A Feasibility Study of a Controlled Human Infection Model (CHIM) With Intradermal Bacillus Calmette-Guérin (BCG) Injection in Malawi

Tuberculosis (TB) is a leading cause of death from a single infectious agent worldwide and is an acknowledged major challenge in Malawi. Globally in 2021, there were an estimated 10.6 million people unwell with TB and an estimated 1.6 million deaths caused by TB. Furthermore, the global TB incidence could be accelerated to an average of 17% per year between 2025 and 2035 owing to the disruption to TB services caused by the COVID pandemic. TB diagnosis is challenging, and drug treatment can be prolonged, harmful, costly, and complex, especially in the increasingly common context of drug resistant M. tuberculosis. For these reasons an effective vaccine to prevent disease is a global public health priority, and drugs to allow shorter courses of effective therapy are urgently needed.

At present, the only licensed vaccine is the bacille Calmette-Guérin (BCG) vaccine (BCG Bulgaria is the Malawi licensed strain). BCG has been administered globally to several billion people over the last 100 years and it has been part of the expanded program on immunisations since the early-1970s. BCG is effective in preventing disseminated TB disease, including tuberculous meningitis in childhood. However, it does not protect against pulmonary TB in many parts of the world, especially in the tropics where the incidence of TB is at its greatest. Since pulmonary TB is associated with the highest morbidity and mortality, the need to develop an effective vaccine against this disease is paramount, especially in Malawi where BCG protection is known to be minimal.

There are several novel vaccines for TB in clinical development, the most clinically advanced of which is M72/AS01E. The evaluation of candidate TB vaccines is challenging, and progress in the field is hampered by the lack of an immunological correlate of protection. Most routinely administered vaccines generate a quantifiable antibody response that correlates strongly with protection. In contrast, protection against TB is critically dependent on the cellular immune response, in particular CD4+ and also probably CD8+ T cell mediated cellular responses. The mechanisms of these responses are not fully understood .

Currently, to assess vaccine efficacy against TB there is no alternative to large randomized controlled trials. These efficacy trials for novel TB vaccines are difficult, long and very costly. For this reason, there is an urgent need for a valid, reliable, and strong evaluation technique to help distinguish between candidate TB vaccines' likely efficacy at Phase 3. Candidate vaccines which have passed successfully through phase I trials and are in Phase 2b efficacy studies could be included in human challenge protocols which could be designed to either measure prevention of infection (POI) or immunological endpoints. This would allow vaccine discovery to accelerate in a cost-effective manner. Similarly, successful development of new, safe and effective TB therapies face multiple challenges. A responsive controlled human infection model of TB infection could accelerate the development of new drugs and promote refinement of drug combination regimens.

Controlled human infection models (CHIMs) provide insight into disease pathogenesis and correlates of immune protection to support the development of novel vaccines.