R61AI161818

Combining Germline-Targeting, B Cell Immunofocusing, and Env-Ab Co-Evolution Strategies to Induce HIV Envelope V2-Apex Broadly Neutralizing Antibodies - Project Summary/Abstract:

The development of an effective HIV vaccine has proven to be a daunting 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. All three approaches have thus far failed to consistently protect nonhuman primates (NHPs) or humans from infection.

This grant aims to elicit BNAbs by means of a novel strategy that combines – for the first time – germline-targeting, immunofocusing, and molecularly guided affinity maturation. This study design evolves from a growing consensus that critical elements to a successful BNAB-based vaccine will be its ability to efficiently bind and activate rare naïve B cell germline precursors of BNAbs; to immunofocus these B cell responses to canonical, conserved BNAB epitopes on the HIV Env trimer and away from off-target strain specific or trimer base epitopes; and to mature or "polish" this BNAB lineage response by a process of molecularly guided Env-Ab coevolution.

The study design proposed in this application addresses each of these three essential requirements as it aims to elicit BNAbs targeting the highly conserved HIV-1 V2-Apex site. The principal investigators (Andrabi and Shaw) have assembled a talented collaborating research team with a strong track record of scientific discovery, bioengineering and molecular tool development, including the discovery of V2-Apex BNABs (Burton), development of germline targeted V2 Apex immunogens (Andrabi), bioengineering of phosphoserine-linked alum nanoparticle antigen displays (Irvine), discovery of V2-Apex immunofocusing chimpanzee simian immunodeficiency viruses (Hahn), creation of CRISPR-Cas9 knock-in mice (Batista), development of next-generation "designer" SHIVs (Shaw), and preclinical-clinical translation (Dey).

The project consists of four aims:
Aim #1 will isolate HIV envelope V2-Apex targeted BNABs from SHIV infected rhesus macaques, identify their UCA's, and generate UCA-expressing knock-in mouse models for vaccine evaluation.
Aim #2 will design novel V2-Apex germline-targeted and immunofocused SOSIP Env trimer immunogens and by mammalian display saturation mutagenesis and structure-guided design present them as soluble proteins or alum-based nanoparticles for enhanced B cell responses.
Aim #3 will optimize germline-targeting and B cell immunofocusing boost strategies in V2-Apex BNAB UCA-expressing KI-mice and outbred rhesus macaques, and will identify in SOSIP Env primed and SHIV infected rhesus macaques, Env "immunotypes" that can drive neutralization breadth.
Aim #4 will design and test, first in KI mice and then in a pivotal preclinical trial in rhesus macaques, an all-SOSIP Env vaccination regimen designed to prime, boost, and affinity-mature BNAB responses in a majority of animals.

If successful, this would be the first example of a vaccine regimen that consistently elicits BNABs in an outbred animal model, and it would represent an important beachhead in HIV-1 vaccine science, one that could be transitioned rapidly by our translational partner into human testing.

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 191044793 United States

Single Zip Code

Change of Recipient Organization (Type 7 Parent Clinical Trial Optional) (PA-21-268)

Amendment Since initial award the End Date has been extended from 03/31/24 to 06/17/24 and the total obligations have increased 215% from $1,505,564 to $4,748,429.