ChAdOx1 85A Aerosol Versus Intramuscular Vaccination in Healthy Adults (TB039)
Condition: Mycobacterium Tuberculosis, Protection Against; Tuberculosis
MeSH terms: Tuberculosis
Study type: Interventional
Phase: Early Phase 1

Summary: 
      This is a dose escalating and a paired-placebo design study to describe the safety and
      immunogenicity profile of candidate TB vaccine ChAdOx1 85A given by aerosol inhaled
      vaccination versus intramuscular (IM) vaccination in adult healthy volunteers.

      It is postulated that the aerosol inhaled route is practical and feasible and has an
      acceptable safety profile, comparable to the systemic safety profile of the IM route of
      administration of ChAdOx1 85A in adult healthy volunteers, and that the aerosol inhaled route
      of administration will induce greater mucosal immunity and comparable systemic immunity when
      compared to the IM (systemic) route of administration in these volunteers.

      Volunteers are followed on a regular basis for safety and immunogenicity, with blood analysis
      for biological safety tests and immune tests.
    

Detailed description: 
      Background:

      Mycobacterium tuberculosis (M.tb) is a pathogen with worldwide preponderance which infects
      humans and causes tuberculosis (TB), a transmissible disease resulting in very high mortality
      and morbidity. A third of the world's population is latently infected with M.tb, and these
      people carry a 10% lifetime risk of developing active life-threatening disease. In 2015,
      there were 10.4 million new cases worldwide and 1.8 million people died of TB. Co-infection
      with human immunodeficiency virus (HIV) greatly increases risk of TB reactivation and death.
      Diagnosis is challenging and drug treatment can be prolonged, harmful, costly and complex.
      For these reasons an effective TB vaccine is a global public health priority.

      The Bacille Calmette-Guérin (BCG) vaccine is the only licensed TB vaccine and it has been
      administered globally to several billion people over a 90 year period. Although it does not
      protect against pulmonary TB in endemic areas, it is effective in preventing disseminated TB
      disease including tuberculous meningitis in childhood. Recently, heterologous "prime-boost"
      vaccination strategies, in which two different candidate vaccines expressing antigens in
      common are given weeks or months apart, have generated strong and sustained cellular immune
      responses correlating with an M.tb protective effect in preclinical animal models. In such a
      "prime-boost" strategy, BCG would therefore be an ideal priming vaccine.

      ChAdOx1 85A is a new adenoviral vaccine based on a vector that is a chimpanzee adenovirus
      isolate Y25 expressing the M.tb antigen 85A. Adenoviruses are attractive candidates for use
      as viral vectors and have been used as vaccine vectors for a number of conditions; however
      the use has been limited by the high level of anti-vector immunity present in humans in whom
      adenovirus is a ubiquitous infection. This has led to the consideration of simian
      adenoviruses, which are not known to cause pathology or illness in humans and to which the
      prevalence of anti-vector antibodies is low.

      The route of M.tb infection is by inhalation of aerosolised infectious droplets containing
      tubercle bacilli, leading to the establishment of primary infection in the lung, which has a
      distinct mucosal immune system characterized by bronchus associated lymphoid tissue (BALT),
      which is well adapted to encounter and process such antigens. Immunising via the airway
      should therefore have the advantage, over other routes, of eliciting protective immune
      responses in the lung mucosa. There is data from preclinical animal models with virally
      vectored vaccines to suggest that immunising the respiratory mucosa may give superior
      protection against respiratory diseases. The inhaled route is a well-established route of
      drug delivery for humans and there are numerous perceived advantages of aerosol inhaled
      vaccination.

      This trial will be the first to evaluate the safety and immunogenicity of candidate TB
      vaccine ChAdOx1 85A given by aerosol inhaled vaccination. Using a paired-placebo design, the
      trial will investigate aerosol vaccination compared to intramuscular vaccination, the latter
      for which initial safety data has already been collected and from which the dosing regimen
      for this trial has been chosen.

      Objective:

      The study aims to describe the safety and immunogenicity profile for ChAdOx1 85A given by
      aerosol inhaled vaccination versus intramuscular (IM) vaccination in adult healthy
      volunteers.

      Methods:

      Thirty-nine subjects will be enrolled into the trial: 29 BCG-vaccinated and 10 BCG-naïve.

      Nine BCG-vaccinated healthy volunteers will receive the ChAdOx1 85A vaccine by aerosol
      inhaled vaccination at three different dose levels (3 volunteers per dose levels, Groups
      A-B-C). Based on the safety profile and immunogenicity results obtained in Groups A, B and C,
      the highest tolerated dose will be determined, and a decision made as to which dose to use
      for subsequent Groups.

      The next 20 BCG-vaccinated subjects will be blinded and randomised in Groups D and E:
      volunteers randomised to the intervention group (D, inhaled aerosol) will receive a
      concurrent intramuscular saline injection, while volunteers in the control group (E,
      intramuscular) will receive a concurrent dose of inhaled saline. This design has the added
      benefit of allowing a distinction to be made between any adverse events attributable to the
      method (including nebuliser device) of vaccine delivery and those attributable to the inhaled
      investigational medicinal product itself.

      In parallel to enrolment of Groups D and E, 10 BCG naïve subjects will be enrolled in Group F
      to receive the highest tolerated dose by aerosol inhaled vaccination.

      After vaccination (day 0), volunteers will then follow a schedule of visits over the six
      months (day 1, day 7, day 14, day 28, day 84 and day 168), for safety and immunological
      follow-up via blood tests and physical examination. Moreover, at day 14, volunteers will
      undergo a bronchoscopy to check for signs of inflammation or other damage and to obtain a
      bronchoalveolar lavage sample and lymph node cytopunction.

      Impact:

      The overall investigational approach with ChAdOx1 85A trials is to develop an effective
      prime-boost vaccination strategy to prevent TB infection, with BCG as the priming vaccine.
    

Intervention name(s): ChadOx1 85A - aerosol; ChadOx1 85A - IM
Intervention type(s): Biological; Biological
Intervention description(s): Aerosol administration through the Omron MicroAIR NE-U22 nebuliser; Intramuscular administration
Allocation: Randomized
Intervention model: Sequential Assignment
Intervention model description: Stage I - dose escalation study (Arms A,B,C) Stage II - experimental arms: randomized (Arms D,E), parallel (Arm F)
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Prevention
Keywords: ChAdOx1 85A; Tuberculosis; vaccination; BCG; Mucosal; Inhaled vaccine