Efficacy Evaluation of an Intradermally Delivered Enterotoxigenic <i>Escherichia coli</i> CF Antigen I Fimbrial Tip Adhesin Vaccine Coadministered with Heat-Labile Enterotoxin with LT(R192G) against Experimental Challenge with Enterotoxigenic <i>E. coli</i> H10407 in Healthy Adult Volunteers
Background. Enterotoxigenic <i>E. coli</i> (ETEC) is a principal cause of diarrhea in travelers, deployed military personnel, and children living in low to middle-income countries. ETEC expresses a variety of virulence factors including colonization factors (CF) that facilitate adherence...
| Main Authors: | , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2024-01-01
|
| Series: | Microorganisms |
| Subjects: | |
| Online Access: | https://www.mdpi.com/2076-2607/12/2/288 |
| _version_ | 1797297439884967936 |
|---|---|
| author | Ramiro L. Gutiérrez Chad K. Porter Clayton Harro Kawsar Talaat Mark S. Riddle Barbara DeNearing Jessica Brubaker Milton Maciel Renee M. Laird Steven Poole Subra Chakraborty Nicole Maier David A. Sack Stephen J. Savarino |
| author_facet | Ramiro L. Gutiérrez Chad K. Porter Clayton Harro Kawsar Talaat Mark S. Riddle Barbara DeNearing Jessica Brubaker Milton Maciel Renee M. Laird Steven Poole Subra Chakraborty Nicole Maier David A. Sack Stephen J. Savarino |
| author_sort | Ramiro L. Gutiérrez |
| collection | DOAJ |
| description | Background. Enterotoxigenic <i>E. coli</i> (ETEC) is a principal cause of diarrhea in travelers, deployed military personnel, and children living in low to middle-income countries. ETEC expresses a variety of virulence factors including colonization factors (CF) that facilitate adherence to the intestinal mucosa. We assessed the protective efficacy of a tip-localized subunit of CF antigen I (CFA/I), CfaE, delivered intradermally with the mutant <i>E. coli</i> heat-labile enterotoxin, LTR192G, in a controlled human infection model (CHIM). Methods. Three cohorts of healthy adult subjects were enrolled and given three doses of 25 μg CfaE + 100 ng LTR192G vaccine intradermally at 3-week intervals. Approximately 28 days after the last vaccination, vaccinated and unvaccinated subjects were admitted as inpatients and challenged with approximately 2 × 10<sup>7</sup> cfu of CFA/I+ ETEC strain H10407 following an overnight fast. Subjects were assessed for moderate-to-severe diarrhea for 5 days post-challenge. Results. A total of 52 volunteers received all three vaccinations; 41 vaccinated and 43 unvaccinated subjects were challenged and assessed for moderate-to-severe diarrhea. Naïve attack rates varied from 45.5% to 64.7% across the cohorts yielding an overall efficacy estimate of 27.8% (95% confidence intervals: −7.5–51.6%). In addition to reducing moderate–severe diarrhea rates, the vaccine significantly reduced loose stool output and overall ETEC disease severity. Conclusions. This is the first study to demonstrate protection against ETEC challenge after intradermal vaccination with an ETEC adhesin. Further examination of the challenge methodology is necessary to address the variability in naïve attack rate observed among the three cohorts in the present study. |
| first_indexed | 2024-03-07T22:21:16Z |
| format | Article |
| id | doaj.art-d8366c0cf5224eef9481b8a7cb3360ea |
| institution | Directory Open Access Journal |
| issn | 2076-2607 |
| language | English |
| last_indexed | 2024-03-07T22:21:16Z |
| publishDate | 2024-01-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Microorganisms |
| spelling | doaj.art-d8366c0cf5224eef9481b8a7cb3360ea2024-02-23T15:28:05ZengMDPI AGMicroorganisms2076-26072024-01-0112228810.3390/microorganisms12020288Efficacy Evaluation of an Intradermally Delivered Enterotoxigenic <i>Escherichia coli</i> CF Antigen I Fimbrial Tip Adhesin Vaccine Coadministered with Heat-Labile Enterotoxin with LT(R192G) against Experimental Challenge with Enterotoxigenic <i>E. coli</i> H10407 in Healthy Adult VolunteersRamiro L. Gutiérrez0Chad K. Porter1Clayton Harro2Kawsar Talaat3Mark S. Riddle4Barbara DeNearing5Jessica Brubaker6Milton Maciel7Renee M. Laird8Steven Poole9Subra Chakraborty10Nicole Maier11David A. Sack12Stephen J. Savarino13Naval Medical Research Command, Silver Spring, MD 20910, USANaval Medical Research Command, Silver Spring, MD 20910, USACenter for Immunization Research, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD 21224, USACenter for Immunization Research, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD 21224, USANaval Medical Research Command, Silver Spring, MD 20910, USACenter for Immunization Research, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD 21224, USACenter for Immunization Research, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD 21224, USANaval Medical Research Command, Silver Spring, MD 20910, USANaval Medical Research Command, Silver Spring, MD 20910, USANaval Medical Research Command, Silver Spring, MD 20910, USADepartment of International Health, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD 21205, USAPATH, Washington, DC 20001, USACenter for Immunization Research, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD 21224, USANaval Medical Research Command, Silver Spring, MD 20910, USABackground. Enterotoxigenic <i>E. coli</i> (ETEC) is a principal cause of diarrhea in travelers, deployed military personnel, and children living in low to middle-income countries. ETEC expresses a variety of virulence factors including colonization factors (CF) that facilitate adherence to the intestinal mucosa. We assessed the protective efficacy of a tip-localized subunit of CF antigen I (CFA/I), CfaE, delivered intradermally with the mutant <i>E. coli</i> heat-labile enterotoxin, LTR192G, in a controlled human infection model (CHIM). Methods. Three cohorts of healthy adult subjects were enrolled and given three doses of 25 μg CfaE + 100 ng LTR192G vaccine intradermally at 3-week intervals. Approximately 28 days after the last vaccination, vaccinated and unvaccinated subjects were admitted as inpatients and challenged with approximately 2 × 10<sup>7</sup> cfu of CFA/I+ ETEC strain H10407 following an overnight fast. Subjects were assessed for moderate-to-severe diarrhea for 5 days post-challenge. Results. A total of 52 volunteers received all three vaccinations; 41 vaccinated and 43 unvaccinated subjects were challenged and assessed for moderate-to-severe diarrhea. Naïve attack rates varied from 45.5% to 64.7% across the cohorts yielding an overall efficacy estimate of 27.8% (95% confidence intervals: −7.5–51.6%). In addition to reducing moderate–severe diarrhea rates, the vaccine significantly reduced loose stool output and overall ETEC disease severity. Conclusions. This is the first study to demonstrate protection against ETEC challenge after intradermal vaccination with an ETEC adhesin. Further examination of the challenge methodology is necessary to address the variability in naïve attack rate observed among the three cohorts in the present study.https://www.mdpi.com/2076-2607/12/2/288enterotoxigenic <i>E. coli</i>CfaEintradermalvaccineefficacyH10407 |
| spellingShingle | Ramiro L. Gutiérrez Chad K. Porter Clayton Harro Kawsar Talaat Mark S. Riddle Barbara DeNearing Jessica Brubaker Milton Maciel Renee M. Laird Steven Poole Subra Chakraborty Nicole Maier David A. Sack Stephen J. Savarino Efficacy Evaluation of an Intradermally Delivered Enterotoxigenic <i>Escherichia coli</i> CF Antigen I Fimbrial Tip Adhesin Vaccine Coadministered with Heat-Labile Enterotoxin with LT(R192G) against Experimental Challenge with Enterotoxigenic <i>E. coli</i> H10407 in Healthy Adult Volunteers Microorganisms enterotoxigenic <i>E. coli</i> CfaE intradermal vaccine efficacy H10407 |
| title | Efficacy Evaluation of an Intradermally Delivered Enterotoxigenic <i>Escherichia coli</i> CF Antigen I Fimbrial Tip Adhesin Vaccine Coadministered with Heat-Labile Enterotoxin with LT(R192G) against Experimental Challenge with Enterotoxigenic <i>E. coli</i> H10407 in Healthy Adult Volunteers |
| title_full | Efficacy Evaluation of an Intradermally Delivered Enterotoxigenic <i>Escherichia coli</i> CF Antigen I Fimbrial Tip Adhesin Vaccine Coadministered with Heat-Labile Enterotoxin with LT(R192G) against Experimental Challenge with Enterotoxigenic <i>E. coli</i> H10407 in Healthy Adult Volunteers |
| title_fullStr | Efficacy Evaluation of an Intradermally Delivered Enterotoxigenic <i>Escherichia coli</i> CF Antigen I Fimbrial Tip Adhesin Vaccine Coadministered with Heat-Labile Enterotoxin with LT(R192G) against Experimental Challenge with Enterotoxigenic <i>E. coli</i> H10407 in Healthy Adult Volunteers |
| title_full_unstemmed | Efficacy Evaluation of an Intradermally Delivered Enterotoxigenic <i>Escherichia coli</i> CF Antigen I Fimbrial Tip Adhesin Vaccine Coadministered with Heat-Labile Enterotoxin with LT(R192G) against Experimental Challenge with Enterotoxigenic <i>E. coli</i> H10407 in Healthy Adult Volunteers |
| title_short | Efficacy Evaluation of an Intradermally Delivered Enterotoxigenic <i>Escherichia coli</i> CF Antigen I Fimbrial Tip Adhesin Vaccine Coadministered with Heat-Labile Enterotoxin with LT(R192G) against Experimental Challenge with Enterotoxigenic <i>E. coli</i> H10407 in Healthy Adult Volunteers |
| title_sort | efficacy evaluation of an intradermally delivered enterotoxigenic i escherichia coli i cf antigen i fimbrial tip adhesin vaccine coadministered with heat labile enterotoxin with lt r192g against experimental challenge with enterotoxigenic i e coli i h10407 in healthy adult volunteers |
| topic | enterotoxigenic <i>E. coli</i> CfaE intradermal vaccine efficacy H10407 |
| url | https://www.mdpi.com/2076-2607/12/2/288 |
| work_keys_str_mv | AT ramirolgutierrez efficacyevaluationofanintradermallydeliveredenterotoxigeniciescherichiacoliicfantigenifimbrialtipadhesinvaccinecoadministeredwithheatlabileenterotoxinwithltr192gagainstexperimentalchallengewithenterotoxigeniciecoliih10407inhealthyadultvolunteers AT chadkporter efficacyevaluationofanintradermallydeliveredenterotoxigeniciescherichiacoliicfantigenifimbrialtipadhesinvaccinecoadministeredwithheatlabileenterotoxinwithltr192gagainstexperimentalchallengewithenterotoxigeniciecoliih10407inhealthyadultvolunteers AT claytonharro efficacyevaluationofanintradermallydeliveredenterotoxigeniciescherichiacoliicfantigenifimbrialtipadhesinvaccinecoadministeredwithheatlabileenterotoxinwithltr192gagainstexperimentalchallengewithenterotoxigeniciecoliih10407inhealthyadultvolunteers AT kawsartalaat efficacyevaluationofanintradermallydeliveredenterotoxigeniciescherichiacoliicfantigenifimbrialtipadhesinvaccinecoadministeredwithheatlabileenterotoxinwithltr192gagainstexperimentalchallengewithenterotoxigeniciecoliih10407inhealthyadultvolunteers AT marksriddle efficacyevaluationofanintradermallydeliveredenterotoxigeniciescherichiacoliicfantigenifimbrialtipadhesinvaccinecoadministeredwithheatlabileenterotoxinwithltr192gagainstexperimentalchallengewithenterotoxigeniciecoliih10407inhealthyadultvolunteers AT barbaradenearing efficacyevaluationofanintradermallydeliveredenterotoxigeniciescherichiacoliicfantigenifimbrialtipadhesinvaccinecoadministeredwithheatlabileenterotoxinwithltr192gagainstexperimentalchallengewithenterotoxigeniciecoliih10407inhealthyadultvolunteers AT jessicabrubaker efficacyevaluationofanintradermallydeliveredenterotoxigeniciescherichiacoliicfantigenifimbrialtipadhesinvaccinecoadministeredwithheatlabileenterotoxinwithltr192gagainstexperimentalchallengewithenterotoxigeniciecoliih10407inhealthyadultvolunteers AT miltonmaciel efficacyevaluationofanintradermallydeliveredenterotoxigeniciescherichiacoliicfantigenifimbrialtipadhesinvaccinecoadministeredwithheatlabileenterotoxinwithltr192gagainstexperimentalchallengewithenterotoxigeniciecoliih10407inhealthyadultvolunteers AT reneemlaird efficacyevaluationofanintradermallydeliveredenterotoxigeniciescherichiacoliicfantigenifimbrialtipadhesinvaccinecoadministeredwithheatlabileenterotoxinwithltr192gagainstexperimentalchallengewithenterotoxigeniciecoliih10407inhealthyadultvolunteers AT stevenpoole efficacyevaluationofanintradermallydeliveredenterotoxigeniciescherichiacoliicfantigenifimbrialtipadhesinvaccinecoadministeredwithheatlabileenterotoxinwithltr192gagainstexperimentalchallengewithenterotoxigeniciecoliih10407inhealthyadultvolunteers AT subrachakraborty efficacyevaluationofanintradermallydeliveredenterotoxigeniciescherichiacoliicfantigenifimbrialtipadhesinvaccinecoadministeredwithheatlabileenterotoxinwithltr192gagainstexperimentalchallengewithenterotoxigeniciecoliih10407inhealthyadultvolunteers AT nicolemaier efficacyevaluationofanintradermallydeliveredenterotoxigeniciescherichiacoliicfantigenifimbrialtipadhesinvaccinecoadministeredwithheatlabileenterotoxinwithltr192gagainstexperimentalchallengewithenterotoxigeniciecoliih10407inhealthyadultvolunteers AT davidasack efficacyevaluationofanintradermallydeliveredenterotoxigeniciescherichiacoliicfantigenifimbrialtipadhesinvaccinecoadministeredwithheatlabileenterotoxinwithltr192gagainstexperimentalchallengewithenterotoxigeniciecoliih10407inhealthyadultvolunteers AT stephenjsavarino efficacyevaluationofanintradermallydeliveredenterotoxigeniciescherichiacoliicfantigenifimbrialtipadhesinvaccinecoadministeredwithheatlabileenterotoxinwithltr192gagainstexperimentalchallengewithenterotoxigeniciecoliih10407inhealthyadultvolunteers |