Decrease in the Effectiveness of Bacille Calmette-Guérin Vaccine against Pulmonary Tuberculosis: A Consequence of Increased Immune Suppression by Microbial Antioxidants, Not Overattenuation
Douglas S. Kernodle
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Departments of Medicine and of Microbiology and Immunology, Vanderbilt University School of Medicine
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Nashville, Tennessee
Mutations that arose in bacille Calmette-Guerin (BCG) daughter strains during decades of in vitro cultivation have long been suspected of reducing the efficacy of the BCG vaccine against pulmonary tuberculosis. Although concern was raised 6 decades ago that BCG had become overattenuated, preferential use of relatively virulent BCG vaccines has not restored efficacy. The recent discovery that as BCG evolved its production of antioxidants increased as a consequence of genomic duplications and other mutations suggests the alternative hypothesis that BCG became better at suppressing oxidant-dependent immune responses. This new model of BCG evolution is supported by evidence indicating that reducing BCG antioxidants enhances immunogenicity. Furthermore, some previously unexplained aspects of the performance of the BCG vaccine in clinical trials now make sense in the context of the new model. Finally, the model suggests that the risk of developing pulmonary tuberculosis is influenced by the balance between host-generated oxidants and microbial antioxidants that activate and suppress, respectively, the antigen-presentation pathways that protect the lungs.
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For almost 9 decades, the live vaccine
Mycobacterium bovis bacille Calmette-Guerin
(BCG) has been used against tuberculosis.
In early studies, BCG vaccine was highly
efficacious. In the 1920s, vaccination of
nursing and medical students with BCG
reduced pulmonary tuberculosis by 80%
[1]. In the 1930s, a trial in North America
found similarly high protection in the first
2 decades after vaccination, with
continued benefit for 6 decades [2, 3]. Yet in
subsequent studies BCG vaccine exhibited
marked variability against pulmonary
tuberculosis and occasionally even appeared
to increase the risk of developing
tuberculosis [4, 5]. This variability is highly
significant (P ! .0001) and is regarded as
being indicative of true biological differences
[4]. Yet despite its flawed record against
pulmonary tuberculosis, BCG remains
reliably efficacious in preventing
tuberculosis meningitis and miliary tuberculosis
in young children [6]. Because pulmonary
tuberculosis is more common than
disseminated tuberculosis, BCG has had a
minimal effect on the global burden of
tuberculosis, estimated at 9.4 million new
active cases and 1.8 million deaths
annually [7].
Several hypotheses attempt to explain
the variable effectiveness of BCG against
pulmonary tuberculosis. These hypotheses
include differences between BCG daughter
strains (substrains), an inadequate dosage
of BCG in some trials, interference by
environmental mycobacteria, genetic
differences in human populations, and
geographic differences in clinical isolates of
M. tuberculosis. These hypotheses have
been summarized elsewhere [4, 5, 8].
This Viewpoint offers a new perspective
on the old idea that the variable efficacy
of the BCG vaccine against pulmonary
tuberculosis involves differences between
BCG daughter strains. In the context of
emerging data that reveal that
mycobacterial antioxidants suppress host
immunity [912] and that antioxidant
production increased as BCG evolved [13, 14],
the relevant literature is reexamined to
reveal an association between BCG daughter
strains that produce large amounts of
antioxidants and poor efficacy against
pulmonary tuberculosis. On the basis of
partial but not fully conclusive evidence, a
new model is proposed in which BCG,
instead of becoming overattenuated,
evolved to become better at suppressing
the CD8+ T cell responses needed for
protection against pulmonary tuberculosis.
The new model further suggests that in
vitro evolution enabled extensively
cultivated BCG substrains to survive longer in
vivo, which made them more effective at
preventing disseminated tuberculosis.
Although overattenuation and increased
immune suppression are mutually exclusive
models of the evolution of BCG, the new
hypothesis is not fully sufficient.
Environmental and genetic factors are also crucial,
especially in the context of their effect on
host oxidant-generating capacity during
vaccination.
EARLY CONCERN
ABOUT OVERATTENUATION
AND IDENTIFICATION
OF PHENOTYPIC DIFFERENCES
AMONG BCG SUBSTRAINS
An early theory regarding the apparent
decline in efficacy of the BCG vaccine against
pulmonary tuberculosis was that the
vaccine had changed over time. In 1949,
Irvine expressed concern that the problem
has now become one of over-attenuation.
Separated from its natural habitat for 42
years, may not attenuation still be
slowly progressing? [15, p 25]. By the
mid1950s, it had been shown that BCG
substrains differ in characteristics, including
growth rate, their ability to persist in vivo,
and their ability to protect mice against
M. tuberculosis infection [1619].
Daughter strains are descendents of BCG; before
modern technologies for preserving
bacteria became (...truncated)