Abstract
Neisseria meningitidis 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.
Highlights
Neisseria meningitidis is a Gram-negative bacterial pathogen that is an obligate colonizer of the human nasopharynx
The most effective way to reduce the burden of invasive meningococcal disease is through immunization, and much effort has been devoted toward the development of meningococcal vaccines
This challenge is exacerbated because N. meningitidis does not naturally colonize the nose of any organism other than humans, which hampers understanding of processes related to nasal colonization, as well as preclinical evaluation of vaccines
Summary
Neisseria meningitidis (the meningococcus) is a Gram-negative bacterial pathogen that is an obligate colonizer of the human nasopharynx. The immune processes that confer protection against meningococcal nasal colonization are poorly understood, making it difficult to target these processes during vaccine design This challenge is exacerbated because N. meningitidis does not naturally colonize the nose of any organism other than humans, which hampers understanding of processes related to nasal colonization, as well as preclinical evaluation of vaccines. We consider the relative contribution of classical correlates of immune protection against invasive meningococcal disease, including serum bactericidal assays, versus other effector mechanisms that contribute to mucosal protection Key in this regard, we highlight the distinction between immune responses elicited by nasal colonization versus parenteral immunization, and we consider differences in the protection afforded by polysaccharide capsule-conjugate versus protein-based vaccines. We consider how the mouse-based models can be used to complement findings from human surveillance and vaccine studies to better understand the mucosal lifestyle of N. meningitidis and its complex interplay with the various immune effector mechanisms
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