A lung-oriented controlled human infection model using live BCG to evaluate tuberculosis immunopathogenicity and vaccine efficacy (TB-CHIM).

Tuberculosis (TB) is one of the deadliest diseases known to man. It has killed over 1 billion people in the last 2 centuries and is currently the biggest infectious disease killer globally. In 2016 there were over 10 million newly diagnosed TB cases and 1.7 million people died (worldwide 3 people die from TB every minute!). In some parts of the world, like Sub-Saharan Africa, the disease is out of control.

TB most commonly affects the lungs and is transmitted through the inhalation of cough droplets, which enter the host's lung and eventually reach the air sacs (alveoli) where the infection takes root. However, if someone inhales TB bacteria it does not necessarily mean that they will develop active TB disease. In most people (~90 to 95%), the immune system is able to either kill or contain the bacteria before they develop disease. However, in ~5-10% of people, the bacteria multiply leading to TB disease.

The immune system is complex with many interacting components. However, how these components work together in the lung to kill the bacteria and prevent disease development is poorly understood. Thus, it remains unclear why some people get the disease while others are protected. This is mainly because most research, up to now, involved animal models and cells from the human blood compartment, which poorly approximate what happens in the human lung. However, several lines of evidence now suggest that a type of white blood cell called a memory T-cell, if "trained", can rapidly recognise and kill the TB bacteria. New research also suggests that antibodies, once thought to have no role in protection, can interact with other cells to kill TB bacteria. We aim to investigate these specific components and how they can protect against development of disease in the human lung. This will give us clues how to design protective interventions against TB.

The best way to eradicate TB is by developing an effective vaccine. Yet the current vaccine used in many countries, BCG, only protects against TB in children and offers little protection in adults, especially in countries where TB is common. About 20 new vaccines are being evaluated but the development process is very long (10 to 15 years) and expensive (about £800 million from start to finish) and most vaccines will fail in the late stages of human testing. Thus, we need a new efficient and more affordable approach, involving small numbers of patients, to choose the best vaccines to move to larger human studies. Another unresolved issue is how best to administer the vaccine. Traditionally, vaccines are given by injection in the skin but inhaling it directly into the lungs may better activate the protective responses against airborne infections like TB.

Our proposed study will attempt to address these unmet needs and unresolved questions by directly infecting the lungs of different groups of test participants (each group showing a different level of susceptibility against TB) with a live weakened strain of TB (called BCG) and examining the immune response before and after infection. This is called a controlled human infection model (CHIM). Such a model more accurately reflects how a person is naturally infected with TB. CHIM has been used in the past to develop vaccines for other disease such as cholera and malaria with great success. We have recently completed a study funded by the Gates Foundation and SA-MRC using a similar model where we have infected the lungs of healthy persons with BCG and a mixture of different proteins from TB bacteria (called PPD) and examined the immune response in the lungs after 3 days. We have established the safety of this CHIM in close to 100 participants. We now need to leverage these gains by using this model to now interrogate which specific aspects of the immune system are protective, refine the system to finalise a model that can be used to triage new vaccine candidates, and to determine the best route by which to administer new vaccines.

Elimination of tuberculosis (TB), a global crisis, is hampered by the lack of an effective vaccine. BCG, a live attenuated TB strain, is generally ineffective in adults. Several promising vaccine candidates have failed phase 2 studies and no subunit vaccines have yet entered phase 3 trials. This is due to our incomplete understanding of TB immuno-pathogenesis, which comes primarily from animal models and studies involving the use of human blood. Another unmet need is uncertainty about the optimal route for TB vaccine administration. A pragmatic method to prioritize the most promising vaccine candidates is urgently needed as existing approaches are time-consuming and extremely expensive.

In our recently completed TB-HART study, we established the safety and feasibility of a first-in-man lung-oriented controlled human infection model (CHIM). Live BCG and sterile PPD were bronchoscopically instilled into the lungs of 3 groups of healthy participants representing a gradient of TB susceptibility (sterilizing immunity; latent TB infection; recurrent TB). Repeat bronchoscopy was performed after 3 days. The gradient-based design allowed us to hierarchically rank different components of the immune response. The next step is to leverage these achievements to gain a more granular understanding of lung-specific host immunity, and to refine a model for rapid and affordable evaluation of vaccine candidates.

TB-CHIM will leverage a similar model to evaluate aspects of longer term (90-day) immunity in the different susceptibility sub-groups (Aim 1), refine a generic challenge model for the evaluation of TB vaccines (Aim 2), and to compare BCG performance when administered via different routes (skin vs. lung; Aim 3). This will likely provide us with (i) vaccination-induced immune mechanisms associated with TB risk (hitherto, poorly understood); (ii) a platform to test the efficacy of future vaccine candidates, and (iii) determine the optimal route of vaccine administration.

The economy

The global economic impact of TB is staggering; a recent KMPG report estimated losses of ~£770 billion to the global economy in the next 15 years. Developing countries with a high disease burden, such as South Africa, are disproportionately affected by TB, costing as much as ~3-4% of its GDP (~£8-11 billion per annum). A vaccine offers the only real hope of eliminating TB. However, vaccine development is a long (10-15 years) and expensive (~£800 million) process. Our CHIM-based approach could potentially accelerate research into understanding host-pathogen interactions, biomarker discovery, and protective immune mechanisms. Indeed, CHIM has greatly benefited vaccine development for other diseases such as malaria and cholera. The knowledge generated from this project could accelerate development of a new TB vaccine and ultimately reduce the disease burden and its associated cost to society. The potential economic benefits of our findings also extend to industry. Application of a CHIM could allow for the rapid and cost-effective evaluation of vaccine candidates and provide cost savings to pharmaceutical and biotechnology companies involved in TB vaccine and diagnostic research.

The general public

TB kills ~1.3 million people globally every year. In South Africa TB is the leading cause of death nationally. Development of a new effective vaccine could markedly reduce the mortality and morbidity, and transmission associated with TB. The project therefore specifically addresses the MRC strategic aim to impact positively on global health, and to assist with bringing the health impacts of fundamental research to people more quickly.
Academic and industrial organisations
Despite decades of research, we still do not fully understand why some individual exposed to TB get the disease while other do not. The knowledge gained from this project could potentially open up new research avenues for the discovery of novel immune pathways, illuminate host-pathogen interactions, identify virulence factors associated with disease progression, and obtain a better understanding of the natural course of disease. This could lead to better diagnostic tools for detecting TB, new vaccines and immunotherapeutic approaches for prevention, and new approaches to prevent transmission by targeting the most at risk populations. Furthermore, a systems biology approach for data analysis using machine learning techniques could be applied to the study of other infectious and non-communicable diseases thereby benefitting the wider scientific community. Similar benefits would extend to the commercial private sector. We have already approached several vaccine developers (GSK, Aeras, SSI) about testing their candidates using CHIM and many have shown interest once the project is completed. Thus the knowledge generated from this project will also lead to partnerships between academia and industry. LSHTM already has links with some of these companies (e.g. GSK). The LSHTM and UCT technology transfer offices will facilitate collaboration at the appropriate time.

Capacity development

The proposal will mentor and train several African and UK scientists and clinicians in various fields of research including immunology, '-omics' technologies, and bronchoscopic lung challenge. This knowledge transfer will benefit academia, the public sector and industry, and will facilitate scientific infrastructure and networks in the UK and South Africa. Team working and project management skills will also be developed. Importantly, multidisciplinary networks will be developed, thus driving sustainable research capacity in TB biology, bioinformatics and public health. Furthermore, several students are expected to be trained on this project, including clinician-scientists, which are in short supply on the African continent. Collectively, these activities will have a multiplier effect.