Vaccine Candidate Double Mutant Variants of Enterotoxigenic <i>Escherichia coli</i> Heat-Stable Toxin
Heat-stable enterotoxin (ST) producing enterotoxigenic <i>Escherichia coli</i> (ETEC) strains are among the top four enteropathogens associated with moderate-to-severe diarrhea in children under five years in low-to-middle income countries, thus making ST a target for an ETEC vaccine. Ho...
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| Format: | Article |
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MDPI AG
2022-02-01
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| Series: | Vaccines |
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| Online Access: | https://www.mdpi.com/2076-393X/10/2/241 |
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| author | Ephrem Debebe Zegeye Yuleima Diaz Pål Puntervoll |
| author_facet | Ephrem Debebe Zegeye Yuleima Diaz Pål Puntervoll |
| author_sort | Ephrem Debebe Zegeye |
| collection | DOAJ |
| description | Heat-stable enterotoxin (ST) producing enterotoxigenic <i>Escherichia coli</i> (ETEC) strains are among the top four enteropathogens associated with moderate-to-severe diarrhea in children under five years in low-to-middle income countries, thus making ST a target for an ETEC vaccine. However, ST must be mutated to abolish its enterotoxicity and to prevent a potential immunological cross-reaction due to its structural resemblance to the human peptides uroguanylin and guanylin. To reduce the risk of eliciting cross-reacting antibodies with our lead STh-A14T toxoid, L9 was chosen as an additional mutational target. A double mutant vaccine candidate immunogen, STh-L9A/A14T, was constructed by conjugation to the synthetic virus-like mi3 nanoparticle using the SpyTag/SpyCatcher technology. This immunogen elicited STh neutralizing antibodies in mice, but with less consistency than STh-A14T peptide control immunogens. Moreover, individual sera from mice immunized with both single and double mutant variants displayed varying levels of unwanted cross-reacting antibodies. The lowest levels of cross-reacting antibodies were observed with STh-L9K/A14T control immunogens, suggesting that it is indeed possible to reduce the risk of eliciting cross-reacting antibodies by mutation. However, mutant-specific antibodies were observed for most double mutant immunogens, demonstrating the delicate balancing act between disrupting cross-reacting epitopes, keeping protective ones, and avoiding the formation of neoepitopes. |
| first_indexed | 2024-03-09T20:55:00Z |
| format | Article |
| id | doaj.art-e763f9970df240b0ae2e3d10e46646a2 |
| institution | Directory Open Access Journal |
| issn | 2076-393X |
| language | English |
| last_indexed | 2024-03-09T20:55:00Z |
| publishDate | 2022-02-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Vaccines |
| spelling | doaj.art-e763f9970df240b0ae2e3d10e46646a22023-11-23T22:25:47ZengMDPI AGVaccines2076-393X2022-02-0110224110.3390/vaccines10020241Vaccine Candidate Double Mutant Variants of Enterotoxigenic <i>Escherichia coli</i> Heat-Stable ToxinEphrem Debebe Zegeye0Yuleima Diaz1Pål Puntervoll2NORCE Norwegian Research Centre, Postboks 22 Nygårdstangen, 5838 Bergen, NorwayNORCE Norwegian Research Centre, Postboks 22 Nygårdstangen, 5838 Bergen, NorwayNORCE Norwegian Research Centre, Postboks 22 Nygårdstangen, 5838 Bergen, NorwayHeat-stable enterotoxin (ST) producing enterotoxigenic <i>Escherichia coli</i> (ETEC) strains are among the top four enteropathogens associated with moderate-to-severe diarrhea in children under five years in low-to-middle income countries, thus making ST a target for an ETEC vaccine. However, ST must be mutated to abolish its enterotoxicity and to prevent a potential immunological cross-reaction due to its structural resemblance to the human peptides uroguanylin and guanylin. To reduce the risk of eliciting cross-reacting antibodies with our lead STh-A14T toxoid, L9 was chosen as an additional mutational target. A double mutant vaccine candidate immunogen, STh-L9A/A14T, was constructed by conjugation to the synthetic virus-like mi3 nanoparticle using the SpyTag/SpyCatcher technology. This immunogen elicited STh neutralizing antibodies in mice, but with less consistency than STh-A14T peptide control immunogens. Moreover, individual sera from mice immunized with both single and double mutant variants displayed varying levels of unwanted cross-reacting antibodies. The lowest levels of cross-reacting antibodies were observed with STh-L9K/A14T control immunogens, suggesting that it is indeed possible to reduce the risk of eliciting cross-reacting antibodies by mutation. However, mutant-specific antibodies were observed for most double mutant immunogens, demonstrating the delicate balancing act between disrupting cross-reacting epitopes, keeping protective ones, and avoiding the formation of neoepitopes.https://www.mdpi.com/2076-393X/10/2/241enterotoxigenic <i>Escherichia coli</i> (ETEC)heat-stable enterotoxin (ST)diarrheatoxoidvaccinecross-reaction |
| spellingShingle | Ephrem Debebe Zegeye Yuleima Diaz Pål Puntervoll Vaccine Candidate Double Mutant Variants of Enterotoxigenic <i>Escherichia coli</i> Heat-Stable Toxin Vaccines enterotoxigenic <i>Escherichia coli</i> (ETEC) heat-stable enterotoxin (ST) diarrhea toxoid vaccine cross-reaction |
| title | Vaccine Candidate Double Mutant Variants of Enterotoxigenic <i>Escherichia coli</i> Heat-Stable Toxin |
| title_full | Vaccine Candidate Double Mutant Variants of Enterotoxigenic <i>Escherichia coli</i> Heat-Stable Toxin |
| title_fullStr | Vaccine Candidate Double Mutant Variants of Enterotoxigenic <i>Escherichia coli</i> Heat-Stable Toxin |
| title_full_unstemmed | Vaccine Candidate Double Mutant Variants of Enterotoxigenic <i>Escherichia coli</i> Heat-Stable Toxin |
| title_short | Vaccine Candidate Double Mutant Variants of Enterotoxigenic <i>Escherichia coli</i> Heat-Stable Toxin |
| title_sort | vaccine candidate double mutant variants of enterotoxigenic i escherichia coli i heat stable toxin |
| topic | enterotoxigenic <i>Escherichia coli</i> (ETEC) heat-stable enterotoxin (ST) diarrhea toxoid vaccine cross-reaction |
| url | https://www.mdpi.com/2076-393X/10/2/241 |
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