Tuberculosis (TB), a disease that has claimed the lives of 1.5 million people annually, is a global health crisis. Despite being largely eradicated in developed nations, a quarter of the world's population carries the Mycobacterium tuberculosis (Mtb) infection. Could an inhaled vaccine be the key to finally eliminating this deadly disease?
The Quest for a Better Vaccine
Associate Professor Andreas Kupz, an investigator at the Australian Institute of Tropical Health and Medicine, James Cook University, has been leading the charge in TB research. He believes that improving the existing Bacillus Calmette-Guérin (BCG) vaccine is the way forward. BCG, currently administered intradermally to children after birth, is not effective against pulmonary TB in adults, and its effectiveness wanes as individuals enter adolescence.
Kupz and his team have explored various approaches to enhance the vaccine's efficacy. They've developed mRNA and peptide-based vaccine candidates, but the literature suggests these new types often fall short compared to BCG when tested in human clinical trials. So, they're focusing on improving BCG itself.
"We've shown that making BCG more like Mtb can induce better protection, but it's a delicate balance between safety and immunogenicity," Kupz explains. By delivering modified BCG strains directly into the lungs, animal models have demonstrated enhanced protection. This approach provides an explanation for why mucosal delivery is more effective than intradermal vaccination and why more virulent strains of BCG offer better protection.
The Promise of Mucosal Delivery
Kupz's team was the first to demonstrate the superior effectiveness of mucosal BCG delivery over intradermal delivery, linking it to tissue-residing T cells. This finding has been further supported by a body of work establishing the efficacy and higher level of protection afforded by mucosal vaccination.
"Understanding the link between BCG virulence, the induction of protective T cells, and their long-term maintenance in the lung is crucial for developing a more effective long-term protection against TB through vaccination," Kupz says.
Clinical Trials and Challenges
Clinical trials at Oxford University are currently investigating the safety and immunogenicity of BCG delivery into human lungs. These trials aim to understand the side effects, optimal BCG dosage, and immune responses induced in the lung. Kupz notes that the COVID-19 pandemic brought TB into the spotlight, but it also reversed the slow decline in TB deaths observed in previous years. The prolonged diagnosis and treatment process for TB, requiring strict adherence to protocols and close monitoring, led to an increase in TB-related deaths during lockdowns, and clinical trials for new vaccines were disrupted.
Addressing Disadvantaged Populations
TB is often described as a disease of poverty and economic distress, affecting vulnerable and marginalized communities. Indigenous communities in Australia, for example, have rates of TB infection that are 5-6 times higher than the Australian-born, non-Indigenous population. The intradermal TB vaccine is still given to newborns in TB-endemic areas like India and Sub-Saharan Africa, and to high-risk populations in northern Australia, mostly Indigenous communities in Cape York and the Torres Strait.
"One of the challenges with TB is that it's not always an active disease. Unlike COVID-19, where illness is often quickly apparent, TB can remain latent in many individuals. About 2 billion people worldwide are infected with Mycobacterium tuberculosis, and most live relatively well with the latent infection," Kupz explains.
The increase in multi-drug resistant (MDR) tuberculosis is a growing concern, with Papua New Guinea being a hotspot for MDR TB, presenting a biosecurity risk due to the free movement of people between the Torres Strait Islands and PNG under the Torres Strait Treaty.
"It's our duty of care to address this issue for our closest neighbor, PNG, and our own communities. MDR TB cases from PNG often need to be treated within our health system, and TB has a large individual economic impact. Finding a better solution for TB that benefits PNG and disadvantaged populations in northern Australia will have a significant positive impact on these communities' health and economy," Kupz adds.
The Future of TB Research
While the RD1-containing strain of BCG being studied by Kupz's team is not yet safe for human use, they have developed a modified BCG strain that induces better immunity without the increased virulence associated with BCG::RD1. However, Kupz emphasizes the need for more funding to develop a better TB vaccine.
"We know mucosal vaccination is better, and we understand why. Now, we need to make it safe enough for mass vaccination in humans. It's a challenging but crucial step towards eliminating TB," he concludes.
The quest for a more effective TB vaccine continues, with researchers like Kupz leading the way towards a future free from this deadly disease.
