Investigating Meningococcal Vaccines in Adults - An Exploratory, Open-label, Immunogenicity Study of a Licensed Meningococcal Capsular Group B Vaccine (4CMenB, Bexsero®) in Adults

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.