Sunday, March 11, 2012

A Vaccine against Tuberculosis Infections

Tuberculosis (TB) results from infection by the bacterium, Mycobacterium tuberculosis. According to the WHO in 2009 around 1.7 million people are thought to have died from TB, with the majority of these deaths occurring in Africa (1). TB is a particular problem in this area due to the high incidence of HIV infection, which acts to suppress the immune system, allowing M. tuberculosis to overcome the body’s defences. In 2008 the number of new cases of TB was still rising each year in regions of Africa, the Eastern Mediterranean and South East Asia (1). With TB being responsible for such a large number of deaths the demand for an effective vaccine against it is great. This article aims to investigate the implications that a novel vaccine against TB might have for reducing the number of deaths caused by M. tuberculosis.
Mycobacterium tuberculosis
One of the difficulties facing eradication of M. tuberculosis is its ability to form latent infections in humans. It achieves this by being able to survive uptake into phagosomes by the host’s phagocytes, which would normally destroy bacteria. The M. tuberculosis bacterium limits the maturation of these phagosomes and prevents them from fusing with lysosomes that would degrade the bacterium (2). Since the bacteria aren’t cleared from the body by the immune system, they persist, with the ability to cause active TB if the host’s immune system becomes suppressed.
M. tuberculosis secretes a variety of proteins during the course of an infection, and it is these proteins that modern vaccines against TB have targeted. For example, ESAT-6 and Ag85b proteins are secreted during the early stages of infection by M. tuberculosis in order to help protect it from the host’s immune responses (3). The Rv2660c protein is thought to play a part in establishing latency due to the fact that is expressed at similar levels in both the early and later stages of M. tuberculosis infection in mice as opposed to only during the start of infection like most other proteins it expresses (3).
Existing Vaccines against Tuberculosis
Currently the only vaccine used for human immunisation against tuberculosis is the BCG vaccine (3). The BCG vaccine is developed from an attenuated strain of Mycobacterium bovis. An attenuated vaccine contains live bacteria that have lost their ability to cause infection in humans. Although there is widespread use of the BCG vaccine, it has several shortcomings which need to be addressed in order to try to reduce the impact of TB, particularly in less economically developed areas where TB is endemic. The BCG vaccine is mostly considered to be effective against TB in children with its impact on adult TB being less marked (4). This is partly due to the decreased effectiveness of the vaccine when there has been previous exposure to mycobacteria (4) and partly because of the poor performance of the BCG vaccine against latent infections (3). On top of this, many studies have indicated that BCG loses its effectiveness with time, giving protection for as little as 10-20 years (5). Since adult infections with TB are the primary cause of new mycobacterial infections in a population, and since they account for the majority of cases of TB (4), these inefficiencies of the BCG vaccine need to be addressed.
Several new vaccines that are hoped to be more effective against TB are now in clinical trials. Such vaccines include subunit vaccines that contain a fusion of antigen proteins associated with M. tuberculosis, for example the H1 vaccine which fuses ESAT-6 and Ag85b antigens (6) and the Mtb72f vaccine (7).
A Novel Vaccine against Tuberculosis
Recent experiments conducted by Aagaard et al. have established a vaccine that could have the potential to reduce the incidence of TB in humans, particularly in those with latent M. tuberculosis infections (3). The H56 vaccine contains a fusion of the antigens found in the H1 vaccine that are associated with early M. tuberculosis infection with a third protein, Rv2660c, which is associated with latent infection by the bacteria.
Experiments by the team have so far shown that the H56 vaccine is able to outperform the currently used BCG vaccine. In tests where mice were injected with one of the vaccines before exposure to M. tuberculosis, it was shown that H56 could lower bacterial counts in the lungs of the mice after six weeks, with the effect of H56 vaccination being greater than BCG vaccination after 12 weeks of infection. Further experiments suggested that H56 is also able to protect mice even if M. tuberculosis exposure has already taken place. Additionally, the team also vaccinated mice with H56 three months after receiving a BCG vaccine to establish whether it would be able to boost the effects of the BCG vaccine. The results showed that with H56 boosting, there were lower bacterial counts in the mice after six weeks of infection than when only BCG vaccination was used. Further experiments also established that after 24 weeks of infection, H56 boosting produced lower counts than when H1 was used to boost BCG vaccination.
Implications of the H56 Vaccine
A vaccine that aims to replace the BCG vaccine must be effective enough to last for a longer portion of a person’s life if it is to improve on the BCG vaccine and be worthwhile developing. The development of a significantly more powerful vaccine is, however, difficult. One of the strengths of the H56 vaccine lies in its ability to boost the BCG vaccine besides simply replacing it. Booster vaccines could be used to restore BCG effectiveness once it begins to diminish in adult life, thereby allowing continued protection against M. tuberculosis. In addition, the apparent ability of H56 to combat latent infections further improves on the BCG vaccine.
As with all vaccines, results in animal studies do not always translate to similar effects in humans. For example, animal trials with the BCG vaccine do not show the exposure-dependent variability in effectiveness seen in humans (4). These discrepancies are likely to arise when previous exposure to other mycobacteria establishes some sort of immunity (4). The attenuated bacteria in the vaccine might not have enough different antigens for a new response to be initiated. Alternatively, the immune responses developed against mycobacteria might prevent the attenuated bacteria in the BCG vaccine from replicating so they do not form a large enough population in the host to bring about a new immune response which the vaccine relies on. Many booster vaccines would face these same problems as it would be highly likely that by the time the booster was administrated, the patient would have been exposed to environmental mycobacteria. Since H56 contains antigens, the vaccine does not depend on replication to generate enough antigen for a response. However it still might not be effective enough to stimulate a new immune response over existing immunity to mycobacteria.
Finally, in individuals that fully recover from TB one would expect immunity against further infection from M. tuberculosis; however this has not been found to be the case (8), implying that it might not be possible for a vaccine to grant full protection either. Nevertheless a method for improving on the immunity that can be established by the BCG vaccine would still be valuable for attempting to reduce the prevalence of TB.
Implications of a New Vaccine in Endemic Countries
Since the majority of deaths due to TB occur in endemic areas such as Africa, a new vaccine that can help reduce these cases will have the greatest benefit for combating TB. Mathematical models used by Ziv et al. (9) predict that using either a high-efficacy vaccine (defined as 50-90% effective) that protects the individual prior to exposure from developing TB or one that limits the progression of the disease after exposure has already occurred could reduce the number of cases of TB by up to a third. Although this will by no means eradicate the presence of M. tuberculosis in endemic areas, it will significantly reduce the number of deaths due to TB as well as limit the development of antibiotic resistant mycobacteria. M. tuberculosis strains are being discovered with resistance to the antibiotics commonly used to treat TB. Many strains show resistance to single antibiotics while some are resistant to multiple drugs used against TB (1). While these strains are still treatable, albeit through more costly second-line drugs that cause more severe side effects, if further resistance develops against these reserve drugs it will become increasingly difficult to control M. tuberculosis infections. A vaccine that lowered the number of TB infections would reduce the reliance on antibiotic drugs for treatment, which in itself would lessen the selection pressure for M. tuberculosis to develop resistance.
Ziv et al. suggest that a new vaccination programme might reduce the number of cases of TB by more than a third if a vaccine can be developed both to tackle existing latent or active infections of M. tuberculosis and prevent infection in individuals that have not yet been exposed to the bacterium(9). Such a vaccine would be more effective because it would tackle the spread of infection from those who are already infected as well as those that might develop TB rapidly on infection with M. tuberculosis. Studies of the H56 vaccine suggest that it may be able to act in such a way.
The H56 vaccine could have the potential to be used in a variety of situations to limit TB. The studies so far imply that it could have the flexibility to be used as a booster in conjunction with previous administration of the BCG vaccine, as a means to preventing the progression of a latent M. tuberculosis infection into TB as well as replacing the BCG vaccine to immunise individuals pre-exposure. If the vaccine can deliver all of these possibilities in humans it should have a strong effect in reducing the incidence of TB, particularly in areas where it is endemic. At the same time, however, these areas are also less economically developed and therefore the cost of implementing a new vaccination programme in these locations might not be feasible.
1. World Health Organisation. WHO Tuberculosis fact sheet [Internet]. World Health Organisation 2010 Nov [cited 2011 Feb 15]; Available from:
2. Finlay BB, Falkow S. Common themes in microbial pathogenicity revisited. Microbiol Mol Biol Rev 1997 Jun [cited 2011 Feb 15];61(2):136-169. Available from:
3. Aagaard C, Hoang T, Dietrich J, Cardona P-J, Izzo A, Dolganov G, Schoolnik GK, Cassidy JP, Billeskov R, Andersen P. A multistage tuberculosis vaccine that confers efficient protection before and after exposure. Nat Med 2011 Feb [cited 2011 Feb 15];17(2):189-194. Available from:
4. Andersen P, Doherty TM. The success and failure of BCG – implications for a novel tuberculosis vaccine. Nat Rev Micro 2005 Aug [cited 2011 Feb 15];3(8):656-662. Available from:
5. Comstock GW, Woolpert SF, Livesay VT. Tuberculosis studies in Muscogee County, Georgia. Twenty-year evaluation of a community trial of BCG vaccination. Public Health Rep 1976 Jun [cited 2011 Feb 15];91(3):276-280. Available from:
6. Doherty TM, Olsen AW, Weischenfeldt J, Huygen K, DʼSouza S, Kondratieva TK, Yeremeev VV, Apt AS, Raupach B, Grode L, Kaufmann S, Andersen P. Comparative Analysis of Different Vaccine Constructs Expressing Defined Antigens from Mycobacterium tuberculosis. Journal of Infectious Diseases 2004 Dec [cited 2011 Feb 15 ];190(12):2146 -2153. Available from:
7. Skeiky YAW, Alderson MR, Ovendale PJ, Guderian JA, Brandt L, Dillon DC, Campos-Neto A, Lobet Y, Dalemans W, Orme IM, Reed SG. Differential immune responses and protective efficacy induced by components of a tuberculosis polyprotein vaccine, Mtb72F, delivered as naked DNA or recombinant protein. J. Immunol 2004 Jun [cited 2011 Feb 15 ];172(12):7618-7628. Available from:
8. Van Rie A, Warren R, Richardson M, Victor TC Gie RP, Enarson DA, Beyers N, van Helden PD. Exogenous Reinfection as a Cause of Recurrent Tuberculosis after Curative Treatment. New Engl J Med 1999 Oct [Cited 2011 Feb 15];341:1174-1179. Available from:
9. Ziv E, Daley CL, Blower S. Potential Public Health Impact of New Tuberculosis Vaccines. Emerg Infect Dis 2004 Sep [Cited 2011 Oct 8];10(9):1529-1535. Available from:

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