Project Summary/Abstract (30 lines) The overarching goal of this CHAVD is to develop a sequential HIV vaccine regimen that induces sustained protective levels of broadly neutralizing antibodies (bnAbs) in humans. bnAbs provide complete protection against HIV infection in preclinical models. We hypothesize that an effective HIV vaccine will need to consistently induce bnAbs against 2-3 different sites on the HIV Envelope glycoprotein (Env) of the virus in most (>90%) of vaccine recipients. Targeting multiple sites is necessary to provide adequate coverage against the huge diversity of global isolates. We propose a sequential strategy in which a series of designed immunogens guide antibody responses from precursors to bnAbs. We are intensely developing and testing immunogens. We have shown proof-of-principle of the sequential strategy in preclinical models and our first three immunogens are entering manufacturing or clinical trials shortly. The second major goal of this CHAVD is to generate immunogens that induce protective non- neutralizing antibody (nnAb) responses that can either act alone or augment the protective activity of bnAb responses. To accomplish this goal, we propose a tiered approach in which the ability of nnAbs to capture infectious virions and to clear infected cells in vivo in two established mouse models will be explored. The most effective nnAbs, alone and in combination with other nnAbs and bnAbs, will then be assessed for their ability to protect nonhuman primates against virus challenge. Protective nnAbs will be used as templates for immunogen design. To support our translational effort, we have organized state-of the-art Manufacturing, Clinical Trials Sample Analysis and Management and Operations units. In addition, we have established twelve Scientific Research Support Units, headed by leaders in their fields, to underpin the diverse scientific and technical capabilities required to execute our comprehensive and highly integrated vaccine program Finally, this CHAVD proposal is built upon a highly successful, innovative and efficient CHAVI- ID program that has made major scientific contributions to the HIV vaccine field. The CHAVD provides the opportunity to advance and translate these contributions into an HIV vaccine.