Unlike glycoconjugate vaccines, subcapsular antigen-based vaccines targeting serogroup B N. meningitidis (Nmen) do not prevent pharyngeal colonisation and are therefore unlikely to induce herd immunity. Nasopharyngeal colonisation with the commensal Neisseria lactamica (Nlac) confers protection against meningococcal colonisation and is associated with reduced risk of invasive disease, potentially through induction of cross-reactive immunity. While cross-reactive antibody and memory B cell responses have been described, the contribution of T cells remains unclear. For other respiratory pathogens (Streptococcus pneumoniae and Bordetella pertussis), protection against nasal colonisation is mediated by Th17 responses, independent of humoral immunity.
We utilised a placebo-controlled Nlac human infection model to investigate whether Nlac colonisation induces Nmen-cross-reactive CD4+ memory T cells (TMEM). Participants were inoculated intra-nasally with 105 CFU Nlac or placebo and circulating antigen-specific CD4+ TMEM quantified and phenotyped at baseline (day 0, [d0]) and at d7, d14 and d28 post-inoculation using a CD154+ magnetic enrichment assay, assessing both effector and central memory subsets.
No significant changes were observed in frequencies of CD154+ single cytokine+ (IFNγ+, IL-17A+, or IL-4/IL-5/IL-13+) Nlac- or Nmen-specific CD4+ TMEM by d28 in Nlac colonised participants (n=16). However, significant reductions were detected in CD154+ cytokine- CD4+ TMEM specific to Nlac (effector memory, d0-d28) and in CD154+ total cytokine+ CD4+ TMEM specific to Nmen (central memory, d0-d7 and d0-d28), suggesting redistribution from peripheral blood to tissues. These changes were absent in placebo recipients (n=9).
Among participants lacking detectable Nlac-specific IL-17A+ CD4+ TMEM at baseline, Nlac colonisation induced significant increases in both Nlac- and Nmen-specific IL-17A+ TMEM by d28, consistent with induction of cross-reactive Th17 immunity. Responses to control antigens remained stable, supporting specificity. Baseline Nlac- and Nmen-specific CD4+ T cell frequencies and induced responses were inversely associated with Nlac colonisation density, suggesting a role for CD4+ T cells in bioburden control.
These findings demonstrate that Nlac colonisation induces dynamic and Nmen-cross-reactive CD4+ TMEM responses, including Th17 responses, which may contribute to protection against meningococcal colonisation. Future studies will evaluate whether genetically modified Nlac expressing meningococcal antigens enhances Nmen T cell responses at the mucosa.