Breaking Transmission with Vaccines: The Case of Tuberculosis

Abstract

Members of the Mycobacterium tuberculosis complex (MTBC) have evolved causing tuberculosis (TB) in different mammalian hosts. MTBC ecotypes have adapted to diverse animal species, with M. bovis being the most common cause of TB in livestock. Cattle-to-human transmission of M. bovis through ingestion of raw milk was common before introduction of the pasteurization process. TB in humans is mainly caused by M. tuberculosis. This bacterium is considered a genetically clonal pathogen that has coevolved with humans due to its ability to manipulate and subvert the immune response. TB is a major public health problem due to airborne person-to-person transmission of M. tuberculosis. The essential yet unanswered question on the natural history of TB is when M. tuberculosis decides to establish latent infection in the host (resambling the lysogenic cycle of lambda phage) or to cause pulmonary disease (comparable to the lytic cycle of lambda phage). In this latter case, M. tuberculosis kills the host with the aim of achieving transmission to new hosts. Combating the TB epidemic requires stopping transmission. M. bovis BCG, the present vaccine against TB, is derived from M. bovis and only protects against disseminated forms of TB. Thus, a priority in TB research is development of new effective vaccines to prevent pulmonary disease. Attenuated vaccines based on M. tuberculosis as MTBVAC are potential candidates that could contribute to break the TB transmission cycle.

Keywords: MTBVAC; Pulmonary tuberculosis; airborne transmission; infectiousness; live attenuated M. tuberculosis vaccines.

FIGURE 1

M. bovis transmission. Infected cattle transmit M. bovis bacteria (orange bacilli) to the neighboring herd members and also during milking. Before milk pasteurization was introduced, M. bovis was an important cause of cattle-to-human transmission of TB. Now M. bovis rarely causes TB outbreaks in humans, and transmission of M. bovis strains between humans is infrequent. Vaccination with BCG (schematized as blue bacilli), starting in the 1920s, was efficient to prevent disseminated forms of TB caused by M. bovis.

FIGURE 2

M. tuberculosis transmission. Humans are the only known reservoir of M. tuberculosis (red bacilli). The M. tuberculosis infectious cycle starts with the transmission of bacilli by the respiratory route from a patient with active pulmonary disease, who aerosolizes M. tuberculosis, placing contacts at risk of infection. Epidemiological data indicate that 9 of every 10 infected individuals are chronically infected in the form of LTBI (gray human shapes); therefore, LTBI constitutes a potential reservoir for transmission. People with LTBI are at risk for TB reactivation at some later time, and 1 of every 10 infected persons will develop clinical disease (black human shapes). The essential question on the natural history of TB is when M. tuberculosis decides to either infect and live with its host in the form of LTBI or to cause active pulmonary disease, which without treatment kills the host, searching the transmission to new hosts. The inner circle shows the lambda phage infectious cycles and their similarities to M. tuberculosis infection and disease. The lysogenic cycle of lambda phage resembles to LTBI, and the lytic cycle of lambda phage is similar to active TB disease caused by M. tuberculosis.

FIGURE 3

Ending TB transmission with vaccines. A patient with active TB disseminates M. tuberculosis (red bacilli) to neighboring individuals. One of every 10 persons is susceptible to TB (black human shapes) and therefore will develop clinical disease in the absence of vaccination. A vaccine able to protect against respiratory forms of TB (blue bacilli) will interrupt the TB transmission cycle, contributing enormously to TB control.