A First in Human Clinical Trial Assessing the Safety and Immunogenicity of Two Intradermally Delivered Enterotoxigenic <i>Escherichia coli</i> CFA/I Fimbrial Tip Adhesin Antigens with and without Heat-Labile Enterotoxin with Mutation LT(R192G)
Introduction: Enterotoxigenic <i>E. coli</i> (ETEC) is a leading cause of diarrhea in travelers as well as for children living in low- to middle-income countries. ETEC adhere to intestinal epithelium via colonization factors (CFs). CFA/I, a common CF, is composed of a polymeric stalk and...
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MDPI AG
2023-11-01
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| Series: | Microorganisms |
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| Online Access: | https://www.mdpi.com/2076-2607/11/11/2689 |
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| author | Ramiro L. Gutiérrez Mark S. Riddle Chad K. Porter Milton Maciel Steven T. Poole Renee M. Laird Michelle Lane George W. Turiansky Abel Jarell Stephen J. Savarino |
| author_facet | Ramiro L. Gutiérrez Mark S. Riddle Chad K. Porter Milton Maciel Steven T. Poole Renee M. Laird Michelle Lane George W. Turiansky Abel Jarell Stephen J. Savarino |
| author_sort | Ramiro L. Gutiérrez |
| collection | DOAJ |
| description | Introduction: Enterotoxigenic <i>E. coli</i> (ETEC) is a leading cause of diarrhea in travelers as well as for children living in low- to middle-income countries. ETEC adhere to intestinal epithelium via colonization factors (CFs). CFA/I, a common CF, is composed of a polymeric stalk and a tip-localized minor adhesive subunit, CfaE. Vaccine delivery by the transcutaneous immunization of dscCfaE was safe but was poorly immunogenic in a phase 1 trial when administered to volunteers with LTR(192G) and mLT. To potentially enhance the immunogenicity of CfaE while still delivering via a cutaneous route, we evaluated the safety and immunogenicity of two CfaE constructs administered intradermally (ID) with or without mLT. Methods: CfaE was evaluated as a donor strand-complemented construct (dscCfaE) and as a chimeric construct (Chimera) in which dscCfaE replaces the A1 domain of the cholera toxin A subunit and assembles non-covalently with the pentamer of heat-labile toxin B (LTB). Subjects received three ID vaccinations three weeks apart with either dscCfaE (1, 5, and 25 µg) or Chimera (2.6 and 12.9 µg) with and without 0.1 µg of mLT. Subjects were monitored for local and systemic adverse events. Immunogenicity was evaluated by serum and antibody-secreting cell (ASC) responses. Results. The vaccine was well-tolerated with predominantly mild and moderate local vaccine site reactions characterized by erythema, induration and post-inflammatory hyperpigmentation. High rates of serologic and ASC responses were seen across study groups with the most robust responses observed in subjects receiving 25 µg of dscCfaE with 0.1 mcg of LT(R192G). Conclusion: Both ETEC adhesin vaccine prototypes were safe and immunogenic when co-administered with mLT by the ID route. The observed immune responses induced with the high dose of dscCfaE and mLT warrant further assessment in a controlled human infection model. |
| first_indexed | 2024-03-09T16:35:50Z |
| format | Article |
| id | doaj.art-fe6b9f7b367f45e58abf63f09712be27 |
| institution | Directory Open Access Journal |
| issn | 2076-2607 |
| language | English |
| last_indexed | 2024-03-09T16:35:50Z |
| publishDate | 2023-11-01 |
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| spelling | doaj.art-fe6b9f7b367f45e58abf63f09712be272023-11-24T14:56:55ZengMDPI AGMicroorganisms2076-26072023-11-011111268910.3390/microorganisms11112689A First in Human Clinical Trial Assessing the Safety and Immunogenicity of Two Intradermally Delivered Enterotoxigenic <i>Escherichia coli</i> CFA/I Fimbrial Tip Adhesin Antigens with and without Heat-Labile Enterotoxin with Mutation LT(R192G)Ramiro L. Gutiérrez0Mark S. Riddle1Chad K. Porter2Milton Maciel3Steven T. Poole4Renee M. Laird5Michelle Lane6George W. Turiansky7Abel Jarell8Stephen J. Savarino9Naval Medical Research Command, Silver Spring, MD 20910, USANaval Medical Research Command, Silver Spring, MD 20910, USANaval Medical Research Command, Silver Spring, MD 20910, USANaval Medical Research Command, Silver Spring, MD 20910, USANaval Medical Research Command, Silver Spring, MD 20910, USANaval Medical Research Command, Silver Spring, MD 20910, USANaval Medical Research Command, Silver Spring, MD 20910, USAUniformed Services University of the Health Sciences, Bethesda, MD 20814, USAWalter Reed National Military Medical Center, Bethesda, MD 20814, USANaval Medical Research Command, Silver Spring, MD 20910, USAIntroduction: Enterotoxigenic <i>E. coli</i> (ETEC) is a leading cause of diarrhea in travelers as well as for children living in low- to middle-income countries. ETEC adhere to intestinal epithelium via colonization factors (CFs). CFA/I, a common CF, is composed of a polymeric stalk and a tip-localized minor adhesive subunit, CfaE. Vaccine delivery by the transcutaneous immunization of dscCfaE was safe but was poorly immunogenic in a phase 1 trial when administered to volunteers with LTR(192G) and mLT. To potentially enhance the immunogenicity of CfaE while still delivering via a cutaneous route, we evaluated the safety and immunogenicity of two CfaE constructs administered intradermally (ID) with or without mLT. Methods: CfaE was evaluated as a donor strand-complemented construct (dscCfaE) and as a chimeric construct (Chimera) in which dscCfaE replaces the A1 domain of the cholera toxin A subunit and assembles non-covalently with the pentamer of heat-labile toxin B (LTB). Subjects received three ID vaccinations three weeks apart with either dscCfaE (1, 5, and 25 µg) or Chimera (2.6 and 12.9 µg) with and without 0.1 µg of mLT. Subjects were monitored for local and systemic adverse events. Immunogenicity was evaluated by serum and antibody-secreting cell (ASC) responses. Results. The vaccine was well-tolerated with predominantly mild and moderate local vaccine site reactions characterized by erythema, induration and post-inflammatory hyperpigmentation. High rates of serologic and ASC responses were seen across study groups with the most robust responses observed in subjects receiving 25 µg of dscCfaE with 0.1 mcg of LT(R192G). Conclusion: Both ETEC adhesin vaccine prototypes were safe and immunogenic when co-administered with mLT by the ID route. The observed immune responses induced with the high dose of dscCfaE and mLT warrant further assessment in a controlled human infection model.https://www.mdpi.com/2076-2607/11/11/2689enterotoxigenic <i>E. coli</i>intradermalvaccineimmunogenicity |
| spellingShingle | Ramiro L. Gutiérrez Mark S. Riddle Chad K. Porter Milton Maciel Steven T. Poole Renee M. Laird Michelle Lane George W. Turiansky Abel Jarell Stephen J. Savarino A First in Human Clinical Trial Assessing the Safety and Immunogenicity of Two Intradermally Delivered Enterotoxigenic <i>Escherichia coli</i> CFA/I Fimbrial Tip Adhesin Antigens with and without Heat-Labile Enterotoxin with Mutation LT(R192G) Microorganisms enterotoxigenic <i>E. coli</i> intradermal vaccine immunogenicity |
| title | A First in Human Clinical Trial Assessing the Safety and Immunogenicity of Two Intradermally Delivered Enterotoxigenic <i>Escherichia coli</i> CFA/I Fimbrial Tip Adhesin Antigens with and without Heat-Labile Enterotoxin with Mutation LT(R192G) |
| title_full | A First in Human Clinical Trial Assessing the Safety and Immunogenicity of Two Intradermally Delivered Enterotoxigenic <i>Escherichia coli</i> CFA/I Fimbrial Tip Adhesin Antigens with and without Heat-Labile Enterotoxin with Mutation LT(R192G) |
| title_fullStr | A First in Human Clinical Trial Assessing the Safety and Immunogenicity of Two Intradermally Delivered Enterotoxigenic <i>Escherichia coli</i> CFA/I Fimbrial Tip Adhesin Antigens with and without Heat-Labile Enterotoxin with Mutation LT(R192G) |
| title_full_unstemmed | A First in Human Clinical Trial Assessing the Safety and Immunogenicity of Two Intradermally Delivered Enterotoxigenic <i>Escherichia coli</i> CFA/I Fimbrial Tip Adhesin Antigens with and without Heat-Labile Enterotoxin with Mutation LT(R192G) |
| title_short | A First in Human Clinical Trial Assessing the Safety and Immunogenicity of Two Intradermally Delivered Enterotoxigenic <i>Escherichia coli</i> CFA/I Fimbrial Tip Adhesin Antigens with and without Heat-Labile Enterotoxin with Mutation LT(R192G) |
| title_sort | first in human clinical trial assessing the safety and immunogenicity of two intradermally delivered enterotoxigenic i escherichia coli i cfa i fimbrial tip adhesin antigens with and without heat labile enterotoxin with mutation lt r192g |
| topic | enterotoxigenic <i>E. coli</i> intradermal vaccine immunogenicity |
| url | https://www.mdpi.com/2076-2607/11/11/2689 |
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