Interrogation of a live-attenuated enterotoxigenic Escherichia coli vaccine highlights features unique to wild-type infection

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

Enterotoxigenic Escherichia coli (ETEC) infections are a common cause of severe diarrheal illness in low- and middle-income countries. The live-attenuated ACE527 ETEC vaccine, adjuvanted with double mutant heat-labile toxin (dmLT), affords clear but partial protection against ETEC challenge in human volunteers. Comparatively, initial wild-type ETEC challenge completely protects against severe diarrhea on homologous re-challenge. To investigate determinants of protection, vaccine antigen content was compared to wild-type ETEC, and proteome microarrays were used to assess immune responses following vaccination and ETEC challenge. Although molecular interrogation of the vaccine confirmed expression of targeted canonical antigens, relative to wild-type ETEC, vaccine strains were deficient in production of flagellar antigens, immotile, and lacked production of the EtpA adhesin. Similarly, vaccination ± dmLT elicited responses to targeted canonical antigens, but relative to wild-type challenge, vaccine responses to some potentially protective non-canonical antigens including EtpA and the YghJ metalloprotease were diminished or absent. These studies highlight important differences in vaccine and wild-type ETEC antigen content and call attention to distinct immunologic signatures that could inform investigation of correlates of protection, and guide vaccine antigen selection for these pathogens of global importance.

Original languageEnglish (US)
Article number37
Journalnpj Vaccines
Volume4
Issue number1
DOIs
StatePublished - Dec 1 2019

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Escherichia coli Vaccines
Enterotoxigenic Escherichia coli
Antigens
Infection
Vaccines
Vaccination
Hot Temperature
Escherichia coli Infections
Synthetic Vaccines
Metalloproteases
Proteome
Volunteers
Diarrhea

ASJC Scopus subject areas

  • Immunology
  • Pharmacology
  • Infectious Diseases
  • Pharmacology (medical)

Cite this

Interrogation of a live-attenuated enterotoxigenic Escherichia coli vaccine highlights features unique to wild-type infection. / 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: npj Vaccines, Vol. 4, No. 1, 37, 01.12.2019.

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 2019, 'Interrogation of a live-attenuated enterotoxigenic Escherichia coli vaccine highlights features unique to wild-type infection', npj Vaccines, vol. 4, no. 1, 37. https://doi.org/10.1038/s41541-019-0131-7
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. / Interrogation of a live-attenuated enterotoxigenic Escherichia coli vaccine highlights features unique to wild-type infection. In: npj Vaccines. 2019 ; Vol. 4, No. 1.
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