The induction of anti-meningococcal B cell responses following controlled human infection with wild-type and genetically modified strains of Neisseria lactamica

Abstract

Neisseria lactamica is a non-pathogenic upper respiratory tract commensal that protects against N. meningitidis colonisation and disease. If the mechanisms underpinning this protective effect were elucidated they could be utilised to guide the development of novel strategies to prevent meningococcal disease. It was hypothesised that anti-meningococcal adaptive cellular immune responses induced following N. lactamica colonisation were responsible for this effect. Furthermore, it was posited that the anti-meningococcal adaptive cellular immune responses mounted following N. lactamica colonisation could be enhanced through genetic modification (GM) of N. lactamica to express heterologous meningococcal antigen. To address these hypotheses, two controlled human infection experiments (CHIME) were performed, the first using wild-type (WT) N. lactamica, and the second using GM N. lactamica expressing the meningococcal adhesin, Neisserial adhesin A (NadA). Data from the first CHIME revealed that colonisation with WT N. lactamica induced N. lactamica-specific IgA, IgM and IgG-secreting plasma cells, and IgG memory B-cells, that were cross reactive with N. meningitidis. Additional post-hoc analyses revealed two particularly interesting findings: (1) that cross-reactive plasma cell and IgG memory B cell responses were only detected amongst volunteers with anti-meningococcal IgG memory B-cell responses at baseline, and (2) that increasing frequencies of N. meningitidis-specific IgG memory B cells at baseline inversely correlated with N. lactamica colonisation density. Together, these findings raised the possibility that pre-existing anti-meningococal IgG memory B cell responses were being boosted by N. lactamica colonisation and were negatively affecting N. lactamica colonisation density. Data derived from the second CHIME confirmed that colonisation with GM N. lactamica expressing NadA was safe and induced NadA-specific IgG plasma cell and memory B-cell responses. Together, data from the CHIMEs supported the conclusions that the protective effect of N. lactamica colonisation on N. meningitidis colonisation and disease may have an immunological basis, and demonstrated that the anti-meningococcal responses induced following N. lactamica colonisation could be enhanced by genetic modification of N. lactamica.

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Identifiers

ORCID for Robert Read: orcid.org/0000-0002-4297-6728

ORCID for Andrew Vaughan: orcid.org/0000-0001-6076-3649

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