Scientific Project One

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ABSTRACT PROJECT ONE We have reported on the design of a germline-targeting recombinant (rec) HIV-1 Env-derived immunogen, 426c.Mod.Core-C4b, that activates naïve B cells that express germline VRC01-class BCRs and on “booster” rec protein immunogen, HxB2.WT.Core-C4b, that improves the maturation of the VRC01-class antibodies elicited by 426c.Mod.Core-C4b. This maturation is, however, incomplete and additional immunizations with heterologous Envs, yet to be identified, will be necessary to complete the maturation process that leads to the production of broadly neutralizing VRC01-class antibodies. The identification of such Envs will require extensive experimentation. To expedite this process, we are exploring alternative vaccination methodologies to rec protein immunizations, such as self-amplifying RNA (saRNA) vaccine platforms. RNA vaccines offer several advantages over rec protein immunogens as the RNA immunogen sequences can easily be modified, they are more easily produced, and they do not require extensive purification steps. Also, they are less expensive and faster to GMP-manufacture and they do not require adjuvants. So far however, not much is known on how the quality of anti-Env B cell and antibody responses elicited by saRNA vaccines and by adjuvanted rec Env protein immunogens compare. To address this point, in this Scientific Project One, we will characterize the VRC01 B cell and antibody responses elicited by the 426c.Mod.Core-C4b germline-targeting Env and the HxB2.WT.Core-C4b boost Env when delivered by saRNA vaccines. We will compare these responses to those generated by the corresponding adjuvanted rec protein nanoparticles. We will also examine whether the form of the immunogen expressed by the saRNA vaccines (either as secreted protein nanoparticles or as membrane-anchored proteins) influences the quality of the VRC01 B cell and antibody responses. In addition, the qualities of the VRC01 B cell and antibody responses will be evaluated in the following three prime-boost modalities: (a) saRNA prime and saRNA boost; (b) saRNA prime and rec protein boost; and (c) rec protein prime and saRNA boost. We propose an accelerated immunization schedule that relies on our expertise on VRC01-class antibodies, Env-immunogen-design, BCR analysis and antibody characterization, as well as our expertise with saRNA vaccine modalities. Our proposed studies are central to the goals of this IPCAVD grant.