Article Figures & Data
Figures
- Fig 1
Subject allocation and retention through study.
- 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.
- Fig 3
Quantitative level of H10407 shedding at day 2 postchallenge. Bars show geometric means and 95% confidence intervals.
- 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
Mean accumulation of loose stools with time from the first diarrheal stool experienced by a subject. Solid line, ACE527 vaccinees; dashed line, = placebo recipients.
- 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
- Table 1
Subject demographics (safety analysis set, n = 70)
Demographic variable Vaccine group (n = 36) Placebo group (n = 34) All (n = 70) No. % No. % No. % Sex Male 28 77.8 26 76.5 54 77.1 Female 8 22.2 8 23.5 16 22.9 Race Black/African American 34 94.4 29 85.3 63 90.0 White 2 5.6 3 8.8 5 7.1 Other 0 0.0 2 5.8 2 2.8 Age, yr (mean ± SD) 35.4 ± 8.78 35.7 ± 9.16 35.6 ± 8.90 - Table 2
Numbers of subjects with treatment-related AEs before challenge by group
MedDRA System Organ Class preferred term Vaccine group (n = 36) Placebo group (n = 34) No. % No. % Any treatment-emergent AE related to vaccinea 17 47.2 16 47.1 Gastrointestinal symptoms Gastrointestinal sounds abnormal 8 22.2 8 23.5 Abdominal pain 10 27.8 5 14.7 Nausea 11 30.6 4 11.8 Defecation urgency 8 22.2 5 14.7 Loose stools (<3 per 24 h) 8 22.2 4 11.8 Diarrhea (>2 per 24 h) 6 16.7 1 2.9 Vomitingb 7 19.4 0 0.0 General symptoms Anorexia 10 27.8 3 8.8 Malaise 7 19.4 5 14.7 Chills 3 8.3 2 5.9 Headache 6 16.7 2 5.9 Dizziness 5 13.9 1 2.9 Myalgia 2 5.6 1 2.9 - Table 3
Numbers of subjects shedding ACE527 and individual strains
Parameter Day No.a % Shedding of individual strains 3 days after either dose ACAM2022 3 25 69.4 24 17 50.0 ACAM2025 3 11 30.6 24 7 20.6 ACAM2027 3 14 38.9 24 19 55.9 Shedding of ACE527 (any strain) on specific days 3 28 77.8 7 12 33.3 21 4 11.1 24 24 70.6 28 6 17.6 31 5 14.7 Any day (3–21) (first dose) 31 86.1 Any day (24–31) (second dose) 24 70.6 Any day (3–31) (either dose) 35 97.2 a n = 36 (dose 1) and n = 34 (dose 2).
- Table 4
Immune responses to vaccine antigens
Antigen No. (%) 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 IgG Serum IgA ALS Any Serum IgG Serum IgA ALS Any LT-B 24 (67) 20 (56) 33 (92) 34 (94) 14 (52) 3 (11) 17 (63) 21 (78) CFA/I 13 (36) 17 (47) 20 (56) 29 (81) 8 (30) 10 (37) 18 (67) 23 (85) CS3 0 (0) 4 (11) 20 (56) 22 (61) CS6 6 (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
Group No. (%) of positive responsesa Day 7 postchallenge Day 28 postchallenge Serum IgG Serum IgA Serum IgG Serum 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
Parameter Value for group Protective efficacy (%) P value (1 sided)a ACE527 (n = 29) Placebo (n = 27) Primary endpoint No. (%) of subjects with moderate or severe diarrhea 15 (51.7) 19 (70.4) 26.6 0.12 Secondary endpoints No. (%) of subjects with severe diarrhea 14 (48.3) 16 (59.3) 18.5 No. (%) of subjects with diarrhea of any severity 16 (55.2) 20 (74.1) 25.5 0.12 Mean total wt (g) of grade 3–5 stoolsb per subject 1163.3 1,724.6 35.3 Median total wt (g) of grade 3–5 stoolsb per subject 390.0 1,128.0 65.4 0.09c Mean no. of grade 3–5 stoolsb per subject 7.2 9.6 25.0 Median no. of grade 3–5 stoolsb per subject 5.0 10.0 50.0 0.13d No. (%) of subjects with moderate to severe nausea 11 (37.9) 12 (44.4) 14.6 No. (%) of subjects with moderate to severe vomiting 8 (27.6) 8 (29.6) 6.8 No. (%) of subjects with moderate to severe abdominal pain/cramps 12 (41.4) 12 (44.4) 6.7 No. (%) of subjects with moderate to severe anorexia 8 (27.6) 14 (51.9) 46.8 0.06 No. (%) of subjects who would have reduced their daily activity if traveling 13 (44.4) 19 (70.4) 36.9 0.05 Mean time (h) to onset of diarrhea 60.05 55.95 6.8 0.14c No. (%) of subjects with moderate to severe ETEC illness 14 (48.3) 16 (59.3) 18.5 CFU of challenge strain per g of stool (geometric mean) 1.1 × 106 2.2 × 107 90.0 0.002 No. (%) of subjects requiring early antibiotic treatment 12 (41.4) 16 (59.3) 30.2 0.14 No. (%) of subjects requiring intravenous fluids 8 (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 stools 12 (41.4) 19 (70.4) 41.2 0.03 No. (%) of subjects producing no grade 3–5 stools 9 (31.0) 3 (11.1) 0.04 Diarrheal output produced in 24 h following first diarrheal stool Mean total wt (g) 599.8 1,102.4 45.6 Median total wt (g) 310.0 488.0 36.5 0.06d ↵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.
