R01AI176520

Designing HIV-1 envelope immunogens to maximize neutralization breadth through use of multiple founder envelope antigens - Project Summary/Abstract

An HIV-1 (HIV) vaccine capable of eliciting broad and potent neutralizing antibody (Ab) response to HIV envelope (Env) remains elusive. HIV has a high mutation rate, Env is highly glycosylated as well as conformationally dynamic and, well-characterized broadly neutralizing responses reported to date have been generated after chronic HIV infection, rather than by candidate HIV vaccines.

Recently, we reported that precursor broadly neutralizing antibodies (bNAbs) can develop during early HIV infection and neutralization breadth was more frequent when multiple HIV variants established infection in an individual, defined here as multiple-founder variant (MFV) infection. Furthermore, Env diversity during initial infection was higher in individuals who developed neutralization breadth. We concluded that Env-specific B cell development within one month of initial HIV infection can predict neutralization breadth years later; this phenomenon highlights the critical importance of these initial interactions, which prime B cells at the earliest stages of HIV infection.

To determine the immunogenicity of an HIV vaccine design based on the MFV concept, we formulated a cocktail of five Env trimer proteins derived from MFV in acute infection. The Env sequences corresponded to 5 founder lineages in one participant. They were further optimized by stabilizing them in a closed conformation using the 'repair and stabilize' strategy developed by Janssen Pharmaceuticals. The cocktail of minimally distant, stabilized Env proteins were formulated with the novel vaccine adjuvant, Army Liposome Formulation Plus QS-21 (ALFQ).

Preliminary immunogenicity data in rabbits demonstrated that this vaccine candidate elicited a greater breadth of neutralizing Ab responses than an equivalent total dose of a single stabilized Env trimer protein. These minimally distant immunogens also elicited a higher magnitude of IgM responses to HIV; a predictor of subsequent neutralization breadth in our studies of early infection.

Therefore, we propose to select an optimal combination of minimally distant HIV Env immunogens that mimic the diversity and development of neutralizing Ab breadth seen in acute infections with MFV in vitro and in vivo. We will optimize the antigenicity of the HIV Env trimer immunogens by comparing native stabilized trimers with Env trimers that have shortened hypervariable (HV) loops and glycan modifications in an attempt to improve their antigenicity (Aim 1).

We will optimize immunogen delivery and display strategies, including multivalent trimeric Envs delivered as messenger RNA (mRNA) and, multivalent immunogen display on self-assembling liposomal cobalt porphyrin phospholiposomes (CoPoP) that afford Env base shielding (Aim 2). We will utilize pre-specified go/no-go criteria to downselect the optimal vaccine regimen of optimized minimally distant HIV vaccine candidates, to evaluate protective immune responses in non-human primate SHIV challenge studies (Aim 3).

Our long-term goal is to develop a multivalent HIV vaccine candidate that elicits protective broadly neutralizing Ab responses for subsequent manufacture and evaluation in human clinical trials.

The Henry M. Jackson Foundation For The Advancement Of Military Medicine

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]

Bethesda, Maryland 208171888 United States

Single Zip Code

Innovation for HIV Vaccine Discovery (R01 Clinical Trial Not Allowed) (PAR-20-158)

Amendment Since initial award the total obligations have increased 426% from $619,289 to $3,259,509.