A Phase I Clinical Trial to Compare the Safety and Immunogenicity of Candidate TB Vaccine ChAdOx1 85A Administered by the Aerosol Inhaled Route and the Intramuscular Route in Healthy Adult Subjects

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.