Phase 2 Shigella Vaccine and Challenge
Phase 2 Shigella Vaccine and Challenge
This is a trial to evaluate the safety, reactogenicity, immunogenicity and efficacy of a 10^6
 cfu dose of an oral live-attenuated S. sonnei vaccine candidate, WRSs2, in up to 120 healthy
 males and non-pregnant females aged 18-49, inclusive. This is a two-phase study, an
 outpatient WRSs2 vaccination phase and an inpatient S. sonnei 53G challenge phase. There are
 three groups in each phase. Outpatient WRSs2 phase: Group 1 will receive two doses of WRSs2
 vaccine; Group 2 will receive one dose of the placebo and one dose of WRSs2 vaccine; Group 3
 will receive two doses of the placebo. All three groups in an inpatient S. sonnei 53G
 challenge phase will receive one dose of S. sonnei 53G challenge. The study will be conducted
 in up to 3 Vaccine Treatment Evaluation Units (VTEU) sites. The study duration is
 approximately 24 months with subject participation duration approximately 8 months. The
 Primary Objective of this study is to estimate vaccine efficacy of 1 and 2 doses of WRSs2 in
 preventing shigellosis, following challenge with S. sonnei strain 53G.
This is a double-blind placebo-controlled trial to evaluate the safety, reactogenicity,
 immunogenicity and efficacy of a 10^6 cfu dose of an oral live-attenuated S. sonnei vaccine
 candidate, WRSs2, in up to 120 healthy males and non-pregnant females aged 18-49, inclusive.
 This is a two-phase study, an outpatient WRSs2 vaccination phase and an inpatient S. sonnei
 53G challenge phase. There are three groups in each phase. Outpatient WRSs2 phase: Group 1
 will receive two doses of WRSs2 vaccine; Group 2 will receive one dose of the placebo and one
 dose of WRSs2 vaccine; Group 3 will receive two doses of the placebo. All three groups in an
 inpatient S. sonnei 53G challenge phase will receive one dose of S. sonnei 53G challenge. The
 study will be conducted in up to 3 Vaccine Treatment Evaluation Units (VTEU) sites. The study
 duration is approximately 24 months with subject participation duration approximately 8
 months. The Primary Objective of this study is to estimate vaccine efficacy of 1 and 2 doses
 of WRSs2 in preventing shigellosis, following challenge with S. sonnei strain 53G. The
 Secondary Objectives are to:1) Evaluate the safety of 1 and 2 doses of WRSs2; 2) Evaluate
 immune responses following vaccination (immunogenicity) with 1 and 2 doses of WRSs2 and after
 challenge with S. sonnei strain 53G by serum anti-LPS and anti-Invaplex IgG and IgA by ELISA;
 3) Determine fecal shedding of S. sonnei after WRSs2 vaccination and 53G challenge by
 qualitative stool culture.
Inclusion Criteria:

 1. Provide informed consent prior to initiation of any study procedures.

 2. Are able to understand and comply with planned study procedures and be available for
 all study visits.

 3. Is 18-49 years of age inclusive and in sufficiently good health* to be safely enrolled
 in this study as determined by medical history, medication use, and abbreviated
 physical exam.

 *Good health is defined by the absence of any exclusionary medical conditions. If the
 subject has another current, ongoing medical condition, the condition cannot meet any
 of the following criteria: 1) first diagnosed within 3 months of enrollment; 2) is
 worsening in terms of clinical outcome in last 6 months; or 3) involves need for
 medication that may pose a risk to subject's safety or impede assessment of adverse
 events or immunogenicity if they participate in the study. Topical, nasal, and inhaled
 medications (with the exception of inhaled corticosteroids as outlined in the Subject
 Exclusion Criteria, herbals, vitamins, and supplements are permitted.

 4. Oral temperature is less than 100.4 degrees Fahrenheit.

 5. Pulse is 50 to 100 beats per minute (bpm), inclusive.

 6. Systolic blood pressure is 90 to 140 mmHg, inclusive.

 7. Diastolic blood pressure is 55 to 90 mmHg, inclusive.

 8. Females of childbearing potential** may enroll if subject has practiced adequate
 contraception*** = / > 30 days prior to enrollment and agrees to continue adequate
 contraception for the entire study.

 **Child-bearing potential is defined as not sterilized via tubal ligation, bilateral
 oophorectomy, salpingectomy, hysterectomy, or successful Essure(R) placement
 (permanent, non-surgical, non-hormonal sterilization) with documented radiological
 confirmation test at least 90 days after the procedure, and still menstruating or <1
 year of the last menses if menopausal.

 ***Adequate contraception includes; non-male sexual relationships, abstinence from
 sexual intercourse with a male partner, monogamous relationship with vasectomized
 partner who has been vasectomized for 180 days or more prior to the subject
 enrollment, barrier methods such as condoms or diaphragms with spermicide, effective
 intrauterine devices, NuvaRing(R), and licensed hormonal methods such as implants,
 injectables, or oral contraceptives ("the pill").

 9. Females of childbearing potential must have a negative urine or serum pregnancy test
 within 24 hours prior to enrollment.

 10. Drug screen for opiates is negative.

 Exclusion Criteria:

 1. Have any disease or medical condition that, in the opinion of the site principal
 investigator or appropriate sub-investigator, is a contraindication to study
 participation****.

 **** Including acute or chronic disease or medical condition that would place the
 subject at an unacceptable risk of injury, render the subject unable to meet the
 requirements of the protocol, or may interfere with the evaluation of responses or the
 subject's successful completion of this trial. These include:

 1. History of inflammatory bowel disease (IBD) (including ulcerative colitis,
 Crohn's disease, indeterminate colitis, or celiac disease).

 2. Irritable bowel syndrome (IBS) within the past 12 months or any active
 uncontrolled gastrointestinal disorders or diseases as assessed by the
 investigator. Including: symptoms or evidence of active gastritis or
 gastroesophageal reflux disease, gastric surgery or gastric acid hyper-secretory
 disorders (e.g., Zollinger-Ellison syndrome), gastrointestinal obstruction,
 ileus, gastric retention, bowel perforation, toxic colitis, persistent infectious
 gastroenteritis, persistent or chronic diarrhea of unknown etiology, Clostridium
 difficile infection.

 3. Known active neoplastic disease (Non-melanoma, treated, skin cancers are
 permitted), a history of any hematologic malignancy, or have used anticancer
 chemotherapy/radiation therapy (cytotoxic) within 3 years prior to study
 enrollment.

 4. Personal or family history of reactive arthritis.

 5. Reported history of HIV, Hepatitis B, or Hepatitis C

 6. History of immunodeficiency due to congenital or hereditary causes, underlying
 illness or treatment.

 2. Positive serology results for HLA-B27, HIV, HBsAg, or HCV antibodies.

 3. Have clinically significant abnormalities as determined by study investigator in other
 screening laboratory tests, as outlined in the protocol.

 4. Have participated in a previous Shigella challenge study or reports having received
 vaccination for Shigella previously.

 5. Have a previously laboratory confirmed case of disease caused by S. sonnei or serology
 positive (>1:2500) for anti S. sonnei LPS IgG ELISA titer at screening.

 6. Has a history of diarrhea in the 14 days prior to enrollment.

 7. Have fewer than 3 stools per week or more than 3 stools per day as the usual
 frequency.

 8. Recent history/current use of immunosuppressive/immunomodulating disease therapy.

 9. Known hypersensitivity to ciprofloxacin or trimethoprim-sulfamethoxazole; sodium
 bicarbonate; or any components of vaccine, placebo, or challenge material.

 10. Received or plan to receive a licensed live vaccine within 30 days prior to
 enrollment.

 11. Received or plan to receive a licensed, inactivated, vaccine (including the seasonal
 flu vaccine) within 14 days before enrollment.

 12. Have a history of severe reactions following previous immunization with any licensed
 or unlicensed vaccine.

 13. Received Ig or other blood products (with exception of Rho D Ig) within 90 days prior
 to enrollment.

 14. Have taken oral or parenteral (including intra-articular) corticosteroids of any dose,
 or high-dose inhaled corticosteroids***** within 30 days prior to enrollment.

 ***** High-dose defined per age as using inhaled high dose per reference chart
 Estimated Comparative Daily Dosages
 https://www.nhlbi.nih.gov/files/docs/guidelines/asthma_qrg.pdf

 15. Have taken antibiotics within 7 days prior to enrollment.

 16. Have taken prescription and/or OTC medication containing loperamide, acetaminophen,
 aspirin, ibuprofen, or other non-steroidal anti-inflammatory < / = 48 hours prior to
 enrollment.

 17. Have a history of alcohol or drug abuse within 1 year prior to enrollment.

 18. Have been hospitalized for psychiatric illness, history of suicide attempt, or
 confinement for danger to self or others within 5 years prior to enrollment.

 19. Work or plan to work in either a health care setting, day care center, or as a food
 handler or have known daily contact with individuals with possible increased
 susceptibility****** to Shigella within 14 days after discharge from inpatient
 challenge.

 ****** Immunocompromised, elderly persons aged 70 years or more, diapered individuals,
 persons with disabilities, children < 2 years old, a woman known to be pregnant or
 nursing, or anyone with diminished immunity. Known daily contact includes contact at
 home, school, day-care, nursing home, or similar places.

 20. Are pregnant, breastfeeding or plan to become pregnant or breastfeed at any given time
 during the study.

 21. Have fever or an acute illness******* as determined by the site principal investigator
 or appropriate sub-investigator, within 72 hours prior to enrollment.

 ******* An acute illness which is nearly resolved with only minor residual symptoms
 remaining is allowable if, in the opinion of the site principal investigator or
 appropriate sub-investigator, the residual symptoms will not interfere with the
 ability to assess safety parameters as required by the protocol

 22. Received an experimental agent (including vaccine, drug, biologic, device, blood
 product, or medication, other than from participation in this trial) within 30 days
 prior to the first study vaccination or expect to receive an investigational product
 during the study period which might affect safety or assessment of study endpoints.