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Vaccines

The Oral, Live Attenuated Enterotoxigenic Escherichia coli Vaccine ACE527 Reduces the Incidence and Severity of Diarrhea in a Human Challenge Model of Diarrheal Disease

Michael J. Darsley, Subhra Chakraborty, Barbara DeNearing, David A. Sack, Andrea Feller, Charlotte Buchwaldt, A. Louis Bourgeois, Richard Walker, Clayton D. Harro
Michael J. Darsley
aTD Vaccines A/S, Skorping, Denmark
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Subhra Chakraborty
bJohns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, USA
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Barbara DeNearing
bJohns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, USA
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David A. Sack
bJohns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, USA
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Andrea Feller
bJohns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, USA
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Charlotte Buchwaldt
aTD Vaccines A/S, Skorping, Denmark
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A. Louis Bourgeois
cPATH, Washington, DC, USA
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Richard Walker
cPATH, Washington, DC, USA
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Clayton D. Harro
bJohns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, USA
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DOI: 10.1128/CVI.00364-12
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  • Fig 1
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    Fig 1

    Subject allocation and retention through study.

  • Fig 2
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    Fig 2

    Quantitative serum IgG responses to LT-B following vaccination and challenge. Titers are expressed as fold increase relative to prevaccination levels, on a log2 scale. Solid circles, ACE527 vaccinees; open circles, placebo recipients. Bars show means and standard errors. Vaccination with ACE527 or placebo was on days 0 and 21, and challenge with H10407 was on day 49. The horizontal dashed line at a 2.5-fold increase is the threshold for a positive response.

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    Fig 3

    Quantitative level of H10407 shedding at day 2 postchallenge. Bars show geometric means and 95% confidence intervals.

  • Fig 4
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    Fig 4

    Frequency distribution of severity of diarrhea based on maximum loose stool output in any 24-hour period within 120 h of challenge. None, 0 g; mild, 1 to 400 g; moderate, 401 to 800 g; severe, 801 to 1,600 g; very severe, >1,600 g. Open bars, ACE527 vaccinees; solid bars, placebo recipients.

  • Fig 5
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    Fig 5

    Mean accumulation of loose stools with time from the first diarrheal stool experienced by a subject. Solid line, ACE527 vaccinees; dashed line, = placebo recipients.

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    Fig 6

    Kaplan-Meier survival analysis of the time to reach the primary endpoint (moderate or severe diarrhea) according to the quantitative level of shedding of H10407 in stool at 2 days after challenge. All subjects for whom quantitative shedding data were available were sorted by the level of shedding. Those below the median level (6.4 × 106 CFU/g) were considered “low shedders,” represented by filled circles, and those above or at the median were considered “high shedders,” represented by open circles.

Tables

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  • Table 1

    Subject demographics (safety analysis set, n = 70)

    Demographic variableVaccine group (n = 36)Placebo group (n = 34)All (n = 70)
    No.%No.%No.%
    Sex
        Male2877.82676.55477.1
        Female822.2823.51622.9
    Race
        Black/African American3494.42985.36390.0
        White25.638.857.1
        Other00.025.822.8
    Age, yr (mean ± SD)35.4 ± 8.7835.7 ± 9.1635.6 ± 8.90
  • Table 2

    Numbers of subjects with treatment-related AEs before challenge by group

    MedDRA System Organ Class preferred termVaccine group (n = 36)Placebo group (n = 34)
    No.%No.%
    Any treatment-emergent AE related to vaccinea1747.21647.1
    Gastrointestinal symptoms
        Gastrointestinal sounds abnormal822.2823.5
        Abdominal pain1027.8514.7
        Nausea1130.6411.8
        Defecation urgency822.2514.7
        Loose stools (<3 per 24 h)822.2411.8
        Diarrhea (>2 per 24 h)616.712.9
        Vomitingb719.400.0
    General symptoms
        Anorexia1027.838.8
        Malaise719.4514.7
        Chills38.325.9
        Headache616.725.9
        Dizziness513.912.9
        Myalgia25.612.9
    • ↵a AEs occurring in more than one subject.

    • ↵b P < 0.05.

  • Table 3

    Numbers of subjects shedding ACE527 and individual strains

    ParameterDayNo.a%
    Shedding of individual strains 3 days after either dose
        ACAM202232569.4
    241750.0
        ACAM202531130.6
    24720.6
        ACAM202731438.9
    241955.9
    Shedding of ACE527 (any strain) on specific days32877.8
    71233.3
    21411.1
    242470.6
    28617.6
    31514.7
    Any day (3–21) (first dose)3186.1
    Any day (24–31) (second dose)2470.6
    Any day (3–31) (either dose)3597.2
    • a n = 36 (dose 1) and n = 34 (dose 2).

  • Table 4

    Immune responses to vaccine antigens

    AntigenNo. (%) of subjects respondinga
    ACE527 recipient response to vaccine by day 41, 20 days after second vaccination (n = 36)Placebo recipient response to H10407 by day 70, 21 days after challenge (n = 27)
    Serum IgGSerum IgAALSAnySerum IgGSerum IgAALSAny
    LT-B24 (67)20 (56)33 (92)34 (94)14 (52)3 (11)17 (63)21 (78)
    CFA/I13 (36)17 (47)20 (56)29 (81)8 (30)10 (37)18 (67)23 (85)
    CS30 (0)4 (11)20 (56)22 (61)
    CS66 (17)5 (14)6 (17)13 (36)
    • ↵a Positive responses are defined as a 2.5-fold increase over baseline titer for serum IgG and IgA and as a 4-fold increase over baseline titer for ALS.

  • Table 5

    Serum antibody responses to O78 LPS

    GroupNo. (%) of positive responsesa
    Day 7 postchallengeDay 28 postchallenge
    Serum IgGSerum IgASerum IgGSerum IgA
    ACE527 (n = 29)2 (6.9)23 (79.3)7 (24.1)22 (75.9)
    Placebo (n = 27)8 (29.6)24 (88.9)13 (48.1)22 (81.5)
    • ↵a Positive responses are defined as a 2.5-fold increase over baseline titer.

  • Table 6

    Incidence and severity of symptoms of ETEC disease after challenge

    ParameterValue for groupProtective efficacy (%)P value (1 sided)a
    ACE527 (n = 29)Placebo (n = 27)
    Primary endpoint
        No. (%) of subjects with moderate or severe diarrhea15 (51.7)19 (70.4)26.60.12
    Secondary endpoints
        No. (%) of subjects with severe diarrhea14 (48.3)16 (59.3)18.5
        No. (%) of subjects with diarrhea of any severity16 (55.2)20 (74.1)25.50.12
        Mean total wt (g) of grade 3–5 stoolsb per subject1163.31,724.635.3
        Median total wt (g) of grade 3–5 stoolsb per subject390.01,128.065.40.09c
        Mean no. of grade 3–5 stoolsb per subject7.29.625.0
        Median no. of grade 3–5 stoolsb per subject5.010.050.00.13d
        No. (%) of subjects with moderate to severe nausea11 (37.9)12 (44.4)14.6
        No. (%) of subjects with moderate to severe vomiting8 (27.6)8 (29.6)6.8
        No. (%) of subjects with moderate to severe abdominal pain/cramps12 (41.4)12 (44.4)6.7
        No. (%) of subjects with moderate to severe anorexia8 (27.6)14 (51.9)46.80.06
        No. (%) of subjects who would have reduced their daily activity if traveling13 (44.4)19 (70.4)36.90.05
        Mean time (h) to onset of diarrhea60.0555.956.80.14c
        No. (%) of subjects with moderate to severe ETEC illness14 (48.3)16 (59.3)18.5
        CFU of challenge strain per g of stool (geometric mean)1.1 × 1062.2 × 10790.00.002
        No. (%) of subjects requiring early antibiotic treatment12 (41.4)16 (59.3)30.20.14
        No. (%) of subjects requiring intravenous fluids8 (27.6)10 (37.0)25.4
    Post hoc analyses
        Severity based only on total vol of loose stool
            No. (%) of subjects producing >800 g of grade 3–5 stools12 (41.4)19 (70.4)41.20.03
            No. (%) of subjects producing no grade 3–5 stools9 (31.0)3 (11.1)0.04
        Diarrheal output produced in 24 h following first diarrheal stool
            Mean total wt (g)599.81,102.445.6
            Median total wt (g)310.0488.036.50.06d
    • ↵a Determined by Fisher's exact test unless otherwise indicated; shown only where P < 0.15. As stool number and output data were not normally distributed, nonparametric tests were applied to assess the significance of differences in the median values.

    • ↵b Only stools which contributed to an episode of diarrhea are included.

    • ↵c Determined by Wilcoxon rank sum test.

    • ↵d Determined by Mann-Whitney test.

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The Oral, Live Attenuated Enterotoxigenic Escherichia coli Vaccine ACE527 Reduces the Incidence and Severity of Diarrhea in a Human Challenge Model of Diarrheal Disease
Michael J. Darsley, Subhra Chakraborty, Barbara DeNearing, David A. Sack, Andrea Feller, Charlotte Buchwaldt, A. Louis Bourgeois, Richard Walker, Clayton D. Harro
Clinical and Vaccine Immunology Nov 2012, 19 (12) 1921-1931; DOI: 10.1128/CVI.00364-12

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The Oral, Live Attenuated Enterotoxigenic Escherichia coli Vaccine ACE527 Reduces the Incidence and Severity of Diarrhea in a Human Challenge Model of Diarrheal Disease
Michael J. Darsley, Subhra Chakraborty, Barbara DeNearing, David A. Sack, Andrea Feller, Charlotte Buchwaldt, A. Louis Bourgeois, Richard Walker, Clayton D. Harro
Clinical and Vaccine Immunology Nov 2012, 19 (12) 1921-1931; DOI: 10.1128/CVI.00364-12
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    • ABSTRACT
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