Genetics as a Route toward Mucosal Vaccine Development

Gordon Dougan

doi:10.1128/9781555818340.ch33

Chapter 33 : Genetics as a Route toward Mucosal Vaccine Development

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Affiliations: 1: Gordon Dougan • Department of Biochemistry, Imperial College of Science, Technology and Medicine, London SW7 2AZ, United Kingdom

Content Type: Monograph

Publication Year: 1994

Category: Microbial Genetics and Molecular Biology; Bacterial Pathogenesis

Book DOI: 10.1128/9781555818340

Chapter DOI: 10.1128/9781555818340.ch33

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Abstract:

A goal in vaccinology is to obtain fully antigenically defined vaccines that can be delivered via mucosal routes, thus avoiding the requirement for injections with needles. Mucosal presentation of some antigens induces a tolerance effect on the immune system when the same antigen is subsequently administered systemically. This phenomenon may be controlled by mechanisms which have evolved to limit potentially damaging immune responses to dietary antigens. Thus, the immune system may be able to partially discriminate between dietary antigens and antigenic components of pathogens. The immune system is also organized into compartments associated with different tissues of the body. The majority of antigens are poor mucosal immunogens. In practical terms, potentially the quickest route toward the development of mucosal vaccines is the use of attenuated variants of mucosal pathogens. Genetic analysis of the genes required for Salmonella virulence has uncovered an array of different genes covering a wide range of functions. The construction of candidate human vaccine strains requires the use of precise gene replacement systems in order to ensure that any introduced mutation is fully characterized. A number of different bacteria have been considered for use as antigen delivery systems, including members of the genera Salmonella and Yersinia. Genetic instability has been a major problem encountered with the use of live Salmonella vaccines for the expression of heterologous antigens. Cholera enterotoxin (CT) and CT-B are potent mucosal antigens. Studies are under way to determine the characteristics of the protein that contributes to this property.

Citation: Dougan G. 1994. Genetics as a Route toward Mucosal Vaccine Development, p 491-506. In Miller V, Kaper J, Portnoy D, Isberg R (ed), Molecular Genetics of Bacterial Pathogenesis. ASM Press, Washington, DC. doi: 10.1128/9781555818340.ch33

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Genetics as a Route toward Mucosal Vaccine Development

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Figure 1

Persistence and immunogenicity of S. typhimurium SH and SL1344 derivatives following intravenous (IV) inoculation into BALB/c mice. The horizontal arrow on the left axis indicates the dose of vaccine administered. Levels of bacteria in the livers (●) and spleens (▲) were measured as described previously ( 44 ). L1 to L4 and S1 to S4 refer to the number of organs (liver [L] or spleen [S]) cleared of bacteria at a particular sampling point. Protection was monitored at 4 or 8 weeks as indicated. Each plus sign represents a log unit of protection against virulent challenge with parenterally administered virulent S. typhimurium. (A) Results for S. typhimurium SH aroA, SH purA, and SH aroA purA, as indicated. (B) Results for S. typhimurium SH purE.

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Figure 1

References

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Tables

Genetics as a Route toward Mucosal Vaccine Development

/content/10.1128/9781555818340.chap33.tab33-1

Table 1

Effects of level of attenuation on immunogenicity of S. typhimurium SLI344 (wild type) defined mutants in BALB/c mice a

a The mutations were all in the S. typhimurium SL1344 background. Wild type refers to the parent strain. All mutations were introduced by using precise genetic methods. Antibody production was monitored by an enzyme-linked immunosorbent assay against whole, inactivated SL1344 bacteria. Data are based on work published previously ( 44 , 45 ).

b The cellular response was measured by using a number of parameters but, in particular, refers to the ability of immunized animals to control an intravenous challenge with L. monocytogenes 2 weeks after vaccination with a single intravenous dose of the attenuated SL1344 derivative.

c —, abscesses and scattered deaths.

d Animals were protected against salmonellosis by using a single oral dose of 109 bacteria.

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10.1128/9781555818340/tab33-1.gif

Table 1

Effects of level of attenuation on immunogenicity of S. typhimurium SLI344 (wild type) defined mutants in BALB/c mice a

c —, abscesses and scattered deaths.

d Animals were protected against salmonellosis by using a single oral dose of 109 bacteria.

/content/10.1128/9781555818340.chap33.tab33-2

Table 2

Influence of route of vaccination and formaldehyde treatment on secretory immune response to pertussis toxoid Ptx-crm in BALB/c mice a

a Levels of antibody were measured by an enzyme-linked immunosorbent assay against Ptx-crm. Ptx-crm + formaldehyde is material treated with formaldehyde to remove the cell-binding activity but retain the holotoxin formation ability. Letters indicate titers in individual mice, i.n., intranasal; s.c, subcutaneous.

b Specific anti-Ptx IgA titers in nasal lavage fluid following intranasal or subcutaneous immunization of mice. Each anti-Ptx IgA value has been corrected for total IgA in each individual lavage.

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Table 2

Influence of route of vaccination and formaldehyde treatment on secretory immune response to pertussis toxoid Ptx-crm in BALB/c mice a

b Specific anti-Ptx IgA titers in nasal lavage fluid following intranasal or subcutaneous immunization of mice. Each anti-Ptx IgA value has been corrected for total IgA in each individual lavage.