Design and optimization of DL-NLTs and molecular adjuvants to increase potency and promote NAb formation in vivo

Project 1 Summary Extensive efforts have been carried out over the years to design a HIV-1 vaccine candidate which elicits robust immune responses supporting broad neutralization and effector T cell responses. Recently the Weiner and Kulp laboratories reported the development of novel DNA-launched, in vivo, self-assembling immunogens, including both DNA launched native like trimers (DL-NLTs) and DNA-launched nanoparticle immunogens (DLNPs). Both DNA launched NLTs and NPs assemble and display appropriate epitopes for neutralizing antibodies while occluding epitopes for non-neutralizing antibodies in vivo. Additionally, they drive robust T cell immunity. These vaccine candidates are being moved to the clinic under studies HVTN-304 and HVTN-305. synDNA facilitates rapid immunogen design, co-delivery of molecular adjuvants, supports expression and assembly of complex structural antigens in vivo, has a safe clinical track record, and maintains boost-ability. Building on progress from our previous IPCAVD, combining these designs, we will be working with Dr. Kulp under Project 2 to formulate DLNPs bearing NLTs displaying Apex and CD4 binding-site B cell lineage targeting Epitopes (DLNP-ACEs). Furthermore, we have designed and characterized several synDNA-encoded molecular adjuvants to support enhanced humoral immunity, cell-mediated immunity, and direct antigen-specific responses to mucosal surfaces. The overarching goal of Project 1 is to combine these novel immunogens with DNA-delivered genetic adjuvant combinations and/or heterologous adjuvant regimens, in dual expressing plasmids developed with Project 3 to support vaccine-induced immunity and represents a great leap forward in the design of HIV-1 vaccines.