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Principal Investigator: Bethany K Crouse
Organization: UNIVERSITY OF MINNESOTA
Fiscal Year: 2021
Award: $26,961
Funding agency: National Institute on Drug Abuse
Project Summary.
In the United States, there are over 2.5 million people diagnosed with opioid use disorder (OUD) and over 47,000
opioid-related fatal overdoses occur annually. Current FDA-approved medications against OUD and overdose
consist of opioid receptor agonists and antagonists, which overall show limited efficacy, adverse effects,
suboptimal patient access and compliance, abuse liability, and illicit diversion. As an alternative or complimentary
strategy to small molecule-based pharmacotherapies, vaccines offer a safe and long-lasting therapeutic or
prophylactic strategy to counteract OUD and fatal overdoses. Anti-opioid vaccines have shown proof of efficacy
and selectivity in reducing opioid-induced antinociception, respiratory depression, bradycardia, opioid
intravenous self-administration, and lethality in animal models. Despite promising pre-clinical data, vaccine
clinical efficacy may still be limited to a subset of immunized individuals that achieve optimal antibody responses
against the target opioid. Hence, the focus of this proposal is to accelerate translation of anti-opioid vaccines
by identifying mechanisms and biomarkers correlated with optimal vaccine-induced protection against opioids.
Our group has previously found that blockade of the cytokine interleukin-4 (IL-4) increased vaccine efficacy
against oxycodone in mice, supporting the hypothesis that changes in IL-4 signaling modulate or predict vaccine
efficacy against opioids. AIM1 tests whether IL-4 modulation underlies cellular and molecular processes involved
in activation of B cell lymphocytes and generation of optimal antibody responses against opioids. AIM1 will test
affinity maturation, isotype switching, antibody secretion kinetics, and transcriptomic changes in opioid-specific
B cells. AIM2 tests whether IL-4 or its downstream signaling components (e.g., IL-4 receptor, STAT6) are
predictive biomarkers of vaccine efficacy in both mice and human patients immunized with an oxycodone
conjugate vaccine currently in Phase I clinical trials (NCT04458545). Results from these studies will provide a
blueprint to develop more effective next-generation vaccine formulations and to identify putative biomarkers
predictive of vaccine efficacy against opioids. Such information will accelerate pre-clinical vaccine development
and support patient stratification in clinical trials and clinical implementation.
Training. Completing the experiments outlined in this proposal will support my training and career goals to
become an independent scientist. This hypothesis-driven project proposes multidisciplinary experiments
allowing me to develop a broad range of technical skills to study a clinically relevant problem in-depth. I will also
be mentored by leaders and experts in the fields of vaccinology, opioid use disorders, and immunology.
Additionally, I will have the unique opportunity to gain expertise in translational science and human immunology
through an ongoing clinical trial of a novel anti-opioid vaccines. This will provide the necessary skills to advance
my career focusing on using innovative immunological principles to develop treatments for substance use
disorder and related comorbid diseases.
Terms: <7S Gamma Globulin><Active Immunization><Adverse effects><Affect><Affinity><Animal Model><Animal Models and Related Studies><Antibodies><Antibody Affinity><Antibody Response><Antibody-Producing Cells><Antigens><B Cell-Activating Factor Receptor><B blood cells><B cell><B cell growth factor><B cells><B-Cell Activation><B-Cell Differentiation Factor-1><B-Cell Growth Factor-1><B-Cell Growth Factor-I><B-Cell Proliferating Factor><B-Cell Stimulating Factor><B-Cell Stimulating Factor-1><B-Cell Stimulation Factor-1><B-Cell Stimulatory Factor-1><B-Cells><B-Lymphocytes><B-cell><BCDF-1><BCGF><BCGF-1><BCSF 1><BSF-1><BSF1><Binding><Binetrakin><Biological Markers><Bradycardia><Brain><Brain Nervous System><CD124 Antigens><CDw124 Antigen><Cell Communication and Signaling><Cell Signaling><Cellular Metabolic Process><Class Switching><Class Switchings><Clinical Data><Clinical Trials><Co-Stimulator><Conjugate Vaccines><Costimulator><D12S1644><Data><Development><Diagnosis><Dihydrohydroxycodeinone><Disease><Disorder><Drug Therapy><Drugs><ELISA><ELISPOT><Early-Stage Clinical Trials><Encephalon><Enzyme-Linked Immunosorbent Assay><Epidermal Thymocyte Activating Factor><FDA approved><Flow Cytofluorometries><Flow Cytofluorometry><Flow Cytometry><Flow Microfluorimetry><Flow Microfluorometry><Funding><Generations><Genetic Polymorphism><Germinal Center><Goals><Haptens><Human><IL-2><IL-4><IL-4 Receptors><IL-4-STAT><IL2 Protein><IL4 Protein><IL4 Receptors><IgG><Immunization><Immunize><Immunobiology><Immunochemical Immunologic><Immunoglobulin Class Switching><Immunoglobulin Class Switchings><Immunoglobulin G><Immunoglobulin-Producing Cells><Immunohistochemistry><Immunohistochemistry Cell/Tissue><Immunohistochemistry Staining Method><Immunologic><Immunologic Sensitization><Immunologic Stimulation><Immunological><Immunological Sensitization><Immunological Stimulation><Immunologically><Immunologics><Immunology><Immunophysiology><Immunostimulation><Individual><Interleukin 2><Interleukin 2 Precursor><Interleukin 4 Receptor><Interleukin II><Interleukin-2><Interleukin-4><Interleukin-4 Precursor><Interleukin-4 Receptor Alpha><Interleukine 2><Interleukine 2 Precursor><Interleukine II><Intracellular Communication and Signaling><Isotype Switching><Isotype Switchings><KLH><KLH antigen><Keyhole Limpet Hemocyanin><Kinetics><Locomotor Activity><Lymph Node Reticuloendothelial System><Lymph node proper><Lymphatic cell><Lymphatic nodes><Lymphocyte><Lymphocyte Mitogenic Factor><Lymphocyte Stimulatory Factor 1><Lymphocytic><MCGF-2><Mast Cell Growth Factor-2><Medical><Medication><Mentors><Messenger RNA><Mice><Mice Mammals><Mitogenic Factor><Modern Man><Molecular><Molecular Interaction><Motor Activity><Murine><Mus><NIH><National Institutes of Health><Opiate agonist><Opiate receptor agonist><Opiates><Opioid><Opioid agonist><Opioid receptor agonist><Overdose><Oxycodeinon><Oxycodone><Oxycodone SR><Oxycontin><Patients><Pharmaceutic Preparations><Pharmaceutical Preparations><Pharmacotherapy><Phase 1 Clinical Trials><Phase I Clinical Trials><Population><Pre-Clinical Model><Preclinical Models><Process><Production><Proteins><RNA Seq><RNA sequencing><RNAseq><Research><Respiratory Depression><Role><Roxicodone><STAT6><STAT6 gene><STAT6B><STAT6C><Sampling><Scientist><Self Administration><Self-Administered><Signal Pathway><Signal Transduction><Signal Transduction Systems><Signaling><Speed><Spleen><Spleen Reticuloendothelial System><Structure of germinal center of lymph node><Substance Use Disorder><T cell growth factor><T-Cell Growth Factor><T-Cell Growth Factor 2><T-Cell Stimulating Factor><T-Cells><T-Lymphocyte><Technical Expertise><Testing><Therapeutic><Thymocyte Stimulating Factor><Training><Translational Research><Translational Science><Translations><United States><United States National Institutes of Health><Vaccinated><Vaccination><Vaccines><Ventilatory Depression><abused drug><abused drugs><activated B cells><adaptive immune response><antibody based test><antibody test><antigen antibody affinity><base><bio-markers><biologic marker><biological signal transduction><biomarker><biomarker identification><career><cell metabolism><cellular metabaolism><clinical efficacy><clinical implementation><clinical relevance><clinically relevant><co-morbid><co-morbidity><combat><comorbidity><cytokine><depressed breathing><depression of breathing><develop a vaccine><development of a vaccine><developmental><disease prevention><disorder prevention><drug abused><drug of abuse><drug treatment><drug/agent><drugs abused><drugs of abuse><enzyme linked immunospot assay><experiment><experimental research><experimental study><flow cytophotometry><human subject><immune modulating strategy><immune modulatory strategy><immunogen><immunomodulatory strategy><improved><individual heterogeneity><individual variability><individual variation><innovate><innovation><innovative><interleukin-4 Stat><intravenous opiate><intravenous opioid><keyhole-limpet hemacyanin><lymph cell><lymph gland><lymph nodes><lymphnodes><mRNA><marker identification><model of animal><model organism><multidisciplinary><new approaches><new vaccines><next generation><next generation vaccines><novel><novel approaches><novel strategies><novel strategy><novel vaccines><opiate injection><opiate overdose><opiate related overdose><opiate use disorder><opioid drug overdose><opioid induced overdose><opioid injection><opioid injector><opioid intoxication><opioid medication overdose><opioid overdose><opioid poisoning><opioid related overdose><opioid toxicity><opioid use disorder><patient response><patient specific response><patient stratification><phase I protocol><polyclonal antibody><polymorphism><pre-clinical><preclinical><predicting response><prediction of response><predictive biomarkers><predictive marker><predictive molecular biomarker><predictive response><predictor of response><prevent><preventing><prophylactic><response><response prediction><responsive patient><side effect><skills><small molecule><social role><stratified patient><substance use treatment><technical skills><therapeutic vaccine><thymus derived lymphocyte><transcriptome sequencing><transcriptomics><translation research><treatment vaccines><vaccine antibodies><vaccine candidate><vaccine development><vaccine efficacy><vaccine for the treatment><vaccine for treatment><vaccine formulation><vaccine induced antibodies><vaccine-induced antibodies><vaccine-induced immunity><vaccine-induced protection><vaccinology>