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Chapter 22 : Toxins as Vaccines and Adjuvants

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Abstract:

Several bacteria produce potent toxins that are entirely, or in part, responsible for the severe diseases caused by the microorganisms. This chapter describes those toxins classically used to prevent disease and the approaches for their future use. Today, it is possible to inactivate toxins and microorganisms by using genetic tools. Therefore, in addition to traditional diphtheria and tetanus vaccines, the acellular pertussis vaccine is also described in the chapter . This represents the first vaccine produced by genetic inactivation of a bacterial toxin. Several methods have been described for the purification of diphtheria and tetanus toxins and are generally based on diafiltration of culture supernatant, precipitation by ammonium sulfate, and, if necessary, purification by gel filtration or ion-exchange chromatography. With these methods, diphtheria and tetanus toxins can be purified to 85 to 95% purity, representing approximately 2,300 and 1,800-2,000 Lf/mg of protein nitrogen for tetanus and diphtheria, respectively, by ammonium sulfate precipitation, whereas the conventional vaccines have a purity of approximately 60%. Pertussis toxin (PT) plays a central role in the pathogenesis of whooping cough and induces protective immunity against infection. As for the other toxins, to be included in vaccines, PT needs to be detoxified. The most powerful mucosal immunogens and adjuvants recognized to date are cholera toxin (CT) and heat-labile enterotoxin (LT). To study the structure-function of CT and LT and to find molecules that are nontoxic but still active as mucosal adjuvants and immunogens, more than 50 site-directed mutations have been generated within these toxins.

Citation: Pizza M, Masignani V, Rappuoli R. 2003. Toxins as Vaccines and Adjuvants, p 311-326. In Burns D, Barbieri J, Iglewski B, Rappuoli R (ed), Bacterial Protein Toxins. ASM Press, Washington, DC. doi: 10.1128/9781555817893.ch22

Key Concept Ranking

Bacterial Vaccines
1.5261823
Infection and Immunity
1.0766493
Immune Systems
1.074996
Bacterial Genetics
1.0358466
Infectious Diseases
0.8529719
Amino Acids
0.7454926
1.5261823
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Figures

Image of Figure 1
Figure 1

(a) Schematic representation of diphtheria toxin (DT) and of the CRM derivatives. (b) Schematic representation of tetanus toxin (TT).

Citation: Pizza M, Masignani V, Rappuoli R. 2003. Toxins as Vaccines and Adjuvants, p 311-326. In Burns D, Barbieri J, Iglewski B, Rappuoli R (ed), Bacterial Protein Toxins. ASM Press, Washington, DC. doi: 10.1128/9781555817893.ch22
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Image of Figure 2
Figure 2

Schematic representation of the genes encoding the five subunits of PT. The mutations introduced by site-directed mutagenesis into the S1 subunit are also reported.

Citation: Pizza M, Masignani V, Rappuoli R. 2003. Toxins as Vaccines and Adjuvants, p 311-326. In Burns D, Barbieri J, Iglewski B, Rappuoli R (ed), Bacterial Protein Toxins. ASM Press, Washington, DC. doi: 10.1128/9781555817893.ch22
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Image of Figure 3
Figure 3

Computer modeling of the S1 subunit of (A) wild-type PT and of (B) PT-9K/129G mutant represented as an -carbon trace. The NAD-binding site is highlighted in yellow; the catalytic residues in position 9 and 129 are shown in yellow for the wild-type PT and in red for the PT-9K/129G mutant, respectively. (See Color Plates following p. 256.)

Citation: Pizza M, Masignani V, Rappuoli R. 2003. Toxins as Vaccines and Adjuvants, p 311-326. In Burns D, Barbieri J, Iglewski B, Rappuoli R (ed), Bacterial Protein Toxins. ASM Press, Washington, DC. doi: 10.1128/9781555817893.ch22
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Image of Figure 4
Figure 4

Antibody response induced by the chemically and genetically detoxified PT.

Citation: Pizza M, Masignani V, Rappuoli R. 2003. Toxins as Vaccines and Adjuvants, p 311-326. In Burns D, Barbieri J, Iglewski B, Rappuoli R (ed), Bacterial Protein Toxins. ASM Press, Washington, DC. doi: 10.1128/9781555817893.ch22
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Image of Figure 5
Figure 5

Schematic representation of (a) LT and (b) CT and of their mutant derivatives.

Citation: Pizza M, Masignani V, Rappuoli R. 2003. Toxins as Vaccines and Adjuvants, p 311-326. In Burns D, Barbieri J, Iglewski B, Rappuoli R (ed), Bacterial Protein Toxins. ASM Press, Washington, DC. doi: 10.1128/9781555817893.ch22
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Image of Figure 6
Figure 6

Three-dimensional structure of the A subunit of wild-type LT (top left panel) and LTK 63 mutant (top right panel) represented as -carbon trace and as solvent-exposed surfaces. The residues in position 63 (serine in the wild-type LT and lysine in the LTK-63 mutant) are indicated by the arrow. Computer modeling of the NAD-binding site of wild-type LT (top left panel) and LT R72 (bottom right panel). The residues in position 72 (alanine in the wild-type LT and arginine in LT R72) are shown in green and red, respectively.

Citation: Pizza M, Masignani V, Rappuoli R. 2003. Toxins as Vaccines and Adjuvants, p 311-326. In Burns D, Barbieri J, Iglewski B, Rappuoli R (ed), Bacterial Protein Toxins. ASM Press, Washington, DC. doi: 10.1128/9781555817893.ch22
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References

/content/book/10.1128/9781555817893.chap22
1. Bennett, M. J.,, and D. Eisenberg. 1994. Refined structure of monomeric diphtheria toxin at 2.3 A resolution. Protein Sci. 3:14641475.
2. Dallas, W. S.,, and S. Falkow. 1980. Amino acid sequence homology between cholera toxin and Escherichia coli heat-labile toxin. Nature 288:499501.
3. Domenighini, M.,, M. Pizza,, M. G. Jobling,, R. K. Holmes,, and R. Rappuoli. 1995. Identification of errors among database sequence entries and comparison of correct amino acid sequences for the heat-labile enterotoxins of Escherichia coli and Vibrio cholerae. Mol. Microbiol. 15:11651167.
4. Hewlett, E. L.,, K. T. Sauer,, G. A. Myers,, J. L. Cowell,, and R. L. Guerrant. 1983. Induction of a novel morphological response in Chinese hamster ovary cells by pertussis toxin. Infect. Immun. 40:11981203.
5. Pappenheimer, A. M., Jr. 1977. Diphtheria toxin. Annu. Rev. Biochem. 46:6994.
6. Pizza, M.,, A. Covacci,, A. Bartoloni,, M. Perugini,, L. Nencioni,, M. T. De Magistris,, L. Villa,, D. Nucci,, R. Manetti,, M. Bugnoli,, F. Giovannoni,, R. Olivieri,, J. T. Barbieri,, H. Sato,, and R. Rappuoli. 1989. Mutants of pertussis toxin suitable for vaccine development. Science 246:497500.
7. Pizza, M.,, V. Masignani,, and R. Rappuoli,. 1999. Molecular, functional and evolutionary aspects of ADP-ribosylating toxins, p. 4572. In J. E. Alouf, and J. H. Freer (ed.), The Comprehensive Sourcebook of Bacterial Protein Toxins, 2nd ed. Academic Press, Ltd., London, United Kingdom.
8. Rappuoli, R.,, M. Pizza,, G. Douce,, and G. Dougan. 1999. Structure and mucosal adjuvanticity of cholera toxin and Escherichia coli heat-labile enterotoxins. Immunol. Today 20:493500.
9. Sekura, R. D. 1985 Pertussis toxin: a tool for studying the regulation of adenylate cyclase. Methods Enzymol. 109:558566.
10. Sixma, T. K.,, S. E. Pronk,, K. H. Kalk,, E. S. Wartna,, B. A. van Zanten,, B. Witholt,, and W. G. Hol. 1991. Crystal structure of a cholera toxin-related heat-labile enterotoxin from E. coli. Nature 351:371377.
11. Trollfors, B.,, J. Taranger,, T. Lagergard,, L. Lind,, V. Sundh,, G. Zachrisson,, C. U. Lowe,, W. Blackwelder,, and J. B. Robbins. 1995. A placebo-controlled trial of a pertussis-toxoid vaccine. N. Engl. J. Med. 333:10451050.
12. Weiss, A. A.,, and E. L. Hewlett. 1986. Virulence factors of Bordetella pertussis. Annu. Rev. Microbiol. 40:661686.

Tables

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Table 1

Conjugate vaccines currently available

Citation: Pizza M, Masignani V, Rappuoli R. 2003. Toxins as Vaccines and Adjuvants, p 311-326. In Burns D, Barbieri J, Iglewski B, Rappuoli R (ed), Bacterial Protein Toxins. ASM Press, Washington, DC. doi: 10.1128/9781555817893.ch22
Generic image for table
Table 2

Toxic and nontoxic properties of PT and PT-9K/129G mutant (7)

Citation: Pizza M, Masignani V, Rappuoli R. 2003. Toxins as Vaccines and Adjuvants, p 311-326. In Burns D, Barbieri J, Iglewski B, Rappuoli R (ed), Bacterial Protein Toxins. ASM Press, Washington, DC. doi: 10.1128/9781555817893.ch22
Generic image for table
Table 3

Adjuvant activity of LTK63 and LTR72 with a variety of antigens by different immunization routes and in different animal models

Citation: Pizza M, Masignani V, Rappuoli R. 2003. Toxins as Vaccines and Adjuvants, p 311-326. In Burns D, Barbieri J, Iglewski B, Rappuoli R (ed), Bacterial Protein Toxins. ASM Press, Washington, DC. doi: 10.1128/9781555817893.ch22

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