ABSTRACT – MODEL SYSTEMS (MODS) CORE Cytomegalovirus (CMV) poses a significant threat to children's health as a major cause of birth defects and brain damage, yet an effective vaccine to prevent congenital CMV (cCMV) transmission remains elusive. Novel strategies to protect against cCMV transmission and disease require tractable preclinical models to de-risk clinical vaccine development. The Model Systems Core (MODS Core), led by Dr. Sallie Permar (contact PI) along with collaborators across 3 national primate centers with enhanced special pathogen-free (SPF) rhesus monkey breeding colonies, has established a highly relevant nonhuman primate (NHP) model in rhesus monkeys (RM) that closely resembles human cCMV transmission and disease after acute rhesus CMV (RhCMV) infection during pregnancy. However, conducting studies in RhCMV-free monkeys remains challenging due to its endemicity in primate colonies. To address this, the MODS Core Specific Aims include; 1) Central coordination to ensure unbiased distribution and protocol adherence of studies in RhCMV- seronegative dams and males among Projects, 2) Decoding of CMV-host interactions and viral placental cell tropism in placental organoid and placentas from RM and humans after vaccination using high-resolution transcriptomics and proteomics technologies, the MODS Core aims to identify cell-type specific gene expression patterns, comparing CMV spread and pathogenesis between RMs and humans in highly relevant in vitro organoid models and in vivo samples obtained from RMs and humans directly; 3) Advanced single-cell and spatial multi-omic technologies to investigate CMV viral pathogenesis and mechanisms of vaccine efficacy at the maternal-fetal interface, identifying candidate therapeutic and immunologic targets for developing better vaccination and treatments to reduce and ameliorate vertical viral transmission. The MODS Core plays a crucial role in coordinating NHP experiments, facilitating sample exchange, conducting single-cell level placental analysis using organoid and placenta models, and providing primary and secondary endpoints for data analysis. Ultimately, the MODS Core's comprehensive approach contributes to the development of effective interventions to eliminate cCMV and serves as the backbone of the overall Program, de-risking novel CMV vaccine candidates and discovering novel vaccine targets in a highly-relevant pre-clinical model.