Effect of colonisation with Neisseria lactamica on cross-reactive anti-meningococcal B cell responses: A randomised, controlled, human infection trial

BACKGROUND: Pharyngeal colonisation by the harmless commensal Neisseria lactamica (Nlac) inhibits Neisseria meningitidis (Nmen) colonisation and has an inverse epidemiological association with meningococcal disease. The mechanisms underpinning this relationship remain unexplained, but could be due to induction of cross-reactive immunity. In this study, we evaluated whether colonisation with Nlac induces Nlac-specific B cell responses cross-reactive with Nmen. METHODS: In a randomised, placebo-controlled, human infection experiment at University Hospital Southampton Clinical Research Facility, UK, healthy adults, aged 18-45 years, were randomised 2:1 to receive intra-nasal inoculation with either 10(5) colony-forming units of Nlac in 1 ml phosphate buffered saline (PBS), or 1 ml PBS alone. Participants, and researchers performing participant sampling and immunological assays, were all blinded to allocation. The primary endpoint was a comparison of circulating Nlac-specific plasma cell (B(PLAS)) and memory B cell (B(MEM)) frequencies post Nlac inoculation (day 7-28), as compared to baseline (day 0), measured using Enzyme-Linked ImmunoSpot (ELISpot) assays. The secondary endpoint was to measure the frequency of Nmen-specific B(PLAS) and B(MEM). The trial is registered with ClinicalTrials.gov (NCT03633474) and is now closed. FINDINGS: n = 31/50 of participants assessed for eligibility between Sep 5, 2018, and Mar 3, 2019, were randomly assigned (n=20 Nlac, n=11 PBS). Amongst Nlac-colonised participants (n=17), median baseline compared to peak post-colonisation Nlac-specific B(PLAS) frequencies (per 10(5) Peripheral Blood Mononuclear Cells) were 0 (IQR 0.0-0.0) versus 5 (1.5-10.5) for IgA-secreting B(PLAS) (P <0.0001), and 0 (0.0-0.0) versus 3 (1.5-9.5) for IgG-secreting B(PLAS) (P <0.0001). Median Nlac-specific IgG B(MEM) frequencies (% of total IgG B(MEM)) increased from 0.0024% (0.0000-0.0097) at baseline to 0.0384% (0.0275-0.0649) at day 28 (P <0.0001). The frequency of Nmen-specific IgA- and IgG-secreting B(PLAS) and IgG B(MEM) also increased significantly amongst Nlac-colonised participants. Nlac- and Nmen-specific B(PLAS) and B(MEM) were unchanged amongst controls. Upper respiratory tract symptoms were reported amongst n=10/20 Nlac-inoculated and n=6/11 PBS-inoculated participants (P >0.99). There were 3 additional adverse events and no serious adverse events. INTERPRETATION: Natural immunity to Nmen following Nlac colonisation may be due to cross-reactive adaptive responses. Exploitation of this microbial mechanism with a genetically modified live vector could protect against Nmen colonisation and disease.