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- - CHASING KOCH'S CHIMERA

Wednesday, 10th of April 2013

• CHASING KOCH'S CHIMERA

 

The Lancet Infectious Diseases, Volume 13, Issue 4, Pages 289 - 291, April 2013

 

Paul Klatser a, Richard Anthony a, Clifton Barry b, Francis Drobniewski c, Sven Hoffner d, Stefan Niemann e,Stephen Gillespie f

 

Also at http://www.thelancet.com/journals/laninf/article/PIIS1473-3099%2813%2970041-0/fulltext

 

 

On March 24, 1882, Robert Koch presented his findings on the discovery of the cause of tuberculosis to the Berlin Physiological Society.1 This presentation was one of the most important in the history of bacteriology. The results set the ground rules of how to establish pathogenicity and led to the initiation of two approaches for tuberculosis control: vaccines and specific antituberculosis chemotherapy. Paul Ehrlich attended the meeting of the society and reasoned that if bacteria could be identified by specific stains, then they could be killed by the same means. In 1909, salvarsan was developed for the treatment of syphilis by Sahachiro Hata in Ehrlich's laboratory. Many years later in 1935, Ehrlich's disciple Gerhard Domagk produced the effective antibacterial dye prontosil.2 Since the introduction of DOTS in 1995, a range of powerful drugs have led to the successful treatment of more than 51 million patients with tuberculosis.3 Additionally, control of the disease by timely diagnosis followed by adequate treatment has led to a decrease in the number of people falling ill and dying from tuberculosis worldwide.4

Koch's commitment to turn his discovery into a practical method to eliminate tuberculosis worldwide led him to try to develop a new product that could treat tuberculosis. At the 10th International Congress of Medicine in Berlin in 1890, Koch announced that “if guinea pigs are treated they cannot be inoculated with tuberculosis and guinea pigs which already are in the late stages of the disease are completely cured, although the body suffers no ill effects from the treatment”.1 However, we now know that his discovery was not a vaccine for tuberculosis but tuberculin, which causes a potentially damaging hypersensitivity reaction.

A strong message of the 2012 World TB day was the need to rapidly develop vaccines for tuberculosis.5 A vaccine is as appealing now as it was more than 120 years ago, and could make a substantial contribution to the elimination of tuberculosis. However, funding for tuberculosis control is under substantial pressure, and increased investment in vaccine development will cause resources to be redistributed. The development of a tuberculosis vaccine, far from being delayed by insufficent funding, is a high-risk and ambitious goal. Most successful vaccines target diseases in which the infection provides long-term protective immunity. Viral agents with one or few serotypes are typical examples—eg, measles or smallpox.

The story of pneumococcal disease provides a cautionary tale about the challenges of creating bacterial vaccines because an antibody against the capsule is protective and can be used as treatment.6 The first attempt by Almoth-Wright6 failed because the various capsular serotypes were not then known. In the mid-20th century, promising progress was abandoned when penicillin became available. Austrian7 created a polysaccharide vaccine containing an increasing number of serotype antigens. Although the vaccine eventually contained 23 serotype polysaccharides and a clear marker of protection was evident, the vaccine failed because young children, elderly people, and individuals with sickle cell disease (ie, individuals in need of protection) could not mount an effective humoral immune response.

By comparison with pneumococcal disease, the creation of a bacterial vaccine for tuberculosis is even less promising. Past tuberculosis infection is unlikely to offer protection, and patients recently treated for tuberculosis can rapidly become reinfected.8 No unequivocal determinants of pathogenicity have been identified—eg, a toxin that can be targeted. Most importantly, no clear marker of protection is available. Tuberculosis vaccines based on BCG seem to offer a reasonable amount of postexposure protection in low-burden settings, but this protection varies substantially worldwide, and many studies have reported little effect.9, 10 Therefore, how to achieve increased protection is unclear. The several vaccine candidates that have entered clinical trials are not designed to prevent infection or achieve sterile immunity, but at best to inhibit or delay tuberculosis reactivation.11 However, with present methods the effect of these vaccines will only become apparent after 10—15 years of expensive trials. No fundamental biological mechanism on which to base a fully protective vaccine for tuberculosis seems to exist, and without this, later-stage vaccine development is speculative.

Even if the perfect vaccine were available, much time and investment would be needed to establish the vaccine's effectiveness and safety. Moreover, without a marker of protection, studies would need to use the development of tuberculosis disease as an endpoint, resulting in either extremely large or extremely long (ie, decades) studies.11 The effect of all but a currently unrealistically effective vaccine should not be overestimated.12 Even in the unlikely event of deployment of an effective vaccine the eradication of tuberculosis might take a century because we need to wait for all latently infected people to die.

We believe that research into the immunology of tuberculosis is of fundamental importance, and that resources need to be directed towards the identification of a marker of protection that could form the foundation of an effective vaccine programme and have an immediate effect on diagnostics and treatment of the disease. As shown by the impressive progress in the past 10 years (eg, the continuing phase 2 and phase 3 trials), investigators now have the technical and scientific knowledge and the methods needed to substantially improve the treatment and diagnosis of tuberculosis. Several new agents are nearing the end of the development process for a multidrug resistant indication.13 If we postulate effective diagnostics methods for active and latent infection, and use short-term and effective treatment for both indications, a well organised eradication programme could succeed in fewer than 20 years.

For many years, leprosy research was dominated by immunology, which has an important role in the pathogenesis and management of the disease, with the hope of developing a vaccine.14 However, shorter bactericidal combination treatments have been a major contributor to the reduction of active leprosy cases to fewer than 250 000 in 2011.15 The eradication paradigm of this closely related disease in terms of taxonomy and immunology should inform future choices for tuberculosis.

In the modern world, we know that a chimera is only a Lycian mythical animal. We challenge the research and public health community to raise its expectations, develop methods for a tuberculosis eradication campaign based on better diagnostics and more effective drugs. We should stop chasing Koch's chimera.

 

PK, RA, CB, FD, SH, and SN are actively involved in improved diagnostics for tuberculosis. SG receives research funding to develop antituberculosis treatment regimens.

References

1 Brock TD. Robert Koch: a life in medicine and bacteriology. Washington, DC: ASM Press, 1999.

2 Raju TN. The Nobel chronicles. 1939: Gerhard Domagk (1895—1964). Lancet 1999; 353: 681. Full Text |PDF(142KB) | CrossRef | PubMed

3 World Health Organization, Tuberculosis. WHO Fact sheet number 104. Reviewed February 2013.http://www.who.int/mediacentre/factsheets/fs104/en/. (accessed March 1, 2013).

4 Dye C, Williams BG. The population dynamics and control of tuberculosis. Science 2010; 328: 856-861.CrossRef | PubMed

5 The Lancet. Tuberculosis control and elimination in 2012 and beyond. Lancet 2012; 379: 1076. Full Text |PDF(115KB) | CrossRef | PubMed

6 Grabenstein JD, Klugman KP. A century of pneumococcal vaccination research in humans. Clin Microbiol Infect 2012; 18: 15-24. CrossRef | PubMed

7 Austrian R. Some observation on the pneumococcus and on the current status of pneumococcal disease and its prevention. Rev infect Dis 1981; 3: 117. PubMed

8 Chiang CY, Riley LW. Exogenous reinfection in tuberculosis. Lancet Infect Dis 2005; 5: 629-636. Summary| Full Text | PDF(111KB) | CrossRef | PubMed

9 Fine PEM. Variation in protection by heterologous immunity. Lancet 1995; 346: 1339-1345. Summary |CrossRef | PubMed

10 Pereira SM, Barreto ML, Pilger D, et al. Effectiveness and cost-effectiveness of first BCG vaccination against tuberculosis in school-age children without previous tuberculin test (BCG-REVAC trial): a cluster-randomised trial. Lancet Inf Dis 2012; 12: 300-306. PubMed

11 Ottenhoff TH, Kaufmann SH. Vaccines against tuberculosis: where are we and where do we need to go?. PLoS Pathog 2012; 8: e1002607. CrossRef | PubMed

12 Abu-Raddad LJ, Sabatelli L, Achterberg JT, et al. Epidemiological benefits of more-effective tuberculosis vaccines, drugs, and diagnostics. Proc Natl Acad Sci USA 2009; 106: 13980-13985. PubMed

13 Mitchison D, Davies G. The chemotherapy of tuberculosis: past, present and future. Int J Tuberc Lung Dis 2012; 16: 724-732. CrossRef | PubMed

14 Rodrigues LC, Lockwood DNJ. Leprosy now: epidemiology, progress, challenges, and research gaps. Lancet Infect Dis 2011; 11: 464-470. Summary | Full Text | PDF(126KB) | CrossRef | PubMed

15 World Health Organization. Leprosy update, 2011. Wkly Epidemiol Rec 2011; 86: 389-399. PubMed

a Royal Tropical Institute (KIT), KIT Biomedical Research, Amsterdam, Netherlands

b National Institutes of Health, NIAID, Tuberculosis Research Section, Bethesda, MD, USA

c Queen Mary and University Colleges, University of London, London, UK

d WHO Supranational Tuberculosis Reference Laboratory, Swedish Institute for Communicable Disease Control, Solna, Sweden

e National Reference Centre for Mycobacteria, Borstel, Germany

f School of Medicine, University of St Andrews, St Andrews, UK