Refinement of DNA-Launched NanoParticles decorated with Apex and CD4bs B cell lineage targeting Envs (DLNP-ACEs)

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Project 2 - Project Summary In order to protect against HIV-1 acquisition, antibody-based vaccines must be able to consistently elicit broadly neutralizing antibodies (bnAbs). bnAb elicitation has proven difficult in humans and non-human primates (NHPs), in part because of the complex developmental pathways bnAbs require to mature, competition from off-target responses to the HIV-1 envelope glycoprotein (Env), and rare precursor B cell frequency. In this project we will develop candidate immunogens to address each of these problems through a variety of approaches. First, we will use structure-based and mammalian display techniques to further enhance the germline targeting ability of our lead candidate, Q23.17 MD39. Using these approaches, we will develop native-like trimers capable of targeting the V2-apex and CD4 binding site bnAb epitopes. These trimer immunogens will additionally be engineered to limit off-target responses by minimizing competition from highly immunodominant non-neutralizing antibody lineages. Furthermore, we will use these constructs to develop novel “germline targeting SHIVs”, and through SHIV-infection will identify boosting immunogens that can guide the development of breadth. Additionally, through structural analysis of the process of Env- Ab coevolution, we aim to identify determinants of bnAb development in infected primates, that will further inform our immunogen design process. Finally, we will complex these with genetic adjuvants developed in project 1 and platform advances in project 3, as well as with our novel DNA-Launched NanoParticle (DLNP) platform. We have shown DLNPs improve the immunogenicity while not requiring the complex cGMP processes that hamper the pace of clinical development for traditional nanoparticle vaccines. We will then down-select immunogens using a variety of innovative mouse models that harbor human B cell lineages, recapitulate human B cell competition and have tunable bnAb precursor frequencies. These mice will provide a benchmark for our lead candidates to be advanced into GMP production. We will test them in a NHP model for heterologous challenge, and through these combined approaches, we aim to demonstrate, for the first time, protection from heterologous tier-2 challenge in NHPs.