Challenge of the Nasopharynx With Neisseria Lactamica Expressing the Meningococcal Protein Neisseria Adhesin A (NadA)
Condition: Meningitis, Bacterial; Neisseria Infection
MeSH terms: Meningitis, Bacterial; Meningitis
Study type: Interventional
Phase: Early Phase 1

Summary: 
      This study is part of a research programme that aims to improve ways of protecting people
      from serious illnesses such as meningitis and sepsis caused by a bacterium called Neisseria
      meningitidis (N. meningitidis), using a closely related but harmless bacterium called
      Neisseria lactamica (N. lactamica). Investigators have previously given nose drops containing
      N. lactamica to over 350 volunteers - this is known as inoculation. In these studies the
      investigators have shown that they can cause colonisation of many inoculated volunteers
      (35-60%) with N. lactamica. Colonisation is when bacteria survive on or in a person without
      causing any illness or disease. N. lactamica specifically colonises the nose and throat.
      Investigators have also shown that colonisation with N. lactamica results in an immune
      (antibody) response.

      In this study investigators will be using a genetically modified version of N. lactamica
      which contains a single gene from N. meningitides. It is anticipated that the presence of
      this gene will change the number of people who are colonised and how long people remain
      colonised for, as well as causing them to produce an immune response to N. meningitides.

      The purpose of this study are to prove that inoculation with this modified N. lactamica does
      not cause any symptoms or illness, and to analyse the immune response produced in healthy
      volunteers.
    

Detailed description: 
      The NadA protein is one of the 4 strongly immunogenic components of the 4CMenB vaccine
      against serogroup B meningococcal disease (Bexsero) and has been demonstrated to be
      immunogenic in terms of generating serum bactericidal antibodies against N. meningitides
      strains that express the cognate NadA. Furthermore, University students vaccinated with
      Bexsero exhibit moderately reduced acquisition of nasopharyngeal carriage of N. meningitidis
      over the course of 12 months after vaccination. These studies imply that NadA expression by
      N. meningitidis may induce systemic and mucosal immunity to NadA during carriage, and that
      immunity directed against NadA may protect against colonisation by N. meningitidis. A greater
      understanding of the mucosal immune mechanisms of protection against pathobionts is essential
      for design of more effective and long lasting vaccines in the future. Then direct way to do
      this would be experimental human challenge with N. meningitidis but this carries potential
      hazard. As N. lactamica human challenge has shown to be safe, an alternative technique to
      investigate mucosal immunity to meningococcal antigens such as NadA will utilise Genetically
      Modified Organisms (GMOs) such as the one described here. Two strains of genetically modified
      N. lactamica will be used in this study, both of which have been derived from a
      beta-D-galactosidase (lacZ)-deficient mutant strain of N. lactamica Y92-1009 (△lacZ). This
      mutant can be differentiated from wild type bacteria when grown on the chromogenic substrate,
      X-gal. Both Genetically modified (GM) strains have demonstrated to remain acutely susceptible
      to killing by normal human serum and retain sensitivity to the front-line antibiotics used
      clinically to treat meningococcal disease (rifampicin, ciprofloxacin and ceftriaxone). The
      efficacy of ciprofloxacin to clear N. lactamica carriage is likely to similar as for N.
      meningitidis, as the organism is extremely sensitive to this antibiotic. Ciprofloxacin has
      been effective in clearing N. lactamica carriage within 24 hours in 100% of 4 individuals
      experimentally colonised in an ongoing human challenge study with wild type N. lactamica
      (unpublished data).
    

Intervention name(s): N. lactamica
Intervention type(s): Biological
Intervention description(s): Genetically modified N. lactamica
Allocation: Non-Randomized
Intervention model: Parallel Assignment
Intervention model description: Cohort
Masking: None (Open Label)
Primary purpose: Prevention
Keywords: meningitis; GMO