Although Tuberculosis (TB) has infected populations for millennia, it remains a leading cause of death worldwide. During this month’s ID / IIDR Rounds, McMaster researchers Dr. Fiona Smaill and Dr. Zhou Xing of the Michael G. DeGroote Institute for Infectious Disease Research presented the many challenges faced with developing effective vaccines against this devastating disease, and described how their 20 plus years of research into TB immunology and vaccine design may have given rise to one of the first effective vaccination strategies in over 95 years.
Dr. Smaill began the rounds with an introduction to the global devastation of TB. TB is a highly contagious, airborne pathogen caused by the organism Mycobacterium tuberculosis (Mtb), which infects a staggering one-third of the world’s population. Of these individuals, 5 to 10% develop active TB disease, which currently results in an upwards of 5000 deaths per day. Although the majority of cases lie within Sub-Saharan Africa and Asia, TB remains relevant within North America, with Nunavut displaying incidence rates of over 200 per 100,000, and multi-drug resistant strains resulting in recent deadly outbreaks in the United States.
Dr. Smaill next discussed the first and only TB vaccine – Bacillus Calmette-Guérin (BCG) – which was developed over 95 years ago. Although BCG offers adequate protection against TB in children, it fails to prevent pulmonary TB in adults. However, despite its low overall efficacy, BCG still remains the standard approach to TB protection, as effective alternatives are yet to be found. Dr. Xing followed Smaill to address why promising vaccine candidates continue to show failed efficiency against active TB, and explain how their current vaccine program differs from the many others in the global clinical pipeline.
To better understand why past TB vaccine strategies have failed to protect against pulmonary TB infection, Xing reviewed the basic host-defense mechanisms of TB. Over thousands of years, Mtb co-evolved with the human immune system to develop sophisticated defense mechanisms that interfere with important immune response checkpoints. When inhaled, the TB pathogen is transferred deep into the body’s respiratory system, where it develops an intracellular niche called a granuloma within the lungs. Here, the infection is able to flourish and cause disruption to the host’s natural immune defenses, prior to the arrival of protective T-cells. Dr. Xing explained how this delay in T-cell recruitment to the site of infection prevents our natural immunity from appropriately clearing Mtb infections in exposed humans. He then pointed out that because the majority of vaccine candidates are designed to mimic this natural immunity, they remain largely ineffective against pulmonary TB.
Vaccine candidates that are designed to induce natural immunity are characterized by a parenteral route of administration; they are systemically injected into either the muscle or the skin. To test whether parenterally administered vaccine candidates result in insufficient protection against pulmonary TB, Smaill & Xing’s team developed an Ad-vectored TB vaccine called AdHu5Ag85A and administered it intramuscularly to mice. Within the lungs of the hosts, the team identified a correlation between delayed T-cell recruitment and lack of protection in the lung. Further, when T-cells were manually recruited to the lungs of these hosts, restored protection resulted.
Based on these findings, Xing’s team developed a novel treatment strategy. By administering their Ad viral-vectored TB vaccination through the respiratory mucosa of mice, the team was able to directly deliver the vaccine to the lung, restoring T-cell recruitment to the site of infection whilst also inducing a greater expression of protective immune cells. Interestingly, they found that this “unnatural immunity” strategy not only enhanced immune protection against pulmonary TB, but offered additional, unintended protection against other bacterial pathogens such as Streptococcus pneumoniae. In further studies with humanized mice (mice with grafted human immune cells), the team was able to show continued T-cell immunity enhancement and protection of the lung. In 2013, the team launched their first human phase 1 trial to prove that their vaccine was safe and well-tolerated in humans when given intramuscularly to healthy volunteers.
Dr. Smaill then returned to the podium to introduce the exciting next step of their vaccine development. Just last Fall, Xing and Smaill’s team at McMaster received over $3.5 million in CIHR Foundation funds and project grants to further test their innovative vaccine strategy. In just a few weeks, a phase 1, open-label clinical trial will begin to evaluate the safety, potency, and immunogenicity of their vaccine when inhaled as an aerosol into the lungs. The data from this study will help move their technology to the next stage of clinical evaluation, with the hope of ultimately carrying out their improved technology as a booster vaccination to BCG in partnership with the biotechnology company, CanSino Biologics.
Zhou and Smaill’s promising vaccine candidate – which has now been in development for over a decade – is the only Canadian vaccine amongst dozens that are currently in the global clinical TB vaccine pipeline. Given the current rise in drug-resistant bacteria, such innovative therapies are not only vital in the global mitigation of TB, but other devastating infectious diseases as well.
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