessed by antigen-specific GC B cells, Tfh, GC-Tfh, and subsequent switched memory B cells (Laudenbach et al ., 2015; Baruffaldi et al ., 2018; Robinson et al ., 2019; Crouse et al ., 2020). Pairing this population with data from FACS index sorting, we were able to show that the cells with the highest affinity to fentanyl were contained in this isotype-switched memory B cell subpopulation (Figure 4A, right panel), which was also enriched for Cd80 and Cd73, two common T-dependent memory B cell markers that are absent from the other subpopulations (Tomayko et al ., 2010).…”

Contribution of Antibody-Mediated Effector Functions to the Mechanism of Efficacy of Vaccines for Opioid Use Disorders

“…As detailed in specific experiments, mice were immunized with either OXY-KLH or OXY-sKLH concurrently with a neutralizing antiIL-4 mAb Ab (clone 11B11, Bio X Cell, West Lebanon, NH) on days À2 and 11 of the vaccination series (0.5 mg/200 ml i.p.) as described previously (21,22). In passive immunization studies, anti-oxycodone mAbs or F(ab9) 2 fragments were delivered i.p.…”

“…Anti-drug conjugate vaccines stimulate T celldependent B cell activation and germinal center formation to generate target-specific Abs (11). While several cellular and molecular targets are involved in this process, our laboratory has found that vaccine efficacy against opioids in mice is impacted by IL-4 signaling (21,22). Specifically, blockade of IL-4 increased vaccine efficacy against oxycodone and fentanyl, which correlated with increased levels of IgG 1 , IgG 2a , and IgG 3 subclasses compared with control.…”

Vaccines against Drug Abuse—Are We There Yet?

“…Current psychotherapy and pharmacotherapy treatments have a number of potential drawbacks, including cost, limited effectiveness, patient non-compliance, social stigma and, in some instances, a disinclination by treatment providers regarding the use of some pharmacotherapies due to regulatory and abuse liability concerns [2,3,8,[14][15][16][17]. Current treatments for smoking cessation have proved beneficial only in the short term [18].…”

“…The conjugate protein/macromolecular carrier is the component of the vaccine that is immunogenic, and is linked to the hapten. The overall structure is known as a hapten-conjugate protein/macromolecular carrier [1][2][3]6,9,11,[14][15][16][17][21][22][23]25,26,29,[32][33][34][35][36][37][38][39][40][41][42]. Adjuvants include aluminum-containing substances that enhance the immune response to an antigen, thereby producing stronger immunity [1,6,8,10,14,25,35].…”