Mechanism-based design of conjugate vaccines against drugs of abuse
Philipp Carter1, Megan Laudenbach2, and Marco Pravetoni2,3
1
Graduate program in Pharmacy, University of Basel, Switzerland.
2
Minneapolis Medical Research Foundation, Minneapolis, MN.
3
Department of Medicine and Pharmacology, University of Minnesota, MN.
Vaccines may offer a promising therapy for drug addiction. Small molecules, such as
oxycodone or nicotine, are made immunogenic by conjugating them to large, foreign
carrier proteins to elicit serum antibodies that bind drug in serum, prevent its distribution
to brain, and subsequently block drug-induced behavior. However, eliciting high levels of
drug-specific serum antibodies has remained one of the biggest challenges in translating
these vaccines to human use. Current clinical-stage vaccines showed proof of efficacy
only in a small subset (~30%) of immunized individuals that had high antibody titers.
Novel strategies are needed to develop more effective addiction vaccines.
Understanding the immunological mechanisms involved in generating drug-specific
antibodies is critical for improving vaccine efficacy
Generation of effective serum antibodies against drugs of abuse is the result of vaccineinduced T cell-dependent B cell activation, which largely occurs via germinal center (GC)
formation in secondary lymphoid organs. Our group has previously shown that the
number of naïve and activated hapten-specific B cells, before and shortly after
immunization, correlates with vaccine efficacy in vivo. Here, we hypothesized that
vaccine efficacy may be enhanced by targeting downstream pathways involved in GCdependent B cell responses. To test this, we co-administered a promising candidate
oxycodone conjugate vaccine with a series of adjuvants and immunomodulators known
to regulate GC formation and compared hapten-specific B cells, oxycodone distribution,
and oxycodone-induced antinociception within these groups. Our preliminary data
suggests that co-administration of IL-4 and IL-6 modulates vaccine efficacy against
oxycodone. Furthermore, IL-2 signaling was blocked by co-administering mAbs directed
against the α-chain of IL-2 receptor (also known as CD25), which enhanced the efficacy
of our vaccine. In contrast, interference of the programmed death-1 (PD-1) signaling
pathway negatively affected vaccines efficacy. Results suggest that modulating specific
downstream regulators of GC-dependent B cell responses (and subsequent antibody
production) can improve vaccine efficacy, but a better understanding of GC formation is
needed to greatly improve antibody response. The long-term goal of these studies is to
develop more effective vaccines by combining conjugate immunogens with
immunomodulators and polymer-based delivery platforms.