This is a research study about an experimental (investigational) oral inactivated whole cell Shigella flexneri 2a killed vaccine (Sf2aWC). Sf2aWC is a killed vaccine that is being made to prevent disease from Shigella., which causes bloody, watery diarrhea. Infants and children living in developing countries experience the greatest consequences of this disease. The purpose of this study is to find a dose of the vaccine that is safe, tolerable, and develops an immune response. About 82 healthy adults, ages 18-45, will participate in this study. This study will require volunteers to stay in the research facility for several nights for the first dose. Participants in Cohorts 2, 3, and 4 will not be required to stay overnight for the second and third doses. Participants will be assigned to receive 1 of 4 vaccine doses by mouth. Study procedures include: stool samples, blood samples and documenting side effects. Participants will be involved in study related procedures for about 8 months.
Despite the public health burden of Shigella spp. on travelers, deployed soldiers and, most significantly, young children in the developing world, there is no licensed vaccine against Shigella. The rationale for using Shigella flexneri 2a whole cell killed vaccine (Sf2aWC), is that it is expected to be especially well tolerated by subjects. If Sf2aWC is safe and immunogenic, it may be combined with S. sonnei and S. flexneri 3a as the basis of a multivalent vaccine, because these three components should cover up to 80% of shigella infections in developing countries and over 90% in developed countries. This is a single site, Phase 1, double-blind, randomized, placebo-controlled, dose-escalation study in healthy adult subjects. Approximately 82 subjects will be enrolled into four separate cohorts and will be randomized to receive Sf2aWC or placebo. The placebo preparation will be bicarbonate buffer. Cohort 1 subjects will receive a single oral dose of Sf2aWC (2.6±0.8 x 10\^8 vp/mL) or placebo. Dosing and 72 hours of supervised post-vaccination safety follow-up will be conducted in the Center for Immunization Research, Johns Hopkins School of Public Health (CIR) Inpatient Unit. Before enrolling subjects in subsequent cohorts, safety data from the previous Cohort(s) through Study Day 7 will be evaluated and reviewed by the Safety Review Committee (SRC). Cohorts 2, 3, and 4 participants will receive three doses of Sf2aWC vaccine or placebo at 0, 1 and 2 months. The first immunization will be administered in the CIR inpatient unit, followed by 72 hours of direct post-immunization observation. If after review by the SRC the first dose appears safe and well tolerated, subsequent doses will be administered on an outpatient basis. Safety will be assessed by solicited symptoms/subject memory aid and laboratory evaluations. Adverse events (AE)s will be graded according to standardized criteria. The immunogenicity outcome measures of interest include serum immunoglobulin G (IgG) and immunoglobulin A (IgA) antibodies by ELISA against S. flexneri 2a Lipopolysaccharide (LPS) and S. flexneri 2a invasive protein antigens (Ipa), cytokine assays, B and T cell memory responses, and vaccine-specific IgA responses. The proposed sample size of twenty per group in Cohorts 2, 3, and 4 would be sufficient to select the appropriate dose to move into the next study phase, providing that a difference in the immunogenicity between the two arms is 20% or greater. Participants will include 82 healthy adult male and female subjects, ages 18 to 45 inclusive. The primary objective of this study is to assess the safety and tolerability of Sf2aWC vaccine when administered in three oral doses over a range of dose levels in healthy adult subjects. The secondary objective is to assess the immunogenicity of the Sf2aWC vaccine over a range of doses in healthy adult subjects.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
QUADRUPLE
Enrollment
82
Shigella flexneri 2a whole cell killed vaccine (Sf2aWC): 2.6±0.8 x 10\^8 vp/mL administered on Day 0
Shigella flexneri 2a whole cell killed vaccine (Sf2aWC): 2.6±0.8 x 10\^9 vp/mL administered on Days 0, 28, and 56
Shigella flexneri 2a whole cell killed vaccine (Sf2aWC): 2.6±0.8 x 10\^10 vp/mL administered on Days 0, 28, and 56
Shigella flexneri 2a whole cell killed vaccine (Sf2aWC): 2.6±0.8 x 10\^11 vp/mL administered on Days 0, 28, and 56
Placebo administered on Day 0 (if 1 dose) or Day 0, 28, and 56 (3 doses)
Center for Immunization Research (CIR) at Johns Hopkins School of Public Health (JHSPH)
Baltimore, Maryland, United States
Johns Hopkins University CIR Isolation Unit
Baltimore, Maryland, United States
Maximum Reactogenicity Per Subject and Treatment Group
Local and systemic reactogenicity was assessed post-vaccination using targeted physical examinations, vital signs and clinical laboratory tests, and diary cards (completed following discharge daily through Day 7). Reactogenicity included: nausea, vomiting, fever, abdominal pain, abdominal cramping, bloating, malaise, headache, decreased appetite, generalized myalgias, chills, light-headedness, constipation, excessive flatulence, reactive arthritis, dysentery, loose stool, diarrhea, hypovolemia, joint pain, defecation urgency, and oral temperature.
Time frame: 7 days after each vaccination (Day 0, Day 35, Day 63)
Frequency of Unsolicited Adverse Events With a Reasonable Possibility That the Study Product Caused the Event
Time frame: 6 months after final vaccination (Day 168 or Day 224)
Number and Percentage of Subjects in Cohort 3 With Positive Immunologic Response in Serum Lipopolysaccharide (LPS) Immunoglobulin A (IgA) Response From Baseline
A positive immunological response is defined as an increase of 4-fold or more over the appropriate baseline value for ALS or an increase of more than 2-fold for serological responses (fold increases will be calculated to 1 decimal place). For all immunology variables, the raw values were first adjusted to the geometric mean of positive controls, and any values \<0.15 were changed to 0.14. The fold-change in response was then calculated as the ratio of each value to the baseline value (so the minimum baseline value was 0.14). Specimens from vaccine recipients in Cohorts 1 and 2 were not tested for immunogenicity data and no data were collected.
Time frame: 35 days
Number and Percentage of Subjects in Cohort 4 With Positive Immunologic Response in Serum Lipopolysaccharide (LPS) Immunoglobulin A (IgA) Response From Baseline
A positive immunological response is defined as an increase of 4-fold or more over the appropriate baseline value for ALS or an increase of more than 2-fold for serological responses (fold increases will be calculated to 1 decimal place). For all immunology variables, the raw values were first adjusted to the geometric mean of positive controls, and any values \<0.15 were changed to 0.14. The fold-change in response was then calculated as the ratio of each value to the baseline value (so the minimum baseline value was 0.14). Specimens from vaccine recipients in Cohorts 1 and 2 were not tested for immunogenicity data and no data were collected.
Time frame: 63 days
Geometric Mean Titer (GMT) of Serum Lipopolysaccharide (LPS) Immunoglobulin A (IgA) Response in Cohort 3
S. flexneri 2a LPS were used as the ELISA antigens. Immunogenicity responses are presented for Cohorts 3 and 4 only. Specimens from vaccine recipients in Cohorts 1 and 2 were not tested for immunogenicity data and no data were collected. For all immunology variables, the raw values were first adjusted to the geometric mean of positive controls, and any values \<0.15 were changed to 0.14.
Time frame: 35 days
Geometric Mean Titer (GMT) of Serum Lipopolysaccharide (LPS) Immunoglobulin A (IgA) Response in Cohort 4
S. flexneri 2a LPS were used as the ELISA antigens. Immunogenicity responses are presented for Cohorts 3 and 4 only. Specimens from vaccine recipients in Cohorts 1 and 2 were not tested for immunogenicity data and no data were collected. For all immunology variables, the raw values were first adjusted to the geometric mean of positive controls, and any values \<0.15 were changed to 0.14.
Time frame: 63 days
Number and Percentage of Subjects in Cohort 3 With Positive Immunologic Response in Serum Lipopolysaccharide (LPS) Immunoglobulin G (IgG) Response From Baseline
A positive immunological response is defined as an increase of 4-fold or more over the appropriate baseline value for ALS or an increase of more than 2-fold for serological responses (fold increases will be calculated to 1 decimal place). For all immunology variables, the raw values were first adjusted to the geometric mean of positive controls, and any values \<0.15 were changed to 0.14. The fold-change in response was then calculated as the ratio of each value to the baseline value (so the minimum baseline value was 0.14). Specimens from vaccine recipients in Cohorts 1 and 2 were not tested for immunogenicity data and no data were collected.
Time frame: 16 weeks
Number and Percentage of Subjects in Cohort 4 With Positive Immunologic Response in Serum Lipopolysaccharide (LPS) Immunoglobulin G (IgG) Response From Baseline
A positive immunological response is defined as an increase of 4-fold or more over the appropriate baseline value for ALS or an increase of more than 2-fold for serological responses (fold increases will be calculated to 1 decimal place). For all immunology variables, the raw values were first adjusted to the geometric mean of positive controls, and any values \<0.15 were changed to 0.14. The fold-change in response was then calculated as the ratio of each value to the baseline value (so the minimum baseline value was 0.14). Specimens from vaccine recipients in Cohorts 1 and 2 were not tested for immunogenicity data and no data were collected.
Time frame: 16 weeks
Geometric Mean Titer (GMT) of Serum Lipopolysaccharide (LPS) Immunoglobulin G (IgG) Response in Cohort 3
S. flexneri 2a LPS were used as the ELISA antigens. Immunogenicity responses are presented for Cohorts 3 and 4 only. Specimens from vaccine recipients in Cohorts 1 and 2 were not tested for immunogenicity data and no data were collected. For all immunology variables, the raw values were first adjusted to the geometric mean of positive controls, and any values \<0.15 were changed to 0.14.
Time frame: 35 days
Geometric Mean Titer (GMT) of Serum Lipopolysaccharide (LPS) Immunoglobulin G (IgG) Response in Cohort 4
S. flexneri 2a LPS were used as the ELISA antigens. Immunogenicity responses are presented for Cohorts 3 and 4 only. Specimens from vaccine recipients in Cohorts 1 and 2 were not tested for immunogenicity data and no data were collected. For all immunology variables, the raw values were first adjusted to the geometric mean of positive controls, and any values \<0.15 were changed to 0.14.
Time frame: 16 weeks
Number and Percentage of Subjects With Positive Immunologic Response in Serum Antibody From Lymphocytes Supernatant (ALS) Lipopolysaccharide (LPS) Immunoglobulin A (IgA) Response From Baseline
A positive immunological response is defined as an increase of 4-fold or more over the appropriate baseline value for ALS or an increase of more than 2-fold for serological responses (fold increases will be calculated to 1 decimal place). For all immunology variables, the raw values were first adjusted to the geometric mean of positive controls, and any values \<0.15 were changed to 0.14. The fold-change in response was then calculated as the ratio of each value to the baseline value (so the minimum baseline value was 0.14). Specimens from vaccine recipients in Cohorts 1 and 2 were not tested for immunogenicity data and no data were collected.
Time frame: 63 days
Geometric Mean Titer (GMT) of Serum Antibody From Lymphocytes Supernatant (ALS) Lipopolysaccharide (LPS) Immunoglobulin A (IgA) Response From Baseline
S. flexneri 2a LPS were used as the ELISA antigens. Immunogenicity responses are presented for Cohorts 3 and 4 only. Specimens from vaccine recipients in Cohorts 1 and 2 were not tested for immunogenicity data and no data were collected. For all immunology variables, the raw values were first adjusted to the geometric mean of positive controls, and any values \<0.15 were changed to 0.14.
Time frame: 63 days
Number and Percentage of Subjects With Positive Immunologic Response in Serum Antibody From Lymphocytes Supernatant (ALS) Lipopolysaccharide (LPS) Immunoglobulin G (IgG) Response From Baseline
A positive immunological response is defined as an increase of 4-fold or more over the appropriate baseline value for ALS or an increase of more than 2-fold for serological responses (fold increases will be calculated to 1 decimal place). For all immunology variables, the raw values were first adjusted to the geometric mean of positive controls, and any values \<0.15 were changed to 0.14. The fold-change in response was then calculated as the ratio of each value to the baseline value (so the minimum baseline value was 0.14). Specimens from vaccine recipients in Cohorts 1 and 2 were not tested for immunogenicity data and no data were collected.
Time frame: 63 days
Geometric Mean Titer (GMT) of Serum Antibody From Lymphocytes Supernatant (ALS) Lipopolysaccharide (LPS) Immunoglobulin G (IgG) Response
S. flexneri 2a LPS were used as the ELISA antigens. Immunogenicity responses are presented for Cohorts 3 and 4 only. Specimens from vaccine recipients in Cohorts 1 and 2 were not tested for immunogenicity data and no data were collected. For all immunology variables, the raw values were first adjusted to the geometric mean of positive controls, and any values \<0.15 were changed to 0.14.
Time frame: 63 days
Number and Percentage of Subjects With Positive Immunologic Response in Invasion Plasmid Antigens B (IpaB) Lymphocytes Supernatant (ALS) Immunoglobulin A (IgA) Response From Baseline
A positive immunological response is defined as an increase of 4-fold or more over the appropriate baseline value for ALS or an increase of more than 2-fold for serological responses (fold increases will be calculated to 1 decimal place). For all immunology variables, the raw values were first adjusted to the geometric mean of positive controls, and any values \<0.15 were changed to 0.14. The fold-change in response was then calculated as the ratio of each value to the baseline value (so the minimum baseline value was 0.14). Specimens from vaccine recipients in Cohorts 1 and 2 were not tested for immunogenicity data and no data were collected.
Time frame: 63 days
Geometric Mean Titer (GMT) of Invasion Plasmid Antigens B (IpaB) Lymphocytes Supernatant (ALS) Immunoglobulin A (IgA) Response
Whole blood samples were collected for determination of ALS (antibody from lymphocytes supernatant). Immunogenicity responses are presented for Cohorts 3 and 4 only. Specimens from vaccine recipients in Cohorts 1 and 2 were not tested for immunogenicity data and no data were collected. For all immunology variables, the raw values were first adjusted to the geometric mean of positive controls, and any values \<0.15 were changed to 0.14.
Time frame: 63 days
Number and Percentage of Subjects With Positive Immunologic Response in Invasion Plasmid Antigen D (IpaD) Lymphocytes Supernatant (ALS) Immunoglobulin A (IgA) Response From Baseline
A positive immunological response is defined as an increase of 4-fold or more over the appropriate baseline value for ALS or an increase of more than 2-fold for serological responses (fold increases will be calculated to 1 decimal place). For all immunology variables, the raw values were first adjusted to the geometric mean of positive controls, and any values \<0.15 were changed to 0.14. The fold-change in response was then calculated as the ratio of each value to the baseline value (so the minimum baseline value was 0.14). Specimens from vaccine recipients in Cohorts 1 and 2 were not tested for immunogenicity data and no data were collected.
Time frame: 63 days
Geometric Mean Titer (GMT) of Invasion Plasmid Antigen D (IpaD) Lymphocytes Supernatant (ALS) Immunoglobulin A (IgA) Response
Whole blood samples were collected for determination of ALS (antibody from lymphocytes supernatant). Immunogenicity responses are presented for Cohorts 3 and 4 only. Specimens from vaccine recipients in Cohorts 1 and 2 were not tested for immunogenicity data and no data were collected. For all immunology variables, the raw values were first adjusted to the geometric mean of positive controls, and any values \<0.15 were changed to 0.14.
Time frame: 63 days
Number and Percentage of Subjects in Cohort 3 With Positive Immunologic Response in Fecal Immunoglobulin A (IgA) Response From Baseline
A positive immunological response is defined as an increase of 4-fold or more over the appropriate baseline value for ALS or an increase of more than 2-fold for serological responses (fold increases will be calculated to 1 decimal place). For all immunology variables, the raw values were first adjusted to the geometric mean of positive controls, and any values \<0.15 were changed to 0.14. The fold-change in response was then calculated as the ratio of each value to the baseline value (so the minimum baseline value was 0.14). Specimens from vaccine recipients in Cohorts 1 and 2 were not tested for immunogenicity data and no data were collected.
Time frame: 16 weeks
Geometric Mean Titer (GMT) of Fecal Immunoglobulin A (IgA) Response in Cohort 3
Immunogenicity responses are presented for Cohorts 3 and 4 only. Specimens from vaccine recipients in Cohorts 1 and 2 were not tested for immunogenicity data and no data were collected. For all immunology variables, the raw values were first adjusted to the geometric mean of positive controls, and any values \<0.15 were changed to 0.14.
Time frame: 16 weeks
Number and Percentage of Subjects in Cohort 3 With Positive Immunologic Response in Total Immunoglobulin A (IgA) Response From Baseline
A positive immunological response is defined as an increase of 4-fold or more over the appropriate baseline value for ALS or an increase of more than 2-fold for serological responses (fold increases will be calculated to 1 decimal place). For all immunology variables, the raw values were first adjusted to the geometric mean of positive controls, and any values \<0.15 were changed to 0.14. The fold-change in response was then calculated as the ratio of each value to the baseline value (so the minimum baseline value was 0.14). Specimens from vaccine recipients in Cohorts 1 and 2 were not tested for immunogenicity data and no data were collected.
Time frame: 16 weeks
Geometric Mean Titer (GMT) of Total Immunoglobulin A (IgA) Response in Cohort 3
Whole blood samples were collected for determination of ALS (antibody from lymphocytes supernatant). Immunogenicity responses are presented for Cohorts 3 and 4 only. Specimens from vaccine recipients in Cohorts 1 and 2 were not tested for immunogenicity data and no data were collected. For all immunology variables, the raw values were first adjusted to the geometric mean of positive controls, and any values \<0.15 were changed to 0.14.
Time frame: 16 weeks
Number and Percentage of Subjects in Cohort 4 With Positive Immunologic Response in Total Immunoglobulin A (IgA) Response From Baseline
A positive immunological response is defined as an increase of 4-fold or more over the appropriate baseline value for ALS or an increase of more than 2-fold for serological responses (fold increases will be calculated to 1 decimal place). For all immunology variables, the raw values were first adjusted to the geometric mean of positive controls, and any values \<0.15 were changed to 0.14. The fold-change in response was then calculated as the ratio of each value to the baseline value (so the minimum baseline value was 0.14). Specimens from vaccine recipients in Cohorts 1 and 2 were not tested for immunogenicity data and no data were collected.
Time frame: 63 days
Geometric Mean Titer (GMT) of Total Immunoglobulin A (IgA) Response in Cohort 4
Whole blood samples were collected for determination of ALS (antibody from lymphocytes supernatant). Immunogenicity responses are presented for Cohorts 3 and 4 only. Specimens from vaccine recipients in Cohorts 1 and 2 were not tested for immunogenicity data and no data were collected. For all immunology variables, the raw values were first adjusted to the geometric mean of positive controls, and any values \<0.15 were changed to 0.14.
Time frame: 63 days
Number and Percentage of Subjects in Cohort 4 With Positive Immunologic Response in Fecal Immunoglobulin A (IgA) Response From Baseline
A positive immunological response is defined as an increase of 4-fold or more over the appropriate baseline value for ALS or an increase of more than 2-fold for serological responses (fold increases will be calculated to 1 decimal place). For all immunology variables, the raw values were first adjusted to the geometric mean of positive controls, and any values \<0.15 were changed to 0.14. The fold-change in response was then calculated as the ratio of each value to the baseline value (so the minimum baseline value was 0.14). Specimens from vaccine recipients in Cohorts 1 and 2 were not tested for immunogenicity data and no data were collected.
Time frame: 63 days
Geometric Mean Titer (GMT) of Fecal Immunoglobulin A (IgA) Response in Cohort 4
Immunogenicity responses are presented for Cohorts 3 and 4 only. Specimens from vaccine recipients in Cohorts 1 and 2 were not tested for immunogenicity data and no data were collected. For all immunology variables, the raw values were first adjusted to the geometric mean of positive controls, and any values \<0.15 were changed to 0.14.
Time frame: 63 days
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