A Phase I Study of the Safety and Immunogenicity of a Recombinant MVA Vaccine Encoding a Secreted Antigen From M. Tuberculosis, Antigen 85A, Delivered Intradermally by a Needle Injection in Healthy Volunteers Who Have Received BCG Immunisation 1 Month Previously
Condition: Tuberculosis
MeSH terms: Tuberculosis
Study type: Interventional
Phase: Phase 1

Summary: 
      This is a phase I study to test the immunogenicity of a recombinant vaccine based on Modified
      Vaccinia Ankara (MVA) expressing the antigen 85A (from Mycobacterium tuberculosis). This
      vaccine is delivered intradermally by a needle injection in healthy volunteers previously
      vaccinated with BCG.
    

Detailed description: 
      This is a phase I study to test the immunogenicity of a recombinant vaccine based on Modified
      Vaccinia Ankara (MVA) expressing the antigen 85A (from Mycobacterium tuberculosis). This
      vaccine is delivered intradermally by a needle injection in healthy volunteers who have
      recieved a BCG immunisation month previously.

        1. Selection of volunteers

           Volunteers for the study will be recruited through advertisements. Each volunteer will
           have received an information sheet concerning the study and will have agreed to
           participate in writing. Volunteers will be given at least 48 hours between reading the
           information leaflet and agreeing to participate. Female volunteers will be told of the
           theoretical risk of congenital anomaly should they become pregnant during the study and
           only those who undertake to take precautions to avoid pregnancy during the study period
           will be eligible. Volunteers will give signed consent for their GP's to be notified
           about their participation in the trial. The GP will be faxed a letter on the day of
           screening and asked to reply if they know of a reason why the volunteer should not take
           part. The signed consent form will also be faxed with the letter.

        2. Screening

           Volunteers will be asked to sign the informed consent form for screening. The following
           will be performed:

             -  Medical history and examination

             -  Laboratory evaluations - including clinical chemistry, haematology, HLA typing,
                anti-vaccinia antibodies, anti-HBV antibodies, anti-HCV antibodies, anti-HIV
                antibodies

             -  Heaf test - to exclude prior exposure to TB

             -  Urinalysis and urine pregnancy test if female

        3. Inclusion Criteria

             -  Healthy adult aged 18-55 years.

             -  Normal medical history and physical examination.

             -  Normal urine dipstick, blood count, liver enzymes, and creatinine.

        4. Exclusion Criteria

             1. Exposure to TB/BCG vaccination at any point. Previous residence in a TB endemic
                area.

             2. Clinically significant history of skin disorder (eczema, psoriasis, etc.), allergy,
                immunodeficiency, cardiovascular disease, respiratory disease, endocrine disorder,
                liver disease, renal disease, gastrointestinal disease, neurological illness,
                psychiatric disorder, drug or alcohol abuse.

             3. Oral or systemic steroid medication or the use of immunosuppressive agents.

             4. Positive HIV antibody test, HCV antibody test or positive HBV serology except
                post-vaccination.

             5. Heaf test greater than Grade 0

             6. Confirmed pregnancy

             7. Previous MVA immunisations

        5. Withdrawal Criteria

             1. Withdrawal of consent by subject for any reason

             2. Loss to follow-up

             3. Non-compliance with study procedures

             4. Protocol violation

             5. Serious adverse event (as defined in Appendix 3)

             6. Any other reason at discretion of the Principal Investigator

             7. Confirmed pregnancy during study period

        6. Immunisation

           On Day 0, subjects will receive a single intradermal injection of 0.1ml BCG (SSI strain)
           over the deltoid muscle. Blood will be taken at 2 weeks and 4 weeks after this
           immunisation. At 4 weeks, after blood has been taken, volunteers will be immunised with
           5 x 107pfu MVA85A in 0.1ml. Subjects will be observed for an hour after MVA85A
           immunisation. Vital signs will be monitored at 30 and 60 minutes post-immunisation.
           Local reactions at the site of administration will be evaluated at 60 minutes.

           A photograph of the injection site may be taken at 48 hours (with written consent). The
           injection site will be reviewed 7 days after each immunization.

           Blood will be taken at the following time points: At the screening visit*, prior to the
           BCG vaccination, 2 weeks and 4 weeks after BCG, *1 week after the MVA85A vaccination, 2
           weeks, 4 weeks, *8 weeks, and *24 weeks after the vaccination. Up to 55 mls will be
           taken at any one time with the total being no more than 500 mls over the study period.
           *Samples taken on these dates will be tested for full blood count and biochemical
           screen. Immunological assays will be performed at all time points to determine vaccine
           immunogenicity. A pregnancy test will be performed prior to vaccination for female
           volunteers. Peripheral blood mononuclear cells will be prepared for cellular
           immunological assays to be performed without or following cryopreservation. Other
           serological measures of immune response, i.e. antibody titres, will be assayed on frozen
           plasma samples.

           All blood tests will be taken within 1-3 days of the due date as described in the
           schedule above.

        7. Endpoints

      The occurance and severity of local side-effects The occurance and severity of systemic
      side-effects The induction of T cell responses (as measured by an interferon-gamma Elispot
      assay).

      Proliferation assays and cytotoxic T cell assays will be performed on strong CD4+ and CD8+
      responses respectively.
    

Intervention name(s): MVA85A
Intervention type(s): Biological
Allocation: Non-Randomized
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Prevention
Keywords: Mycobacterium tuberculosis; 85A antigen; Recombinant Modified Vaccinia Virus Ankara; Phase I study; Immunogenicity; BCG