Improved Mimotope Structures and Scaffolds for Prime-Boost Strategies

Novartis Vaccines And Diagnostics, Inc., Cambridge MA

Investigators

Linked publications & trials

Abstract

Efforts to generate vaccines that elicit broadly neutralizing antibodies have been thwarted by features of the[unreadable] HIV-1 envelope glycoprotein (Env) that limit access to conserved, neutralizing epitopes and difficulties in[unreadable] mimicking neutralizing structures in vaccine constructs. These challenges apply especially to the[unreadable] pretransmembrane region (PTM) of gp41, which is the target of approximately half of the broadly neutralizing[unreadable] monoclonals that have been identified (2F5, 4E10, Z13), and the coiled-coil domain of the gp41 prehairpin[unreadable] intermediate, which is the target of the broadly-active fusion inhibitor T20 (Enfuvirtide) and a recently[unreadable] described neutralizing antibody D5. Here we propose to create and evaluate rationally-designed gp41[unreadable] immunogens that present PTM, coiled-coil, and other HIV mimotopes in stable, highly exposed, oligomeric[unreadable] structures for eliciting broadly neutralizing antibodies. These studies will further investigate the influence of[unreadable] the virion membrane and virus-like particle (VLP) structure on antibody induction, especially for PTM[unreadable] determinants, by comparing gp41 oligomers in the context of VLPs or soluble immunogens. The[unreadable] immunogens utilize a novel, oligomeric gp41 scaffold, in which the N- and C-heptad repeats (HR) of SIV[unreadable] serve as a trimerization domain and the transmembrane domain (TM) and cytoplasmic tail of HIV serve as[unreadable] targeting signals for incorporationg oligomers into VLPs. We have shown that this gp41 scaffold allows[unreadable] insertion of large regions of Env between the trimerizaton and TM domains, without impairing oligomer[unreadable] assembly or incorporation of the gp41 immunogen into VLPs. The gp41 scaffold also contains an alternative[unreadable] insertion site, between the N- and C-HR, which may also be used to provide a highly exposed, loop context[unreadable] for evaluating some epitopes. Specific aims include creating and evaluating the following Env determinants[unreadable] presented in the oligomeric gp41 scaffold in VLP and soluble formats: 1) PTM region containing the 2F5 and[unreadable] 4E10 epitopes; 2) N-HR coiled-coil region 3) combination inserts involving PTM, coiled coil, and other HIV[unreadable] neutralizing mimotopes. Immunogens will be extensively characterized, evaluated as single immunogens,[unreadable] and directly compared with other immunogens in the program. Promising constructs will be further assessed[unreadable] in prime-boost combinations involving other vectors and immunogens in the program, with different[unreadable] formulations and adjuvants.[unreadable]