Human Experimental Challenge With Enterotoxigenic Escherichia coli Elicits Immune Responses to Canonical and Novel Antigens Relevant to Vaccine Development

Subhra Chakraborty, Arlo Randall, Tim J. Vickers, Doug Molina, Clayton D. Harro, Barbara DeNearing, Jessica Brubaker, David Allen Sack, Louis Bourgeois, Philip L. Felgner, Xiaowu Liang, Sachin Mani, Heather Wenzel, R. Reid Townsend, Petra E. Gilmore, Michael J. Darsley, David A. Rasko, James M. Fleckenstein

Research output: Contribution to journalArticle

Abstract

Background: Enterotoxigenic Escherichia coli (ETEC) is a major cause of diarrheal illness in the developing world. Enterotoxigenic E coli vaccinology has been challenged by genetic diversity and heterogeneity of canonical antigens. Examination of the antigenic breadth of immune responses associated with protective immunity could afford new avenues for vaccine development. Methods: Antibody lymphocyte supernatants (ALS) and sera from 20 naive human volunteers challenged with ETEC strain H10407 and from 10 volunteers rechallenged 4-6 weeks later with the same strain (9 of whom were completely protected on rechallenge) were tested against ETEC proteome microarrays containing 957 antigens. Results: Enterotoxigenic E coli challenge stimulated robust serum and mucosal (ALS) responses to canonical vaccine antigens (CFA/I, and the B subunit of LT) as well as a small number of antigens not presently targeted in ETEC vaccines. These included pathovar-specific secreted proteins (EtpA, EatA) as well as highly conserved E coli antigens including YghJ, flagellin, and pertactin-like autotransporter proteins, all of which have previously afforded protection against ETEC infection in preclinical studies. Conclusions: Taken together, studies reported here suggest that immune responses after ETEC infection involve traditional vaccine targets as well as a select number of more recently identified protein antigens that could offer additional avenues for vaccine development for these pathogens.

Original languageEnglish (US)
Pages (from-to)1436-1446
Number of pages11
JournalThe Journal of infectious diseases
Volume218
Issue number9
DOIs
StatePublished - Sep 22 2018

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Enterotoxigenic Escherichia coli
Vaccines
Antigens
Escherichia coli Infections
Volunteers
Escherichia coli Vaccines
Lymphocytes
Flagellin
Proteins
Genetic Heterogeneity
Antibodies
Proteome
Serum
Immunity
Escherichia coli

ASJC Scopus subject areas

  • Immunology and Allergy
  • Infectious Diseases

Cite this

Human Experimental Challenge With Enterotoxigenic Escherichia coli Elicits Immune Responses to Canonical and Novel Antigens Relevant to Vaccine Development. / Chakraborty, Subhra; Randall, Arlo; Vickers, Tim J.; Molina, Doug; Harro, Clayton D.; DeNearing, Barbara; Brubaker, Jessica; Sack, David Allen; Bourgeois, Louis; Felgner, Philip L.; Liang, Xiaowu; Mani, Sachin; Wenzel, Heather; Townsend, R. Reid; Gilmore, Petra E.; Darsley, Michael J.; Rasko, David A.; Fleckenstein, James M.

In: The Journal of infectious diseases, Vol. 218, No. 9, 22.09.2018, p. 1436-1446.

Research output: Contribution to journalArticle

Chakraborty, S, Randall, A, Vickers, TJ, Molina, D, Harro, CD, DeNearing, B, Brubaker, J, Sack, DA, Bourgeois, L, Felgner, PL, Liang, X, Mani, S, Wenzel, H, Townsend, RR, Gilmore, PE, Darsley, MJ, Rasko, DA & Fleckenstein, JM 2018, 'Human Experimental Challenge With Enterotoxigenic Escherichia coli Elicits Immune Responses to Canonical and Novel Antigens Relevant to Vaccine Development', The Journal of infectious diseases, vol. 218, no. 9, pp. 1436-1446. https://doi.org/10.1093/infdis/jiy312
Chakraborty, Subhra ; Randall, Arlo ; Vickers, Tim J. ; Molina, Doug ; Harro, Clayton D. ; DeNearing, Barbara ; Brubaker, Jessica ; Sack, David Allen ; Bourgeois, Louis ; Felgner, Philip L. ; Liang, Xiaowu ; Mani, Sachin ; Wenzel, Heather ; Townsend, R. Reid ; Gilmore, Petra E. ; Darsley, Michael J. ; Rasko, David A. ; Fleckenstein, James M. / Human Experimental Challenge With Enterotoxigenic Escherichia coli Elicits Immune Responses to Canonical and Novel Antigens Relevant to Vaccine Development. In: The Journal of infectious diseases. 2018 ; Vol. 218, No. 9. pp. 1436-1446.
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abstract = "Background: Enterotoxigenic Escherichia coli (ETEC) is a major cause of diarrheal illness in the developing world. Enterotoxigenic E coli vaccinology has been challenged by genetic diversity and heterogeneity of canonical antigens. Examination of the antigenic breadth of immune responses associated with protective immunity could afford new avenues for vaccine development. Methods: Antibody lymphocyte supernatants (ALS) and sera from 20 naive human volunteers challenged with ETEC strain H10407 and from 10 volunteers rechallenged 4-6 weeks later with the same strain (9 of whom were completely protected on rechallenge) were tested against ETEC proteome microarrays containing 957 antigens. Results: Enterotoxigenic E coli challenge stimulated robust serum and mucosal (ALS) responses to canonical vaccine antigens (CFA/I, and the B subunit of LT) as well as a small number of antigens not presently targeted in ETEC vaccines. These included pathovar-specific secreted proteins (EtpA, EatA) as well as highly conserved E coli antigens including YghJ, flagellin, and pertactin-like autotransporter proteins, all of which have previously afforded protection against ETEC infection in preclinical studies. Conclusions: Taken together, studies reported here suggest that immune responses after ETEC infection involve traditional vaccine targets as well as a select number of more recently identified protein antigens that could offer additional avenues for vaccine development for these pathogens.",
author = "Subhra Chakraborty and Arlo Randall and Vickers, {Tim J.} and Doug Molina and Harro, {Clayton D.} and Barbara DeNearing and Jessica Brubaker and Sack, {David Allen} and Louis Bourgeois and Felgner, {Philip L.} and Xiaowu Liang and Sachin Mani and Heather Wenzel and Townsend, {R. Reid} and Gilmore, {Petra E.} and Darsley, {Michael J.} and Rasko, {David A.} and Fleckenstein, {James M.}",
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AU - Chakraborty, Subhra

AU - Randall, Arlo

AU - Vickers, Tim J.

AU - Molina, Doug

AU - Harro, Clayton D.

AU - DeNearing, Barbara

AU - Brubaker, Jessica

AU - Sack, David Allen

AU - Bourgeois, Louis

AU - Felgner, Philip L.

AU - Liang, Xiaowu

AU - Mani, Sachin

AU - Wenzel, Heather

AU - Townsend, R. Reid

AU - Gilmore, Petra E.

AU - Darsley, Michael J.

AU - Rasko, David A.

AU - Fleckenstein, James M.

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N2 - Background: Enterotoxigenic Escherichia coli (ETEC) is a major cause of diarrheal illness in the developing world. Enterotoxigenic E coli vaccinology has been challenged by genetic diversity and heterogeneity of canonical antigens. Examination of the antigenic breadth of immune responses associated with protective immunity could afford new avenues for vaccine development. Methods: Antibody lymphocyte supernatants (ALS) and sera from 20 naive human volunteers challenged with ETEC strain H10407 and from 10 volunteers rechallenged 4-6 weeks later with the same strain (9 of whom were completely protected on rechallenge) were tested against ETEC proteome microarrays containing 957 antigens. Results: Enterotoxigenic E coli challenge stimulated robust serum and mucosal (ALS) responses to canonical vaccine antigens (CFA/I, and the B subunit of LT) as well as a small number of antigens not presently targeted in ETEC vaccines. These included pathovar-specific secreted proteins (EtpA, EatA) as well as highly conserved E coli antigens including YghJ, flagellin, and pertactin-like autotransporter proteins, all of which have previously afforded protection against ETEC infection in preclinical studies. Conclusions: Taken together, studies reported here suggest that immune responses after ETEC infection involve traditional vaccine targets as well as a select number of more recently identified protein antigens that could offer additional avenues for vaccine development for these pathogens.

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