University Of Montana

DEVELOPMENT OF UM-1098: A NOVEL SYNTHETIC TH17 INDUCING ADJUVANT AND DELIVERY SYSTEM

UMRB SNOWPACK AND SOIL MOISTURE MONITORING NETWORK OF THE MONTANA SATOC FOR INSTALLATION OF MONITORING SITES.

UMRB PROJECT - MONTANA

SYNTHETIC AND FORMULATION PROCESS DEVELOPMENT AND SCALE-UP OF THE LEAD FENTANYL VACCINE SUFFICIENT FOR CGMP MANUFACTURE AT A CMO (2) DEVELOPMENT AND QUALIFICATION OF ANALYTICAL ASSAYS NECESSARY FOR API AND FINAL PRODUCT RELEASE, (3) DEVELOPMENT OF FINAL PRODUCT RELEASE SPECIFICATIONS AND COA, (4) PREPARATION OF PRE-CGMP LOTS OF VACCINE ON SUFFICIENT SCALE TO CONDUCT ALL NON-CLINICAL IND ENABLING STUDIES (5) OVERSIGHT OF GLP TOXICOLOGY STUDIES AT A CMO AND (6) OVERSIGHT OF VACCINE MANUFACTURING UNDER CGMP CONTROLS AT A CMO

THE PROPOSED STUDIES WILL FOCUS ON DEVELOPMENT OF AN ADJUVANTED VACCINE FORMULATION TARGETING FENTANYL, FENTANYL ANALOGS, HEROIN, HEROIN ANALOGS, OR MIXTURES OF HEROIN/FENTANYL THROUGH EITHER SINGLE-VALENT OR MULTI-VALENT VACCINE STRATEGIES. THESE VACCINES WILL BE INITIALLY SCREENED IN MICE FOR IMMUNOGENICITY, AND THEN TESTED FOR EFFICACY IN REDUCING OPIOID DISTRIBUTION TO THE BRAIN, AND FOR REDUCING OPIOID-INDUCED ANTINOCICEPTION, RESPIRATORY DEPRESSION AND BRADYCARDIA IN RATS AND MINIATURE PIGS (MINI-PIGS). ALL STUDIES INVOLVING MICE AND RATS WILL BE CONDUCTED IN THE LABORATORY OF DR. PRAVETONI LOCATED IN EITHER THE DEPARTMENT OF PSYCHIATRY & BEHAVIORAL SCIENCES AT THE UNIVERSITY OF WASHINGTON SCHOOL OF MEDICINE, OR AT HIS FORMER AFFILIATION THE DEPARTMENT OF PHARMACOLOGY AT THE UNIVERSITY OF MINNESOTA MEDICAL SCHOOL. DR. PRAVETONI WILL SUPERVISE STUDIES INVOLVING MINI-PIGS, WHICH WILL BE CONDUCTED AT THE UNIVERSITY OF MINNESOTA COLLEGE OF VETERINARY MEDICINE AND SUPERVISED BY DR. ALONSO GUEDES, DVM, PHD. BOTH THE UNIVERSITY OF WASHINGTON AND UNIVERSITY OF MINNESOTA HAVE AAALAC-ACCREDITED FACILITIES AND COMPLY TO THE GUIDELINES OF THEIR RESPECTIVE INSTITUTIONAL ANIMAL CARE AND USE COMMITTEE (IACUC). DR. PRAVETONI WILL BE RESPONSIBLE FOR ANIMAL STUDIES AND IACUC COMPLIANCE AT ALL SITES. DR. PRAVETONI€„¢S TEAM WILL ALSO MANAGE CDMO ACTIVITIES AT CAMBREX AND GBI TO MANUFACTURE GMP GRADE MATERIALS.

THE PURPOSE OF STUDIES AT THE HENNEPIN HEALTHCARE RESEARCH INSTITUTE (HHRI) SITE IS TO TEST LEAD VACCINES TARGETING HEROIN AND FENTANYL FOR THEIR ABILITY TO REDUCE THE ADDICTIVE EFFECTS OF THESE DRUGS IN RATS. IN ADDITION, HHRI WILL EXAMINE WHETHER COMBINING THESE VACCINES INTO A BIVALENT FORMULATION WILL ALTER THEIR EFFICACY. THE WORK REQUIRED TO ACCOMPLISH THIS INVOLVES A SERIES OF FIVE STUDIES IN WHICH THE EFFECTS OF VACCINATION ON HEROIN AND FENTANYL SELF-ADMINISTRATION AND WITHDRAWAL WILL BE EXAMINED IN RATS. THE FIRST EXPERIMENT WILL TEST THE EFFICACY OF A LEAD HEROIN AND BIVALENT VACCINE AT REDUCING HEROIN SELF-ADMINISTRATION (HSA). THE SECOND EXPERIMENT WILL TEST THE EFFICACY OF A LEAD FENTANYL AND BIVALENT VACCINE AT REDUCING FENTANYL SELF-ADMINISTRATION (FSA). THE THIRD EXPERIMENT WILL TEST THE EFFICACY OF THE BIVALENT VACCINE AT REDUCING COCAINE SELFADMINISTRATION TO CONFIRM THE BEHAVIORAL SPECIFICITY OF THE VACCINE. THE FOURTH AND FIFTH EXPERIMENTS WILL TEST WHETHER THE BIVALENT VACCINE PRECIPITATES HEROIN OR FENTANYL WITHDRAWAL, RESPECTIVELY, USING AN INTRACRANIAL SELF-STIMULATION ASSAY.

A. PRODUCT DEVELOPMENT ACTIVITIES SPECIFICALLY, THE SUBCONTRACTOR SHALL: 1. PROVIDE THE EQUIPMENT, FACILITIES, PERSONNEL AND OTHER RESOURCES M72 PRODUCTION. A. SUB-ACTIVITY: THE SUBCONTRACTOR WILL PRODUCE M72 ON SUFFICIENT QUANTITIES TO SUPPORT ALL FORMULATION AND PRE-CLINICAL ACTIVITIES UNDER THIS AWARD. 2. PROVIDE THE EQUIPMENT, FACILITIES, PERSONNEL AND OTHER RESOURCES FOR THE IN VITRO AND EX VIVO EVALUATION OF THE OPTIMIZED UM-1098 FORMULATIONS. A. SUB-ACTIVITY: THE SUBCONTRACTOR WILL CONDUCT A SERIES OF ESTABLISHED IN VITRO ASSAYS FOR THE COMPARATIVE EVALUATION OF OPTIMIZED UM-1098 POTENCY AND RECEPTOR SPECIFICITY THROUGH CYTOKINE PROFILING AND RECEPTOR SPECIFICITY ASSAYS. B. SUB-ACTIVITY: THE SUBCONTRACTOR WILL COMPLETE MULTIOMICS STUDIES TO IDENTIFY BIOMARKERS PREDICTING ANTIGEN-SPECIFIC ADAPTIVE IMMUNE RESPONSE, USING A SERIES OF SOPHISTICATED EX VIVO ASSAYS TO DETERMINE THE MECHANISMS OF VACCINE-MEDIATED IMMUNITY. 3. PROVIDE THE EQUIPMENT, FACILITIES, PERSONNEL AND OTHER RESOURCES FOR THE IN VIVO EVALUATION OF THE OPTIMIZED UM-1098 FORMULATIONS. A. SUB-ACTIVITY: THE SUBCONTRACTOR WILL CONDUCT A COMPREHENSIVE IN VIVO EVALUATION OF THE SAFETY AND IMMUNOGENICITY OF THE OPTIMIZED UM-1098 FORMULATIONS IN MICE. B. SUB-ACTIVITY: THE SUBCONTRACTOR WILL IDENTIFY THE OPTIMAL UM-1098 VACCINE FORMULATION, DOSE, AND TIMING. C. SUB-ACTIVITY: THE SUBCONTRACTOR WILL COMPLETE A COMPREHENSIVE EVALUATION OF THE LEAD UM-1098 FORMULATIONS IN MURINE VACCINATION AND MTB CHALLENGE STUDIES IN WT AND HUMANIZED MINCLE/MCL MICE. D. SUB-ACTIVITY: THE SUBCONTRACTOR WILL ASSESS THE PRE-CLINICAL (IND-ENABLING) SAFETY AND EFFICACY OF UM-1098 IN A NHP VACCINATION AND MTB CHALLENGE STUDY. E. SUB-ACTIVITY: THE SUBCONTRACTOR WILL CONDUCT STUDIES TO ASSESS THE MECHANISMS OF VACCINE-MEDIATED IMMUNITY AND IMMUNOPATHOLOGY FOLLOWING PATHOGEN CHALLENGE. B. QUALITY ASSURANCE, QUALITY CONTROL, DATA MANAGEMENT SPECIFICALLY, THE SUBCONTRACTOR SHALL: 1. COMPLETE QUARTERLY, SEMI-ANNUAL AND ANNUAL TECHNICAL AND FINANCIAL REPORTS TO FACILITATE CONTRACTOR TO FOLLOW THE SCHEDULE PROVIDED IN THE BAA AND EXECUTED CONTRACT AGREEMENT. 2. ATTEND ANNUAL REVIEW MEETINGS TO PROVIDE AN UPDATE ON DEVELOPMENT CONTRACT PROGRESS AND FUTURE DIRECTIONS. 3. PROVIDE THE NECESSARY BIOSTATISTICAL SUPPORT TO ENSURE RESEARCH REPRODUCIBILITY AND RIGOR. 4. PROVIDE THE NECESSARY IT SYSTEMS TO ENSURE AN APPROPRIATE LEVEL OF DATA MANAGEMENT AND INTEGRITY. C. PROJECT MANAGEMENT SPECIFICALLY, THE SUBCONTRACTOR SHALL: 1. PROVIDE THE PROJECT MANAGEMENT AND ORGANIZATIONAL FRAMEWORK NECESSARY TO SUPPORT ALL ACTIVITIES OUTLINED IN THIS SUBCONTRACT. 2. PROVIDE THE NECESSARY FINANCE, ADMINISTRATIVE, BUSINESS, AND LEGAL STAFF NECESSARY FOR PERFORMANCE OF THIS CONTRACT. 3. THE SUBCONTRACTOR ACKNOWLEDGES THE GOVERNMENT’S RIGHT TO MODIFY THE MILESTONES, PROGRESS, SCHEDULE, BUDGET, OR PRODUCT TO ADD OR DELETE PRODUCTS, PROCESS OR SCHEDULE AS THE NEED MAY ARISE. 4. THE SUBCONTRACTOR ACKNOWLEDGES THAT ACTIVITIES WITHIN THE SUBCONTRACT’S STATEMENT OF WORK SHALL ONLY BE CONDUCTED AS REQUESTED AND APPROVED BY THE CONTRACTOR’S AUTHORIZED OFFICIAL OR DESIGNEE. THE SUBCONTRACTOR MAY NOT CONDUCT WORK ON THE SUBCONTRACT WITHOUT PRIOR APPROVAL FROM THE CONTRACTOR’S AUTHORIZED OFFICIAL OR DESIGNEE; AND APPROVAL TO CARRY OUT SPECIFIC ACTIVITIES WILL BE LINKED TO APPROVAL BY THE CONTRACTOR’S REPRESENTATIVE OF THE SCOPE OF WORK, FOLLOWING SUBCONTRACT AWARD, AND RECEIPT OF TECHNICAL PROGRESS REPORTS.

DIGITAL TWIN APPROACH IS BASED ON MERGING TWO EXISTING MODELING METHODS: FIRST-PRINCIPLES AND DATA-DRIVEN. MERGING TWO MODELING TECHNIQUES ALLOWS A MORE COMPLETE MODEL AS THE TWO APPROACHES COMPLEMENTS EACH OTHER COMBINING THEIR STRENGTHS AND ELIMINATING WEAKNESSES. THE FIRST-PRINCIPLES MODELING RELIES ON EITHER ORDINARY OR PARTIAL DIFFERENTIAL EQUATIONS DERIVED FROM KNOWN PHYSICS OR HUMAN PHYSIOLOGY LAWS AND PRINCIPLES. WHILE BEING A POWERFUL TOOL IN INVESTIGATING SYSTEM’S RESPONSE TO DIFFERENT INPUTS, THE FIRST-PRINCIPLES SYSTEMS DO NOT USE THE MOST CURRENT DATA AND CANNOT REFLECT THE IMMEDIATE CONDITIONS OF HUMAN PHYSIOLOGY. ALSO, THE FIRST-PRINCIPLES MODEL MAY NOT CONSIDER ALL FACTORS AFFECTING HUMAN’S RESPONSE TO STRESS AS SOME OF THEM ARE NOT KNOWN OR TWO COMPLEX TO DERIVE. ON THE OTHER HAND, THE ARTIFICIAL INTELLIGENCE/MACHINE LEARNING (AI/ML) -BASED DATA-DRIVEN MODELS CAN USE THE MOST RECENTLY COLLECTED DATA TO PRODUCE PARAMETERS PREDICTIONS AND CAN BE ADAPTED TO THE MOST IMMEDIATE DATA. HOWEVER, THESE DATA-DRIVEN ALGORITHMS TEND TO OVERFIT THE DATA AND MOST OF THEM LACK EXPLAINABILITY. DATA OVERFITTING LEADS TO MODELS WHICH PERFORM VERY WELL WITHING THE RANGE OF TRAINING DATA, HOWEVER, BREAKS DOWN ONCE THE NEW DATA ARE OUTSIDE OF THE HISTORICAL DATA. THE LACK OF EXPLAINABILITY UNDERMINES TRUST IN THESE MODELS AND LEADS TO RELUCTANCE IN ACCEPTING THEM FOR HUMAN-SAFETY RELATED APPLICATIONS. THE DIGITAL TWIN APPROACH ADDRESSES THE WEAKNESSES OF THESE TWO MODELING APPROACHES AND ALSO OFFERS AN OPPORTUNITY TO PROVIDE AN ANTICIPATORY PHYSIOLOGIC GUIDANCE TO THE MILITARY PERSONNEL BY FIRST APPLYING THE ANTICIPATED GUIDANCE TO THE TWIN MODEL PRIOR ADVISING IT TO THE PERSONNEL. THIS PROJECT WILL DEVELOP DIGITAL TWIN MODELS BASED ON PHYSICS-INFORMED DEEP NEURAL NETWORKS (PIDNNS). THE PHYSICS-INFORMED DEEP NEURAL NETWORKS (PIDNNS) WILL CONSIST OF THE FIRST-PRINCIPLE SCENARIO MODEL DEVELOPED AT USARIEM AND DATA-DRIVEN PART REPRESENTED BY A DEEP NEURAL NETWORK DEVELOPED BASED ON DATA COLLECTED FROM WEARABLE SENSOR SUITS. THE SCENARIO MODEL DEVELOPED AT USARIEM, WAS DESIGNED TO ESTIMATE AND PREDICT CORE TEMPERATURE, HEART RATE, AND SWEAT RATE, WITHOUT REQUIRING PRIOR KNOWLEDGE AND DIRECT MEASUREMENT OF THESE PHYSIOLOGICAL VARIABLES. THE UNDERLYING MODEL FOR SCENARIO SIMULATES THE TIME COURSE OF CORE TEMPERATURE VARIATIONS, WHILE TAKING INTO ACCOUNT DIFFERENT FACTORS THAT AFFECT HUMAN THERMOREGULATION. THE TEMPERATURE DISTRIBUTION WITHIN THE HUMAN BODY IS REPRESENTED BY A LUMP-PARAMETER MODEL CONSISTING OF SIX CONCENTRIC CYLINDRICAL COMPARTMENTS. HEAT FLOW IS THEN MODELED BY A SET OF MACROSCOPIC ENERGY CONSERVATION EQUATIONS BASED ON HEAT CONVECTION BETWEEN THE CENTRAL BLOOD COMPARTMENT AND THE ADJACENT CORE, MUSCLE, FAT, AND VASCULAR SKIN COMPARTMENTS; RADIAL HEAT CONDUCTION BETWEEN EVERY PAIR OF ADJACENT COMPARTMENTS; AND AIR CONVECTION, RADIATION, AND SWEAT EVAPORATION BETWEEN THE SUPERFICIAL AVASCULAR SKIN LAYER AND THE ENVIRONMENT AND TRANSITION THROUGH THE CLOTHING THE ENERGY CONSERVATION EQUATIONS ARE REPRESENTED BY A SET OF SIX ORDINARY DIFFERENTIAL EQUATIONS THAT CAN BE EXPRESSED AS A SYSTEM.

DEVELOP AND ADVANCE A DURABLE CROSS-PROTECTIVE ADJUVANTED H5N1 AND H5N2 SUBUNIT VACCINES.