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Principal Investigator: Michael Dennis Raleigh
Organization: WASHINGTON UNIVERSITY
Fiscal Year: 2019
Award: $193,057
Funding agency: National Institute on Drug Abuse
PROJECT SUMMARY.
The goal of this CEBRA is to integrate cutting-edge concepts from nanotechnology, immunology, and
addiction to develop nanovaccines to treat heroin and prescription opioid abuse and prevent fatal overdose.
Opioid abuse is a major national emergency in the US with an enormous cost in human tragedy as well as
health care costs. Abuse of heroin and prescription drugs such as oxycodone is increasing annually, and
everyday more than 90 people die of opioid overdose. While medications to treat opioid addiction are
available, their use is limited from side effects, tight prescription guidelines, and restricted availability. We
expected that development of immunotherapies to treat addiction will provide safe and cost-effective
alternatives to opioid-based medications. Vaccines elicit opioid-specific antibodies that sequester opioids in
the periphery, limit free (unbound) opioid distribution to the brain, and prevent opioid-induced behavior and
toxicity. In the clinic, addiction vaccines have the potential to augment existing pharmacotherapies, and
prevent fatal overdose upon relapse in abstinent users. We propose the use of rationally designed peptide
amphiphiles (PAs) as carriers for oxycodone and heroin haptens and investigate vaccine efficacy in pre-clinical
models. We propose two aims: Aim 1) Test the efficacy of opioid vaccines containing PA nanocarriers to
induce opioid-specific antibodies that block heroin and oxycodone distribution to the brain and Aim 2) Generate
multivalent PA-based nanovaccines that target both heroin and oxycodone and test vaccine efficacy in pre-
clinical models of opioid abuse. Our approach will be to synthesize and characterize PAs conjugated to
oxycodone and heroin haptens and investigate the effect of nanocarrier morphology and charge on the
quantity and quality of the opioid-specific antibody response in immunized mice. We will also test the role of T
cell helper epitopes and exogenous adjuvants in improving antibody titers and affinity in combination with PA
nanocarriers. Further, we will develop bivalent vaccines composed of oxycodone PAs and heroin PAs and test
their efficacy to block opioid distribution to the brain of immunized mice challenged with single or cumulative
opioid dosing. Promising formulations will be tested in mouse models of opioid-evoked antinociception, motor
activity and respiratory depression and also confirmed in an outbred mouse strain. Successful completion of
these studies will generate novel nanomaterials-based opioid vaccines and provide a framework for the
development of vaccines against other drugs of abuse.
Terms: <ATGN><Adanon><Adjuvant><Affinity><Agonist><Althose><Alum Adjuvant><American><Antibodies><Antibody Affinity><Antibody Response><Antibody titer measurement><Antigenic Determinants><Antigens><Attenuated><Behavior><Binding Determinants><Biomedical Engineering><Blocking Antibodies><Blood - brain barrier anatomy><Blood-Brain Barrier><Brain><Brain Nervous System><Buffers><Buprenorphine><CNS Nervous System><Carrier Proteins><Central Nervous System><Cessation of life><Charge><Clinic><Clinical><Clinical Evaluation><Clinical Testing><Cocaine><Cocaine Addiction><Cocaine Dependence><Common Rat Strains><Conjugated Carrier><Death><Development><Diacetylmorphine><Diamorphine><Dihydrohydroxycodeinone><Dolophine><Dose><Drug Prescribing><Drug Prescriptions><Drug Targeting><Drug Therapy><Drug usage><Drugs><Emergencies><Emergency Situation><Encephalon><Epidemic><Epitopes><FDA approved><Formulation><Funding><Generations><Goals><Guidelines><Haptens><Head><Health><Health Care Costs><Health Costs><Healthcare Costs><Helper Cells><Helper T-Cells><Helper T-Lymphocytes><Helper-Inducer T-Cells><Helper-Inducer T-Lymphocyte><Hemato-Encephalic Barrier><Heroin><Heroin Abuse><Heroin Users><Homolog of Drosophila TOLL><Human><Hydrophobicity><Immune response><Immunity><Immunization><Immunize><Immunologic Sensitization><Immunologic Stimulation><Immunological Sensitization><Immunological Stimulation><Immunological response><Immunologically Directed Therapy><Immunology><Immunostimulation><Immunotherapy><Individual><Inducer Cells><Inducer T-Lymphocytes><KLH><KLH antigen><Keyhole Limpet Hemocyanin><Lead><Link><Lipid A><Liposomal><Liposomes><Locomotor Activity><Medication><Methadone><Methadose><Mice><Mice Mammals><Modern Man><Morphology><Motor Activity><Mouse Strains><Murine><Mus><Nalorex><Naloxone><Naltrexone><Nanotechnology><Nature><Nemexin><Neuraxis><Nicotine><Nicotine Dependence><Opiate Addiction><Opiate Dependence><Opiates><Opioid><Outcome><Overdose><Oxycodeinon><Oxycodone><Oxycodone SR><Oxycontin><Pb element><Peptides><Pharmaceutic Preparations><Pharmaceutical Preparations><Pharmacotherapy><Polymers><Pre-Clinical Model><Preclinical Models><Prevention><Property><Rat><Rats Mammals><Rattus><ReVia><Relapse><Reporting><Respiratory Depression><Role><Roxicodone><Self Administration><Self-Administered><Series><Surface><Survey Instrument><Surveys><Synthetic Immunogens><Synthetic Vaccines><TLR4><TLR4 gene><Tail><Testing><Toll Homologue><Toxic effect><Toxicities><Transport Protein Gene><Transport Proteins><Transporter Protein><United States><Vaccinated><Vaccination><Vaccines><Ventilatory Depression><Vivitrol><abused drug><abused drugs><addiction><addictive disorder><alum><aluminum sulfate><analog><antibody titering><antigen antibody affinity><aqueous><base><bio-engineered><bio-engineers><bioengineering><clinical test><cost><cost effective><depressed breathing><depression of breathing><design><designing><develop a vaccine><development of a vaccine><developmental><drug abused><drug of abuse><drug treatment><drug use><drug/agent><drugs abused><drugs of abuse><efficacy testing><endogenous opiate><endogenous opioids><heavy metal Pb><heavy metal lead><host response><immune drugs><immune therapeutic approach><immune therapeutic interventions><immune therapeutic regimens><immune therapeutic strategy><immune therapy><immune-based therapies><immune-based treatments><immuno therapy><immunogen><immunogenicity><immunoresponse><improved><keyhole-limpet hemacyanin><licit opioid><mouse model><murine model><nano carrier><nano fiber><nano materials><nano particle><nano tech><nano technology><nano vaccine><nano-sized particle><nano-technological><nanocarrier><nanofiber><nanofibrous><nanomaterials><nanoparticle><nanosized particle><nanotech><nanotechnological><nanovaccine><new vaccines><next generation vaccines><nicotine addiction><nicotine dependent><nicotine vaccination><nicotine vaccine><non-compliance><non-compliant><non-medical opioid use><noncompliance><noncompliant><nonmedical opioid use><novel><novel vaccines><opiate abuse><opiate drug abuse><opiate medication><opiate misuse><opiate overdose><opiate related overdose><opiate use disorder><opioid abuse><opioid addiction><opioid dependence><opioid dependent><opioid drug abuse><opioid drug overdose><opioid induced overdose><opioid intoxication><opioid medication><opioid medication abuse><opioid medication overdose><opioid misuse><opioid overdose><opioid poisoning><opioid prescription drug abuse><opioid related overdose><opioid toxicity><opioid use disorder><pre-clinical development><pre-clinical efficacy><preclinical development><preclinical efficacy><prescribed opiate><prescribed opioid><prescription opiate><prescription opiate abuse><prescription opioid><prescription opioid abuse><prevent><preventing><public health relevance><research clinical testing><side effect><small molecule><social><social role><synthetic opiate><synthetic opioid><synthetic peptide><therapeutic vaccine><toll-like receptor 4><treatment vaccines><vaccine candidate><vaccine development><vaccine efficacy><vaccine evaluation><vaccine for the treatment><vaccine for treatment><vaccine formulation><vaccine screening><vaccine testing>