Evaluation of the safety, tolerability, and immunogenicity of an oral, inactivated whole-cell shigella flexneri 2a vaccine in healthy adult subjects

Subhra Chakraborty, Clayton Harro, Barbara DeNearing, Jay Bream, Nicole Bauers, Len Dally, Jorge Flores, Lillian Van De Verg, David A. Sack, Richard Walker

Research output: Research - peer-reviewArticle

Abstract

Shigella causes high morbidity and mortality worldwide, but there is no licensed vaccine for shigellosis yet. We evaluated the safety and immunogenicity of a formalin-inactivated whole-cell Shigella flexneri 2a vaccine, Sf2aWC, given orally to adult volunteers. In a double-blind, placebo-controlled trial, 82 subjects were randomized to receive three doses of vaccine in dose escalation (2.6±0.8×108,×109,×1010, and×1011 vaccine particles/ml). Vaccine safety was actively monitored, and antigen-specific systemic and mucosal immune responses were determined in serum, antibody in lymphocyte supernatant (ALS), and fecal samples. Cytokines were measured in the serum. Sf2aWC was well tolerated and generally safe at all four dose levels. The vaccine resulted in a dose-dependent immune response. At the highest dose, the vaccine induced robust responses to lipopolysaccharide (LPS) in both serum and ALS samples. The highest magnitude and frequency of responses occurred after the first dose in almost all samples but was delayed for IgG in serum. Fifty percent of the vaccinees had a>4-fold increase in anti-LPS fecal antibody titers. Responses to invasion plasmid antigens (Ipa) were low. The levels of interleukin-17 (IL-17), IL-2, gamma interferon (IFN- ), tumor necrosis factor alpha (TNF- ), and IL-10 were increased, and IL-8 was decreased immediately after first dose, but these changes were very transient. This phase I trial demonstrated that the Sf2aWC vaccine, a relatively simple vaccine concept, was safe and immunogenic. The vaccine elicited immune responses which were comparable to those induced by a live, attenuated Shigella vaccine that was protective in prior human challenge studies.

LanguageEnglish (US)
Pages315-325
Number of pages11
JournalClinical and Vaccine Immunology
Volume23
Issue number4
DOIs
StatePublished - Apr 1 2016

Fingerprint

Shigella flexneri
Healthy Volunteers
Vaccines
Safety
Serum
Antibodies
Lipopolysaccharides
Lymphocytes
Antigens
Shigella Vaccines
Bacillary Dysentery
Mucosal Immunity
Attenuated Vaccines
Shigella
Interleukin-17
Interleukin-8
Interleukin-10
Formaldehyde
Interferon-gamma
Interleukin-2

ASJC Scopus subject areas

  • Clinical Biochemistry
  • Immunology
  • Immunology and Allergy
  • Microbiology (medical)

Cite this

Evaluation of the safety, tolerability, and immunogenicity of an oral, inactivated whole-cell shigella flexneri 2a vaccine in healthy adult subjects. / Chakraborty, Subhra; Harro, Clayton; DeNearing, Barbara; Bream, Jay; Bauers, Nicole; Dally, Len; Flores, Jorge; Van De Verg, Lillian; Sack, David A.; Walker, Richard.

In: Clinical and Vaccine Immunology, Vol. 23, No. 4, 01.04.2016, p. 315-325.

Research output: Research - peer-reviewArticle

Chakraborty, Subhra ; Harro, Clayton ; DeNearing, Barbara ; Bream, Jay ; Bauers, Nicole ; Dally, Len ; Flores, Jorge ; Van De Verg, Lillian ; Sack, David A. ; Walker, Richard. / Evaluation of the safety, tolerability, and immunogenicity of an oral, inactivated whole-cell shigella flexneri 2a vaccine in healthy adult subjects. In: Clinical and Vaccine Immunology. 2016 ; Vol. 23, No. 4. pp. 315-325
@article{223aab74815f4177a49e45e11e29d9c8,
title = "Evaluation of the safety, tolerability, and immunogenicity of an oral, inactivated whole-cell shigella flexneri 2a vaccine in healthy adult subjects",
abstract = "Shigella causes high morbidity and mortality worldwide, but there is no licensed vaccine for shigellosis yet. We evaluated the safety and immunogenicity of a formalin-inactivated whole-cell Shigella flexneri 2a vaccine, Sf2aWC, given orally to adult volunteers. In a double-blind, placebo-controlled trial, 82 subjects were randomized to receive three doses of vaccine in dose escalation (2.6±0.8×108,×109,×1010, and×1011 vaccine particles/ml). Vaccine safety was actively monitored, and antigen-specific systemic and mucosal immune responses were determined in serum, antibody in lymphocyte supernatant (ALS), and fecal samples. Cytokines were measured in the serum. Sf2aWC was well tolerated and generally safe at all four dose levels. The vaccine resulted in a dose-dependent immune response. At the highest dose, the vaccine induced robust responses to lipopolysaccharide (LPS) in both serum and ALS samples. The highest magnitude and frequency of responses occurred after the first dose in almost all samples but was delayed for IgG in serum. Fifty percent of the vaccinees had a>4-fold increase in anti-LPS fecal antibody titers. Responses to invasion plasmid antigens (Ipa) were low. The levels of interleukin-17 (IL-17), IL-2, gamma interferon (IFN- ), tumor necrosis factor alpha (TNF- ), and IL-10 were increased, and IL-8 was decreased immediately after first dose, but these changes were very transient. This phase I trial demonstrated that the Sf2aWC vaccine, a relatively simple vaccine concept, was safe and immunogenic. The vaccine elicited immune responses which were comparable to those induced by a live, attenuated Shigella vaccine that was protective in prior human challenge studies.",
author = "Subhra Chakraborty and Clayton Harro and Barbara DeNearing and Jay Bream and Nicole Bauers and Len Dally and Jorge Flores and {Van De Verg}, Lillian and Sack, {David A.} and Richard Walker",
year = "2016",
month = "4",
doi = "10.1128/CVI.00608-15",
volume = "23",
pages = "315--325",
journal = "Clinical and Vaccine Immunology",
issn = "1556-6811",
publisher = "American Society for Microbiology",
number = "4",

}

TY - JOUR

T1 - Evaluation of the safety, tolerability, and immunogenicity of an oral, inactivated whole-cell shigella flexneri 2a vaccine in healthy adult subjects

AU - Chakraborty,Subhra

AU - Harro,Clayton

AU - DeNearing,Barbara

AU - Bream,Jay

AU - Bauers,Nicole

AU - Dally,Len

AU - Flores,Jorge

AU - Van De Verg,Lillian

AU - Sack,David A.

AU - Walker,Richard

PY - 2016/4/1

Y1 - 2016/4/1

N2 - Shigella causes high morbidity and mortality worldwide, but there is no licensed vaccine for shigellosis yet. We evaluated the safety and immunogenicity of a formalin-inactivated whole-cell Shigella flexneri 2a vaccine, Sf2aWC, given orally to adult volunteers. In a double-blind, placebo-controlled trial, 82 subjects were randomized to receive three doses of vaccine in dose escalation (2.6±0.8×108,×109,×1010, and×1011 vaccine particles/ml). Vaccine safety was actively monitored, and antigen-specific systemic and mucosal immune responses were determined in serum, antibody in lymphocyte supernatant (ALS), and fecal samples. Cytokines were measured in the serum. Sf2aWC was well tolerated and generally safe at all four dose levels. The vaccine resulted in a dose-dependent immune response. At the highest dose, the vaccine induced robust responses to lipopolysaccharide (LPS) in both serum and ALS samples. The highest magnitude and frequency of responses occurred after the first dose in almost all samples but was delayed for IgG in serum. Fifty percent of the vaccinees had a>4-fold increase in anti-LPS fecal antibody titers. Responses to invasion plasmid antigens (Ipa) were low. The levels of interleukin-17 (IL-17), IL-2, gamma interferon (IFN- ), tumor necrosis factor alpha (TNF- ), and IL-10 were increased, and IL-8 was decreased immediately after first dose, but these changes were very transient. This phase I trial demonstrated that the Sf2aWC vaccine, a relatively simple vaccine concept, was safe and immunogenic. The vaccine elicited immune responses which were comparable to those induced by a live, attenuated Shigella vaccine that was protective in prior human challenge studies.

AB - Shigella causes high morbidity and mortality worldwide, but there is no licensed vaccine for shigellosis yet. We evaluated the safety and immunogenicity of a formalin-inactivated whole-cell Shigella flexneri 2a vaccine, Sf2aWC, given orally to adult volunteers. In a double-blind, placebo-controlled trial, 82 subjects were randomized to receive three doses of vaccine in dose escalation (2.6±0.8×108,×109,×1010, and×1011 vaccine particles/ml). Vaccine safety was actively monitored, and antigen-specific systemic and mucosal immune responses were determined in serum, antibody in lymphocyte supernatant (ALS), and fecal samples. Cytokines were measured in the serum. Sf2aWC was well tolerated and generally safe at all four dose levels. The vaccine resulted in a dose-dependent immune response. At the highest dose, the vaccine induced robust responses to lipopolysaccharide (LPS) in both serum and ALS samples. The highest magnitude and frequency of responses occurred after the first dose in almost all samples but was delayed for IgG in serum. Fifty percent of the vaccinees had a>4-fold increase in anti-LPS fecal antibody titers. Responses to invasion plasmid antigens (Ipa) were low. The levels of interleukin-17 (IL-17), IL-2, gamma interferon (IFN- ), tumor necrosis factor alpha (TNF- ), and IL-10 were increased, and IL-8 was decreased immediately after first dose, but these changes were very transient. This phase I trial demonstrated that the Sf2aWC vaccine, a relatively simple vaccine concept, was safe and immunogenic. The vaccine elicited immune responses which were comparable to those induced by a live, attenuated Shigella vaccine that was protective in prior human challenge studies.

UR - http://www.scopus.com/inward/record.url?scp=84964918021&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84964918021&partnerID=8YFLogxK

U2 - 10.1128/CVI.00608-15

DO - 10.1128/CVI.00608-15

M3 - Article

VL - 23

SP - 315

EP - 325

JO - Clinical and Vaccine Immunology

T2 - Clinical and Vaccine Immunology

JF - Clinical and Vaccine Immunology

SN - 1556-6811

IS - 4

ER -