Abstract Human noroviruses (HuNoV) are the major cause of acute non-bacterial, epidemic gastroenteritis, resulting in ~200,000 deaths/year, mostly in infant, elderly and immunosuppressed groups. HuNoV vaccines are under development but the results are mixed, in part reflecting antigenic seniority, virus diversity and escape. Our premise is that the function, epitope specificity and atomic level understanding of the virus type specific and broadly cross reactive epitopes in the virion that elicit neutralizing antibody will reveal the mechanisms of protective humoral immunity, which in turn is required for the design of more effective immunogens and vaccination strategies. Consequently, our program is designed to critically inform the development of broadly effective HuNoV vaccines that target highly prevalent, medically important genogroup II strains (GII.4 and GII.2). To achieve these goals, we have relevant time-ordered sample sets from cohorts of vaccinated individuals, natural infections and human challenge studies which are leveraged throughout the program to elucidate the fundamental mechanisms governing protective immunity, virus escape and pandemic strain emergence. We have also assembled a complementary group of renown experts to elucidate the essential issues in HuNoV serological immunity, identify the key neutralizing epitopes targeted by type specific and broadly protective immunity, and reveal the molecular mechanisms governing HuNoV neutralization, antigenic seniority and broad protective immunity. Moreover, the program is designed to translate these novel findings to improved 2nd generation structure-guided HuNoV vaccine immunogens which are designed to improve the breadth and durability of humoral immune responses associated with protective immunity. To achieve these goals, the program has three specific aims. In aim 1, we will define the HuNoV-specific serological antibody repertoire and produce recombinant antibodies for detailed structure and molecular analyses. In aim 2, we identify type specific and broadly cross neutralizing antibodies and use molecular approaches to identify key interacting epitopes. In aim 3, we will solve the atomic level structure of several relevant antibodies with the P domain of the capsid protein to delineate the structural basis for HBGA blockade and neutralization and use structure-guided strategies to increase immunogenic breadth and antigen stability, leading to improved vaccine function in vivo.