Investigating Meningococcal Vaccines in Adults
Condition: Meningococcal Vaccines; Meningococcal Infections; Neisseria Meningitidis; Factor H-binding Protein, Neisseria Meningitidi
MeSH terms: Meningococcal Infections
Study type: Interventional

Summary: 
      This study will be an open label, exploratory immunogenicity study conducted by the Oxford
      Vaccine Group, University of Oxford. This study will investigate the breadth of protective
      activity of serum anti-FHbp antibody responses of adults immunized with 4CMenB (Bexsero®)
      vaccine as well as investigating the nature of the B-cell and T-cell responses induced by
      vaccination.

      The investigators aim to enroll 15 to 20 healthy adults aged 18 to 60, who will be immunized
      with two doses of 4CMenB (Bexsero®) two months apart according to the licensed schedule.
      Blood samples will be obtained at baseline and after each dose of vaccine.
    

Detailed description: 
      Neisseria meningitidis (N. meningitidis, meningococcus) is a leading cause of bacterial
      meningitis and septicaemia worldwide. The introduction of serotype specific glycoconjugate
      vaccines into the routine infant immunization schedule, in countries such as the United
      Kingdom, has led to dramatic reductions in the burden of disease. The development of
      effective vaccines against capsular group B N. meningitidis has long been an unmet need and
      has necessitated the development of novel approaches to vaccine design. In 2013, the first
      capsular group B meningococcal vaccine was licensed in the UK. The new vaccine (4CMenB, trade
      name Bexsero ®), is manufactured by Novartis Vaccines and contains four components - a
      recombinant Factor H binding protein (FHbp), Neisseria meningitidis capsular group B
      Neisseria Heparin Binding Antigen (NHBA) fusion protein, recombinant Neisseria meningitidis
      group B Neisserial adhesin A (NadA) protein and Outer membrane vesicles (OMV) from Neisseria
      meningitidis group B strain NZ98/254 containing PorA P1.4. This multicomponent vaccine is
      also referred to as the "four component meningococcal B" or "4CMenB" vaccine.

      Factor H binding protein is an important virulence factor expressed on the surface of N.
      meningitidis and is a key component of the 4CMenB vaccine. It has been established that the
      function of FHbp is to bind human complement factor H, whose physiological function in turn
      is to act as an important down-regulator of the host alternative complement pathway. Binding
      of human factor H to the bacterial surface via FHbp is thought to interfere with complement
      mediated lysis and is an important immune evasion strategy of N. meningitidis. Consequently,
      FHbp is a logical target for a protective vaccine against capsular group B N. meningitidis.

      There remain several gaps in our knowledge about the underlying mechanisms by which human
      antibodies to FHbp elicit complement mediated bactericidal activity. In humans immunised with
      vaccines containing FHbp, the antigen (FHbp) is expected to form a complex with human factor
      H. The precise epitopes targeted by anti-FHbp antibodies in vaccinees have not been fully
      elucidated. Conceivably, the formation of a FHbp-factor H complex following vaccination may
      prevent the exposure of key FHbp epitopes. Therefore, it is not known whether the interaction
      between FHbp and human Factor H affects the bactericidal activity of antibodies produced
      following vaccination with 4CMenB.

      This study will investigate the breadth of protective activity of serum anti-FHbp antibody
      responses of adults immunized with 4CMenB (Bexsero®) vaccine as well as investigating the
      nature of the B-cell and T-cell responses induced by vaccination.

      We aim to enroll 15 to 20 healthy adults aged 18 to 60, who will be immunized with two doses
      of 4CMenB (Bexsero®) two months apart according to the licensed schedule. Sera will be
      obtained at baseline and after each dose of vaccine, which will be assayed for IgG antibody
      responses to FHbp by ELISA, as well as for bactericidal activity against a panel of
      genetically diverse meningococcal strains and for the ability to inhibit binding of FH to
      FHbp. Other assays for meningococcal immunity may also be performed such as antibody binding
      to live bacteria measured by flow cytometry, and the ability of the serum antibodies to
      confer passive protection in an infant rat bacteraemia model. Laboratory analyses to quantify
      the B- and T-cell responses specific to the 4CMenB vaccine will be performed using peripheral
      blood mononuclear cells (PBMCs) derived from study participants sampled before, and after
      each dose. We will also explore whether the formation of the FH-FHbp complex results in the
      generation of cross-reactive antibodies directed against Factor H.

      This will be the first study in humans to explore in detail the anti-FHbp characteristics
      generated following immunization with 4CMenB (Bexsero®) and offers a unique opportunity to
      use a licensed vaccine to improve our understanding of how to induce efficient protective
      responses. It is hoped that the results obtained from this study will contribute to our
      understanding of the host response to vaccination against capsular group B N. meningitidis.
    

Intervention name(s): 4CMenB (Bexsero®) - Novartis Vaccines and Diagnostics
Intervention type(s): Biological
Intervention description(s): 4CMenB vaccine (Bexsero - Novartis Vaccines and Diagnostics) 0.5ml intra-muscularly; two doses, administered 2 months apart. Each dose of vaccine contains recombinant Neisseria meningitidis group B NHBA fusion protein (50 micrograms); recombinant Neisseria meningitidis group B NadA protein (50 micrograms); recombinant Neisseria meningitidis group B FHbp fusion protein (50 micrograms) and Outer membrane vesicles (OMV) from Neisseria meningitidis group B strain NZ98/254 (25 micrograms measured as amount of total protein containing the PorA P1.4)
Intervention MeSH terms: Lactitol
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Basic Science