Regulation of Mucosal Immune Response to Systemic MenB Vaccine
Condition: Meningococcal Infections
MeSH terms: Meningococcal Infections
Study type: Interventional
Phase: Phase 2

Summary: 
      Meningitis or septicaemia (blood poisoning) caused by group B meningococcal infection (MenB)
      is an important cause of death and disability in the UK. Prevention through vaccination
      therefore remains a key public health priority. Research from national "meningitis" vaccine
      programmes against MenC, Hib and Streptococcus pneumoniae show us that their success is in
      part due to their ability to protect both the vaccinated and the unvaccinated, so-called herd
      immunity. This protection probably occurs by reducing carriage of these meningitis bacteria
      in the back of the throat (mucosal immunity). How this happens is poorly understood but our
      research shows that naturally acquired immunity (transient contact between the immune system
      and the meningococcus in the back of the throat without causing disease) may impact on this
      process. We believe that to develop a MenB vaccine that is able to cause mucosal immunity and
      prevent MenB carriage, it is important to understand the interaction between natural immunity
      and vaccination. In this study we propose to administer MenB vaccine to adults in order to
      investigate this process. Our findings will provide important insights into Men B immunity,
      inform the design of novel vaccine strategies and allow the rational testing of new vaccines
      as they become available.
    

Detailed description: 
      Meningitis or septicaemia (blood poisoning) caused by group B meningococcal infection (MenB)
      is an important cause of death and disability in the UK. Our research shows that naturally
      acquired mucosal immunity (transient contact between the immune system and the meningococcus
      in the back of the throat without causing disease) may impact on the ability of new Men B
      vaccines to protect both the vaccinated and the unvaccinated, so called herd immunity. We ask
      the question, do specialised immune cells called CD25+ regulatory T cells (Treg) operating in
      the back of the throat explain the failure of immunisation to boost mucosal T cell immunity
      in teenagers and young adults?

      PURPOSE & OBJECTIVES: MenB is the commonest cause of bacterial meningitis in the UK, and is a
      frequent cause of septicaemia in children and young adults. Death may occur in up to 20% of
      individuals and long term sequelae are frequent amongst those that survive. In contrast to a
      highly successful MenC vaccine programme, the burden of MenB disease remains considerable.
      Prevention through vaccination is therefore a key public health priority in the UK. This
      project will inform the development of a broadly protective MenB vaccine. We propose to: 1)
      Determine the nature of the mucosal CD25+ Treg population that regulates MenB immunity. 2)
      Establish whether naturally induced mucosal CD25+ Treg activity in adults and adolescents
      modulates the mucosal immune response to systemic MenB OMV vaccination. 3) Investigate the
      impact of this regulation on mucosal B cell memory

      DESIGN: This phase II, open label, randomised, single centre study of a MenB vaccine will
      utilise cells isolated from human tonsils to measure vaccine-induced T cell immune responses
      to MenB in adults and adolescents. Comparisons will be made with a control unvaccinated
      population. RECRUITMENT: Ear, Nose and Throat surgeons will be approached to agree to the
      participation of their patients in the study. Subjects will be invited by letter to express
      an interest in the study. Interested individuals will then be contacted by study medics who
      will provide the appropriate subject information sheet. All study visits and clinical
      procedures will be undertaken at University Hospitals Bristol NHS Foundation Trust, Bristol.
      Study clinical personnel will then obtain written informed consent for participation from the
      subject. No study procedure will be undertaken until written informed consent is given.
      Following confirmation of inclusion and exclusion criteria, subjects will be enrolled in the
      study.

      RANDOMISATION: On inclusion in the study, subjects will be allocated the next available
      subject number. Subjects enrolled into the study will be assigned a 5-digit subject number.
      The first two digits identify the study site. The next three digits identify the subject
      within the site and will be assigned sequentially, with 001 corresponding to the first
      subject enrolled. The subject number will determine the treatment group to which the subject
      is randomised according to a computer-generated block randomisation procedure.

      INCLUSION / EXCLUSION: Individuals eligible to be enrolled in this study are male and female
      subjects. The eligibility of subjects to take part in the study will be assessed by a
      dedicated Vaccine Study doctor or nurse prior to enrolment.

      Inclusion criteria:

        -  written informed consent and agreement for samples to be sent overseas

        -  adults and adolescents 16-40 years scheduled to undergo routine tonsillectomy

        -  in good health at the time of entry into the study as determined by medical history,
           physical examination and clinical judgment of the investigator

        -  availability for all the visits scheduled in the study

      Exclusion criteria:

        -  tonsillectomy for allergic conditions

        -  receipt of or intent to immunize with any vaccination (other than influenza vaccine or
           post-exposure tetanus vaccination) or investigational agents within 50 days prior to
           enrolment and throughout the study period

        -  previous receipt of any MenB vaccine

        -  chronic administration (defined as more than 14 days) of immunosuppressants or other
           immune-modifying drugs (Inhaled and topical steroids will not be allowed.)

        -  history of confirmed or suspected meningococcal infection or close contact with an
           individual with culture or PCR proven N. meningitidis serogroup B within the previous 60
           days

        -  pregnancy (or plans to become pregnant during study)* or breast feeding

        -  not taking or unwilling to take sufficient measures to avoid pregnancy occurring for the
           duration of the study period**

        -  any chronic or progressive disease (eg neoplasm, cardiac, respiratory, liver,
           gastrointestinal, renal, neurological disease, autoimmune disease, blood dyscrasias or
           diathesis) or history of dependence/abuse of drugs or alcohol • any confirmed or
           suspected immunosuppressive or immunodeficient condition, including human
           immunodeficiency virus (HIV) infection

        -  administration of immunoglobulins and/or any blood products in the last year or planned
           administration during the study period

        -  history of any anaphylactic shock, asthma, urticaria or any other allergic reaction
           after previous vaccinations, or known hypersensitivity to any vaccine component

        -  fever (oral temperature equal to or greater than 38.5°C) within the past 24 hours or
           significant acute or chronic infection within the previous 7 days

        -  significant acute or chronic infections requiring systemic antibiotic treatment within
           the past 14 days

        -  not available for all the visits scheduled during the study period

        -  any condition which, in the opinion of the investigator, might interfere with the
           evaluation of the study objectives

        -  participation in another clinical trial within last 90 days or planned for during the
           study

             -  A pregnancy test (urine) on the scheduled day of each vaccination will be required
                for any female wishing to participate in the study as well as giving basic
                menstrual cycle information to cover the period in which and individual may be
                pregnant but this would not be ascertained by the chemical test.

                  -  Females of childbearing age who have not used or do not plan to use acceptable
                     birth control measures for the duration of the study. Oral, injected or
                     implanted hormonal contraceptive, diaphragm or condom with spermicidal agent
                     or intrauterine device are considered acceptable forms of birth control. If
                     sexually active the subject should have been using one of the accepted birth
                     control methods at least two months prior to study entry.
    

Intervention name(s): NZ MenB OMV vaccine (NZ98/254)
Intervention type(s): Biological
Intervention description(s): 3 doses by intramuscular injection
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Primary purpose: Prevention
Keywords: Neisseria meningitidis; Mucosal; Vaccination; Immunity; T cells; T regulatory cells