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

基于纳米技术的平台，用于开发针对阿片类药物使用障碍（OUD）的下一代疫苗

• 批准号: 10751208
• 负责人: Fatima Alamin Awad Alkareem Hamid
• 金额: $ 3.5万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-01 至 2026-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10751208
• 关键词: Acceleration; Active Immunization; Address; Adjuvant; Affect; Affinity; Agonist; Antibodies; Antibody Response; Antibody titer measurement; Antigen-Presenting Cells; Antigens; B Cell Proliferation; B cell differentiation; B-Cell Activation; B-Lymphocytes; Biodistribution; Biological Availability; Bradycardia; Brain; CD4 Positive T Lymphocytes; COVID-19 vaccine; Cell Cycle Kinetics; Cells; Clinical; Clinical Trials; Communication; Communities; Complex; Conjugate Vaccines; Data; Dendritic Cells; Development; Drug Targeting; Economic Burden; Ensure; Epidemic; FDA approved; Fellowship; Fentanyl; Flow Cytometry; Formulation; Funding; Future; Glycolates; Haptens; Helper-Inducer T-Lymphocyte; Hybrids; Immunoglobulin G; Immunoglobulins; Immunohistochemistry; Immunology; Immunomodulators; In Vitro; Individual; Injections; Innate Immune Response; Kinetics; Lipid A; Lipids; Liposomes; Macrophage; Measures; Memory; Memory B-Lymphocyte; Mentors; Mentorship; Methods; Modeling; Molecular; Monitor; Motor Activity; Mus; Nanotechnology; National Institute of Drug Abuse; Natural Immunity; Nature; Nicotine; Opioid; Opioid agonist; Overdose; Oxycodone; Patients; Pharmaceutical Preparations; Pharmacology; Pharmacotherapy; Phase I Clinical Trials; Plasma; Plasma Cells; Polymers; Positioning Attribute; Pre-Clinical Model; Preclinical Testing; Process; Public Health; Quantitative Reverse Transcriptase PCR; Research; Rewards; Safety; Scientist; Self Administration; Serum; Site; Spleen; Structure of germinal center of lymph node; Substance Use Disorder; Substance abuse problem; TLR4 gene; TLR7 gene; Testing; Time; Training; Translational Research; Translations; Vaccinated; Vaccination; Vaccine Design; Vaccines; Ventilatory Depression; abuse liability; adaptive immune response; adaptive immunity; addiction; antagonist; antinociception; career; design; draining lymph node; fluorescence imaging; immune activation; immunogenicity; improved; in vivo; in vivo evaluation; in vivo imaging; individual variation; lipid nanoparticle; lymph nodes; migration; multidisciplinary; nanocarrier; nanoformulation; nanoparticle; nanovaccine; next generation; nicotine vaccine; novel; novel strategies; novel vaccines; opioid use; opioid use disorder; overdose death; pharmacologic; poly(lactic acid); polyclonal antibody; prevent; prophylactic; public health emergency; rational design; recruit; resiquimod; response; secondary lymphoid organ; side effect; skills; success; targeted delivery; therapeutically effective; time use; trafficking; vaccine candidate; vaccine delivery; vaccine development; vaccine efficacy; vaccine evaluation; vaccine formulation; vaccine platform; vaccinology

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.

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