[R21] Evaluation of HIV-1 Env-C3d constructs on nanoparticles for structure, function and immunogenicity.
Ente: National Institute of Allergy and Infectious Diseases
Scadenza: 2028-06-30
Importo max: 276.000 EUR
Paese: US
Descrizione
SUMMARY
A broadly effective HIV-1 vaccine remains a high priority to eliminate the spread of this highly pathogenic virus
in the human population. Broadly neutralizing antibodies (bNAbs) against the viral envelope (Env) trimeric spike
are induced in a small population of infected people primarily owing to continuous activation of the immune
system by the replicating virus to fine tune antibody responses to multiple sites of vulnerability on Env trimer.
Elicitation of such bNAbs by vaccination is highly challenging and would probably need a series of candidate
vaccine immunogens that effectively prime and boost to achieve neutralization breadth. Recently, we have
elicited broadly cross-reactive serum and serum IgG responses in multiple macaques immunized with a series
of recombinant highly stable and homogeneous Env NFL trimers either as soluble trimers or arrayed at high-
density on the surface of stable covalent trimer-liposomes. The antibodies from these studies targeted the
gp120:gp120 domain interface encompassing the highly conserved CD4 binding site (CD4bs) and the trimer
apex respectively. We previously designed Env fused with one copy of molecular adjuvant C3d to further improve
the immunogenicity in vivo. We will evaluate Env-C3d candidates with two and three copies of C3d domains per
gp160 subunit (+/- Fc domain) in C57BL/6 and Alloy mice for germinal center formation, antigen retention,
longevity, cross-neutralizing antibodies, responder frequency and epitope targeting. Analysis and evaluation of
the Env-C3d fusion candidates both in vitro and in vivo will have broader implications in vaccine design for
multiple pathogens.
Istituzione: SCRIPPS RESEARCH INSTITUTE, THE
PI: Shridhar Bale
Progetto: 1R21AI203583-01
Settori: National Institute of Allergy and Infectious Diseases
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