Now Available for Public Comment: Notice of Proposed Rulemaking (NPRM) for FDAAA 801 and NIH Draft Reporting Policy for NIH-Funded Trials

Shigella Sonnel O-SPC/rBRU Conjugate Vaccine

This study has been completed.
Sponsor:
Information provided by:
National Institutes of Health Clinical Center (CC)
ClinicalTrials.gov Identifier:
NCT01369927
First received: June 8, 2011
Last updated: February 19, 2014
Last verified: April 2013
  Purpose

The active ingredient of this Shigella sonnei O-SP-core conjugate vaccine is a saccharide-protein conjugate composed of a fragment of S. sonnei LPS. The saccharide component consists of an average of 3.5 repeat units of the O-SP plus the core region of the LPS (O-SPC). The O-SPC is covalently bound to the recombinant non-toxic exoprotein B of Clostridium difficile.

The objective of this phase of the study is to determine if this vaccine is safe and can induce IgG antibody type-specific immunity to shigellosis in adults. The overall objective is to determine if this vaccine can elicit higher levels of IgG antibody than the previous experimental vaccines made with the full length O-SP, shown to be > 70% efficacious in greater than or equal to3 year old children, to induce type-specific immunity to shigellosis in younger children.

Sixty 18-49 years-old healthy adults will be recruited in Israel. Volunteers will be vaccinated on a random basis with one i.m. injection of 10 or 25 micrograms of the investigational conjugate vaccine. Local and systemic reactions will be observed at 30 minutes, and the volunteers will be instructed to take their temperature and examine the injection site for redness and swelling and fill out a questionnaire at 6, hours and daily for 7 days after vaccination. The volunteers will visit the clinic at 24 or 48 hours following the injection and any time they request it. The study will commence with 5 volunteers injected with the 10ug dose to be followed, if no severe adverse reactions occur, by 5 volunteers injected with the 25ug dose. If a severe adverse reaction occurs on 1 of the 5 volunteers in either group, 5 more will be injected with that dose. If there are no severe adverse reactions the study will proceed. If there is one more severe reaction the study will be halted and re-evaluated by the IRB and the FDA.

Vaccine-induced antibodies will be measured at 1 and 6 months after immunization, and compared to those elicited by our previous S. sonnei conjugate vaccines.

There is a body of evidence that a critical level of serum IgG antibody to the O-specific polysaccharide domain of LPS confers type-specific immunity to S. sonnei as well as to other Shigella:

  1. Shigellosis is rarely observed in infants up to the age of 4-6 months. The most obvious explanation for this is that maternally-derived serum IgG provides this immunity;
  2. There is an age-related development of IgG anti-LPS antibodies that, in many instances, is not induced by the homologous bacteria but by non-pathogenic cross-reacting enteric bacteria;
  3. The highest incidence, morbidity, and mortality occur during 6 months to 6 years of age when the maternally-derived serum anti-O-SP has waned and the naturally-derived antibodies have not yet appeared;
  4. One injection of a S. sonnei-rEPA conjugate showed significant protection against shigellosis in Israeli Defense Force soldiers. Vaccinees who developed shigellosis showed significantly lower serum IgG responses to the homologous LPS than those did not.The high antibody level induced by the conjugate vaccine indicates the positive correlation between the serum IgG anti-LPS levels and immunity to S. sonnei infection;
  5. Following Phase 1 and Phase 2 studies that showed safety and age-related immunogenicity, a double-blinded randomized and vaccine-controlled Phase 3 evaluation of S. sonnei and S. flexneri type 2a O-specific polysaccharide (O-SP) protein conjugates was conducted among 1-4 year-olds in Israel.

For recipients of the S. sonnei conjugate 71.1% efficacy was shown among 3-4 year-old recipients, no efficacy was shown for recipients of S. flexneri 2a. There was no statistically significant efficacy for either vaccine in the 1-3 year-olds. Levels of serum IgG anti-O-SP were elevated according to the vaccine the children received but G.M. levels declined rapidly several months after the last injection. Our interpretation is that the age-related efficacy of the Shigella conjugates was due to the conjugate-induced O-SP antibody levels. Accordingly, we have developed a method to increase the immunogenicity of the conjugates to approach the antibody levels of Israeli soldiers shown to be protected by our S. sonnei O-SP.

Low-molecular-mass O-SP-core (O-SPC) fragments were isolated from S. sonnei LPS, and bound by their reducing ends to the carrier protein. The O-SPC conjugates used oxime linkages between the terminal Kdo residues at the reducing ends of the S. sonnei saccharides and aminooxy linkers bound to the carrier. The coupling reaction was carried out at a neutral pH and room temperature. The carrier protein was a mutant non-toxic Clostridium difficile exotoxin B. IgG antibody levels induced in young outbred mice by this new S. sonnei O-SPC conjugate were significantly higher than those elicited by the O-SP conjugates.


Condition Intervention Phase
Immunogenicity
Shigellosis
Biological: Shigella Sonnei O-SPC/rBRU
Phase 1

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Investigator)
Primary Purpose: Prevention
Official Title: Shigella Sonnel O-SPC/rBRU Conjugate Vaccine

Resource links provided by NLM:


Further study details as provided by National Institutes of Health Clinical Center (CC):

Primary Outcome Measures:
  • Vaccine safety

Secondary Outcome Measures:
  • Induction of IgG antibody type-specific immunity to shigellosis in adults.
  • Tertiary: Induction of higher levels of IgG antibody than the previous experimental vaccines made with full length O-SP for type specific immunity to shigellosis in younger children.

Estimated Enrollment: 60
Study Start Date: May 2011
Study Completion Date: April 2013
Primary Completion Date: April 2013 (Final data collection date for primary outcome measure)
Intervention Details:
    Biological: Shigella Sonnei O-SPC/rBRU
    N/A
  Show Detailed Description

  Eligibility

Ages Eligible for Study:   18 Years to 49 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   Yes
Criteria
  • ELIGIBILITY AND EXCLUSION CRITERIA:

Healthy adults, 18 to 49 years of age of either sex who do not have any of the following conditions will be eligible to participate:

  1. A chronic or progressive disease requiring chronic medication,
  2. History of splenectomy or abnormal immune system,
  3. History of neurological symptoms or signs, or mental illness,
  4. Anaphylactic shock following administration of any vaccine or any other severe allergic reaction,
  5. Women who are pregnant or intend to become pregnant during the vaccine study,
  6. Had S. sonnei shigellosis in the past year or received a S. sonnei vaccine previously,
  7. Have received systemic steroids during the month preceding Shigella vaccination,
  8. Had cancer, HIV/AIDS, Hepatitis B or C, Guillain Barre Syndrome, chronic skin disease or have abnormal liver functions or blood counts.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01369927

Locations
Israel
Schneider Children's Hospital
Petach Tikva, Israel
Sponsors and Collaborators
Investigators
Principal Investigator: Feng-Ying C Lin, M.D. Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
  More Information

Publications:
ClinicalTrials.gov Identifier: NCT01369927     History of Changes
Other Study ID Numbers: 999911138, 11-CH-N138
Study First Received: June 8, 2011
Last Updated: February 19, 2014
Health Authority: United States: Federal Government

Keywords provided by National Institutes of Health Clinical Center (CC):
Shigellosis
Safety and Immunogenicity
Conjugate Vaccine

Additional relevant MeSH terms:
Dysentery, Bacillary
Bacterial Infections
Digestive System Diseases
Dysentery
Enterobacteriaceae Infections
Gastroenteritis
Gastrointestinal Diseases
Gram-Negative Bacterial Infections
Intestinal Diseases

ClinicalTrials.gov processed this record on November 27, 2014