Hapten-specific naïve B cells are biomarkers of vaccine efficacy against drugs of abuse

Abstract

Vaccination against drugs of abuse shows efficacy in animal models, yet few subjects achieve effective serum antibody titers in clinical studies. A barrier to translation is the lack of pre-vaccination screening assays that predict the most effective conjugate vaccines or subjects amenable to vaccination. To address this obstacle, we developed a fluorescent antigen-based enrichment method paired with flow cytometry to characterize hapten-specific B cells. Using this approach, we studied naïve and activated B cells specific for structurally-related model haptens based on derivatization of the morphinan structure at the C6 position on oxycodone or at the C8 position on hydrocodone, and showing different pre-clinical efficacy against the prescription opioid oxycodone. Prior to vaccination, naïve B cells exhibited relative higher affinity for the more effective C6-derivatized oxycodone-based hapten (6OXY) and the 6OXY-specific naïve B cell population contained a higher number of B cells with greater affinity for free oxycodone. Higher affinity of naïve B cells for hapten or oxycodone reflected greater efficacy of vaccination in blocking oxycodone distribution to brain in mice. Shortly after immunization, activated hapten-specific B cells were detected prior to oxycodone-specific serum antibodies and provided earlier evidence of vaccine failure or success. Analysis of hapten-specific naïve and activated B cells may aid rational vaccine design and provide screening tools to predict vaccine clinical efficacy against drugs of abuse or other small molecules.

Biologics to treat substance use disorders: Current status and new directions

“…A greater frequency of vaccine-specific B or T cells correlates with more effective immunization against SUD. 40,41,43 Early appearance of anti-oxycodone Ab predicted vaccine efficacy in blocking oxycodone distribution to the brain in mice (Fig. 1A and B, reproduced from ref.…”

“…The frequency of na€ ıve and/or early-activated haptenspecific B cells correlated post-immunization Ab responses and vaccine efficacy against oxycodone 40,43 and nicotine. 41 The size of the polyclonal hapten-specific IgM high na€ ıve and memory B cell and GC B cell subsets best correlated with post-vaccination serum anti-drug IgG Ab titers and vaccine efficacy against drug distribution or drug-induced behavior in mice.…”

“…33,34 The strength of this approach is that very rare antigen-specific B and T cells are detected prior to, or shortly after immunization. [35][36][37][38][39] To date, this approach has been used to test the effect of hapten structure, 40,41 adjuvant, 42 or host genetics 42 on the B cell response to vaccines for SUD. This strategy has also been used to study the relationship between antigen-specific B and T cells and individual variability in post-immunization Ab titers, or efficacy against drug distribution and drug-induced behavior in mice.…”

“…41,43 These studies found that na€ ıve and early-activated B cells can discriminate between structurally-related haptens, and that the size of the polyclonal hapten-specific B cell population determines vaccine immunogenicity and efficacy against drugs of abuse. 40,41 When comparing individuals, differences in the population size of hapten-specific B cells and carrier-specific T cells are found before and/or after immunization in individual mice, and correlate to vaccine immunogenicity and efficacy. 41,43 Hence, analysis of na€ ıve and early-activated B and T cells could be used to examine vaccine formulations and individual variability across subjects.…”

“…59,60 Consistently, individual variability of similar magnitude has been found in the polyclonal hapten-specific B cell population in blood, peripheral lymph nodes and spleen of various mouse strains, before and after immunization with vaccines for oxycodone and nicotine. [40][41][42][43] Multiple mechanisms may underlie the pre-and post-immunization variability in the antigenspecific B and T cell subsets and contribute to individual vaccine efficacy. Apoptosis and antigen affinity affect the heterogeneity of the primary immune response by limiting differentiation of a single na€ ıve B cell shortly after immunization.…”