Investigating Meningococcal Vaccines in Adults
Investigating Meningococcal Vaccines in Adults
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.
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.
Inclusion Criteria:

 -  Participant is willing and able to give informed consent for participation in the
 study.

 -  Male or Female, aged 18 years to 60 years inclusive on the day of first vaccination.

 -  To be in good health as determined by medical history, physical examination and
 clinical judgment of the investigators.

 -  Agree (in the Investigator's opinion) to comply with all study requirements

 -  Agree to allow his or her General Practitioner (and/or Consultant if appropriate), to
 be notified of participation in the study

 -  Agree to provide their National Insurance/Passport number for the purposes of TOPS
 registration and bank account information for the purpose of reimbursement for the
 duration of their participation.

 Exclusion Criteria:

 -  Have any known or suspected impairment or alteration of immune function, resulting
 from, for example:

 -  Congenital or acquired immunodeficiency (including IgA deficiency)

 -  Human Immunodeficiency Virus (HIV) infection or symptoms/signs suggestive of an
 HIV-associated condition

 -  Autoimmune disease

 -  Receipt of immunosuppressive therapy such as anti-cancer chemotherapy or
 radiation therapy within the preceding 12 months or long-term systemic
 corticosteroid therapy.

 -  Chronic illness that could interfere with immunological function or donation of
 the required volumes of blood (e.g. cardiac or renal disease, diabetes, or
 auto-immune disorders).

 -  Receipt of a live vaccine within 4 weeks prior to vaccination or a killed vaccine
 within 7 days prior to vaccination.

 -  History of group B meningococcal vaccination

 -  Have received a dose of a meningococcal groups A, C, W, Y conjugate vaccine within 30
 days of enrolment or wish to receive a dose of this vaccine during the study period.

 -  Plan to receive any vaccine other than the study vaccine within 4 weeks following
 vaccination.

 -  History of severe allergic reaction after vaccination or known hypersensitivity to any
 vaccine component

 -  History of meningococcal disease

 -  Receipt of blood, blood products, or plasma derivatives within the past 3 months.

 -  Recent significant blood donation (e.g., to the National Blood Service) within 8 weeks
 of enrolment, or plans to donate blood during the study period.

 -  Thrombocytopenia or any bleeding disorder.

 -  Pregnancy as confirmed by a positive pregnancy test, or currently breastfeeding.

 -  Enrolled in another study, which, in the opinion of the investigator, could compromise
 the integrity of either study being conducted.

 -  A member of staff on the delegation log

 -  According to the TOPS database, have recently taken part in a significant number of
 other studies, which, in the opinion of the investigator, warrant exclusion from
 further studies.

 -  Have any condition, which, in the opinion of the investigator, might interfere with
 the evaluation of the study objectives.