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AUTHOR COMMENTARIES - From Special Topics

Tuberculosis - January 2009
Interview Date: June 2009
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Peter Andersen Peter Andersen
From the Special Topic of Tuberculosis
Tuberculosis (TB) is a major cause of morbidity and mortality throughout the world. This deadly infectious disease, mainly caused by Mycobacterium tuberculosis, kills approximately 3 million people each year. Although almost all deaths occur in high epidemic countries, the disease is a problem in developed countries, particularly those with immigrant populations.

The only vaccine presently available for clinical use is Bacille Calmette-Guérin (BCG), the effectiveness of which remains a matter of controversy. BCG generally induces a high level of acquired resistance in animal models of TB, but several human trials in developing countries have failed to demonstrate significant protection. Notably, BCG is not approved for use in the United States because BCG vaccination impairs the specificity of the tuberculin skin test for diagnosis of TB infection. In 1993 the World Health Organization identified TB as a global health emergency, and called for the development of new vaccines.


According to our Special Topics analysis of TB research over the past decade, the work of Professor Peter Andersen ranks at #3 by total cites and by total number of papers, based on 104 papers cited a total of 4,135 times. In Essential Science IndicatorsSM from Clarivate Analytics, Professor Andersen's record includes 240 papers, the majority of which are classified under Immunology or Clinical Medicine, cited a total of 6,219 times between January 1, 1999 and February 28, 2009. Professor Andersen is Vice President of Vaccine Research and Development at Statens Serum Institut (SSI), Copenhagen, Denmark.

Below, ScienceWatch.com's European correspondent Dr. Simon Mitton talks with Professor Andersen about his highly cited work, especially with regard to vaccines.

 Your research has been focused on the identification and characterization of immunologically important antigens and immune mechanisms responsible for protection against M. tuberculosis and other human pathogens. How did you enter this field?

I have a university degree in veterinary science and a Doctor of Science degree in medical science, both from the University of Copenhagen. So basically I trained as a veterinarian, graduating in 1988, and I completed the D.Sc. in 1996. I started vaccine research and immunology while still an undergraduate, but that was in the veterinary field. Then I saw an opportunity advertised by SSI, which was a short introductory position funded by the WHO on vaccine research for the prevention of TB. I was fortunate to get the position, and managed to secure funding afterwards for several temporary positions, finally getting a permanent position at SSI.

 Why did you choose tuberculosis as the disease to work on?

Well, as a young scientist I wanted to work in a field with a global impact. The global need for a new TB vaccine was very obvious, thanks to the efforts of WHO that had highlighted the failure of BCG in the large vaccine trial conducted in Chingleput, India, in 1968–76. The scale of the global emergency was such that I decided to invest a significant part of my life in trying to tackle the problem. So in a sense I considered the situation from an idealistic point of view.

"Within the next six to seven years we will get efficacy data from the leading vaccines in trials and therefore proof of concept as to the strategy that we have pursued for many years."

Concerning the science, I was very interested in the mystery surrounding protective immunity to TB. Scientists had at that time convincingly demonstrated that only live vaccine gave efficient protection against the disease whereas non-viable vaccine preparations failed to do so, but there was no good explanation to account for this difference. The tremendous challenge of understanding what protective immunity was all about appealed to me.

 One of your earliest papers related to TB research is the 1991 Infection and Immunity article, "Proteins released from Mycobacterium tuberculosis during growth," (Andersen P, et al., 59[6]: 1905-10, June 1991). What made this paper so important, and how much has the field changed since this paper was published?

The focus that I introduced at that time on antigens secreted from live mycobacteria turned out to be very appealing route for searching for vaccine targets from a live intracellular pathogen. This had been touched upon by other investigators, but I wanted to get a detailed understanding of the difference between live and killed bacteria—in other words, a signature that would be characteristic of the live multiplying bacteria.

The paper was therefore the first rigorous attempt to define the mixture of secreted antigens with the aim to understand if among these antigens you could identify protective antigens responsible for the high activity of live vaccines that produced these antigens in contrast to killed bacterial preparations rich in intracellular and cell wall associated antigens.

For many years that paper was crucial to our understanding of the composition of this complex pool of proteins, and it has attracted interest up to the present day. In terms of how the field has changed, today I would apply higher-resolution techniques for studying the diversity of the proteins, but the basic principle would be more or less the same.

 I next want to discuss two of your highly cited papers from the Lancet. I’d like to begin with "Specific immune-based diagnosis of tuberculosis," (Andersen P, et al., 356[9235]: 1099-104, 23 September 2000).

Yes, in this paper we reviewed a recent development in the field of TB diagnosis, and that was the use of the interferon gamma tests for the detection of TB infection. The reason why this was very timely was due to our identification of the ESAT-6 and CFP-10 antigens that are both highly specific for M. tuberculosis and lacking in all strains of BCG and the majority of atypical mycobacteria.

That observation, coupled with the fact that these are strong T-cell antigens that induce high levels of interferon gamma, made us suggest that you could actually use these antigens for a diagnostic test based on the induction of interferon gamma in TB infected individuals. That’s what the paper is reviewing and suggesting. The paper founded a completely new research field and novel diagnostic tests which today is referred to interferon-gamma release assays, or IGRA. Today this has become the gold standard for the detection of TB infection.

 In the Special Topics analysis your Lancet paper of 2003 is top of the citation list (Ewer K, et al., "Comparison of T-cell-based assay with tuberculin skin test for diagnosis of Mycobacterium tuberculosis infection in a school tuberculosis outbreak," Lancet 361(9364): 1168-73, 5 April 2003). How does that paper relate to the 2000 paper?

"The global need for a new TB vaccine was very obvious, thanks to the efforts of WHO that had highlighted the failure of BCG in the large vaccine trial conducted in Chingleput, India, in 1968–76."

That study was led by Professor Ajit Lalvani, who is now at Imperial College London. The paper is a beautiful demonstration that the approach I just described actually worked in a practical context, which was a TB outbreak in a school in the UK. The paper makes a direct comparison of an interferon gamma test and the tuberculin skin test.

Something that is carefully described in this paper is the correlation of the tests with the degree of exposure to the index case. The ESAT-6-based test had a very high correlation with the degree of exposure, thus showing that it is a splendid and much more precise diagnostic test than the skin test.

 Speaking of the ESAT-6 developments, several papers about this feature in the highly cited list. Is it a candidate vaccine?

Yes. The ESAT story all started with us identifying a low-molecular-mass fraction of secreted antigens as being immuno-dominant. This showed up in mice, cattle, and humans infected with TB. We analyzed and separated this fraction, which was a tedious exercise because of the low concentrations of many of these small molecules. Back then we didn’t really think of such small molecules as complete proteins, but more like proteolytic fragments of larger molecules. But then we identified ESAT-6 and it turned out to be the archetype of a family of ESAT-like proteins, which are very important in the host-pathogen interaction.

ESAT-6 and CFP-10 turned out to have a great potential both for the diagnostic tests that I have already described and as vaccine candidates. They were soon recognized in the field as very strongly recognized by T cells during infection and therefore included as a positive control in many studies of human antigen recognition. As they were also associated with mycobacterial virulence and localized in the original deletion that resulted in the attenuation of BCG, they soon became favorite antigens for TB diagnosis, vaccine research, and studies of host-pathogen interactions. I am therefore not surprised that they have been repeatedly cited.

Most recently we have used them in fusion molecules where we have combined them with other vaccine antigens, two of which are now in clinical trials.

 Where do you see these new vaccines going in the next few years, in terms of their clinical application?

Within the next six to seven years we will get efficacy data from the leading vaccines in trials and therefore proof of concept as to the strategy that we have pursued for many years. If they are successful we will make sure that they reach the populations in need as fast as possible.

One of the remaining problems that will be the research focus for the next period is the one-third of the global population that is already latently infected. The central goal will be to develop a vaccine strategy that will work post-exposure, in other words a vaccine that when administered to latently infected individuals will prevent re-activation of TB.

Professor Peter Andersen, DVM DMSc
Department of Infectious Disease Immunology
Statens Serum Institut
Copenhagen, Denmark

Peter Andersen's current most-cited paper in Essential Science Indicators, with 238 cites:
Ewer K, et al., "Comparison of T-cell-based assay with tuberculin skin test for diagnosis of Mycobacterium tuberculosis infection in a school tuberculosis outbreak," Lancet 361(9364): 1168-73, 5 April 2003. 238 cites. Source: Essential Science Indicators from Thomson Reuters.

This paper is the top paper in the Tuberculosis Diagnosis and Tests Research Front Map.

KEYWORDS: TUBERCULOSIS, DIAGNOSIS, VACCINE, IMMUNE MECHANISMS, ANTIGENS, PROTECTIVE IMMUNITY, LIVE PATHOGEN, KILLED BACTERIAL PREPARATIONS, INTERFERON GAMMA TESTS, ESAT-6, CFP-10, TUBERCULIN SKIN TESTLATENT INFECTION.

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Special Topics : Tuberculosis : Peter Andersen Interview - Special Topic of Tuberculosis