U19AI188562

Rationally designed targeted immunogens to elicit HIV envelope V2-APEX broadly neutralizing antibodies - Overall: Project summary

Our primary goal in this IPCAVD program is to develop a germline-targeting priming immunogen for the HIV envelope V2-APEX broadly neutralizing antibody (BNAB) site.

We aim to test its ability to activate V2-APEX BNAB precursors in preclinical animal models and manufacture it under GMP standards for human clinical testing.

To address this comprehensively, in this IPCAVD grant proposal we have assembled a highly skilled team of investigators with expertise in rational protein design, bioengineering, B and T cell immunology, vaccine evaluation models, antibody discovery, and viral immunology and pathogenesis.

We hypothesize that BNAB B cell germline-targeting, immunofocusing and molecularly guided affinity maturation are the essential components of an effective vaccine strategy for eliciting protective HIV Env V2-APEX targeted BNAB responses.

Leveraging our strong preliminary work in targeted immunogen development, novel vaccine delivery platforms, adjuvants, and immune monitoring tools, this IPCAVD proposal integrates these elements for testing rationally designed prime-boost vaccination strategies in relevant pre-clinical animal models.

The overall specific aims of this IPCAVD program are:

Aim #1. Rationally design HIV Env V2-APEX BNAB-site-targeting vaccines through reverse vaccine engineering.

Aim #2. Develop vaccination strategies for inducing epitope-targeted HIV BNAB responses using novel preclinical animal models and vaccine delivery platforms.

Aim #3. GMP-manufacture the lead germline-targeting vaccine immunogen with the goal for human clinical testing to induce BNAB B cell responses.

This IPCAVD application builds on a foundation of success in eliciting V2 APEX BNABs in multiple rhesus macaques (RMs) by novel simian-human immunodeficiency virus (SHIV) infections and then deconvoluting Env-AB coevolution pathways to identify novel candidate prime and boost immunogens.

From 150 SHIV-infected RMs, we identified the Q23 Env as our lead platform.

Our IPCAVD comprises three projects:

Project 1, through reverse vaccine engineering approaches, will further develop a Q23 Env-based germline-targeting immunogen to most efficiently engage multiple rhesus and human V2-APEX BNAB B cell precursors in vivo and by ex vivo analyses.

This is the crux of successful BNAB induction.

Project 1 will also design mRNA-launched trimer boost immunogens for expanding the breadth of NAB responses.

Project 2 will assess the in vivo priming efficiency of the germline-targeted immunogen, and neutralization breadth expansion ability of the mRNA-launched trimer boost strategies, first in the V2-APEX BNAB UCA expressing KI mice, and subsequently in the NHP model.

We will down-select the Q23 germline-targeting priming immunogen and this will be GMP-manufactured in collaboration with Project 3, with the goal of human clinical evaluation.

If successful, our immunogen regimen could swiftly transition into human clinical testing to induce protective BNABs against HIV.

Trustees Of The University Of Pennsylvania

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]

Philadelphia, Pennsylvania 19104 United States

Single Zip Code

Integrated Preclinical / Clinical AIDS Vaccine Development Program (IPCAVD) (U19 Clinical Trial Not Allowed) (PAR-23-033)