From the Special Topic of
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
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
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.
ScienceWatch.com's European correspondent Dr. Simon
Mitton talks with Professor Andersen about his highly cited
work, especially with regard to
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
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
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
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: 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: 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
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
Speaking of the ESAT-6 developments, several papers
about this feature in the highly cited list. Is it a candidate
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
Professor Peter Andersen, DVM DMSc
Department of Infectious Disease Immunology
Statens Serum Institut
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.