PROJECT SUMMARY An HIV vaccine represents our best opportunity for eliciting durable, protective immunity and ending the decades-long AIDS pandemic. To be successful, an antibody-based HIV vaccine must reliably induce broadly neutralizing antibodies (bnAbs), most likely via a series of immunogens or mixtures of immunogens delivered sequentially. To avoid viral escape, bnAbs of at least 2-3 distinct specificities must be induced concurrently. Thus, a more holistic view of HIV vaccine composition would resemble a matrix of immunogens rather than a sequence. Constructing a single set of immunogens that reliably induce breadth against just one epitope is a daunting challenge. Succeeding in the exponentially more difficult task of assembling a cohesive immunogen matrix will require significant improvements in the speed and granularity with which we can design and evaluate vaccines. Here, we propose a solution: by embedding multi-omics technology at each stage of immunogen development, we can unlock a revolutionary increase in scale while simultaneously improving the depth and resolution of our analyses. The Multi-Omics Vaccine Evaluation (MOVE) Consortium brings together a multi- disciplinary team of expert investigators with a long history of productive collaboration. Our central hypothesis is that deeply integrating advanced multi-omics approaches throughout our iterative vaccine development pipeline will speed the discovery of an HIV vaccine by allowing us to operate concurrently across multiple immunogens. Our overall mission is to accelerate development of an HIV vaccine by parallelizing the design and testing of a matrix of complementary immunogens that reliably induce broad, durable immunity. To accomplish our objectives, we propose the following Specific Aims: Specific Aim 1: Profile the human immunogenicity of a novel V2 apex-focusing Env trimer. Specific Aim 2: Evaluate Q23-elicited immune responses, candidate boosting immunogens, and delivery strategies in humanized animal models. Specific Aim 3: Develop the Q23 backbone into a multi-epitope priming immunogen.