TB vaccines: progress and problems

doi:10.1016/S1471-4906(01)01865-8

Trends in Immunology

Volume 22, Issue 3, 1 March 2001, Pages 160-168

https://doi.org/10.1016/S1471-4906(01)01865-8 Get rights and content

Abstract

Tuberculosis (TB) is the biggest killer worldwide of any infectious disease, a situation worsened by the advent of the HIV epidemic and the emergence of multi-drug resistant strains of Mycobacterium tuberculosis. The existing vaccine, Mycobacterium bovis bacille Calmette–Guérin (BCG), has proven inefficient in several recent field trials. There is currently intense research using cutting-edge vaccine technology to combat this ancient disease. However, it is necessary to understand why BCG has failed before we can rationally develop the next generation of vaccines. Several hypotheses that might explain the failure of BCG and the strategies designed to address these shortcomings are discussed.

Section snippets

The BCG vaccine

BCG was developed at the start of this century and is the most widely used vaccine in the world. It was developed by attenuation of M. bovis, which is closely related to M. tuberculosis (>90% DNA homology), and recent data indicate that a large number of mutations have taken place during the long in vitro propagation of this strain 5, 6. It is known that these mutations have resulted in the deletion of a great many open reading frames (ORFs; 16 deletions encoding 129 ORFs reported so far),

Characteristics of acquired cellular immunity to TB

The hallmark of cellular immunity to TB is the formation of granulomas in the lung with a centre of infected macrophages and a marginal zone containing lymphocytes (Fig. 1). Studies of TB infection in mice have demonstrated that immune mice are characterized by a highly accelerated recruitment of memory cells, formation of granulomas and control of bacterial multiplication ¹². The acquired cellular immune response to M. tuberculosis is complex: CD4⁺ and CD8⁺ T cells, as well as unconventional T

Antigen discovery in the post-genomic era

The M. tuberculosis genome contains approximately 4000 different ORFs, which potentially encode the same number of proteins ⁴. The uncovering of the complete TB genome represents a major breakthrough in TB vaccine research and has been accompanied by considerable progress in antigen discovery. From a few defined proteins, recent progress in translating the genome information into proteins produced (the so-called proteome) has resulted in two-dimensional electrophoresis (2DE) maps comprising

Antigen selection and vaccine design for pre- and post-infection vaccines

Some of the most promising vaccine candidate antigens, antigen 85 A/B, ESAT-6 and heat shock protein 60 (HSP60) (Table 1), are strongly recognized, during the course of natural infection, in the same animal model in which they promote a protective immune response if administered as a pre-infection vaccine (Fig. 3a) ⁴¹. Furthermore, the same immunodominant antigens are recognized by TB patients and their healthy contacts ⁴². Therefore, there is no evidence to support the hypothesis that

Strategies for TB vaccine development

An ideal vaccine against TB would fulfil several theoretical requirements (Box 2). However, none of the vaccine technologies tested lives up to all of these ideal characteristics and, in a practical sense, candidates that fall short in one or more of these characteristics could still prove useful.

From challenge experiments in animals to clinical trials in humans

How to choose the most promising candidate vaccine to enter into clinical trials is a complicated but important question. Because there is still no good in vitro correlate of protective immunity (IFN-γ is the best but is far from sufficient), the best approach seems to be the evaluation of experimental vaccines in animal challenge studies. Currently, novel TB vaccines are tested in the mouse, guinea pig and, more recently, primate models of TB (⁶⁸). Most vaccines are screened in the mouse model

Conclusion and perspectives

Recent years have witnessed several new scientific advances in our understanding of the immunological mechanisms and targets for a protective immune response against TB. Today, it is scientifically feasible to develop a novel TB vaccine and many groups have provided compelling evidence for the potential of novel vaccines using a variety of different strategies. However, our current knowledge of the complexity of this disease and its different manifestations in different populations have

Acknowledgements

I thank T.M. Doherty for helpful discussions and excellent drawings, A.W. Olsen, K. Weldingh and L. Holten-Andersen for critical reading of the manuscript, and S. Lomborg for expert secretarial assistance.

References (77)

G.A. Rook
The effect of two distinct forms of cell-mediated response to mycobacteria on the protective efficacy of BCG
Tubercle
(1981)
S. Stenger
Granulysin: a lethal weapon of cytolytic T cells
Immunol. Today
(1999)
D.B. Moody
The CD-1 restricted T-cell response to mycobacteria
Res. Immunol.
(1996)
E.B. Bell
CD4⁺ T cell memory, CD45R subsets and the persistence of antigen – a unifying concept
Immunol. Today
(1998)
G. Falero-Diaz
Intranasal vaccination of mice against infection with Mycobacterium tuberculosis
Vaccine
(2000)
N. Dhiman et al.
Protective efficacy of mycobacterial 71 kDa cell wall associated protein using poly (DL-lactide-co-glycolide) microparticles as carrier vehicles
FEMS Immunol. Med. Microbiol.
(1998)
S. Morris
The immunogenicity of single and combination DNA vaccines against tuberculosis
Vaccine
(2000)
P. Andersen
Specific immune-based diagnosis of tuberculosis
Lancet
(2000)
World Health Organization (2000) Tuberculosis. Fact Sheet No. 104, WHO...
S.H. Kaufmann
Is the development of a new tuberculosis vaccine possible?
Nat. Med.
(2000)

P.E. Fine

The BCG story: lessons from the past and implications for the future

Rev. Infect. Dis. (Suppl)

(1989)

S.T. Cole

Deciphering the biology of Mycobacterium tuberculosis from the complete genome sequence

Nature

(1998)

M.A. Behr

Comparative genomics of BCG vaccines by whole-genome DNA microarray

Science

(1999)

S.V. Gordon

Identification of variable regions in the genomes of tubercle bacilli using bacterial artificial chromosome arrays

Mol. Microbiol.

(1999)

R.L. Skjot

Comparative evaluation of low-molecular-mass proteins from Mycobacterium tuberculosis identifies members of the ESAT-6 family as immunodominant T-cell antigens

Infect. Immun.

(2000)

P. Andersen

Recall of long-lived immunity to Mycobacterium tuberculosis infection in mice

J. Immunol.

(1995)

Smith, D. (1995) Protective Efficacy of BCG in Experimental Tuberculosis, S....

C.E. Palmer et al.

Effects of infection with atypical mycobacteria on BCG vaccination and tuberculosis

Am. Rev. Respir. Dis.

(1966)

P. Andersen

Host responses and antigens involved in protective immunity to Mycobacterium tuberculosis

Scand. J. Immunol.

(1996)

S.H.E. Kaufmann et al.

Immunity to mycobacteria with emphasis on tuberculosis: implications for rational design of an effective tuberculosis vaccine

Chem. Immunol.

(1998)

P. Ravn

Human T cell responses induced by vaccination with Mycobacterium bovis bacillus Calmette-Guérin

J. Immunol.

(1997)

E. Jouanguy

Interferon-gamma receptor deficiency in an infant with fatal Bacille Calmette–Guérin infection

New Engl. J. Med.

(1996)

R. de Jong

Severe mycobacterial and Salmonella infections in interleukin-12 receptor-deficient patients

Science

(1998)

I.M. Orme

Cytokine secretion by CD4 T lymphocytes acquired in response to Mycobacterium tuberculosis infection

J. Immunol.

(1993)

E.B. Lindblad

Adjuvant modulation of immune responses to tuberculosis subunit vaccines

Infect. Immun.

(1997)

R. Hernandez-Pando

Pathogenesis of tuberculosis in mice exposed to low and high doses of an environmental mycobacterial saprophyte before infection

Infect. Immun.

(1997)

G.T. Seah

Type 2 cytokine gene activation and its relationship to extent of disease in patients with tuberculosis

J. Infect. Dis.

(2000)

C.G. Feng

Increase in gamma interferon-secreting CD8(+), as well as CD4(+), T cells in lungs following aerosol infection with Mycobacterium tuberculosis

Infect. Immun.

(1999)

N.V. Serbina et al.

Early emergence of CD8(+) T cells primed for production of type 1 cytokines in the lungs of Mycobacterium tuberculosis-infected mice

Infect. Immun.

(1999)

J.L. Flynn

Major histocompatibility complex class I-restricted T cells are required for resistance to Mycobacterium tuberculosis infection

Proc. Natl. Acad. Sci. USA.

(1992)

S.M. Behar

Susceptibility of mice deficient in CD1D or TAP1 to infection with Mycobacterium tuberculosis

J. Exp. Med.

(1999)

C.H. Ladel

Immune response to Mycobacterium bovis bacille Calmette–Guérin infection in major histocompatibility complex class I- and II-deficient knock-out mice: contribution of CD4 and CD8 T cells to acquired resistance

Eur. J. Immunol.

(1995)

C.G. Feng et al.

CD4⁺ and CD8⁺ T cells mediate adoptive immunity to aerosol infection of Mycobacterium bovis bacillus Calmette–Guérin

J. Infect. Dis.

(2000)

L. van Pinxteren

Control of latent Mycobacterium tuberculosis infection is dependent on CD8 T cells

Eur. J. Immunol.

(2000)

C.A. Scanga

Depletion of CD4(+) T cells causes reactivation of murine persistent tuberculosis despite continued expression of interferon gamma and nitric oxide synthase 2

J. Exp. Med.

(2000)

R.A. Seder et al.

Vaccines against intracellular infections requiring cellular immunity

Nature

(2000)

J.A. Sterne

Does the efficacy of BCG decline with time since vaccination?

Int. J. Tuberc. Lung Dis.

(1998)

I.M. Orme

Characteristics and specificity of acquired immunologic memory to Mycobacterium tuberculosis infection

J. Immunol.

(1988)

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According to the World Health Organization (WHO), tuberculosis (TB) is the leading cause of death triggered by a single infectious agent, worldwide. Bacillus Calmette-Guerin (BCG) is the only currently licensed anti-TB vaccine. However, other strategies, including modification of recombinant BCG vaccine, attenuated Mycobacterium tuberculosis (Mtb) mutant constructs, DNA and protein subunit vaccines, are under extensive investigation. As whole pathogen vaccines can trigger serious adverse reactions, most current strategies are focused on the development of safe anti-TB subunit vaccines; this is especially important given the rising TB infection rate in immunocompromised HIV patients. The whole Mtb genome has been mapped and major antigens have been identified; however, optimal vaccine delivery mode is still to be established. Isolated protein antigens are typically poorly immunogenic so adjuvants are required to induce strong and long-lasting immune responses. This article aims to review the developmental status of anti-TB subunit vaccine adjuvants.
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Among the various strategies to improve vaccines against infectious diseases, targeting of antigens to dendritic cells (DCs), which are professional antigen presenting cells (APCs), has received increased attention in recent years. Here, we investigated whether a synthetic peptide region named RVG, originated from Rabies Virus Glycoprotein that binds to the α-7 subunit of the nicotinic acetylcholine receptors (AchR-α7) of APCs, could be used for the delivery of Mycobacterium tuberculosis (Mtb) peptide antigens to DCs and macrophages. Mouse bone marrow derived DCs (BMDCs) and human THP-1 macrophages stimulated with RVG fused peptide epitopes 85B₂₄₁ and 85B₉₆ (represent Ag85B_241-256 and Ag85B_96-111, respectively) from antigen 85B (Ag85B) of Mtb showed enhanced antigen presentation as compared to unfused peptide epitopes and BCG. Further, BMDCs stimulated with RVG fused 85B₂₄₁ showed higher levels of IL-12 positive cells. Consistent with in vitro data, splenocytes of mice immunized with RVG-85B₂₄₁ showed increased number of antigen specific IFN-γ, IL-2, and TNF-α producing cells in relation to splenocytes from mice immunized with 85B₂₄₁ alone. These results suggest that RVG may be a promising tool to develop effective alternate vaccines against tuberculosis (TB).
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Trends in Immunology

ReviewTB vaccines: progress and problems

Abstract

Section snippets

The BCG vaccine

Characteristics of acquired cellular immunity to TB

Antigen discovery in the post-genomic era

Antigen selection and vaccine design for pre- and post-infection vaccines

Strategies for TB vaccine development

From challenge experiments in animals to clinical trials in humans

Conclusion and perspectives

Acknowledgements

Tubercle

Immunol. Today

Res. Immunol.

Immunol. Today

Vaccine

FEMS Immunol. Med. Microbiol.

Vaccine

Lancet

Is the development of a new tuberculosis vaccine possible?

Nat. Med.

The BCG story: lessons from the past and implications for the future

Rev. Infect. Dis. (Suppl)

Deciphering the biology of Mycobacterium tuberculosis from the complete genome sequence

Nature

Comparative genomics of BCG vaccines by whole-genome DNA microarray

Science

Identification of variable regions in the genomes of tubercle bacilli using bacterial artificial chromosome arrays

Mol. Microbiol.

Comparative evaluation of low-molecular-mass proteins from Mycobacterium tuberculosis identifies members of the ESAT-6 family as immunodominant T-cell antigens

Infect. Immun.

Recall of long-lived immunity to Mycobacterium tuberculosis infection in mice

J. Immunol.

Effects of infection with atypical mycobacteria on BCG vaccination and tuberculosis

Am. Rev. Respir. Dis.

Host responses and antigens involved in protective immunity to Mycobacterium tuberculosis

Scand. J. Immunol.

Immunity to mycobacteria with emphasis on tuberculosis: implications for rational design of an effective tuberculosis vaccine

Chem. Immunol.

Human T cell responses induced by vaccination with Mycobacterium bovis bacillus Calmette-Guérin

J. Immunol.

Interferon-gamma receptor deficiency in an infant with fatal Bacille Calmette–Guérin infection

New Engl. J. Med.

Severe mycobacterial and Salmonella infections in interleukin-12 receptor-deficient patients

Science

Cytokine secretion by CD4 T lymphocytes acquired in response to Mycobacterium tuberculosis infection

J. Immunol.

Adjuvant modulation of immune responses to tuberculosis subunit vaccines

Infect. Immun.

Pathogenesis of tuberculosis in mice exposed to low and high doses of an environmental mycobacterial saprophyte before infection

Infect. Immun.

Type 2 cytokine gene activation and its relationship to extent of disease in patients with tuberculosis

J. Infect. Dis.

Increase in gamma interferon-secreting CD8(+), as well as CD4(+), T cells in lungs following aerosol infection with Mycobacterium tuberculosis

Infect. Immun.

Early emergence of CD8(+) T cells primed for production of type 1 cytokines in the lungs of Mycobacterium tuberculosis-infected mice

Infect. Immun.

Major histocompatibility complex class I-restricted T cells are required for resistance to Mycobacterium tuberculosis infection

Proc. Natl. Acad. Sci. USA.

Susceptibility of mice deficient in CD1D or TAP1 to infection with Mycobacterium tuberculosis

J. Exp. Med.

Immune response to Mycobacterium bovis bacille Calmette–Guérin infection in major histocompatibility complex class I- and II-deficient knock-out mice: contribution of CD4 and CD8 T cells to acquired resistance

Eur. J. Immunol.

CD4+ and CD8+ T cells mediate adoptive immunity to aerosol infection of Mycobacterium bovis bacillus Calmette–Guérin

J. Infect. Dis.

Control of latent Mycobacterium tuberculosis infection is dependent on CD8 T cells

Eur. J. Immunol.

Depletion of CD4(+) T cells causes reactivation of murine persistent tuberculosis despite continued expression of interferon gamma and nitric oxide synthase 2

J. Exp. Med.

Vaccines against intracellular infections requiring cellular immunity

Nature

Does the efficacy of BCG decline with time since vaccination?

Int. J. Tuberc. Lung Dis.

Characteristics and specificity of acquired immunologic memory to Mycobacterium tuberculosis infection

J. Immunol.

Review
TB vaccines: progress and problems

CD4⁺ and CD8⁺ T cells mediate adoptive immunity to aerosol infection of Mycobacterium bovis bacillus Calmette–Guérin