Prophylactic Efficacy of Hyperimmune Bovine Colostral Antiadhesin Antibodies Against Enterotoxigenic Escherichia coli Diarrhea: A Randomized, Double-Blind, Placebo-Controlled, Phase 1 Trial

Stephen J. Savarino, Robin McKenzie, David R. Tribble, Chad K. Porter, Aisling O'Dowd, Joyce A. Cantrell, Stephanie A. Sincock, Steven T. Poole, Barbara Denearing, Colleen M. Woods, Hye Kim, Shannon L. Grahek, Carl Brinkley, Joseph H. Crabb, Louis Bourgeois

Research output: Contribution to journalArticle

Abstract

Background. Tip-localized adhesive proteins of bacterial fimbriae from diverse pathogens confer protection in animal models, but efficacy in humans has not been reported. Enterotoxigenic Escherichia coli (ETEC) commonly elaborate colonization factors comprising a minor tip adhesin and major stalk-forming subunit. We assessed the efficacy of antiadhesin bovine colostral IgG (bIgG) antibodies against ETEC challenge in volunteers. Methods. Adults were randomly assigned (1:1:1) to take oral hyperimmune bIgG raised against CFA/I minor pilin subunit (CfaE) tip adhesin or colonization factor I (CFA/I) fimbraie (positive control) or placebo. Two days before challenge, volunteers began a thrice-daily, 7-day course of investigational product administered in sodium bicarbonate 15 minutes after each meal. On day 3, subjects drank 1 × 10 9 colony-forming units of colonization factor I (CFA/I)-ETEC strain H10407 with buffer. The primary efficacy endpoint was diarrhea within 120 hours of challenge. Results. After enrollment and randomization, 31 volunteers received product, underwent ETEC challenge, and were included in the per protocol efficacy analysis. Nine of 11 placebos developed diarrhea, 7 experiencing moderate to severe disease. Protective efficacy of 63% (P =.03) and 88% (P =.002) was observed in the antiadhesin bIgG and positive control groups, respectively. Conclusions. Oral administration of anti-CFA/I minor pilin subunit (CfaE) antibodies conferred significant protection against ETEC, providing the first clinical evidence that fimbrial tip adhesins function as protective antigens.

Original languageEnglish (US)
Pages (from-to)7-13
Number of pages7
JournalJournal of Infectious Diseases
Volume216
Issue number1
DOIs
StatePublished - Jul 1 2017

Fingerprint

Enterotoxigenic Escherichia coli
Diarrhea
Placebos
Antibodies
Fimbriae Proteins
Volunteers
Immunoglobulin G
Bacterial Fimbriae
Bacterial Adhesins
Sodium Bicarbonate
Random Allocation
Adhesives
Oral Administration
Meals
Buffers
Stem Cells
Animal Models
Antigens
Control Groups
Proteins

Keywords

  • adhesins
  • bovine antibodies
  • enteroxigenic Escherichia coli infections
  • humans
  • passive protection.

ASJC Scopus subject areas

  • Immunology and Allergy
  • Infectious Diseases

Cite this

Prophylactic Efficacy of Hyperimmune Bovine Colostral Antiadhesin Antibodies Against Enterotoxigenic Escherichia coli Diarrhea : A Randomized, Double-Blind, Placebo-Controlled, Phase 1 Trial. / Savarino, Stephen J.; McKenzie, Robin; Tribble, David R.; Porter, Chad K.; O'Dowd, Aisling; Cantrell, Joyce A.; Sincock, Stephanie A.; Poole, Steven T.; Denearing, Barbara; Woods, Colleen M.; Kim, Hye; Grahek, Shannon L.; Brinkley, Carl; Crabb, Joseph H.; Bourgeois, Louis.

In: Journal of Infectious Diseases, Vol. 216, No. 1, 01.07.2017, p. 7-13.

Research output: Contribution to journalArticle

Savarino, SJ, McKenzie, R, Tribble, DR, Porter, CK, O'Dowd, A, Cantrell, JA, Sincock, SA, Poole, ST, Denearing, B, Woods, CM, Kim, H, Grahek, SL, Brinkley, C, Crabb, JH & Bourgeois, L 2017, 'Prophylactic Efficacy of Hyperimmune Bovine Colostral Antiadhesin Antibodies Against Enterotoxigenic Escherichia coli Diarrhea: A Randomized, Double-Blind, Placebo-Controlled, Phase 1 Trial', Journal of Infectious Diseases, vol. 216, no. 1, pp. 7-13. https://doi.org/10.1093/infdis/jix144
Savarino, Stephen J. ; McKenzie, Robin ; Tribble, David R. ; Porter, Chad K. ; O'Dowd, Aisling ; Cantrell, Joyce A. ; Sincock, Stephanie A. ; Poole, Steven T. ; Denearing, Barbara ; Woods, Colleen M. ; Kim, Hye ; Grahek, Shannon L. ; Brinkley, Carl ; Crabb, Joseph H. ; Bourgeois, Louis. / Prophylactic Efficacy of Hyperimmune Bovine Colostral Antiadhesin Antibodies Against Enterotoxigenic Escherichia coli Diarrhea : A Randomized, Double-Blind, Placebo-Controlled, Phase 1 Trial. In: Journal of Infectious Diseases. 2017 ; Vol. 216, No. 1. pp. 7-13.
@article{4134cd0f055a425ea7d8ca9fe0bb6330,
title = "Prophylactic Efficacy of Hyperimmune Bovine Colostral Antiadhesin Antibodies Against Enterotoxigenic Escherichia coli Diarrhea: A Randomized, Double-Blind, Placebo-Controlled, Phase 1 Trial",
abstract = "Background. Tip-localized adhesive proteins of bacterial fimbriae from diverse pathogens confer protection in animal models, but efficacy in humans has not been reported. Enterotoxigenic Escherichia coli (ETEC) commonly elaborate colonization factors comprising a minor tip adhesin and major stalk-forming subunit. We assessed the efficacy of antiadhesin bovine colostral IgG (bIgG) antibodies against ETEC challenge in volunteers. Methods. Adults were randomly assigned (1:1:1) to take oral hyperimmune bIgG raised against CFA/I minor pilin subunit (CfaE) tip adhesin or colonization factor I (CFA/I) fimbraie (positive control) or placebo. Two days before challenge, volunteers began a thrice-daily, 7-day course of investigational product administered in sodium bicarbonate 15 minutes after each meal. On day 3, subjects drank 1 × 10 9 colony-forming units of colonization factor I (CFA/I)-ETEC strain H10407 with buffer. The primary efficacy endpoint was diarrhea within 120 hours of challenge. Results. After enrollment and randomization, 31 volunteers received product, underwent ETEC challenge, and were included in the per protocol efficacy analysis. Nine of 11 placebos developed diarrhea, 7 experiencing moderate to severe disease. Protective efficacy of 63{\%} (P =.03) and 88{\%} (P =.002) was observed in the antiadhesin bIgG and positive control groups, respectively. Conclusions. Oral administration of anti-CFA/I minor pilin subunit (CfaE) antibodies conferred significant protection against ETEC, providing the first clinical evidence that fimbrial tip adhesins function as protective antigens.",
keywords = "adhesins, bovine antibodies, enteroxigenic Escherichia coli infections, humans, passive protection.",
author = "Savarino, {Stephen J.} and Robin McKenzie and Tribble, {David R.} and Porter, {Chad K.} and Aisling O'Dowd and Cantrell, {Joyce A.} and Sincock, {Stephanie A.} and Poole, {Steven T.} and Barbara Denearing and Woods, {Colleen M.} and Hye Kim and Grahek, {Shannon L.} and Carl Brinkley and Crabb, {Joseph H.} and Louis Bourgeois",
year = "2017",
month = "7",
day = "1",
doi = "10.1093/infdis/jix144",
language = "English (US)",
volume = "216",
pages = "7--13",
journal = "Journal of Infectious Diseases",
issn = "0022-1899",
publisher = "Oxford University Press",
number = "1",

}

TY - JOUR

T1 - Prophylactic Efficacy of Hyperimmune Bovine Colostral Antiadhesin Antibodies Against Enterotoxigenic Escherichia coli Diarrhea

T2 - A Randomized, Double-Blind, Placebo-Controlled, Phase 1 Trial

AU - Savarino, Stephen J.

AU - McKenzie, Robin

AU - Tribble, David R.

AU - Porter, Chad K.

AU - O'Dowd, Aisling

AU - Cantrell, Joyce A.

AU - Sincock, Stephanie A.

AU - Poole, Steven T.

AU - Denearing, Barbara

AU - Woods, Colleen M.

AU - Kim, Hye

AU - Grahek, Shannon L.

AU - Brinkley, Carl

AU - Crabb, Joseph H.

AU - Bourgeois, Louis

PY - 2017/7/1

Y1 - 2017/7/1

N2 - Background. Tip-localized adhesive proteins of bacterial fimbriae from diverse pathogens confer protection in animal models, but efficacy in humans has not been reported. Enterotoxigenic Escherichia coli (ETEC) commonly elaborate colonization factors comprising a minor tip adhesin and major stalk-forming subunit. We assessed the efficacy of antiadhesin bovine colostral IgG (bIgG) antibodies against ETEC challenge in volunteers. Methods. Adults were randomly assigned (1:1:1) to take oral hyperimmune bIgG raised against CFA/I minor pilin subunit (CfaE) tip adhesin or colonization factor I (CFA/I) fimbraie (positive control) or placebo. Two days before challenge, volunteers began a thrice-daily, 7-day course of investigational product administered in sodium bicarbonate 15 minutes after each meal. On day 3, subjects drank 1 × 10 9 colony-forming units of colonization factor I (CFA/I)-ETEC strain H10407 with buffer. The primary efficacy endpoint was diarrhea within 120 hours of challenge. Results. After enrollment and randomization, 31 volunteers received product, underwent ETEC challenge, and were included in the per protocol efficacy analysis. Nine of 11 placebos developed diarrhea, 7 experiencing moderate to severe disease. Protective efficacy of 63% (P =.03) and 88% (P =.002) was observed in the antiadhesin bIgG and positive control groups, respectively. Conclusions. Oral administration of anti-CFA/I minor pilin subunit (CfaE) antibodies conferred significant protection against ETEC, providing the first clinical evidence that fimbrial tip adhesins function as protective antigens.

AB - Background. Tip-localized adhesive proteins of bacterial fimbriae from diverse pathogens confer protection in animal models, but efficacy in humans has not been reported. Enterotoxigenic Escherichia coli (ETEC) commonly elaborate colonization factors comprising a minor tip adhesin and major stalk-forming subunit. We assessed the efficacy of antiadhesin bovine colostral IgG (bIgG) antibodies against ETEC challenge in volunteers. Methods. Adults were randomly assigned (1:1:1) to take oral hyperimmune bIgG raised against CFA/I minor pilin subunit (CfaE) tip adhesin or colonization factor I (CFA/I) fimbraie (positive control) or placebo. Two days before challenge, volunteers began a thrice-daily, 7-day course of investigational product administered in sodium bicarbonate 15 minutes after each meal. On day 3, subjects drank 1 × 10 9 colony-forming units of colonization factor I (CFA/I)-ETEC strain H10407 with buffer. The primary efficacy endpoint was diarrhea within 120 hours of challenge. Results. After enrollment and randomization, 31 volunteers received product, underwent ETEC challenge, and were included in the per protocol efficacy analysis. Nine of 11 placebos developed diarrhea, 7 experiencing moderate to severe disease. Protective efficacy of 63% (P =.03) and 88% (P =.002) was observed in the antiadhesin bIgG and positive control groups, respectively. Conclusions. Oral administration of anti-CFA/I minor pilin subunit (CfaE) antibodies conferred significant protection against ETEC, providing the first clinical evidence that fimbrial tip adhesins function as protective antigens.

KW - adhesins

KW - bovine antibodies

KW - enteroxigenic Escherichia coli infections

KW - humans

KW - passive protection.

UR - http://www.scopus.com/inward/record.url?scp=85024484949&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85024484949&partnerID=8YFLogxK

U2 - 10.1093/infdis/jix144

DO - 10.1093/infdis/jix144

M3 - Article

C2 - 28541500

AN - SCOPUS:85024484949

VL - 216

SP - 7

EP - 13

JO - Journal of Infectious Diseases

JF - Journal of Infectious Diseases

SN - 0022-1899

IS - 1

ER -