A Phase 1 dose escalating study of double mutant heat-labile toxin LTR192G/L211A (dmLT) from Enterotoxigenic Escherichia coli (ETEC) by sublingual or oral immunization

David I. Bernstein, Marcela F. Pasetti, Rebecca Brady, Amanda D. Buskirk, Rezwanul Wahid, Michelle Dickey, Mitchell Cohen, Holly Baughman, Jill El-Khorazaty, Nicole Maier, Marcelo B. Sztein, Shahida Baqar, Louis Bourgeois

Research output: Contribution to journalArticle

Abstract

Background: The public health burden of Enterotoxigenic Escherichia coli (ETEC) is high but no vaccine is specifically approved to prevent ETEC infections. Methods: We performed a Phase 1, dose escalation study (1–50 µg) evaluating the sublingual (SL) delivery of the double mutant heat-labile toxin LTR192G/L211A (dmLT) in 80 healthy adult volunteers. The primary objective was safety and the secondary was the immunogenicity of the dmLT. Subjects received 3 doses of dmLT at days 1, 15, and 29. Subjects receiving the first dose at each dosage level were observed overnight in a research facility. The second and third doses were administered on an outpatient basis. Data from cohorts 1–4 were used to select the cohort 5 dose (25 µg), comparing SL and oral routes. Results: The vaccine appeared safe and well tolerated with only rare development of vomiting or diarrhea. The serum anti-dmLT IgA and IgG and neutralizing antibody responses were modest after any of the SL immunizations. Serum IgA and IgG titers were increased at the higher antigen doses (25 or 50 µg) but the percent with 4-fold increases was at best 38% for both IgA and IgG. The 4-fold increase among subjects receiving all 3 doses was 43% for both IgA and IgG. Antibody titers following oral administration were, in general, significantly higher than after SL. The frequency of IgA- or IgG-ASCs in circulation were somewhat vaccine dose dependent and were detected at a moderate level. However, antibodies in saliva or stool were rarely detected. Post-vaccination increases in T cells or cytokine production were also infrequent. Conclusion: The dmLT vaccine formulation evaluated here was safe but only moderately immunogenic at doses up to 50 µg when administered by the SL or oral route. Studies at higher doses with better formulations appear warranted.

Original languageEnglish (US)
JournalVaccine
DOIs
StateAccepted/In press - Jan 1 2018
Externally publishedYes

Fingerprint

Enterotoxigenic Escherichia coli
oral vaccination
enterotoxigenic Escherichia coli
Immunoglobulin A
Immunization
toxins
Vaccines
Immunoglobulin G
Hot Temperature
heat
mutants
dosage
Escherichia coli Infections
Antibodies
Neutralizing Antibodies
Serum
vaccines
Saliva
Antibody Formation
Vomiting

Keywords

  • dmLT
  • Escherichia coli
  • ETEC
  • Oral
  • Sublingual
  • Vaccine

ASJC Scopus subject areas

  • Molecular Medicine
  • Immunology and Microbiology(all)
  • veterinary(all)
  • Public Health, Environmental and Occupational Health
  • Infectious Diseases

Cite this

A Phase 1 dose escalating study of double mutant heat-labile toxin LTR192G/L211A (dmLT) from Enterotoxigenic Escherichia coli (ETEC) by sublingual or oral immunization. / Bernstein, David I.; Pasetti, Marcela F.; Brady, Rebecca; Buskirk, Amanda D.; Wahid, Rezwanul; Dickey, Michelle; Cohen, Mitchell; Baughman, Holly; El-Khorazaty, Jill; Maier, Nicole; Sztein, Marcelo B.; Baqar, Shahida; Bourgeois, Louis.

In: Vaccine, 01.01.2018.

Research output: Contribution to journalArticle

Bernstein, David I. ; Pasetti, Marcela F. ; Brady, Rebecca ; Buskirk, Amanda D. ; Wahid, Rezwanul ; Dickey, Michelle ; Cohen, Mitchell ; Baughman, Holly ; El-Khorazaty, Jill ; Maier, Nicole ; Sztein, Marcelo B. ; Baqar, Shahida ; Bourgeois, Louis. / A Phase 1 dose escalating study of double mutant heat-labile toxin LTR192G/L211A (dmLT) from Enterotoxigenic Escherichia coli (ETEC) by sublingual or oral immunization. In: Vaccine. 2018.
@article{57b4851bbadd427e80d43d1e81541c49,
title = "A Phase 1 dose escalating study of double mutant heat-labile toxin LTR192G/L211A (dmLT) from Enterotoxigenic Escherichia coli (ETEC) by sublingual or oral immunization",
abstract = "Background: The public health burden of Enterotoxigenic Escherichia coli (ETEC) is high but no vaccine is specifically approved to prevent ETEC infections. Methods: We performed a Phase 1, dose escalation study (1–50 µg) evaluating the sublingual (SL) delivery of the double mutant heat-labile toxin LTR192G/L211A (dmLT) in 80 healthy adult volunteers. The primary objective was safety and the secondary was the immunogenicity of the dmLT. Subjects received 3 doses of dmLT at days 1, 15, and 29. Subjects receiving the first dose at each dosage level were observed overnight in a research facility. The second and third doses were administered on an outpatient basis. Data from cohorts 1–4 were used to select the cohort 5 dose (25 µg), comparing SL and oral routes. Results: The vaccine appeared safe and well tolerated with only rare development of vomiting or diarrhea. The serum anti-dmLT IgA and IgG and neutralizing antibody responses were modest after any of the SL immunizations. Serum IgA and IgG titers were increased at the higher antigen doses (25 or 50 µg) but the percent with 4-fold increases was at best 38{\%} for both IgA and IgG. The 4-fold increase among subjects receiving all 3 doses was 43{\%} for both IgA and IgG. Antibody titers following oral administration were, in general, significantly higher than after SL. The frequency of IgA- or IgG-ASCs in circulation were somewhat vaccine dose dependent and were detected at a moderate level. However, antibodies in saliva or stool were rarely detected. Post-vaccination increases in T cells or cytokine production were also infrequent. Conclusion: The dmLT vaccine formulation evaluated here was safe but only moderately immunogenic at doses up to 50 µg when administered by the SL or oral route. Studies at higher doses with better formulations appear warranted.",
keywords = "dmLT, Escherichia coli, ETEC, Oral, Sublingual, Vaccine",
author = "Bernstein, {David I.} and Pasetti, {Marcela F.} and Rebecca Brady and Buskirk, {Amanda D.} and Rezwanul Wahid and Michelle Dickey and Mitchell Cohen and Holly Baughman and Jill El-Khorazaty and Nicole Maier and Sztein, {Marcelo B.} and Shahida Baqar and Louis Bourgeois",
year = "2018",
month = "1",
day = "1",
doi = "10.1016/j.vaccine.2018.12.011",
language = "English (US)",
journal = "Vaccine",
issn = "0264-410X",
publisher = "Elsevier BV",

}

TY - JOUR

T1 - A Phase 1 dose escalating study of double mutant heat-labile toxin LTR192G/L211A (dmLT) from Enterotoxigenic Escherichia coli (ETEC) by sublingual or oral immunization

AU - Bernstein, David I.

AU - Pasetti, Marcela F.

AU - Brady, Rebecca

AU - Buskirk, Amanda D.

AU - Wahid, Rezwanul

AU - Dickey, Michelle

AU - Cohen, Mitchell

AU - Baughman, Holly

AU - El-Khorazaty, Jill

AU - Maier, Nicole

AU - Sztein, Marcelo B.

AU - Baqar, Shahida

AU - Bourgeois, Louis

PY - 2018/1/1

Y1 - 2018/1/1

N2 - Background: The public health burden of Enterotoxigenic Escherichia coli (ETEC) is high but no vaccine is specifically approved to prevent ETEC infections. Methods: We performed a Phase 1, dose escalation study (1–50 µg) evaluating the sublingual (SL) delivery of the double mutant heat-labile toxin LTR192G/L211A (dmLT) in 80 healthy adult volunteers. The primary objective was safety and the secondary was the immunogenicity of the dmLT. Subjects received 3 doses of dmLT at days 1, 15, and 29. Subjects receiving the first dose at each dosage level were observed overnight in a research facility. The second and third doses were administered on an outpatient basis. Data from cohorts 1–4 were used to select the cohort 5 dose (25 µg), comparing SL and oral routes. Results: The vaccine appeared safe and well tolerated with only rare development of vomiting or diarrhea. The serum anti-dmLT IgA and IgG and neutralizing antibody responses were modest after any of the SL immunizations. Serum IgA and IgG titers were increased at the higher antigen doses (25 or 50 µg) but the percent with 4-fold increases was at best 38% for both IgA and IgG. The 4-fold increase among subjects receiving all 3 doses was 43% for both IgA and IgG. Antibody titers following oral administration were, in general, significantly higher than after SL. The frequency of IgA- or IgG-ASCs in circulation were somewhat vaccine dose dependent and were detected at a moderate level. However, antibodies in saliva or stool were rarely detected. Post-vaccination increases in T cells or cytokine production were also infrequent. Conclusion: The dmLT vaccine formulation evaluated here was safe but only moderately immunogenic at doses up to 50 µg when administered by the SL or oral route. Studies at higher doses with better formulations appear warranted.

AB - Background: The public health burden of Enterotoxigenic Escherichia coli (ETEC) is high but no vaccine is specifically approved to prevent ETEC infections. Methods: We performed a Phase 1, dose escalation study (1–50 µg) evaluating the sublingual (SL) delivery of the double mutant heat-labile toxin LTR192G/L211A (dmLT) in 80 healthy adult volunteers. The primary objective was safety and the secondary was the immunogenicity of the dmLT. Subjects received 3 doses of dmLT at days 1, 15, and 29. Subjects receiving the first dose at each dosage level were observed overnight in a research facility. The second and third doses were administered on an outpatient basis. Data from cohorts 1–4 were used to select the cohort 5 dose (25 µg), comparing SL and oral routes. Results: The vaccine appeared safe and well tolerated with only rare development of vomiting or diarrhea. The serum anti-dmLT IgA and IgG and neutralizing antibody responses were modest after any of the SL immunizations. Serum IgA and IgG titers were increased at the higher antigen doses (25 or 50 µg) but the percent with 4-fold increases was at best 38% for both IgA and IgG. The 4-fold increase among subjects receiving all 3 doses was 43% for both IgA and IgG. Antibody titers following oral administration were, in general, significantly higher than after SL. The frequency of IgA- or IgG-ASCs in circulation were somewhat vaccine dose dependent and were detected at a moderate level. However, antibodies in saliva or stool were rarely detected. Post-vaccination increases in T cells or cytokine production were also infrequent. Conclusion: The dmLT vaccine formulation evaluated here was safe but only moderately immunogenic at doses up to 50 µg when administered by the SL or oral route. Studies at higher doses with better formulations appear warranted.

KW - dmLT

KW - Escherichia coli

KW - ETEC

KW - Oral

KW - Sublingual

KW - Vaccine

UR - http://www.scopus.com/inward/record.url?scp=85058412412&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85058412412&partnerID=8YFLogxK

U2 - 10.1016/j.vaccine.2018.12.011

DO - 10.1016/j.vaccine.2018.12.011

M3 - Article

C2 - 30563789

AN - SCOPUS:85058412412

JO - Vaccine

JF - Vaccine

SN - 0264-410X

ER -