By Amanda Rachel Brunetti

Tuberculosis, caused by infection with Mycobacterium tuberculosis, is the top infectious cause of death in the world. An estimated 1.5 million people died of tuberculosis (TB) infection in 2018 alone. Transmission of M. tuberculosis (Mtb) is primarily airborne, occurring via the inhalation of respiratory droplets from persons with active infection. 

Mycobacterium tuberculosis Image/CDC

TB is an ongoing global public health concern. According to the most recent WHO Global Tuberculosis Report, the incidence of TB cases worldwide in 2018 was estimated between 9.0 and 11.1 million. Considered a disease of poverty, incident cases occur predominantly in low and middle income countries, particularly in sub-Saharan Africa and Southeast Asia. 

The Bacille Calmette-Guérin (BCG) vaccine has been available since 1921 and remains the only approved prophylactic method for the prevention of TB infection, despite its varied efficacy. BCG is composed of a live attenuated (weakened) form of Mycobacterium bovis, a bacteria closely related to Mtb. The high variability of BCG to prevent pulmonary TB, the primary cause of morbidity and mortality, represents a major component of the global failure to prevent the spread of Mtb. 

Historically, BCG has been administered via an intradermal injection in the upper arm. Researchers at the National Institute of Allergy and Infectious Diseases (NIAID) have recently suggested that a change in the administration route of the vaccine can have a major impact on its efficacy.

In a study published by Darrah et al., rhesus macaques were immunized against Mtb using three routes: intradermal (ID), aerosol (AE), and intravenous (IV). For 24 weeks following vaccination, blood and fluid samples from each macaque were evaluated to determine the elicited immune response. Macaques who received the IV administration of BCG produced the highest durable levels of T cells. 

At six months, all macaques were challenged with Mtb and disease progression was tracked for 12 weeks. PET-CT imaging and quantitative analysis of bacterial burden revealed that nine of 10 macaques immunized via IV were highly protected against Mtb. Six of these macaques had no detectable Mtb, and the remaining three had an extremely low presence of the bacterium. Compared to those vaccinated by AE or ID, the macaques who received IV BCG had a significantly more robust immune response. 

These findings have major implications for the future of TB prevention and control. Vaccination is the most cost-effective, long-term control measure for any infectious disease, and TB is no exception. An improvement in BCG immunization methods, potentially by administration route, is critical in the effort to stop the global TB epidemic.