Safety and Immunogenicity of Two Live, Attenuated Oral Shigella Sonnei Vaccines: WRSs2 and WRSs3

NCT01336699 | Completed Phase 1 FDA Drug

• 2 other identifiers: 09-0009HHSN272201300016I
• Study Type: interventional
• Target: 89
• Locations: 1 country
• Sites: 1

Brief Summary

Phase 1, randomized, double-blind, placebo controlled, dose-escalation, inpatient study of single doses of S. sonnei. Health adult subjects, ranging in age from 18 to 45 years of age (inclusive) will be screened. Enroll serial groups up to 90 subjects. The primary objective is to evaluate safety and tolerance of WRSs2 by monitoring presence, frequency and severity of clinical signs and symptoms. A secondary objective is to evaluate the immune response in blood and stool following ingestion of WRSs2 and WRSs3.

Conditions

Shigella Infection

Keywords

Shigella sonnei; shigellosis; vaccine; WRSs2; WRSs3

Outcome Measures

Primary Outcomes (2)

• Frequency, duration, and severity of the following solicited symptoms: diarrhea, nausea, vomiting, fever, and abdominal cramping, also frequency of dysentery, and dehydration, and occurrence of abnormal clinical laboratory values

  Day 0-14

• Occurrence of vaccine-associated serious adverse events (SAEs)

  Day 0 to Day 180

Secondary Outcomes (6)

• Cell Mediated Immunogenicity: Measure memory B-cell response to Shigella specific antigens.

  Day 0, 28 and 56

• Fecal shedding of vaccine - duration of detectable fecal presence of WRSs2 and WRSs3 by polymerase chain reaction (PCR) and culture.

  Day 0 to 10, 14 and 28

• Mucosal immunogenicity: i) IgA-ASC and IgG ASC and ALS response to Shigella antigens: S. sonnei LPS, IpaB, IpaC, IpaD, and S. sonnei Invaplex 50

  Day -1, 5, 7, 9 and 14

• Mucosal immunogenicity: ii) Fecal IgA response to Shigella antigens: S. sonnei LPS, IpaB, IpaC, IpaD, and S. sonnei Invaplex 50

  Day -1, 0, 3, 7, 10, 14 and 28

• Secondary infectious spread of different vaccine strains to participants. Secondary infections will be measured by assessing fecal shedding using product-specific PCR.

  Day 0 to 10, 14 and 28

Study Arms (5)

Cohort A

EXPERIMENTAL

WRSs2 vaccine 1x10\^3 colony-forming units (cfu) orally (8 patients), WRSs3 vaccine 1x10\^3 cfu orally (8 patients), Placebo 30 ml orally (2 patients)

Other: Placebo; Biological: WRSs2; Biological: WRSs3

Cohort B

EXPERIMENTAL

WRSs2 vaccine 1x10\^4 colony-forming units (cfu) orally (8 patients), WRSs3 vaccine 1x10\^4 cfu orally (8 patients), Placebo 30 ml orally (2 patients)

Other: Placebo; Biological: WRSs2; Biological: WRSs3

Cohort C

EXPERIMENTAL

WRSs2 vaccine 1x10\^5 colony-forming units (cfu) orally (8 patients), WRSs3 vaccine 1x10\^5 cfu orally (8 patients), Placebo 30 ml orally (2 patients)

Other: Placebo; Biological: WRSs2; Biological: WRSs3

Cohort D

EXPERIMENTAL

WRSs2 vaccine 1x10\^6 colony-forming units (cfu) orally (8 patients), WRSs3 vaccine 1x10\^6 cfu orally (8 patients), Placebo 30 ml orally (2 patients)

Other: Placebo; Biological: WRSs2; Biological: WRSs3

Cohort E

EXPERIMENTAL

WRSs2 vaccine 1x10\^7 colony-forming units (cfu) orally (8 patients), WRSs3 vaccine 1x10\^7 cfu orally (8 patients), Placebo 30 ml orally (2 patients)

Other: Placebo; Biological: WRSs2; Biological: WRSs3

Interventions

Placebo OTHER

Placebo comparator: 1 or 1.5 ml of sterile normal saline 0.9% added to 30 mL of 0.9% sterile normal saline, given orally.

Cohort A; Cohort B; Cohort C; Cohort D; Cohort E

WRSs2 BIOLOGICAL

WRSs2 is a live, attenuated Shigella sonnei vaccine product, given orally at five escalating doses from 1x10\^3 colony-forming units (cfu) to 1x10\^7 cfu.

Cohort A; Cohort B; Cohort C; Cohort D; Cohort E

WRSs3 BIOLOGICAL

WRSs3 is a live, attenuated Shigella sonnei vaccine product, given orally at five escalating doses from 1x10\^3 colony-forming units (cfu) to 1x10\^7 cfu.

Cohort A; Cohort B; Cohort C; Cohort D; Cohort E

Eligibility Criteria

• Age: 18 Years - 45 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• \- Male or non-pregnant female between 18 and 45 years of age (inclusive). - General good health, without (a) significant medical illness, (b) clinically significant physical examination findings as determined by the PI, and (c) screening laboratory values outside the site's normal limits. - Demonstrate comprehension of the protocol procedures and knowledge of study by passing a written examination (pass grade \>/=70 percent) on day -1. - Willing to participate after informed consent obtained. Willingness to participate for an inpatient stay lasting up to 13 days and an outpatient follow-up lasting 6 months from vaccination. Subject must be willing to not smoke during the inpatient stay. - Available for all planned follow-up visits. - Negative serum pregnancy test at screening and negative urine pregnancy test on the day of admission to the inpatient phase for female subjects of childbearing potential. Females of childbearing potential must agree to use an efficacious method of birth control (birth control pills, injection hormonal contraceptive, implant hormonal contraceptive, hormonal patch, IUD, sterilization by hysterectomy or tubal ligation, spermicidal products and barrier methods such as cervical sponge, diaphragm, or condom) within two months of vaccination and during the entire study. Abstinence is acceptable. A woman is eligible if she is monogamous with a vasectomized partner. - Willing to not donate blood for up to 12 months after completion of the inpatient phase of the study - Willing to refrain from participation in another investigational vaccine or drug trial at least until after completion of the 6 month follow-up safety call.

You may not qualify if:

• \- Presence of significant medical conditions such as, gastrointestinal disease (such as active gall bladder disease, peptic ulcer, active gastritis or gastroesophageal reflux disease, inflammatory bowel disease, irritable bowel syndrome, or diverticulitis), or a history of bowel surgery (with an exception of appendectomy, or herniorrhaphy) which in the opinion of the investigator precludes participation in the study. - History of cancer (other than a healed skin lesion), heart disease (in the hospital for a heart attack, have an irregular heartbeat, or have had have postural hypotension in the past year), unconsciousness (other than a single brief "concussion"), seizures (other than with fever when \<5 years old), autoimmune disease (trouble fighting off infections), history of arthritis within the past 10 years, or eating disorder. - History within the past 5 years of alcohol or drug abuse, hospitalization for psychiatric illness, history of suicide attempt or confinement for danger to self or others, a diagnosis of schizophrenia, bi-polar disease, or other severe (disabling) chronic psychiatric diagnosis. Subjects who are receiving a single antidepressant drug and are stable for at least 3 months prior to enrollment without decompensating are allowed enrollment into the study. - A positive urine test for opiates. - A chronic disease (such as hypertension, hyperlipidemia or anxiety/depression) for which doses of prescription medications are not stable for at least the past 3 months. - A diagnosis of Diabetes. - Scheduled use of steroids (with the exception of inhaled steroids) or other immunosuppressive medication, medicines to stop diarrhea, or medicines for pain or fever, including non-steroidal anti-inflammatory drugs (i.e. ibuprofen). - History of immunosuppressive illness, or immunodeficiency including IgA deficiency or have household contacts who are immunocompromised. - Screening serological tests positive for HepB, HepC, Human immunodeficiency virus (HIV) or rapid plasma reagin (RPR) (syphilis). - A clinically significant abnormality on physical examination, including a systolic blood pressure \>140 mm Hg or diastolic blood pressure \>90 mm Hg, or a resting pulse \>100 beats/min or \<55 beats/min (\<50 beats/min for conditioned athletes). - Pregnant, nursing, or plan to become pregnant within 6 months of receipt of the study product. - In the 4 weeks following vaccine, subject will be living with or having daily contact with elderly persons aged 70 years or more, diapered individuals, persons with disabilities, children \< 5 years old, or a woman known to be pregnant or nursing, or anyone with diminished immunity. This includes contact at home, school, day-care, nursing homes, or similar places. - Are a health care worker, work in a day care center for children or the elderly, or work as food handler. - Work with food, such as in restaurants or cafeterias in the 4 weeks following vaccination. - Have been in the hospital 3 or more times for infections like pneumonia or meningitis, or have known collagen vascular disease (i.e. Systemic Lupus Erythematosus \[SLE\] or dermatomyositis). - Anti-Shigella sonnei LPS IgG antibody titer in serum \>1:2500. - Travel to Shigella endemic area in the past 12 months. - HLA B27 positive during medical screening. - Have abnormal screening llaboratory test results per Table 4 Acceptable Laboratory Values in Section 8.1.2.1 and the clinical laboratory's normal values for complete blood count (CBC) \[white blood cells (WBC), Hemoglobin (HgB), platelets, and neutrophil and lymphocyte count\], creatinine, total bilirubin, aspartate aminotransferase (AST), alanine aminotransferase (ALT), s odium, potassium, and urinalysis \[urine protein, urine glucose and urine red blood cells (RBC)\]. - Stool positive for Salmonella, Shigella, Campylobacter, Cholera or Yersinia, parasites, or pathogenic protozoa. - Allergy to sodium bicarbonate, ciprofloxacin, Bactrim (sulfamethoxazole and trimethoprim), or have a known allergy to any component of the vaccine. - Fewer than 3 stools per week or more than 3 stools per day on a regular basis. Loose or liquid stools other than on an occasional basis. - History of diarrhea in the 2 weeks prior to day of vaccination. - Use of laxatives, antacids, or other agents to lower stomach acidity at least weekly. - History of allergy or intolerance to soy or soy products. - Use of antibiotics during the 7 days before dosing or proton pump inhibitors, H2 blockers, or antacids within 48 hours of dosing. - Have a temperature of \>/=100.4 degrees Fahrenheit orally or illness within 3 days of the inpatient visit. - History of or expected exposure to Shigella by infection, challenge, vaccination or laboratory work during the active study period (28 days post vaccination). - Use of any investigational drug or any investigational vaccine within 30 days preceding vaccination, or planned use during the 60 days after receipt of the study agent. - Have taken a licensed, live vaccine within 28 days or a licensed inactivated vaccine within 14 days of receiving this study vaccine. - Long-term use of oral steroids, parenteral steroids, or high-dose inhaled steroids (\>800 ug/day of beclomethasone dipropionate or equivalent) within the preceding 6 months (Nasal, intra-articular, and topical steroids are allowed). - Inability to comply with inpatient rules and regulations. - Has any other condition that in the opinion of the Investigator, would jeopardize the safety or rights of a participant or would render the subject unable to comply with the protocol. - Use of prescription and/or over the counter (OTC) medications that contain acetaminophen, aspirin, ibuprofen, and other non-steroidal anti-inflammatory drugs, during the 48 hours prior to investigational product administration. - Receipt of blood or blood products within the past six months.

Sponsors & Collaborators

• National Institute of Allergy and Infectious Diseases (NIAID): lead

Study Sites (1)

Cincinnati Children's Hospital Medical Center - Infectious Diseases

Cincinnati, Ohio, 45229-3039, United States

Location

Related Publications (1)

• Venkatesan MM, Ballou C, Barnoy S, McNeal M, El-Khorazaty J, Frenck R, Baqar S. Antibody in Lymphocyte Supernatant (ALS) responses after oral vaccination with live Shigella sonnei vaccine candidates WRSs2 and WRSs3 and correlation with serum antibodies, ASCs, fecal IgA and shedding. PLoS One. 2021 Nov 18;16(11):e0259361. doi: 10.1371/journal.pone.0259361. eCollection 2021.

  PMID: 34793505 DERIVED

MeSH Terms

Conditions

Dysentery, Bacillary

Condition Hierarchy (Ancestors)

Enterobacteriaceae Infections; Gram-Negative Bacterial Infections; Bacterial Infections; Bacterial Infections and Mycoses; Infections; Dysentery; Gastroenteritis; Gastrointestinal Diseases; Digestive System Diseases; Intestinal Diseases

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, INVESTIGATOR
• Purpose: PREVENTION
• Intervention Model: PARALLEL
• Sponsor Type: NIH
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: April 14, 2011
• First Posted: April 18, 2011
• Study Start: January 7, 2013
• Primary Completion: May 12, 2015
• Study Completion: May 12, 2015
• Last Updated: January 28, 2019

Record last verified: 2015-10-14

Locations

US (1)