U19AI160546

Conjugate Nanoparticle Platform Development for HIV-1 Envelope Immunogens - Abstract

Overall, HIV-1 broadly neutralizing antibodies (bNAbs) have been shown to be protective in animal models of HIV-1 infection. However, current vaccine regimens have not been successful in eliciting bNAbs in humans. To address this challenge, the B cell lineage vaccine design approach aims to administer multiple immunogens in a specific sequence to guide the maturation of bNAbs. One roadblock that has been identified is the presence of somatic mutations that encode key amino acids for antibody function, but are rarely made by the somatic mutation enzyme activation-induced cytidine deaminase.

The central hypothesis of our vaccine design is that antibodies encoding these improbable mutations will be rare. Therefore, vaccine immunogens will need to have a higher affinity for antibodies with these desired amino acid changes in order to select for them. However, the only antigen for HIV-1 bNAbs is HIV-1 envelope (Env), which is poorly immunogenic and generally has low affinity for bNAb precursors.

To overcome these obstacles, we and others have found that designing Envs with high affinity for bNAb precursors and multimerizing them on nanoparticles (NPs) can enhance antigen trafficking to germinal centers and provide avidity. However, Env trimer NPs can have low expression and present misfolded Env trimers that elicit non-neutralizing antibodies.

This application is significant because it aims to establish a cGMP-compliant vaccine platform that rapidly generates higher quality HIV-1 Env trimer NP vaccines without time-consuming iterative immunogen design. This platform utilizes the sortase A enzyme to site-specifically covalently link well-folded HIV-1 Env trimers to intact Helicobacter pylori ferritin NPs. The resulting HIV-1 Env trimer sortase A-conjugated NPs (SCNPs) display only well-folded Env trimers and have successfully initiated CD4 binding site bNAb lineages in human bNAb precursor knock-in mice and CD4BS Nabs in rhesus macaques in preliminary studies.

The SCNP platform is universal in nature as it can incorporate diverse viral type I fusion proteins by simply adding a 6-amino acid sortase A tag to their C-terminus. In Specific Aim 1, we will compare the ability of monovalent and bivalent HIV-1 Env SCNPs to guide affinity maturation of CD4 binding site bNAbs in humanized mice and rhesus macaques. In Specific Aim 2, we will produce and assemble two CD4 binding site bNAb-targeting HIV-1 Env trimer SCNPs (CH505 TF SCNP and a second sequential Env trimer SCNP) under cGMP conditions.

This program will deliver an optimized cGMP process for making SCNPs, two cGMP-produced Env trimer SCNPs, and additional ferritin and sortase A components for the manufacture of future immunogens. The CH505 TF Env trimer SCNPs will be used in a Phase I trial through the HIV Vaccine Trial Network. Ultimately, the impact of this platform is that it will enable multiple Env trimer SCNPs to be made rapidly under cGMP, making it feasible to conduct iterative testing in clinical trials of complete sequential nanoparticle vaccines that target bNAbs.

Duke University

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]

Durham, North Carolina 277103011 United States

Single Zip Code

Integrated Preclinical / Clinical AIDS Vaccine Development Program (IPCAVD) (U19 Clinical Trial Not Allowed) (PAR-20-120)

Amendment Since initial award the total obligations have increased 402% from $4,719,580 to $23,711,949.