R01AI168048

Rational Design and Efficacy Testing of Vaccines against HCV - Project Summary

An estimated 71 million people worldwide are infected with HCV and are at heightened risk for severe liver disease, including fibrosis, cirrhosis, and hepatocellular carcinoma. Although effective directly-acting antiviral treatment is available, only an HCV vaccine will help prevent infection, associated pathologies, and effectively reduce global disease burden.

Cumulative evidence has shown that both B and T cell immunity contribute to the control of acute HCV infection. A major challenge is the high variability across the genome, especially in the envelope E1E2 glycoproteins, the natural target of protective antibodies. An E1E2-based immunogen will need to elicit broadly neutralizing antibodies (BNAbs) to multiple epitopes to overcome the high antigenic diversity of HCV isolates and be of sufficient titers to achieve protective immunity.

Our approach is supported by our recent data that a secreted form of E1E2 (SE1E2) maintains its native-like properties and can elicit broader neutralizing antibody responses than the membrane-bound form of E1E2 and secreted E2. Also, we have shown that presentation of SE1E2 as multivalent virus-mimicking polymer assemblies (VMPAs) that include HCV core protein can elicit cellular immune responses to SE1E2 and core antigens with potential immunopotentiating activity for B and T cell responses.

Accordingly, our central hypothesis is that rational structure-guided design of E1E2 and co-formulation with conserved HCV T cell antigens as a VMPA vaccine will lead to optimal presentation of conserved BNAB epitopes and elicit long-lasting B and T cell mediated immunity. Towards this end, we propose the following specific aims:

Aim 1: Rational E1E2 antigen design. We will advance our structure-guided E1E2 design to increase the immunogenicity of BNAB epitopes and stabilize the native-like SE1E2 complex using synthetic scaffolds.

Aim 2: Structural characterization of HCV envelope complexes. We will structurally characterize the E1E2 heterodimer complexed with key BNABs, and new structures will be used for further E1E2 optimization.

Aim 3: Formulation and characterization of virus-mimicking polymer assemblies. We plan to further develop supramolecular assemblies of E1E2 for multimeric presentation of E1E2 and T cell antigens.

Aim 4: Immunological evaluation of B and T cell responses in animal models. Immunological assessment of our vaccine candidates will be performed in mice, guinea pigs, and macaques. These studies will include an examination of the specificity of neutralizing antibody responses as well as systemic and tissue resident memory T cells.

Aim 5: Vaccine efficacy in challenge model systems. Protection studies will utilize the only two available challenge models. The first, an immunocompetent humanized mouse model, to test the protective efficacy of our lead vaccine candidates. The second, a human-mouse liver chimeric model that can be infected with antigenically diverse clinical HCV isolates, to demonstrate serum antibodies from vaccinated macaques passively transferred to the chimeric mice will be protective.

The overall program will lead to a rationally designed vaccine candidate to induce broadly neutralizing antibodies and long-term memory T cell responses to prevent HCV infection.

College Park University Of Maryland

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]

College Park, Maryland 207425103 United States

Single Zip Code

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

Amendment Since initial award the total obligations have increased 307% from $1,410,544 to $5,737,237.