TUBERCULOSIS AND THE BCG VACCINE: NOT QUITE GOOD ENOUGH
Mycobacterium tuberculosis is one of the most virulent pathogens, infecting one third of the world’s total population (1). Tuberculosis (TB), of which M. tuberculosis is the causative agent, has become a frightening epidemic, killing almost two million people annually (1). The development of the Mycobacterium bovis bacilli Calmette-Géurin (BCG) vaccine in 1921 and its subsequent routine use in infants in developed countries has succeeded in reducing the incidence of TB (2). The effectiveness of BCG varies greatly though with geographic location – ranging from 0-80%. The failure of BCG is of particular importance in the developing world where rates of TB are much higher. This is thought to be due in part to an increased exposure to environmental mycobacteria, and is further propagated by the reduced socio-economic status and HIV pandemic in these countries that encourage the spread of TB (2). Here, the pathology of tuberculosis, the successes and shortcomings of BCG, and novel vaccine approaches to prevent tuberculosis will be presented.
How is TB spread?
The mechanism of infection for Mycobacterium tuberculosis has been well established and is clearly understood. The infectious bacterial particles are inhaled as aerosol droplets, typically formed as a result of a cough or sneeze by an infected person. These exhaled particles are known to linger in the air for several hours, and the amount of bacteria required to cause an infection has been estimated to be only a single bacillus (3). Once in the lung tissue, the bacteria are phagocytosed by alveolar macrophages. Normally, a pathogen is taken up into a phagosome within the macrophage whereby a decrease in acidity within this environment causes it to fuse with a lysosome. Exposure to hydrolytic enzymes cause degradation of the pathogen and thus limits the infection – this being the classical role of the macrophage in the immune response (3). It has been demonstrated in vitro that macrophages infected with M. tuberculosis fail to acidify and do not fuse with lysosomes (4). The ability of M. tuberculosis to alter the function of the macrophage and evade degradation underlies its pathogenicity by allowing its replication within the cell to occur, and the infection to persist.
Infection of the lung tissue leads to an inflammatory response involving the induction of cytokines that recruit mononuclear cells (neutrophils, natural killer cells, CD4+ and CD8+ T cells) from the bloodstream to the area of infection. These cells surround the infected macrophages in an attempt to contain the infection and form what is known as a granuloma. This is the landmark of tuberculosis – a mass of infected macrophages contained by foamy macrophages, lymphocytes and a web of extracellular matrix (collagen fibers) for structural support (3). This form of M. tuberculosis infection is latent – there are no symptoms of the disease and the person cannot pass the infection on to others. Containment usually fails when there is a change in the immune status of the person, and the infection becomes active. The granuloma necrotizes, and rupturing of the cells releases the replicating bacilli into the airways. A productive cough forms and droplets of bacilli are then released to the air where they can infect another person. Changes in immune status that force a latent infection to an active one can be anything from old age or malnutrition, to HIV infection. The latter two lend support to the high rates of TB in underdeveloped countries where HIV infection and inadequate food supply put many people at risk of contracting tuberculosis (3).
BCG – Hardly Prevention Perfection
BCG is currently the only vaccine that exists against TB, and is the most widely used vaccine in the world (5). BCG is an attenuated strain of M. bovis and was developed in France in 1921, and then distributed internationally 3 years later. More than 3 billion people have received this vaccine and the end of the TB epidemic in Europe was attributed to its administration (2). Clinical studies have confirmed that BCG can be effective – in fact, BCG is extremely effective in infants and consistently protects against TB. The vaccine is also very effective in animal models. In contrast, BCG fails when administered to adults, as well as those with a positive tuberculin skin test. Additionally, the variability in effectiveness across the globe is an issue, particularly the inefficacy of the vaccine in developing countries where TB rates are highest (5).
How can the inconsistencies in BCG effectiveness be explained? Failure of BCG have centered on the theory that exposure to environmental mycobacteria has a negative effect on the action of the vaccine. The two most popular hypotheses based on prior sensitization to mycobacteria are the masking hypothesis and the blocking hypothesis (2).
Masking vs. Blocking Hypotheses
The masking hypothesis suggests that previous exposure to mycobacteria will confer some degree of protection against M. tuberculosis due to a high amount of antigenic similarity between strains of mycobacteria. BCG, then, may not be effective because it does not offer a great deal of protection above what has already been acquired. The blocking hypothesis also maintains that prior sensitization negatively impacts vaccine efficacy, although it proposes that exposure to environmental mycobacteria interferes with the replication of the vaccine. This replication is required for the vaccine to ‘take’ and its ability to develop an immune response against the antigen.
Both hypotheses are feasible explanations for the failures of BCG mentioned earlier. It is reasonable to think that most adults will have been exposed to some mycobacteria in their lifetime by the time BCG is administered. It can also explain the geographical differences in BCG take – poorly developed countries (particularly the tropics and Africa) have a greater environmental mycobacteria load and therefore, would not respond as well to BCG. Likewise, individuals with a positive tuberculin skin test have clearly been exposed to M. tuberculosis or a related strain. These hypotheses also support the efficacy in neonates and animal models – both have had no exposure to mycobacteria of any kind and so it would be expected that the vaccine would work most efficiently for them.
There is clearly a relationship between mycobacteria sensitization and BCG efficacy but is still unclear which hypothesis provides the true explanation. It is likely that both theories have a role to play. Another drawback to BCG is its limited course of effectiveness. The protection offered by vaccination is not life-long, with most studies showing that BCG is protective for only 10-20 years (6). It has been suggested that the development of an improved vaccine for the prevention of infant tuberculosis is not necessary, and the focus should shift to the development of a BCG booster vaccine to prolong the protection offered by vaccination (6).
Novel TB Vaccines
Potential TB vaccines currently in clinical trials fall into one of two groups: live mycobacterial vaccines or subunit vaccines (7). Live vaccines, such as BCG, are made by attenuating or genetically modifying M. tuberculosis or a related strain. Adding or deleting certain genes has proven effective in animal models as a way to increase the efficacy of the original vaccine. The goal of this approach is to inactivate virulent genes while still retaining the ability to induce an immune response. The live BCG urease-deficient mutant is just one of these vaccines that are being investigated. This mutant is unable to stop the phagosome from maturing, and it contains a gene addition that damages the phagosome membrane, potentially increasing the amount of antigen that can leak out and be presented to T cells (5).
Conversely, subunit vaccines deliver specific mycobacterial antigens (as protein, peptides, DNA or live vectors) (5). They stimulate specific CD4+ cell populations that recognize the antigen versus a live vaccine which stimulates many T cell populations simultaneously.
Of course, with the development of a new vaccine it is important to consider the shortcomings of the original BCG and try to ‘fill the holes’ so to speak. Any live strain, whether recombinant or attenuated, would be ineffective in a pre-sensitized individual. The same problem arises with subunit vaccines – any pre-existing antibodies to another vaccination for instance, might block the activity of the vaccine antigenic molecule.
New vaccines that are effective against primary infection by M. tuberculosis are only half the battle in the prevention of TB. The ability of M. tuberculosis to infect a person and remain dormant for many years is an important feature of TB and must be considered when developing a novel preventative approach. How can those with latent infections be treated? Can the progression to active tuberculosis be prevented? What about individuals that have already been exposed via environmental mycobacteria? And how to prevent re-infection in someone who has already been vaccinated but is no longer protected? The answers to these questions will shape the path of future TB vaccine development.
References
1. DeAngelis CD, Flanagin A. Tuberculosis – A Global Problem Requiring a Global Solution. American Medical Association 2005 293(22): 2793-94.
2. Andersen P, Doherty TM. The success and failure of BCG – implications for a novel tuberculosis vaccine. Nature Reviews Microbiology 2005 3:656-662.
3. Russell DG. Who put the tubercle in tuberculosis? Nature Reviews Microbiology 2007 5: 39-47.
4. Mwandumba HC et al. Mycobacterium tuberculosis resides in nonacidified vacuoles in endocytically competent alveolar macrophages from patients with tuberculosis and HIV infection. J. Immunol. 2004 172: 4592-4598.
5. Franco-Paredes C, Rouphael N, del Rio C, Santos-Preciado, JI. Vaccination strategies to prevent tuberculosis in the new millennium: from BCG to new vaccine candidates. Int Society for Infectious Diseases 2006 10:93-102.
6. Sterne JA, Rodrigues LC, Guedes IN. Does the efficacy of BCG decline with time since vaccination? Int. J. Tuberc. Lung Dis. 1998 2: 200-207.
7. Martin C. Tuberculosis vaccines: past, present and future. Current Opinion in Pulmonary Medicine 2006 12:186-191.