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Microbial Immunity and Vaccines | Spotlight

Safety and Immunogenicity of an Enterotoxigenic Escherichia coli Vaccine Patch Containing Heat-Labile Toxin: Use of Skin Pretreatment To Disrupt the Stratum Corneum

Gregory M. Glenn, Christina P. Villar, David C. Flyer, A. Louis Bourgeois, Robin McKenzie, Robert M. Lavker, Sarah A. Frech
Gregory M. Glenn
1IOMAI Corporation, 20 Firstfield Road, Gaithersburg, Maryland 20878
2Center for Immunization Research, Johns Hopkins Bloomberg School of Public Health, Johns Hopkins University, 624 North Broadway, Baltimore, Maryland 21205
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  • For correspondence: gglenn@iomai.com
Christina P. Villar
1IOMAI Corporation, 20 Firstfield Road, Gaithersburg, Maryland 20878
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David C. Flyer
1IOMAI Corporation, 20 Firstfield Road, Gaithersburg, Maryland 20878
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A. Louis Bourgeois
2Center for Immunization Research, Johns Hopkins Bloomberg School of Public Health, Johns Hopkins University, 624 North Broadway, Baltimore, Maryland 21205
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Robin McKenzie
2Center for Immunization Research, Johns Hopkins Bloomberg School of Public Health, Johns Hopkins University, 624 North Broadway, Baltimore, Maryland 21205
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Robert M. Lavker
3Northwestern University School of Medicine, Department of Dermatology, 303 East Chicago Avenue, Chicago, Illinois 60611
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Sarah A. Frech
1IOMAI Corporation, 20 Firstfield Road, Gaithersburg, Maryland 20878
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DOI: 10.1128/IAI.01740-06
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  • FIG. 1.
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    FIG. 1.

    Immunogenicity of LT delivered by TCI. Following pretreatment of the skin with a nonwoven abrasive EKG prep pad to disrupt the stratum corneum, a wet patch containing 50 μg of one of three lots of LT was applied to the pretreated area on days 0 and 21. Serum samples obtained on days 0, 21, 42, 90, and 381 were analyzed to determine the presence of anti-LT IgG and IgA by ELISA. There were no significant differences between the anti-LT immune responses of the three groups (P < 0.05). The serum antibody levels for the combined treatment groups are expressed in ELISA units; the bars indicate geometric means, and the error bars indicate 95% confidence intervals. The percentages are percentages of seroconversion (a twofold increase compared with the baseline for IgG and a fourfold increase for IgA).

  • FIG. 2.
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    FIG. 2.

    LT toxin neutralization by LT immune sera. Serum samples obtained on days 0, 21, 42, 90, and 381 from subjects vaccinated on days 0 and 21 with 50 μg of LT by TCI were tested to determine their abilities to neutralize LT in a Y-1 serum neutralization assay. The serum antibody levels for the combined treatment groups are expressed as average ED50s, and the error bars indicate 95% confidence intervals.

  • FIG. 3.
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    FIG. 3.

    Comparison of neutralization of LT and CT toxins by LT immune sera. Pooled serum samples obtained on days 0 and 42 from subjects vaccinated on days 0 and 21 with 50 μg of LT by TCI were tested to determine their abilities to neutralize CT in a Y-1 serum neutralization assay. Toxin activity is indicated by the reduction in OD530, which reflects the number of neutral red-stained cells remaining after treatment. Toxin neutralization of both LT and CT by serum is shown.

  • FIG. 4.
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    FIG. 4.

    Anti-LT serum IgG induced following a live infectious challenge. Subjects received an oral infectious challenge consisting of 1 × 109 viable ETEC E2447A LT+ ST+ bacteria. Serum samples obtained on day 0, as well as on days 7 and 28 following the oral challenge, were analyzed to determine the presence of anti-LT IgG by ELISA. The serum antibody levels are expressed in ELISA units; the bars indicate geometric means, and the error bars indicate 95% confidence intervals. The percentages are percentages of seroconversion.

  • FIG. 5.
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    FIG. 5.

    Serological recognition of LT by sera from CTB-vaccinated subjects. Sera obtained from subjects 35 days after vaccination with a single dose of an oral whole-cell cholera vaccine containing 1 mg CTB and killed V. cholerae cells were analyzed to determine their recognition of LT, using an ELISA. The serum antibody levels are expressed in ELISA units; the bars indicate geometric means, and the error bars indicate 95% confidence levels. The percentage is the percentage of seroconversion.

  • FIG. 6.
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    FIG. 6.

    Correlation between net TEWL and fold increase in the IgG titer. TEWL was measured on the skin before pretreatment and after skin pretreatment but before patch application in 51 of 59 subjects at day 42. Individual net TEWL (posttreatment TEWL − baseline TEWL) at the time of vaccination is plotted against the increase in anti-LT IgG at day 42 (r = 0.59, P = 0.001).

  • FIG. 7.
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    FIG. 7.

    Biopsy of control and nonwoven abrasive pad-treated human skin. After informed consent, a shave biopsy of human skin was obtained from a control site (A) and a site that was treated with 15 strokes of a nonwoven abrasive EKG pad (B). The skin was formalin fixed and stained using hematoxylin and eosin. The three layers of the skin, the stratum corneum, epidermis, and dermis, are visible, and in the group pretreated with the nonwoven abrasive pad a modest decrease in the thickness of the stratum corneum is visible.

Tables

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  • TABLE 1.

    LT IgG GMT for subjects immunized transcutaneously

    Study dayGMT (EU)
    Group 1 (n = 20)Group 2 (n = 20)Group 3 (n = 20)All treatments (n = 60)
    0369656a514499
    215,2178,5535,5956,297
    4212,73412,98810,93912,185
    9010,77214,35011,22212,016
    • ↵ a P = 0.008 for a pairwise comparison of group 1 and group 2 using the covariate-adjusted and unadjusted generalized linear model.

  • TABLE 2.

    TEWL resultsa

    GroupnTEWL(g/m2/h)
    BaselineAfter pretreatment of skinNet
    nMean (SD)RangenMean (SD)RangenMean (SD)Range
    118187.6 (2.2)4.2-11.21721.9 (16.1)8.8-74.21714.2 (15.6)3.2-65.9
    217167.2 (2.1)3.0-11.21620.3 (9.4)10.0-45.41613.2 (9.2)4.29-37.4
    316176.9 (2.1)2.0-10.81718.2 (9.3)7.3-34.71711.3 (8.7)1.4-27.1
    All51517.3 (2.1)b2.0-11.225020.1 (11.9)b7.3-74.25012.9 (11.5)1.4-65.9
    • ↵ a Baseline TEWL, TEWL after pretreatment of the skin at day 42, and net TEWL were determined. The net TEWL was calculated by subtracting the baseline TEWL from the TEWL after skin pretreatment. The differences between groups for baseline TEWL, TEWL after skin pretreatment, and net TEWL were not significant (P > 0.005, as determined by a t test).

    • ↵ b The differences between the group TEWL and the combined subject TEWL after skin pretreatment and baseline TEWL were significant (P < 0.01).

  • TABLE 3.

    Summary of stratum corneum cell layer measurements

    SubjectNo. of strokesNo. of stratum corneum cell layers removed (mean ± SD)% Reduction
    001None (control)17 ± 2.0
    1512.5 ± 0.726
    209.0 ± 1.547
    002None (control)18.8 ± 2.2
    1514.1 ± 1.525
    207.9 ± 2.158
    003None (control)22.0 ± 1.8
    1514.4 ± 1.735
    2011.8 ± 2.446
    MeanNone (control)19.3
    1513.729
    209.650
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Safety and Immunogenicity of an Enterotoxigenic Escherichia coli Vaccine Patch Containing Heat-Labile Toxin: Use of Skin Pretreatment To Disrupt the Stratum Corneum
Gregory M. Glenn, Christina P. Villar, David C. Flyer, A. Louis Bourgeois, Robin McKenzie, Robert M. Lavker, Sarah A. Frech
Infection and Immunity Apr 2007, 75 (5) 2163-2170; DOI: 10.1128/IAI.01740-06

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Safety and Immunogenicity of an Enterotoxigenic Escherichia coli Vaccine Patch Containing Heat-Labile Toxin: Use of Skin Pretreatment To Disrupt the Stratum Corneum
Gregory M. Glenn, Christina P. Villar, David C. Flyer, A. Louis Bourgeois, Robin McKenzie, Robert M. Lavker, Sarah A. Frech
Infection and Immunity Apr 2007, 75 (5) 2163-2170; DOI: 10.1128/IAI.01740-06
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KEYWORDS

bacterial toxins
enterotoxins
Escherichia coli Infections
Escherichia coli Proteins
Escherichia coli Vaccines
immunization
skin

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