R01AI192197

DESIGN OF SINGLE-SHOT SEQUENTIAL IMMUNIZATION REGIMENS FOR HIV USING ATOMIC LAYER DEPOSITION TECHNOLOGY. - PROJECT TITLE: DESIGN OF SINGLE-SHOT SEQUENTIAL IMMUNIZATION REGIMENS FOR HIV USING ATOMIC LAYER DEPOSITION TECHNOLOGY PROJECT SUMMARY/ABSTRACT 30 LINES OR LESS: PRECLINICAL STUDIES AND EARLY STAGE HUMAN TRIALS EVALUATING PASSIVELY TRANSFERRED BROADLY NEUTRALIZING ANTIBODIES (BNABS) SUGGEST THAT A VACCINE CAPABLE OF ELICITING BNABS WOULD PROVIDE EFFECTIVE PROTECTION FROM HIV INFECTION. HOWEVER, BNAB INDUCTION THROUGH VACCINATION IS A MAJOR CHALLENGE. WE HAVE DEVELOPED AN IMMUNOGEN SERIES TARGETING THE CD4 BINDING SITE BNAB EPITOPE ON HIV ENV USING GERMLINE TARGETING TO PRIME APPROPRIATE B CELL PRECURSORS, AND THEN SHEPHERD THE BCR MUTATIONS OF THESE RECRUITED B CELLS THROUGH A SERIES OF BOOSTER VACCINATIONS, WHERE EACH ENGINEERED IMMUNOGEN PROMOTES KEY MUTATIONS ALONG THE PATH TO BNAB DEVELOPMENT. IN A RIGOROUS HUMANIZED MOUSE MODEL, A NEAR-COMPLETE VACCINE REGIMEN HAS BEEN DEMONSTRATED, LEADING TO EPITOPE-SPECIFIC MABS CAPABLE OF BINDING TO HETEROLOGOUS WILDTYPE HIV ENV TRIMERS. HOWEVER, THIS REGIMEN INVOLVES UP TO 5 OR 6 SHOTS, WHICH WOULD BE CHALLENGING TO IMPLEMENT IN GLOBAL VACCINATION CAMPAIGNS. TO OVERCOME THIS HURDLE, WE HAVE DEVELOPED A VACCINE FORMULATION STRATEGY THAT CAN DELIVER MULTIPLE BOOSTS OVER TIME FROM A SINGLE INJECTION. ATOMIC LAYER DEPOSITION (ALD) IS USED TO “CAP” SPRAY-DRIED MICROPARTICLE VACCINE FORMULATIONS WITH A THIN LAYER OF ALUMINA. ON INJECTION, THE VACCINE UNDERGOES A RAPID RELEASE FROM THE ALD PARTICLE ONCE THE ALUMINA COATING DISSOLVES, AND THE TIMING OF VACCINE RELEASE CAN BE PRECISELY DETERMINED BY THE THICKNESS OF THE ALD COATING. BY INJECTING ALD PARTICLES CONTAINING A SERIES OF BOOSTER IMMUNOGENS CAPPED BY ALUMINA COATINGS OF DISTINCT THICKNESS, A SERIES OF IMMUNOGEN (AND ADJUVANT) EXPOSURES CAN BE PRE- PROGRAMMED FROM A SINGLE IMMUNIZATION. HERE WE PROPOSE TO CARRY OUT SYSTEMATIC STUDIES TO APPLY THIS TECHNOLOGY TO SEQUENTIAL IMMUNIZATION REGIMENS TARGETING THE DEVELOPMENT OF BNABS AGAINST THE CD4 BINDING SITE, ESTABLISH THE LIMITS OF SUCH SINGLE-SHOT FORMULATIONS, AND DEVELOP A MECHANISTIC UNDERSTANDING OF IMMUNE RESPONSES ELICITED BY ALD VACCINE FORMULATIONS. OUR SPECIFIC AIMS ARE TO (1) CHARACTERIZE KEY PROCESS PARAMETERS GOVERNING ALD VACCINE FORMULATION FUNCTION, (2) APPLY ALD TECHNOLOGY FOR SINGLE-SHOT SEQUENTIAL IMMUNIZATIONS IN A HUMANIZED MOUSE MODEL TARGETING THE CD4BS, AND (3) OPTIMIZE ALD TECHNOLOGY FOR SEQUENTIAL DELIVERY OF MRNA VACCINES. THESE STUDIES WILL PROVIDE IMPORTANT INSIGHTS INTO THE IMMUNOLOGY AND PRACTICAL POTENTIAL OF ALD VACCINES FOR ENABLING SEQUENTIAL IMMUNIZATION REGIMENS THAT MAY BE CRITICAL FOR A SUCCESSFUL HIV VACCINE. THIS TECHNOLOGY IS BEING COMMERCIALLY DEVELOPED FOR CGMP VACCINE MANUFACTURING, AND THESE STUDIES WILL PROVIDE IMPORTANT PRECLINICAL DATA TO SUPPORT TRANSLATION TO HUMAN HIV VACCINE TRIALS.

Scripps Research Institute

TO ASSIST PUBLIC AND PRIVATE NONPROFIT INSTITUTIONS AND INDIVIDUALS TO ESTABLISH, EXPAND AND IMPROVE BIOMEDICAL RESEARCH AND RESEARCH TRAINING IN INFECTIOUS DISEASES AND RELATED AREAS, TO CONDUCT DEVELOPMENTAL RESEARCH, TO PRODUCE AND TEST RESEARCH MATERIALS. TO ASSIST PUBLIC, PRIVATE AND COMMERCIAL INSTITUTIONS TO CONDUCT DEVELOPMENTAL RESEARCH, TO PRODUCE AND TEST RESEARCH MATERIALS, TO PROVIDE RESEARCH SERVICES AS REQUIRED BY THE AGENCY FOR PROGRAMS IN INFECTIOUS DISEASES, AND CONTROLLING DISEASE CAUSED BY INFECTIOUS OR PARASITIC AGENTS, ALLERGIC AND IMMUNOLOGIC DISEASES AND RELATED AREAS. PROJECTS RANGE FROM STUDIES OF MICROBIAL PHYSIOLOGY AND ANTIGENIC STRUCTURE TO COLLABORATIVE TRIALS OF EXPERIMENTAL DRUGS AND VACCINES, MECHANISMS OF RESISTANCE TO ANTIBIOTICS AS WELL AS RESEARCH DEALING WITH EPIDEMIOLOGICAL OBSERVATIONS IN HOSPITALIZED PATIENTS OR COMMUNITY POPULATIONS AND PROGRESS IN ALLERGIC AND IMMUNOLOGIC DISEASES. BECAUSE OF THIS DUAL FOCUS, THE PROGRAM ENCOMPASSES BOTH BASIC RESEARCH AND CLINICAL RESEARCH. SMALL BUSINESS INNOVATION RESEARCH (SBIR) PROGRAM EXPANDS AND IMPROVES PRIVATE SECTOR PARTICIPATION IN BIOMEDICAL RESEARCH. THE SBIR PROGRAM INTENDS TO INCREASE AND FACILITATE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT, TO INCREASE SMALL BUSINESS PARTICIPATION IN FEDERAL RESEARCH AND DEVELOPMENT, AND TO FOSTER AND ENCOURAGE PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN TECHNOLOGICAL INNOVATION. THE SMALL BUSINESS TECHNOLOGY TRANSFER (STTR) PROGRAM STIMULATES AND FOSTERS SCIENTIFIC AND TECHNOLOGICAL INNOVATION THROUGH COOPERATIVE RESEARCH AND DEVELOPMENT CARRIED OUT BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, TO FOSTER TECHNOLOGY TRANSFER BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, TO INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT, AND TO FOSTER AND ENCOURAGE PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN TECHNOLOGICAL INNOVATION. RESEARCH CAREER DEVELOPMENT AWARDS SUPPORT THE DEVELOPMENT OF SCIENTISTS DURING THE FORMATIVE STAGES OF THEIR CAREERS. INDIVIDUAL NATIONAL RESEARCH SERVICE AWARDS (NRSAS) ARE MADE DIRECTLY TO APPROVE APPLICANTS FOR RESEARCH TRAINING IN SPECIFIED BIOMEDICAL SHORTAGE AREAS. IN ADDITION, INSTITUTIONAL NATIONAL RESEARCH SERVICE AWARDS ARE MADE TO ENABLE INSTITUTIONS TO SELECT AND MAKE AWARDS TO INDIVIDUALS TO RECEIVE TRAINING UNDER THE AEGIS OF THEIR INSTITUTIONAL PROGRAM.

93.855 - Allergy and Infectious Diseases Research

National Institute of Allergy and Infectious Diseases (NIAID) [HHS - NIH]

California United States

State-Wide

NIH Research Project Grant (Parent R01 Clinical Trial Not Allowed) (PA-20-185)