Rational Vaccine Development — A New Trend in Tuberculosis Control
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《新英格兰医药杂志》
Viable Mycobacterium bovis bacille Calmette–Guérin (BCG) is one of the most widely used vaccines to control tuberculosis. Administered as a single shot to newborns, it prevents severe disease and reduces mortality among children, but it does not protect against pulmonary tuberculosis in children or adults. With 9 million new, mostly pulmonary cases and nearly 2 million deaths from tuberculosis each year, there is a great need for improved vaccines against this devastating disease. A new study of vaccine efficacy by Grode and colleagues1 therefore comes as welcome news.
The immune response to mycobacteria relies predominantly on T-cell immunity, rather than antibody production. Optimal immune activation against M. tuberculosis infection appears to involve both CD4+ and CD8+ T cells2: thus, antigens must be presented by major-histocompatibility-complex (MHC) class II molecules to activate CD4+ T cells as well as by MHC class I molecules to activate CD8+ T cells. When BCG is used for vaccination, the bacilli are taken up by macrophages, where they reside within the phagosome, a membrane-enclosed vacuole (Figure 1A). To avoid being killed and digested by the acid-dependent enzymes of the phagosome, the organism blocks acidification of this compartment. Microbacterial urease helps maintain a higher pH, thereby reducing the flow of antigens to the surface of the macrophage, where they are presented to T cells. Antigens that are processed in the phagosome normally gain access to MHC class II molecules, and thus, BCG primes CD4+ T cells. But for antigen to bind MHC class I molecules (and thus activate CD8+ cells), they must be processed in the cytoplasm of the infected cell, and so BCG fails to elicit an optimal CD8+ T-cell response.
Figure 1. Toward a Better BCG Vaccine.
In Panel A, after vaccination, conventional BCG is taken up by the macrophage into a membrane-bound phagosome. Here, BCG produces urease, which counters the normal acidification of the phagosome, establishing a neutral pH. Inside the neutral phagosome, BCG thrives. Antigens are processed through the MHC class II pathway for presentation to CD4+ T cells. Grode et al.1 recently tested a new recombinant BCG vaccine, in which the urease gene is deleted and a copy of the gene encoding lysin, taken from Listeria monocytogenes, is inserted (Panel B). The modified BCG vaccine is taken up into the phagosome where, in the absence of urease, normal acidification occurs. The recombinant BCG produces lysin, which punches holes in the surrounding membrane, allowing BCG to escape into the cytoplasm, which leads to apoptosis and killing of the bacillus. Antigens from the BCG that escape into the cytoplasm are processed through the MHC class I pathway and presented to CD8+ T cells. Antigens from the BCG in the remaining intact phagosomes are processed through the MHC class II pathway and presented to CD4+ T cells. As a result, immunization with the improved BCG vaccine leads to a broader and more effective immune response and better protection against mycobacterial infection.
By knocking out the BCG urease gene, Grode et al.1 engineered a recombinant bacillus with an impaired ability to counter the acidification of phagosomes (Figure 1B). In addition, the authors inserted a lysin gene from Listeria monocytogenes that punctures the membrane of the phagosome under acidic conditions, eventually leading to disintegration of the membrane and release of the bacilli into the cytoplasm. BCG antigens thereby gain access to both MHC class I and class II molecules, activating both CD8+ and CD4+ T cells. Escape of the bacilli into the cytoplasm also triggers apoptosis, which in turn kills the bacilli and releases antigen. Released antigens can then be taken up by adjacent antigen-presenting cells (dendritic cells), which process the antigen and stimulate the activation of additional T cells through a mechanism termed "cross-priming."
The authors tested the vaccine's safety and efficacy in a mouse vaccination-and-challenge model.1 After vaccination, animals were challenged by infection with one of the most virulent clinical isolates of M. tuberculosis described to date.3 This pathogen, known as the W-Beijing strain, has spread throughout Southeast Asia, eastern Europe, and southern Africa. The new recombinant BCG vaccine provided better protection against infection by H37Rv, a laboratory strain of M. tuberculosis commonly used in such challenges, and a clinically derived W-Beijing strain. In contrast to many previous studies of tuberculosis vaccine that used a mouse model of infection, in this study protection was monitored for more than 200 days to ensure that the immune response was robust and long-lasting.
This candidate tuberculosis vaccine is likely to be more effective than the existing vaccine in humans, because it appears to induce a stronger protective response, targets both CD8+ and CD4+ T cells, is safer than the current BCG vaccine in infected animals, and provides protective immunity against some of the most virulent clinical strains circulating in human populations. The vaccine has been licensed to the Vaccine Project Management Foundation (Hannover, Germany), which fosters the translation of basic research findings into the clinic, and will soon enter phase 1 clinical trials.
Source Information
From the Public Health Research Institute, International Center for Public Health, Newark, N.J.
References
Grode L, Seiler P, Baumann S, et al. Increased vaccine efficacy against tuberculosis of recombinant Mycobacterium bovis bacille Calmette-Guerin mutants that secrete listeriolysin. J Clin Invest 2005;115:2472-2479.
Lazarevic V, Flynn J. CD8+ T cells in tuberculosis. Am J Respir Crit Care Med 2002;166:1116-1121.
Manca C, Tsenova L, Bergtold A, et al. Virulence of a Mycobacterium tuberculosis clinical isolate in mice is determined by failure to induce Th1 type immunity and is associated with induction of IFN-alpha/beta. Proc Natl Acad Sci U S A 2001;98:5752-5757.(Gilla Kaplan, Ph.D.)
The immune response to mycobacteria relies predominantly on T-cell immunity, rather than antibody production. Optimal immune activation against M. tuberculosis infection appears to involve both CD4+ and CD8+ T cells2: thus, antigens must be presented by major-histocompatibility-complex (MHC) class II molecules to activate CD4+ T cells as well as by MHC class I molecules to activate CD8+ T cells. When BCG is used for vaccination, the bacilli are taken up by macrophages, where they reside within the phagosome, a membrane-enclosed vacuole (Figure 1A). To avoid being killed and digested by the acid-dependent enzymes of the phagosome, the organism blocks acidification of this compartment. Microbacterial urease helps maintain a higher pH, thereby reducing the flow of antigens to the surface of the macrophage, where they are presented to T cells. Antigens that are processed in the phagosome normally gain access to MHC class II molecules, and thus, BCG primes CD4+ T cells. But for antigen to bind MHC class I molecules (and thus activate CD8+ cells), they must be processed in the cytoplasm of the infected cell, and so BCG fails to elicit an optimal CD8+ T-cell response.
Figure 1. Toward a Better BCG Vaccine.
In Panel A, after vaccination, conventional BCG is taken up by the macrophage into a membrane-bound phagosome. Here, BCG produces urease, which counters the normal acidification of the phagosome, establishing a neutral pH. Inside the neutral phagosome, BCG thrives. Antigens are processed through the MHC class II pathway for presentation to CD4+ T cells. Grode et al.1 recently tested a new recombinant BCG vaccine, in which the urease gene is deleted and a copy of the gene encoding lysin, taken from Listeria monocytogenes, is inserted (Panel B). The modified BCG vaccine is taken up into the phagosome where, in the absence of urease, normal acidification occurs. The recombinant BCG produces lysin, which punches holes in the surrounding membrane, allowing BCG to escape into the cytoplasm, which leads to apoptosis and killing of the bacillus. Antigens from the BCG that escape into the cytoplasm are processed through the MHC class I pathway and presented to CD8+ T cells. Antigens from the BCG in the remaining intact phagosomes are processed through the MHC class II pathway and presented to CD4+ T cells. As a result, immunization with the improved BCG vaccine leads to a broader and more effective immune response and better protection against mycobacterial infection.
By knocking out the BCG urease gene, Grode et al.1 engineered a recombinant bacillus with an impaired ability to counter the acidification of phagosomes (Figure 1B). In addition, the authors inserted a lysin gene from Listeria monocytogenes that punctures the membrane of the phagosome under acidic conditions, eventually leading to disintegration of the membrane and release of the bacilli into the cytoplasm. BCG antigens thereby gain access to both MHC class I and class II molecules, activating both CD8+ and CD4+ T cells. Escape of the bacilli into the cytoplasm also triggers apoptosis, which in turn kills the bacilli and releases antigen. Released antigens can then be taken up by adjacent antigen-presenting cells (dendritic cells), which process the antigen and stimulate the activation of additional T cells through a mechanism termed "cross-priming."
The authors tested the vaccine's safety and efficacy in a mouse vaccination-and-challenge model.1 After vaccination, animals were challenged by infection with one of the most virulent clinical isolates of M. tuberculosis described to date.3 This pathogen, known as the W-Beijing strain, has spread throughout Southeast Asia, eastern Europe, and southern Africa. The new recombinant BCG vaccine provided better protection against infection by H37Rv, a laboratory strain of M. tuberculosis commonly used in such challenges, and a clinically derived W-Beijing strain. In contrast to many previous studies of tuberculosis vaccine that used a mouse model of infection, in this study protection was monitored for more than 200 days to ensure that the immune response was robust and long-lasting.
This candidate tuberculosis vaccine is likely to be more effective than the existing vaccine in humans, because it appears to induce a stronger protective response, targets both CD8+ and CD4+ T cells, is safer than the current BCG vaccine in infected animals, and provides protective immunity against some of the most virulent clinical strains circulating in human populations. The vaccine has been licensed to the Vaccine Project Management Foundation (Hannover, Germany), which fosters the translation of basic research findings into the clinic, and will soon enter phase 1 clinical trials.
Source Information
From the Public Health Research Institute, International Center for Public Health, Newark, N.J.
References
Grode L, Seiler P, Baumann S, et al. Increased vaccine efficacy against tuberculosis of recombinant Mycobacterium bovis bacille Calmette-Guerin mutants that secrete listeriolysin. J Clin Invest 2005;115:2472-2479.
Lazarevic V, Flynn J. CD8+ T cells in tuberculosis. Am J Respir Crit Care Med 2002;166:1116-1121.
Manca C, Tsenova L, Bergtold A, et al. Virulence of a Mycobacterium tuberculosis clinical isolate in mice is determined by failure to induce Th1 type immunity and is associated with induction of IFN-alpha/beta. Proc Natl Acad Sci U S A 2001;98:5752-5757.(Gilla Kaplan, Ph.D.)