Mutants of the Escherichia coli heat-labile enterotoxin as safe and strong adjuvants for intranasal delivery of vaccines
Cholera toxin and Escherichia coli heat-labile enterotoxin are powerful mucosal adjuvants but their high toxicity hampers their use in humans. Site-directed mutagenesis has allowed the generation of several cholera toxin and E. coli heat-labile enterotoxin mutants with abolished or strongly reduced...
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| Veröffentlicht in: | Expert review of vaccines 2003-04, Vol.2 (2), p.285-293 |
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| description | Cholera toxin and Escherichia coli heat-labile enterotoxin are powerful mucosal adjuvants but their high toxicity hampers their use in humans. Site-directed mutagenesis has allowed the generation of several cholera toxin and E. coli heat-labile enterotoxin mutants with abolished or strongly reduced toxicity that still retain strong mucosal adjuvanticity. Among them, LTK63 (Ser to Lys substitution at position 63 in the A subunit) is completely nontoxic and LTR72 (Ala to Arg at position 72) retains a very low residual enzymatic activity. Both of them have been shown to be safe and effective in enhancing the immunogenicity of intranasally coadministered vaccines, also resulting in protective responses in several animal models. Clinical grade preparations of these mutants have now been produced, tested in animals and proven to be totally safe. Indeed, they did not induce any inflammatory event in the respiratory tract nor, more importantly, in the olfactory bulbs and in the meninges. The fully nontoxic LTK63 mutant has now been successfully tested in human volunteers with a trivalent subunit influenza vaccine. |
| doi_str_mv | 10.1586/14760584.2.2.285 |
| format | Article |
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Site-directed mutagenesis has allowed the generation of several cholera toxin and E. coli heat-labile enterotoxin mutants with abolished or strongly reduced toxicity that still retain strong mucosal adjuvanticity. Among them, LTK63 (Ser to Lys substitution at position 63 in the A subunit) is completely nontoxic and LTR72 (Ala to Arg at position 72) retains a very low residual enzymatic activity. Both of them have been shown to be safe and effective in enhancing the immunogenicity of intranasally coadministered vaccines, also resulting in protective responses in several animal models. Clinical grade preparations of these mutants have now been produced, tested in animals and proven to be totally safe. Indeed, they did not induce any inflammatory event in the respiratory tract nor, more importantly, in the olfactory bulbs and in the meninges. The fully nontoxic LTK63 mutant has now been successfully tested in human volunteers with a trivalent subunit influenza vaccine.</description><identifier>ISSN: 1476-0584</identifier><identifier>EISSN: 1744-8395</identifier><identifier>DOI: 10.1586/14760584.2.2.285</identifier><identifier>PMID: 12899578</identifier><language>eng</language><publisher>England: Informa Healthcare</publisher><subject>adjuvants ; Adjuvants, Immunologic - administration & dosage ; Administration, Intranasal ; Analysis ; Animals ; Bacterial Toxins - administration & dosage ; Bacterial Toxins - genetics ; Cholera ; Cholera toxin ; Contamination ; Drug therapy, Combination ; Enterotoxins - administration & dosage ; Enterotoxins - genetics ; Enzymes ; Escherichia coli ; Escherichia coli - genetics ; Escherichia coli - immunology ; Escherichia coli Proteins ; Humans ; Immunity, Mucosal ; Influenza ; Influenza Vaccines - administration & dosage ; mucosal ; Mutation ; Safety ; Vaccines ; Vaccines - administration & dosage</subject><ispartof>Expert review of vaccines, 2003-04, Vol.2 (2), p.285-293</ispartof><rights>2003 Future Drugs Ltd. All rights reserved. 2003</rights><rights>COPYRIGHT 2003 Expert Reviews Ltd.</rights><rights>Copyright Expert Reviews Ltd. 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Site-directed mutagenesis has allowed the generation of several cholera toxin and E. coli heat-labile enterotoxin mutants with abolished or strongly reduced toxicity that still retain strong mucosal adjuvanticity. Among them, LTK63 (Ser to Lys substitution at position 63 in the A subunit) is completely nontoxic and LTR72 (Ala to Arg at position 72) retains a very low residual enzymatic activity. Both of them have been shown to be safe and effective in enhancing the immunogenicity of intranasally coadministered vaccines, also resulting in protective responses in several animal models. Clinical grade preparations of these mutants have now been produced, tested in animals and proven to be totally safe. Indeed, they did not induce any inflammatory event in the respiratory tract nor, more importantly, in the olfactory bulbs and in the meninges. The fully nontoxic LTK63 mutant has now been successfully tested in human volunteers with a trivalent subunit influenza vaccine.</description><subject>adjuvants</subject><subject>Adjuvants, Immunologic - administration & dosage</subject><subject>Administration, Intranasal</subject><subject>Analysis</subject><subject>Animals</subject><subject>Bacterial Toxins - administration & dosage</subject><subject>Bacterial Toxins - genetics</subject><subject>Cholera</subject><subject>Cholera toxin</subject><subject>Contamination</subject><subject>Drug therapy, Combination</subject><subject>Enterotoxins - administration & dosage</subject><subject>Enterotoxins - genetics</subject><subject>Enzymes</subject><subject>Escherichia coli</subject><subject>Escherichia coli - genetics</subject><subject>Escherichia coli - immunology</subject><subject>Escherichia coli Proteins</subject><subject>Humans</subject><subject>Immunity, Mucosal</subject><subject>Influenza</subject><subject>Influenza Vaccines - administration & dosage</subject><subject>mucosal</subject><subject>Mutation</subject><subject>Safety</subject><subject>Vaccines</subject><subject>Vaccines - administration & dosage</subject><issn>1476-0584</issn><issn>1744-8395</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2003</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>BENPR</sourceid><recordid>eNp9UU1v1DAQjRCIfsCdE7I4ccliJ3bswKmqWkAq4gJna9YfjVdeu9jOtvvvcdhFFUigOcxI896bj9c0rwheESaGd4TyATNBV90Sgj1pTgmntBX9yJ7WurbbpX_SnOW8wbinI-PPmxPSibFW4rR5-DIXCCWjaFGZDLrKajLJqckBUtE7NBkorYe18waZUEyKJT64gCCjDNYgCBrlkmK4RaA38-6XmI0JuVASBMjgkTbe7UzaL0N2oJQLJr9onlnw2bw85vPm-_XVt8tP7c3Xj58vL25aRbkorRaG9lTrTo9AhaXCEAKD5gysBmU7janAhHCuMB6sAA79mnENMGrMiFb9efP2oHuX4o_Z5CK3LivjPQQT5yzrKxgWghJeoW_-gm7inELdTo6ko5R3ZKig1QF0C95IF2ysZ6oa2mydisHY-il50Q2MCs7YoooPBJVizslYeZfcFtJeEiwXF-VvF2W3hGCV8vq4yLzeGv1IONpWAR8OgGV-2sJ9TF7LAnsfk61fVy7L_j_y7_9gV4t9mRQk83jwP8k_AQnSvyo</recordid><startdate>20030401</startdate><enddate>20030401</enddate><creator>Peppoloni, Samuele</creator><creator>Ruggiero, Paolo</creator><creator>Contorni, Mario</creator><creator>Morandi, Maurizio</creator><creator>Pizza, Mariagrazia</creator><creator>Rappuoli, Rino</creator><creator>Podda, Audino</creator><creator>Giudice, Giuseppe Del</creator><general>Informa Healthcare</general><general>Taylor & Francis</general><general>Expert Reviews Ltd</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>3V.</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>8AO</scope><scope>8C1</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>AN0</scope><scope>BENPR</scope><scope>CCPQU</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>K9.</scope><scope>M0S</scope><scope>M1P</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>7QL</scope><scope>C1K</scope></search><sort><creationdate>20030401</creationdate><title>Mutants of the Escherichia coli heat-labile enterotoxin as safe and strong adjuvants for intranasal delivery of vaccines</title><author>Peppoloni, Samuele ; Ruggiero, Paolo ; Contorni, Mario ; Morandi, Maurizio ; Pizza, Mariagrazia ; Rappuoli, Rino ; Podda, Audino ; Giudice, Giuseppe Del</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c478t-d8e434dd2d9a48f48e11a6d75afdacf2d04801177c006f8a7a3b57daa9d051dc3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2003</creationdate><topic>adjuvants</topic><topic>Adjuvants, Immunologic - administration & dosage</topic><topic>Administration, Intranasal</topic><topic>Analysis</topic><topic>Animals</topic><topic>Bacterial Toxins - administration & dosage</topic><topic>Bacterial Toxins - genetics</topic><topic>Cholera</topic><topic>Cholera toxin</topic><topic>Contamination</topic><topic>Drug therapy, Combination</topic><topic>Enterotoxins - administration & dosage</topic><topic>Enterotoxins - genetics</topic><topic>Enzymes</topic><topic>Escherichia coli</topic><topic>Escherichia coli - genetics</topic><topic>Escherichia coli - immunology</topic><topic>Escherichia coli Proteins</topic><topic>Humans</topic><topic>Immunity, Mucosal</topic><topic>Influenza</topic><topic>Influenza Vaccines - administration & dosage</topic><topic>mucosal</topic><topic>Mutation</topic><topic>Safety</topic><topic>Vaccines</topic><topic>Vaccines - administration & dosage</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Peppoloni, Samuele</creatorcontrib><creatorcontrib>Ruggiero, Paolo</creatorcontrib><creatorcontrib>Contorni, Mario</creatorcontrib><creatorcontrib>Morandi, Maurizio</creatorcontrib><creatorcontrib>Pizza, Mariagrazia</creatorcontrib><creatorcontrib>Rappuoli, Rino</creatorcontrib><creatorcontrib>Podda, Audino</creatorcontrib><creatorcontrib>Giudice, Giuseppe Del</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>ProQuest Central (Corporate)</collection><collection>Health & Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Medical Database (Alumni Edition)</collection><collection>ProQuest Pharma Collection</collection><collection>Public Health Database</collection><collection>Hospital Premium Collection</collection><collection>Hospital Premium Collection (Alumni Edition)</collection><collection>ProQuest Central (Alumni) (purchase pre-March 2016)</collection><collection>ProQuest Central (Alumni Edition)</collection><collection>ProQuest Central UK/Ireland</collection><collection>British Nursing Database</collection><collection>ProQuest Central</collection><collection>ProQuest One Community College</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>Medical Database</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>ProQuest Central China</collection><collection>Bacteriology Abstracts (Microbiology B)</collection><collection>Environmental Sciences and Pollution Management</collection><jtitle>Expert review of vaccines</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Peppoloni, Samuele</au><au>Ruggiero, Paolo</au><au>Contorni, Mario</au><au>Morandi, Maurizio</au><au>Pizza, Mariagrazia</au><au>Rappuoli, Rino</au><au>Podda, Audino</au><au>Giudice, Giuseppe Del</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Mutants of the Escherichia coli heat-labile enterotoxin as safe and strong adjuvants for intranasal delivery of vaccines</atitle><jtitle>Expert review of vaccines</jtitle><addtitle>Expert Rev Vaccines</addtitle><date>2003-04-01</date><risdate>2003</risdate><volume>2</volume><issue>2</issue><spage>285</spage><epage>293</epage><pages>285-293</pages><issn>1476-0584</issn><eissn>1744-8395</eissn><abstract>Cholera toxin and Escherichia coli heat-labile enterotoxin are powerful mucosal adjuvants but their high toxicity hampers their use in humans. Site-directed mutagenesis has allowed the generation of several cholera toxin and E. coli heat-labile enterotoxin mutants with abolished or strongly reduced toxicity that still retain strong mucosal adjuvanticity. Among them, LTK63 (Ser to Lys substitution at position 63 in the A subunit) is completely nontoxic and LTR72 (Ala to Arg at position 72) retains a very low residual enzymatic activity. Both of them have been shown to be safe and effective in enhancing the immunogenicity of intranasally coadministered vaccines, also resulting in protective responses in several animal models. Clinical grade preparations of these mutants have now been produced, tested in animals and proven to be totally safe. Indeed, they did not induce any inflammatory event in the respiratory tract nor, more importantly, in the olfactory bulbs and in the meninges. The fully nontoxic LTK63 mutant has now been successfully tested in human volunteers with a trivalent subunit influenza vaccine.</abstract><cop>England</cop><pub>Informa Healthcare</pub><pmid>12899578</pmid><doi>10.1586/14760584.2.2.285</doi><tpages>9</tpages></addata></record> |
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| ispartof | Expert review of vaccines, 2003-04, Vol.2 (2), p.285-293 |
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| subjects | adjuvants Adjuvants, Immunologic - administration & dosage Administration, Intranasal Analysis Animals Bacterial Toxins - administration & dosage Bacterial Toxins - genetics Cholera Cholera toxin Contamination Drug therapy, Combination Enterotoxins - administration & dosage Enterotoxins - genetics Enzymes Escherichia coli Escherichia coli - genetics Escherichia coli - immunology Escherichia coli Proteins Humans Immunity, Mucosal Influenza Influenza Vaccines - administration & dosage mucosal Mutation Safety Vaccines Vaccines - administration & dosage |
| title | Mutants of the Escherichia coli heat-labile enterotoxin as safe and strong adjuvants for intranasal delivery of vaccines |
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