| Summary: | <i>Neisseria meningitidis</i> causes a devastating invasive disease but is also a normal colonizer of the human nasopharynx. Due to the rapid progression of disease, the best tool to protect individuals against meningococcal infections is immunization. Clinical experience with polysaccharide conjugate vaccines has revealed that an ideal meningococcal vaccine must prevent both invasive disease and nasal colonization, which confers herd immunity. However, not all meningococcal vaccines are equal in their ability to prevent nasal colonization, for unknown reasons. Herein, we describe recent efforts to utilize humanized mouse models to understand the impact of different meningococcal vaccines on nasal colonization. These mice are susceptible to nasal colonization, and they become immune following live nasal infection or immunization with matched capsule-conjugate or protein-based vaccines, replicating findings from human work. We bring together insights regarding meningococcal colonization and immunity from clinical work with findings using humanized mouse models, providing new perspective into the different determinants of mucosal versus systemic immunity. Then, we use this as a framework to help focus future studies toward understanding key mechanistic aspects left unresolved, including the bacterial factors required for colonization and immune evasion, determinants of nasal mucosal protection, and characteristics of an ideal meningococcal vaccine.
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