Nanotechnology-based platform for the development of next-generation vaccines against opioid use disorder (OUD)

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Project Abstract: The highly complex OUD and overdose epidemic poses a huge public health and economic burden. Current FDA-approved pharmacotherapies against OUD and overdose use opioid receptor agonists and antagonists. These therapies show overall limited efficacy, due to their side effects, suboptimal patient access and compliance, and liability for abuse and diversion. Vaccines offer a new treatment option that is both alternative and complementary to existing measures. Preclinical testing demonstrated anti-opioids vaccines as a highly selective long-lasting treatment and prophylactic strategy that protects against opioid-induced antinociception, motor activity, respiratory depression, bradycardia, and self-administration in pre-clinical models. Previous clinical trials of addiction vaccines showed proof of efficacy in those subjects who achieved the highest antibody (Ab) titers, highlighting the need to design more effective vaccines and understanding the basis for variability in individual efficacy. Hence, this proposal focuses on developing next-generation nanoparticle-based anti-opioid vaccines and deciphering molecular and cellular mechanisms underlying their efficacy. Our team developed a novel lipid polymer hybrid nanoparticles (LPNP) platform, that enhanced the efficacy of conjugate vaccines against nicotine and oxycodone. Based on these preliminary data, we propose further dissecting the molecular basis of this increased efficacy and testing how nanovaccines composition, and adjuvant display determine innate and adaptive immune activation and whether specific cellular and molecular mechanisms underlie vaccine efficacy against OUD. AIM1 will test the effect of different polymers and adjuvant display methods on efficacy of nanovaccine against oxycodone. As well as how nanoformulation of conjugate vaccine affect the delivery and bioavailability of vaccine components. Studies will investigate vaccine efficacy in mice, IgG antibody titer and Ig subclass and vaccine kinetics in terms of biodistribution, accumulation and localization within spleen and lymph nodes. AIM2 will elucidate whether different nanovaccine formulations show distinctions in innate and adaptive immune responses. Studies will dissect innate immunity in vitro activation and in vivo dynamics in response to vaccination, addressing key cell subsets contributing to efficacy, as well as assess the magnitude of B cell responses. Results will provide a model vaccine that can be easily adapted to other abused substances. Such information will guide future vaccine design and the rational selection of the most appropriate formulation for a given antigen. The proposed mentored studies and this F31 fellowship are invaluable training and professional development opportunity as I strive to become an independent scientist. This hypothesis-driven multidisciplinary project encompasses various state-of-art approaches that are prerequisites to excel in translational research at the interface of immunology, pharmacology and substance abuse. The mentorship of NIDA-funded experts will ensure the successful completion of the proposed studies and the effective communication of research findings to the scientific community.