PROJECT SUMMARY/ABSTRACT This application proposes to continue as the Statistical and Data Management Center (SDMC) for the HIV Vaccine Trials Network (HVTN). To meet the statistical and data management goals described in RFA-AI-19- 002, and ultimately to achieve the scientific goal of the HVTN − to develop a safe and globally effective HIV vaccine − seven specific aims will be addressed: Aim 1, to accomplish all specific aims using high-quality, timely, cost-efficient, and secure data management and safety monitoring by adhering to clinical data management standards and regulatory requirements and by using state-of-the-art, CDISC Standards compliant data systems that enable data exchange and provisioning; Aim 2, to provide innovative statistical/computational biology study design and data analysis for standardized, phase 1-2a clinical trials that evaluate safety and immunogenicity of candidate HIV vaccines, including “fast-track” iterative trials to screen vaccines for their ability to elicit broadly neutralizing antibodies, and that evaluate safety, pharmacokinetics, and immunological functions of directly administered broadly neutralizing monoclonal antibodies (mAbs); Aim 3, to support the HVTN Laboratory Center with data management, statistical methods, and data analysis for developing immunological and virological assays and data analysis pipelines, toward vaccine immunogenicity characterization, systems vaccinology, and modeling of mAb concentrations and functions; Aim 4, to provide robust and efficient design and analysis of phase 2b test-of-concept and phase 3 trials to assess vaccine efficacy or mAb efficacy to prevent HIV infection, including strategies for integrating other HIV prevention modalities into trial designs; Aim 5, to employ novel quantitative methods for assessing within the phase 2b and 3 efficacy trials correlates of vaccine or mAb protection, where the correlates are based on markers measuring immune responses to vaccination or mAb concentration, human immune genetics, and genetic and immunological features of HIV viruses; Aim 6, to adapt the functions of Aims 1−5 to vaccine or mAb clinical trials of HIV-exposed and HIV-unexposed infants; and Aim 7, to adapt applicable functions of Aims 1−6 for tuberculosis vaccine clinical trials. Novel quantitative methodologies will be developed in support of the specific aims, to increase the efficiency, rigor, and scientific impact of the HVTN program. The research will be accomplished in harmonization with the HVTN Leadership and Operations Core and the HVTN Laboratory Center, and in collaboration with other HIV/AIDS research networks. Aim 5 encapsulates the HVTN’s research approach to achieving a globally effective HIV vaccine, in that: (1) Iterative evaluation of refined versions of partially effective vaccine and mAb regimens will be required; (2) Correlates of vaccine protection are the key scientific tool for driving this iterative evaluation; (3) All Aim 1−4 research activities are ultimately directed toward achieving high-quality correlates of vaccine protection; and (4) Following licensure of an HIV vaccine, correlates of vaccine protection provide the basis for bridging efficacy to new populations, hence facilitating widespread vaccination that will be essential for ending the HIV pandemic.

PROJECT NARRATIVE Despite recent advances in biomedical interventions that reduce the risk of HIV acquisition, worldwide an estimated 1.7 million people acquired HIV in 2018. Eliminating the pandemic will require a safe and effective HIV vaccine. Only through human clinical trials held to the highest scientific, ethical and regulatory standards will the goal of an HIV vaccine be realized.