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 105 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 (BPLAS) and memory B cell (BMEM) 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 BPLAS and BMEM. 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 BPLAS frequencies (per 105 Peripheral Blood Mononuclear Cells) were 0 (IQR 0.0-0.0) versus 5 (1.5-10.5) for IgA-secreting BPLAS (P <0.0001), and 0 (0.0-0.0) versus 3 (1.5-9.5) for IgG-secreting BPLAS (P <0.0001). Median Nlac-specific IgG BMEM frequencies (% of total IgG BMEM) 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 BPLAS and IgG BMEM also increased significantly amongst Nlac-colonised participants. Nlac- and Nmen-specific BPLAS and BMEM 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.


Inclusion criteria
• Healthy adults aged 18 to 45 years inclusive on the day of enrolment.
• Fully conversant in the English language.
• Able and willing (in the investigator's opinion) to comply with all study requirements.
• Written informed consent to participate in the study.
• For females only, willingness to practice continuous effective contraception (see below) during the study and negative pregnancy test at visit 1 (screening).
• Willingness to take an antibiotic regimen after inoculation according to the study protocol †

Exclusion criteria
• Active smokers • N. meningitidis or N. lactamica detected following culture of throat swab or nasal wash taken before the challenge.
• Individuals who have a current infection at the time of inoculation.
• Individuals who have been involved in other clinical studies/trials involving receipt of an investigational product over the last 12 weeks or if there is planned use of an investigational product during the study period.
• Individuals who have previously been involved in clinical studies/trials investigating meningococcal vaccines or experimental challenge with N. lactamica.
• Use of oral or intravenous antibiotics within the period 30 days prior to the challenge.
• Any confirmed or suspected immunosuppressive or immunocompromised state, including HIV infection, asplenia, history of recurrent severe infections or use (more than 14 days) of immunosuppressant medication within the past 6 months (topical/inhaled steroids are allowed).
• Use of immunoglobulins or blood products within 3 months prior to enrolment.
• History of blood donation within the past 12 weeks for male volunteers, or 16 weeks for female volunteers ‡ .
• Allergy to yeast extract.
• Contraindications to the use of ciprofloxacin, specifically a history of epilepsy, prolonged QT interval, hypersensitivity to quinolones or a history of tendon disorders related to quinolone use † .
• Any other significant disease, disorder, or finding which may significantly increase the risk to the volunteer because of participation in the study, affect the ability of the volunteer to participate in the study, or impair interpretation of the study data, for example recent surgery to the nasopharynx.
• Occupational, household or intimate contact with immunosuppressed persons.