R01AI167716

B Cell Lineage Directed Rational Vaccine Strategies Based on CAP256SU Env-Ab Coevolution - Project Summary/Abstract:

The development of an effective HIV vaccine remains a major challenge. Previous strategies for HIV vaccine design aimed to elicit protective T cell responses, non-neutralizing antibodies, broadly neutralizing antibodies (BNAbs), or some combination of the three but have failed to protect against infection. This grant aims to elicit BNAbs by a novel strategy that combines priming of multiple V2 apex BNAb germline precursors, immunofocused boosting, and molecularly-guided affinity-maturation.

This study design derives from a growing consensus that critical elements to a successful BNAB-based vaccine will be its ability to:

I) Efficiently activate and expand multiple rare naïve BNAB-encoding B cell precursors;
II) Immunofocus these B cell responses to canonical, conserved BNAB epitopes on the HIV Env trimer and away from off-target epitopes; and
III) Affinity-mature this response by a process of molecularly-guided Env-Ab co-evolution.

The study design proposed in this application addresses each of these three critical aspects of BNAB elicitation. Importantly, we propose to target the V2 apex BNAB supersite because of its unique vulnerabilities, which allow it to be targeted by BNABs with less somatic hypermutation and affinity maturation, without V-gene insertions or deletions, and with less restriction for particular light chain pairings.

Our proposal is thus unique among the constellation of other HIV-1 vaccine programs that target relatively more challenging BNAB targets such as the CD4BS, V3-glycan patch, fusion peptide, or MPER.

The project includes three aims:

Aim #1: Will isolate HIV envelope V2-apex site BNABs from CAP256.SU Env SHIV (Simian-Human Immunodeficiency Virus)-infected rhesus macaques (RMs), identify their unmutated common ancestors (UCAs) through lineage-tracing by next-gen sequencing, and infer through Env-Ab co-evolution analyses CAP256.SU "Env immunotypes" that select for affinity-maturation and neutralization breadth.

Aim #2: Will develop CAP256.SU trimer immunogens that exhibit enhanced affinity for V2 apex BNAB UCAs by employing in-vitro directed reverse vaccine engineering that targets multiple rhesus and human V2 apex BNAB UCAs. We will validate this optimized CAP256.SU GT-trimer for native configuration and prepare it as a soluble SOSIP trimer and nanoparticle-displayed trimer for testing as a prime to activate multiple rare V2-apex BNAB B cell precursors in outbred RMs.

Aim #3: Will investigate a B cell lineage-based prime-boost immunization strategy in RMs to induce V2-apex BNAB responses by rationally engineered Env trimer protein immunizations. Novel aspects of this vaccination regimen will be an HIV-1 Env SOSIP prime that activates multiple germline precursor B cells; a V2 apex immunofocused boost using MT145KDV5 SOSIP Env (a simian immunodeficiency virus Env from chimpanzees that retains selective antigenic cross-reactivity with HIV-1 in V2 apex C-strand epitopes), and "polishing" immunizations with Env SOSIP trimers corresponding to affinity-graded V2 apex antigens from Env-Ab coevolution analyses from SHIV.CAP256.SU infected RMs.

This study will be the first of its kind, and if successful in inducing BNABs in RMs, would represent a new paradigm for lineage-based vaccine design.

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

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

Amendment Since initial award the total obligations have increased 317% from $881,590 to $3,679,422.