Defining the Immune Response to Nasopharyngeal Colonisation by the Commensal Neisseria Lactamica
Condition: Meningitis, Bacterial
MeSH terms: Meningitis, Bacterial; Meningitis
Study type: Interventional
Phase: Early Phase 1

Summary: 
      Neisseria meningitidis is a 'bad bacteria' which lives harmlessly in the nose and throat of
      many young adults (a process called colonisation). However, it can occasionally cause serious
      disease including meningitis. Vaccines have proven effective in preventing disease associated
      with a number of strains of this bacterium, however some disease-causing strains are not
      covered by currently available vaccines. This research is focused on exploring new approaches
      to preventing colonisation and disease caused by this bacterium.

      Neisseria lactamica is a 'good bacteria' that colonises the nose and throat of young
      children. It does not cause disease in healthy people. In a previous study it has been
      demonstrated that the introduction of Neisseria lactamica into the noses of healthy adult
      volunteers resulted in a significant decrease in Neisseria meningitidis colonisation.
      However, it is not yet understood why this effect occurs. One theory is that the immune
      response the body mounts in response to colonisation with the 'good bacteria' cross-reacts
      with the 'bad bacteria' and in so doing eradicates the bad bacteria from the nose and throat.
      This study aims to outline the nature of the immune responses mounted in response to
      colonisation with the good bacteria, N. lactamica, after introducing it into the noses of
      healthy adult volunteers. In addition, the study aims to establish how the introduction of
      the good bacteria changes the other bacterial populations that live in the nose and throat.
    

Detailed description: 
      The clinical trial is a controlled, volunteer blinded, N. lactamica human challenge study to
      enable N. lactamica-specific cellular immune responses to be outlined in detail. In addition,
      The aim is to determine whether responses directed towards N. lactamica are cross-reactive
      with N. meningitidis.

      Following enrolment onto the study, non-meningococcal carriers (as determined by
      microbiological culture of nasopharyngeal wash and retropharyngeal swab) will be challenged
      intra-nasally with either 10-5 cfu of N. lactamica wild-type strain Y92-1009 (30,31)
      suspended in sterile phosphate buffered saline (PBS), as used in previous studies, or PBS
      alone (control group).

      Following inoculation on Day 0, biological samples (nasal wash, nasal secretion, throat swabs
      and blood) will be taken from all volunteers on days +7 (+/-3), +14(+/-3) and +28(+/-5)
      post-challenge. On the day of inoculation (Day 0) the biological samples listed will be taken
      except for the nasal wash.

      N. lactamica-specific B-cell and CD4+ memory T-cell responses will be measured in blood using
      a selection of in vitro assays and the results compared longitudinally in N. lactamica
      challenged (colonised or non-colonised) vs. control challenged subjects. The experiments will
      establish the nature of T-cell and B-cell memory responses and plasma B-cell responses
      induced in response to N. lactamica colonisation and will determine if these responses are
      cross-reactive with N. meningitidis. Mucosal immune profiling and microbiome analyses will be
      performed on nasal secretion and nasal bacterial samples, respectively. Any remaining
      biological samples (following experiments performed to meet the current study objectives)
      will be transferred to our registered human tissue bank to enable future studies following
      additional ethics approval by the relevant bodies.
    

Intervention name(s): N. lactamica; PBS only
Intervention type(s): Biological; Other
Intervention description(s): Stocks of N. lactamica (strain Y92-1009, sequence type 3493, clonal complex 613) in Frantz medium containing 30% (v/v) glycerol have been previously prepared using the Good Manufacturing Practices pharmaceutical manufacturing facilities at Public Health England (Porton Down, United Kingdom).; Sterile PBS only containing no bacteria
Allocation: Randomized
Intervention model: Parallel Assignment
Intervention model description: Volunteers will be blinded to the inoculum type received (i.e. N. lactamica or PBS control) throughout the study duration. Nasal secretion and throat swabs will be taken to enable mucosal immune profiling and microbiome analyses to be performed. Subjects will be screened for nasopharyngeal N. meningitidis carriage -28 to -7 days (visit 1) and non-Neisseria spp. carriers will be challenged with either 105 cfu N. lactamica suspended in PBS or PBS only control (day 0, visit 2). Volunteers identified as carriers of N. meningitidis at visit 1 will be excluded from the study and will not progress to experimental human challenge. Biological samples (nasal secretion, microbiome swab and blood) will be collected from volunteers who progress to the challenge (visit 2, Day 0) and on days +7 (+/-3), +14 (+/-3) and +28 (+/-5) post-challenge. Nasal wash sampling will not be taken at the challenge visit (Day 0) but will be taken on days +7(+/-3), +14 (+/-3) and +28 (+/-5) post-challenge.
Masking: Single (Participant)
Primary purpose: Prevention
Keywords: Healthy volunteer; Human Challenge study