Current Perspectives and Future Directions in the Immunogenicity Landscape of Norovirus Vaccines.

Human norovirus (HuNoV) is a leading cause of acute gastroenteritis worldwide, causing severe illness and death in vulnerable populations, including infants and the elderly. Despite advances in norovirus vaccine candidates such as virus-like particles (VLPs), adenovirus-based oral vaccines, and mRNA vaccines, no vaccine has been approved yet. Current clinical trials primarily target the GI.1 and GII.4 genotypes responsible for most outbreaks. However, the extensive genetic diversity of HuNoV, along with continual antigenic evolution, poses significant challenges for developing broadly protective vaccines. Recent advances in experimental tools, including human intestinal enteroid cultures and surrogate neutralization assays, have improved norovirus vaccine efficacy assessment. Nevertheless, the lack of robust culture systems and animal models that faithfully mimic human infection continues to limit comprehensive evaluation of immune responses to diverse variants. Moreover, standardized correlates of protection, particularly those addressing mucosal immunity critical for infection prevention, remain to be established. This review integrates current immunogenicity assessment methodologies and evaluates ongoing HuNoV vaccine strategies, with emphasis on variant strain selection and platform technologies. We discuss key challenges related to population diversity, immune imprinting, and the complex interplay between systemic and mucosal immune responses as influenced by vaccine delivery routes and adjuvant formulations. By integrating recent advances in vaccine platforms, immunological tools, and delivery strategies, this review provides a framework for addressing critical obstacles in norovirus vaccine development. Such integrative perspectives are crucial for developing safe, effective, and broadly protective vaccines that offer meaningful benefits to global health.