P01AI181597

Rna-based hiv-1 chimera vaccines encoding a trimerizing host self-protein protomer linked to a viral mper-tm segment - summary – overall while there is an urgent need for vaccines eliciting broadly neutralizing antibodies (bnabs) against the highly mutable hiv-1 retrovirus to stem its global spread, this goal remains elusive. Antibodies produced against trimeric gp160 sites of vulnerability during natural infection drive retroviral mutation further, diversifying quasi- species in individuals.

One apparent exception is the conserved membrane-proximal external region (mper) site, critical for hemifusion/fusion and which is stealth, largely immersed in lipid and only transiently revealed during spontaneous ectodomain tilting. Liposome-arrayed mper segments induce specific antibodies in mice but without neutralizing activity, explained by the restricted antibody access to the native mper residing in a narrow “crawl space” between the viral membrane below and the base of the gp120 and gp41 protomers of the trimeric gp160 envelop.

Biomaterial formulation of polymer “steric clouds” on liposomes or alternative origami- based approaches on nanodiscs to limit access to the mper, akin to that mandated by the trimer three-fold axis, were technically cumbersome and confounded by the uncertainty of mper topology. Our recent analysis of the structure and dynamics of nanodisc-embedded trimeric hiv-1 spike protein provides compelling data for alternative design.

In addition, synthetic rna lipid nanoparticle (lnp) encapsulation technology obviates vaccine challenges with hydrophobic proteins such as the mper and adjacent transmembrane segment (mper-tm). This p01 comprises two projects. Project 1 shall determine the immunogenicity of rna vaccines encoding mper-tm trimers fused to structurally suitable self-proteins to focus antibody responses against the conjoint membrane arrayed viral mper-tm, with the self-proteins imposing steric restriction comparable to that exerted by the gp160 ectodomain on the native mper. Sero logical, single b cell, recombinant mab methods, neutralization assays and ig bioinformatic analyses are applied.

Automated computational searches of the pdb informed by single-particle cryo-electron microscopy (cryo-em) structures and using rna technology reveal antigenicity and immunogenicity of construct design for planned immunization studies in normal as well as knock- in mice harboring human ig d3-3 and jh6 gene segments for long cdrh3 loop generation. Project 2 will perform cryo-em and x-ray crystallographic studies to compare existing and additional hiv-1 patient-derived bnabs obtained from biobanked serial samples (osier, iavi) with those that are vaccine elicited, in the context of nanodisc-arrayed mper immunogens and native spike protein.

We shall investigate ig requirements of somatic hypermutation (shm), fab molecular dynamics (md) and co-evolution of antibody approach angles and affinities of bnabs of igg1 and igg3 isotypes. Projects 1 & 2 shall be performed by kim/weissman (dfci/upenn) and reinherz (dfci), respectively, with four technology components: mrna-lnp vaccine synthesis by weissman (u penn); cryo-em by walz (rockefeller), x-ray crystallography by tan (aps) and kwong (nih); and md by huang (texas a&m). Administrative (reinherz) and antibody (seaman, bidmc) cores serve all.

Dana-Farber Cancer 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]

Boston, Massachusetts 022155418 United States

Single Zip Code

NIAID Investigator Initiated Program Project Applications (P01 Clinical Trial Not Allowed) (PAR-22-225)

Amendment Since initial award the total obligations have increased 96% from $2,356,969 to $4,613,193.