Evaluation of the safety, immunogenicity, and efficacy in healthy adults of four doses of live oral hybrid Escherichia coli-Shigella flexneri 2a vaccine strain EcSf2a-2

Karen L. Kotloff, Genevieve A. Losonsky, James P. Nataro, Steven S. Wasserman, Thomas L. Hale, David N. Taylor, John W. Newland, Jeral C. Sadoff, Samuel B. Formal, Myron M. Levine

Research output: Contribution to journalArticle

Abstract

In previous trials, live invasive Escherichia coli-Shigella flexneri 2a hybrid vaccine candidate EcSf2a-2, administered to adult volunteers as 3 doses of ca. 2×109 colony forming units (c.f.u.) spaced over one week, induced fever and/or diarrhea in 11% of subjects and provided only limited protection (36% efficacy) against illness following challenge with virulent S. flexneri 2a. We sought to improve the clinical safety of this vaccine by administering a lower inoculum, and to enhance protective immunity by administering additional booster doses at 2 weeks. Twenty-one healthy adults were immunized with ca. 7×108 c.f.u. of EcSf2a-2 on days 0, 3, 14, and 17. The vaccine consistently colonized the intestine without causing serious adverse reactions; mild consistenly colonized the intestine without causing serious adverse reactions; mild diarrhea developed in one subject and low grade fever in another. Vaccination elicited an antibody secreting cell (ASC) response to lipopolysaccharide (LPS) in all subjects, which was highest on day 7 and notably diminished thereafter on days 10, 16, 21, and 24, suggesting that active mucosal immunity developed rapidly. The magnitude of the response was modest (geometric mean peak = 16 IgA ASC 106 peripheral blood mononuclear cells) and an IgG serological response to LPS was detected in only 19% of subjects. Following experimental challenge with virullent S. flexneri 2a administered with bicarbonate buffer, shigellosis (diarrhea, dysentery, or fever) developed in 10 of 16 vaccine recipients (63%) and in 12 of 14 unvaccinated controls (86%), resulting in a vaccine efficacy of 27% (95% confidence limits -197, 82, p = 0.15, 1-tailed). We conclude that four doses of EcSf2a-2 spaced over 17 days at inocula that are well-tolerated do not confer significant protection against illness following experimental challenge of healthy adult volunteers.

Original languageEnglish (US)
Pages (from-to)495-502
Number of pages8
JournalVaccine
Volume13
Issue number5
DOIs
StatePublished - 1995
Externally publishedYes

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Shigella flexneri
mouth
Vaccines
immune response
vaccines
Escherichia coli
Safety
fever
dosage
Diarrhea
diarrhea
Antibody-Producing Cells
Fever
lipopolysaccharides
volunteers
Intestines
Lipopolysaccharides
inoculum
intestines
Stem Cells

Keywords

  • mucosal immunity
  • Phase I study
  • shigella flexneri

ASJC Scopus subject areas

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

Cite this

Evaluation of the safety, immunogenicity, and efficacy in healthy adults of four doses of live oral hybrid Escherichia coli-Shigella flexneri 2a vaccine strain EcSf2a-2. / Kotloff, Karen L.; Losonsky, Genevieve A.; Nataro, James P.; Wasserman, Steven S.; Hale, Thomas L.; Taylor, David N.; Newland, John W.; Sadoff, Jeral C.; Formal, Samuel B.; Levine, Myron M.

In: Vaccine, Vol. 13, No. 5, 1995, p. 495-502.

Research output: Contribution to journalArticle

Kotloff, KL, Losonsky, GA, Nataro, JP, Wasserman, SS, Hale, TL, Taylor, DN, Newland, JW, Sadoff, JC, Formal, SB & Levine, MM 1995, 'Evaluation of the safety, immunogenicity, and efficacy in healthy adults of four doses of live oral hybrid Escherichia coli-Shigella flexneri 2a vaccine strain EcSf2a-2', Vaccine, vol. 13, no. 5, pp. 495-502. https://doi.org/10.1016/0264-410X(94)00011-B
Kotloff, Karen L. ; Losonsky, Genevieve A. ; Nataro, James P. ; Wasserman, Steven S. ; Hale, Thomas L. ; Taylor, David N. ; Newland, John W. ; Sadoff, Jeral C. ; Formal, Samuel B. ; Levine, Myron M. / Evaluation of the safety, immunogenicity, and efficacy in healthy adults of four doses of live oral hybrid Escherichia coli-Shigella flexneri 2a vaccine strain EcSf2a-2. In: Vaccine. 1995 ; Vol. 13, No. 5. pp. 495-502.
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abstract = "In previous trials, live invasive Escherichia coli-Shigella flexneri 2a hybrid vaccine candidate EcSf2a-2, administered to adult volunteers as 3 doses of ca. 2×109 colony forming units (c.f.u.) spaced over one week, induced fever and/or diarrhea in 11{\%} of subjects and provided only limited protection (36{\%} efficacy) against illness following challenge with virulent S. flexneri 2a. We sought to improve the clinical safety of this vaccine by administering a lower inoculum, and to enhance protective immunity by administering additional booster doses at 2 weeks. Twenty-one healthy adults were immunized with ca. 7×108 c.f.u. of EcSf2a-2 on days 0, 3, 14, and 17. The vaccine consistently colonized the intestine without causing serious adverse reactions; mild consistenly colonized the intestine without causing serious adverse reactions; mild diarrhea developed in one subject and low grade fever in another. Vaccination elicited an antibody secreting cell (ASC) response to lipopolysaccharide (LPS) in all subjects, which was highest on day 7 and notably diminished thereafter on days 10, 16, 21, and 24, suggesting that active mucosal immunity developed rapidly. The magnitude of the response was modest (geometric mean peak = 16 IgA ASC 106 peripheral blood mononuclear cells) and an IgG serological response to LPS was detected in only 19{\%} of subjects. Following experimental challenge with virullent S. flexneri 2a administered with bicarbonate buffer, shigellosis (diarrhea, dysentery, or fever) developed in 10 of 16 vaccine recipients (63{\%}) and in 12 of 14 unvaccinated controls (86{\%}), resulting in a vaccine efficacy of 27{\%} (95{\%} confidence limits -197, 82, p = 0.15, 1-tailed). We conclude that four doses of EcSf2a-2 spaced over 17 days at inocula that are well-tolerated do not confer significant protection against illness following experimental challenge of healthy adult volunteers.",
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T1 - Evaluation of the safety, immunogenicity, and efficacy in healthy adults of four doses of live oral hybrid Escherichia coli-Shigella flexneri 2a vaccine strain EcSf2a-2

AU - Kotloff, Karen L.

AU - Losonsky, Genevieve A.

AU - Nataro, James P.

AU - Wasserman, Steven S.

AU - Hale, Thomas L.

AU - Taylor, David N.

AU - Newland, John W.

AU - Sadoff, Jeral C.

AU - Formal, Samuel B.

AU - Levine, Myron M.

PY - 1995

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