Human norovirus (HNV) is considered the most common cause of viral gastroenteritis worldwide, yet there is a deficit in our understanding of protective immunity against HNV. Such information is critical to vaccines currently being developed, as they are likely to have the highest impact in low-to-middle income countries (LMICs). Several cohort studies suggest that children are repeatedly exposed early in life to HNV in South America, South East Asia, and Africa. To determine if this repeated, early exposure leads to more robust antibody responses with regards to cross-genotype responses as well as duration of protective immunity, and in order to understand when a vaccine would be most effective to deliver in a person’s life, a more thorough understanding of HNV humoral immunity must be achieved. A lack of robust neutralization assays with which to test patient sera has limited our abilities to conduct large-scale and longitudinal immunological studies. Until the recent advent of the enteroid cell culture system, the field lacked a platform to screen for neutralizing antibodies. Instead, surrogate neutralization assays utilizing virus-like particles (VLPs) and their ability to bind histo-blood group antigens (HBGAs) were used to screen for potentially protective antibodies. Increases in HBGA blockade antibody titers have been correlated with increased protection against HNV challenge. With the time and technical demand of both enteroid cell culture and VLP-based screens, we aimed to create more deployable, alternative assays and screen naturally infected children for protective antibodies. In Chapter 2, we discuss a norovirus luciferase-based approach for measuring HBGA blockade antibodies and provide data that the specificity matches that of the standard VLP-based assay. In Chapter 3, we discuss an unconventional approach to studying the entry of nonenveloped HNV – the HNV pseudoparticle system. Anchored in the membrane of enveloped lentiviral particles, VSVg-VP1 appears to dictate target cell entry, allowing the system to be used in studying HNV attachment, viral uptake, and antibody neutralization. In Chapter 4, we discuss the application of the luciferase-based HBGA blockade assay in a Vietnamese birth cohort. We measured the duration and breadth of humoral responses elicited by children who had multiple HNV exposures early in life. Finally, in Chapter 5, we discuss ongoing work isolating potentially cross-genotype HBGA blockade antibodies from broadly reactive individuals. It is our aim to better understand the antigenic landscape of the highly diverse HNV so that better antiviral and vaccine designs can be achieved.