This Consortium for HIV/AIDS Vaccine Development (CHAVD) will apply state-of-the-art technologies and immunologic tools to focus on iterative, rational vaccine design that will lead to a successful final vaccine design. Much work in previous years has led to this critical juncture in HIV-1 vaccine development where the route forward has become clearer to a protective HIV-1 vaccine. The rationale for this grant is that the first 13 years of the Center for HIV/AIDS Vaccine Immunology programs defined the roadblocks preventing a vaccine, developed first generation HIV-1 immunogens to induce HIV-1 protective antibodies and established a translational pipeline to accelerate HIV-1 vaccine development. The overall goal of this grant is to develop an effective HIV-1 vaccine for global use. There are two foci proposed in the CHAVD: Focus 1, strategies for induction of HIV-1 broadly neutralizing antibodies (bnAbs), and Focus 2, strategies for induction of protective HIV-1 non-neutralizing antibodies. In Focus 1, our overall goal is to design Env immunogens that will elicit multiple specificities of bnAbs. Here the CHAVD team will design immunogens that induce bnAbs, induce optimal CD4 T cell help for bnAb induction, transiently down-modulate constraints from negative regulatory cells and immune tolerance mechanisms, and allow for disfavored bnAb B cell lineages to develop. In Focus 2, our overall goal is to develop multivalent immunogens that induce broad and potent protective non- neutralizing HIV-1 antibodies (NNAbs). The Management and Operations Unit will oversee the CHAVD translational pipeline, and each of our six Science Research Support Units (SRSUs) will provide key elements of immunogen design or pre-clinical evaluation of candidate immunogens. Once designed and tested in bnAb knock-in mice or in macaques, promising vaccine candidates that pass our go-no go criteria will be vetted by the CHAVD Scientific Product Development Committee and DAIDS, then produced for clinical trials in our GMP Production Unit at Duke and tested in Phase I trials by the HIV Vaccine Trials Network. Our Clinical Trials Sample Analysis Unit will determine the immunogenicity achieved and provide feedback on immune responses induced in man to Focus 1 or Focus 2 and our SRSUs for iterative improvement of immunogens. We expect that by the end of this grant, a final vaccine candidate will be delivered to the NIAID that has reproducibly induced durable levels of either bnAbs or protective NNAbs in rhesus macaques (RMs) or in a Phase I trial in humans, or in both.