A First in Human Clinical Trial Assessing the Safety and Immunogenicity of Two Intradermally Delivered Enterotoxigenic Escherichia coli CFA/I Fimbrial Tip Adhesin Antigens with and without Heat-Labile Enterotoxin with Mutation LT(R192G)

Ramiro L Gutiérrez; Mark S Riddle; Chad K Porter; Milton Maciel Jr; Steven T Poole; Renee M Laird; Michelle Lane; George W Turiansky; Abel Jarell; Stephen J Savarino

doi:10.3390/microorganisms11112689

A First in Human Clinical Trial Assessing the Safety and Immunogenicity of Two Intradermally Delivered Enterotoxigenic Escherichia coli CFA/I Fimbrial Tip Adhesin Antigens with and without Heat-Labile Enterotoxin with Mutation LT(R192G)

Microorganisms. 2023 Nov 2;11(11):2689. doi: 10.3390/microorganisms11112689.

Authors

Ramiro L Gutiérrez¹, Mark S Riddle¹, Chad K Porter^{1

2}, Milton Maciel Jr^{1

2

3}, Steven T Poole^{1

3}, Renee M Laird^{1

3}, Michelle Lane¹, George W Turiansky², Abel Jarell⁴, Stephen J Savarino^{1

2}

Affiliations

¹ Naval Medical Research Command, Silver Spring, MD 20910, USA.
² Uniformed Services University of the Health Sciences, Bethesda, MD 20814, USA.
³ Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc., Bethesda, MD 20817, USA.
⁴ Walter Reed National Military Medical Center, Bethesda, MD 20814, USA.

Abstract

Introduction: Enterotoxigenic E. coli (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.

Keywords: enterotoxigenic E. coli; immunogenicity; intradermal; vaccine.

Grants and funding

This study was conducted under support of the Military Infectious Disease Research Program. This work was supported, in part, by the Bill & Melinda Gates Foundation (OPP1112376). Under the grant conditions of the Foundation, a Creative Commons Attribution 4.0 Generic License has already been assigned to the Author Accepted Manuscript version that might arise from this submission.