P01AI157299

Eliciting Neutralizing Antibodies and B Cell Responses Using Novel HIV Env Immunogens in Non-Human Primates

Neutralizing antibodies are likely to be required for an effective HIV-1 vaccine. However, few candidate vaccines efficiently elicit broadly neutralizing antibodies (BNAbs) following vaccination. Recently, the VRC Working Group has elicited fusion peptide-directed BNABs in guinea pigs and non-human primates (NHPs). Similarly, we recently elicited BNABs in rabbits following heterologous NFL (uncleaved) trimer-liposome prime:boosting at Scripps. In these experiments, we activated B cell responses with targeted N-glycan deletions in the priming immunizations. We isolated two rabbit BNABs that recapitulate the serum activity, targeting two distinct sites of Env vulnerability. The elicitation of neutralizing responses was enhanced by targeted N-glycan deletion, high-density liposomal array, and heterologous trimer restorative boosting Env.

In independent experiments in guinea pigs, we have also elicited BNABs in multiple animals using an N-glycan deletion, heterologous Env NFL prime:boost approach. These recent outcomes are encouraging inroads toward the successful solution of a 3-decade-long problem. The new era of near-native trimeric spike mimics, coupled with particulate array, structure-informed design, and high-resolution analysis of Env-specific B cell and lymph node responses, afford new opportunities to more efficiently elicit BNABs.

We propose an integrated, multi-faceted approach blending the expertise of world leaders in HIV Env trimer design, analysis of B cell responses and antibodies following vaccination, NHP immune tissue analysis, and EM-based analysis of ongoing immune responses and high-resolution antibody:trimer interactions. We will use well-ordered trimer prime:boosting that elicited BNABs in rabbits and guinea pigs to elicit such responses in NHPs, translating success in small animals to NHPs using novel immunogen design and presentation in Project 1 (Wyatt) and immunization of NFL trimers into NHPs via Core B (Silvestri).

We will use "real-time" serum Fab-to-trimer binding evaluated by EM polyclonal IgG epitope mapping (EMPEM) in Core C (Ward) in complement with rapid monoclonal antibody (MAB) NGS-based MAB cloning, sequencing, and functional expression in Project 2 (Karlsson Hedestam). In collaboration with the VRC (Mascola), we will define either non-neutralizing MABs to mask unwanted non-neutralizing epitopes or to better display the epitopes of cross-neutralizing MABs. We will compare NFL trimer-liposomes to cell surface NFL trimer array expressed from the exciting mRNA lipid encapsulation technology.

We will assess if immunization in the juvenile NHP B cell repertoire compared to adult macaques will better generate BNABs as is observed during human infection. To follow our discovery of a Tier 2 CD4 binding site (CD4BS)-directed BNAB following trimer-liposome vaccination, termed E70, we will target the CD4BS by directed NFL trimer deglycosylation in the NHPs. Based on our recent discovery of the very broadly neutralizing vaccine-induced MAB, 1C2, we will also focus on the GP41:120 trimer interface.

Leveraging these initial leads, we will undertake a multifaceted, cross-component integrated approach to guide the elicitation of BNABs in NHPs following vaccination with near-native, uncleaved NFL Env trimers.

Scripps Research Institute

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]

La Jolla, California 920371000 United States

Single Zip Code

HIV Vaccine Research and Design (HIVRAD) Program (P01 Clinical Trial Not Allowed) (PAR-18-319)

Amendment Since initial award the total obligations have increased 433% from $3,242,006 to $17,277,936.