Salmonella Conjugates CVD 1000: Study of Responses to Vaccination With Trivalent Invasive Salmonella Disease Vaccine

Study Overview
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Brief Summary
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This is a randomized, placebo-controlled dose-escalation study. The main purpose of this research is to test the safety and measure the immune response of the trivalent vaccine against invasive Salmonella disease. The vaccine will be tested over a range of doses.

Official Title
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Phase 1 Randomized, Placebo-Controlled, Dose-Escalation Study of the Safety, Reactogenicity, and Immunogenicity of Trivalent (S. Enteritidis/S. Typhimurium/S. Typhi Vi) Conjugate Vaccine Against Invasive Salmonella Disease Administered Parenterally to Healthy U.S. Adults

Conditions
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Risk Reduction

Intervention / Treatment
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* Biological: Trivalent Invasive Salmonella Disease Vaccine (6.25 µg)
* Biological: Trivalent Invasive Salmonella Disease Vaccine (12 µg)
* Biological: Trivalent Invasive Salmonella Disease Vaccine (25 µg)
* Biological: Trivalent Invasive Salmonella Disease Vaccine (highest, well-tolerated dose among Cohorts A-C)
* Other: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Ability to provide written informed consent Age 18 - 45 years, inclusive Good general health as determined by: vital signs (heart rate <100 bpm; blood pressure systolic >90 mm Hg and ≤150 mm Hg; diastolic >45 mm Hg and ≤90 mm Hg; oral temperature <100.4ºF), medical history, and a physical examination† within 45 days before administration of first dose of vaccine. Expressed interest and availability to fulfill the study requirements For females of child-bearing potential*, must agree to acceptable birth control&, 4 weeks before enrollment and through 4 weeks after last vaccination. Agrees not to participate in another clinical trial at any time during the study period. Agrees to allow for the indefinite storage of blood samples for future research use. Exclusion Criteria: History of typhoid vaccination or known history of typhoid infection within 5 years Unacceptable laboratory abnormality from screening (prior to first vaccination) or upon safety laboratory testing (prior to second vaccination) as listed below. Laboratories with abnormalities which are possibly transient in nature may be repeated one time. Hemoglobin, white blood cell (WBC) count, absolute neutrophil count (ANC), or platelet count of an unacceptable value, according to Appendix B Creatinine, AST, ALT, total bilirubin, or C-reactive protein of an unacceptable value, according to Appendix B Positive serology for hepatitis C or HIV antibody or hepatitis B surface antigen. (Subjects will be informed if their results are positive for hepatitis C, HIV antibody or hepatitis B surface antigen and will be referred to a primary care provider for follow up of these abnormal laboratory tests.) For women of child-bearing potential, positive serum pregnancy test (during screening within 45 days of enrollment) or positive urine pregnancy test (prior to and within 24 hours of administering each dose of vaccine). Nursing mother. Temperature > 38.0°C (100.4°F) or symptoms of an acute self-limited illness such as an upper respiratory infection or gastroenteritis within 3 days prior to each dose of vaccine. Medical, occupational, or family problems as a result of alcohol or illicit drug use during the past 12 months. Diagnosis of schizophrenia or other major psychiatric disease Failure to pass Comprehension Assessment Tool during screening (70% correct answers are required to pass). Receipt of an experimental agent (vaccine, drug, device, etc.) within 28 days before enrollment or expects to receive an experimental agent during the study period. Receipt of any licensed vaccine within 2 weeks (for inactivated vaccines) or 4 weeks (for live vaccines) before enrollment in this study. Known sensitivity to any ingredient in the study vaccine, including a history of severe allergic reaction to tetanus vaccine. Receipt of immunoglobulin or other blood product within the 3 months prior to vaccination in this study. Immunosuppression as a result of an underlying illness or treatment with immunosuppressive or cytotoxic drugs, or use of anticancer chemotherapy or radiation therapy within the preceding 36 months. Long-term use (>2 weeks) of oral or parenteral steroids (glucocorticoids), or high-dose inhaled steroids (>800 mcg/day of beclomethasone dipropionate or equivalent) within the preceding 6 months (nasal and topical steroids are allowed). Other condition that in the opinion of the investigator would jeopardize the safety or rights of a volunteer participating in the trial or would render the subject unable to comply with the protocol.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 45 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Sequential Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cohort A (Step 1)<br>Individuals receive one dose of either 6.25 µg of the trivalent vaccine or placebo. Subsequent blood samples are taken for immunological testing. | Biological: Trivalent Invasive Salmonella Disease Vaccine (6.25 µg)<br>* 6.25 µg of the conjugate vaccine is administered via one intramuscular injection into the deltoid muscle on Study Day 1.<br>Other: Placebo<br>* 0.5 mL of buffer and preservative is administered via one or two intramuscular injections(s) into the deltoid muscle on Study Day 1 (and 29 if two doses are given).<br>|
| Experimental: Cohort B (Step 2)<br>Individuals receive one dose of either 12.5 µg of the trivalent vaccine or placebo. Subsequent blood samples are taken for immunological testing. | Biological: Trivalent Invasive Salmonella Disease Vaccine (12 µg)<br>* 12 µg of the conjugate vaccine is administered via one intramuscular injection into the deltoid muscle on Study Day 1.<br>Other: Placebo<br>* 0.5 mL of buffer and preservative is administered via one or two intramuscular injections(s) into the deltoid muscle on Study Day 1 (and 29 if two doses are given).<br>|
| Experimental: Cohort C (Step 3)<br>Individuals receive one dose of either 25 µg of the trivalent vaccine or placebo. Subsequent blood samples are taken for immunological testing. | Biological: Trivalent Invasive Salmonella Disease Vaccine (25 µg)<br>* 25 µg of the conjugate vaccine is administered via one intramuscular injection into the deltoid muscle on Study Day 1.<br>Other: Placebo<br>* 0.5 mL of buffer and preservative is administered via one or two intramuscular injections(s) into the deltoid muscle on Study Day 1 (and 29 if two doses are given).<br>|
| Experimental: Cohort D<br>Individuals receive one or two doses of the highest, well-tolerate dose among Cohorts A-C of the trivalent vaccine or placebo. Subsequent blood samples are taken for immunological testing. | Biological: Trivalent Invasive Salmonella Disease Vaccine (highest, well-tolerated dose among Cohorts A-C)<br>* The highest, well-tolerated dose of the conjugate vaccine among Cohorts A-C is administered via one or two intramuscular injection(s) into the deltoid muscle on Study Day 1 (and 29 if two doses are given).<br>Other: Placebo<br>* 0.5 mL of buffer and preservative is administered via one or two intramuscular injections(s) into the deltoid muscle on Study Day 1 (and 29 if two doses are given).<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Frequency and Severity of Solicited Local and Systemic AEs | To assess the frequency and severity of solicited local (i.e., injective site) and systemic (such as fever) AEs during the first 7 days following each dose of vaccine. | Approximately one year | 
| Frequency and Severity of Unsolicited AEs and SAEs | To assess the frequency and severity of unsolicited AEs within 28 days of each dose of vaccine and the occurrence of any SAEs through 6 months after the last dose of vaccine | Approximately two years | 
| Proportion of Responders | To measure the proportion of subjects that achieve a four-fold increase in titer, as compared to baseline, of specific serum IgG anti-COPS (S. Enteritidis or S. Typhimurium), anti-Vi (S. Typhi) polysaccharide, and anti-FliC (S. Enteritidis or S. Typhimurium) antibody at days 29 and 57, as measured by ELISA. | Approximately one and a half years |