Safety, Immunogenicity and Efficacy of Shigella Conjugate Vaccines in 1-4 Year Olds in Israel

This study has been completed.
Sponsor:
Collaborators:
The Chaim Sheba Medical Center
Schneider Children's Medical Center, Israel
Information provided by (Responsible Party):
National Institutes of Health Clinical Center (CC) ( Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) )
ClinicalTrials.gov Identifier:
NCT00368316
First received: August 22, 2006
Last updated: June 21, 2012
Last verified: June 2012
  Purpose

Shigellosis remains a serious and frequent disease throughout the world. Development of vaccines has been difficult because shigellae are habitants of and pathogens for humans only and there is no consensus about the mechanism(s) of immunity to this pathogen.

Incomplete, but compelling evidence, indicates that a critical level of serum IgG anti-LPS confers immunity to shigellosis. Important data come from our clinical trial in the Israel Defense Forces (IDF) recruits. A randomized, double-blind, vaccine-controlled study showed that the S. sonnei-rEPA elicited 74% protection against shigellosis occurring about 3 months after vaccination (p=0.001). This vaccine conferred 43% (p=0.04) protection in one company during an outbreak up to 14 days following vaccination suggesting that our Shigella conjugates might be of value in epidemics. The efficacy of S. sonnei-rEPA was correlated with the level of vaccine-induced IgG antibodies.

The highest incidence, morbidity, and mortality of shigellosis is in young children. But serum antibody responsiveness to polysaccharide-based vaccines is age-dependent and infants and young children respond poorly or not at all to both disease and vaccination. The safety and immunogenicity of these Shigella conjugates in 4 to 6 years-old children in Israel was demonstrated. But although the fold rise in anti-LPS was similar in the children, the level of anti-LPS elicited by the conjugates was lower than in adults. We improved the immunogenicity of Shigella conjugates as shown in mice and then in adult humans. Now we apply to evaluate the safety, immunogenicity and efficacy of these improved conjugates in 1 to 4 years-old children in Israel.

In Israel, shigellosis is common especially in children. S. sonnei (Group D) comprise about 60% of the isolates followed by S. flexneri (Group B): Shigella dysenteriae type 1 (Group A) is not found. We propose to administer 2 injections of either S. sonnei-CRM9 or S. flexneri type 2a-rEPAsucc 6 weeks apart in a random double-blind fashion to about 6,000 1 to 4 year-olds. Active surveillance of the vaccinees for enteric infections will be maintained for at least 2 years to evaluate the effect of vaccination.


Condition Intervention Phase
Shigellosis
Biological: Shigella conjugate vaccines
Phase 3

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor)
Primary Purpose: Prevention
Official Title: Phase 3 Study (Safety, Immunogenicity and Efficacy) of Improved Shigella Conjugate Vaccines in 1-4 Year Olds in Israel

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

Primary Outcome Measures:
  • Number of Participants With Adverse Events [ Time Frame: Monitored for 7 days per participant following each injection for initial group of 500, 2 days for extended study of up to 5500 additional children ] [ Designated as safety issue: Yes ]
    Number of participants with events per vaccine type and dose occuring in >=5% of participants


Secondary Outcome Measures:
  • Geometric Mean Immunoglobulin G (IgG) Anti-Lipopolysaccharide (LPS) Levels [ Time Frame: Injections were administered 6 weeks apart and IgG anti-LPS levels determined >2 weeks after second vaccine dose. Each of the 15 sites also took a sample/week randomly chosen, for 2 years of follow up and blood samples from patients with disease ] [ Designated as safety issue: No ]
    Age-related homologous IgG anti-LPS levels

  • Percentage of Efficacy [ Time Frame: During 2 years post vaccination ] [ Designated as safety issue: No ]
    Percent efficacy is defined as ((disease rate of controls minus disease rate of vaccinees) divided by disease rate of controls) times 100


Enrollment: 2799
Study Start Date: January 2003
Study Completion Date: February 2009
Primary Completion Date: January 2008 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: S. sonnei conjugate vaccine
Shigella sonnei O-specific polysaccharide covalently bound to recombinant exoprotein A of Pseudomonas aeruginosa
Biological: Shigella conjugate vaccines
Shigella sonnei-rEPA and Shigella flexneri2a rEPA vaccines
Other Names:
  • S. sonnei O-SP-rEPA conjugate.
  • S. flexneri 2a O-SP-rEPA conjugate.
Experimental: S. flexneri 2a conjugate vaccine
Shigella flexneri 2a O-specific polysaccharide covalently bound to recombinant exoprotein A of pseudomonas aeruginosa
Biological: Shigella conjugate vaccines
Shigella sonnei-rEPA and Shigella flexneri2a rEPA vaccines
Other Names:
  • S. sonnei O-SP-rEPA conjugate.
  • S. flexneri 2a O-SP-rEPA conjugate.

Detailed Description:

Shigellosis remains a serious and frequent disease throughout the world. Development of vaccines has been difficult because shigellae are habitants of and pathogens for humans only and there is no consensus about the mechanism/s of immunity to this pathogen.

Incomplete, but compelling evidence, indicates that a critical level of serum IgG anti-LPS confers immunity to shigellosis. A randomized, double-blind, vaccine-controlled study in Israel Defense Force (IDF) recruits showed that the S. sonnei-rEPA elicited 74% protection against shigellosis occurring about 3 months after vaccination (p=0.001). This vaccine also conferred 43% (p=0.04) protection in one company during an outbreak up to 17 days following vaccination suggesting that our Shigella conjugates might be of value in epidemics. The efficacy of S. sonnei-rEPA was correlated with the level of vaccine-induced IgG antibodies.

The highest incidence, morbidity, and mortality of shigellosis is in young children. But serum antibody responsiveness to it is age dependent and infants and young children respond poorly or not at all to polysaccharide antigens following disease, administration of attenuated strains of Shigella or vaccination with whole cell vaccines. The safety and immunogenicity of similar Shigella conjugates in 4 to 7 years-old children in Israel was demonstrated. But, although the fold rise in anti-LPS was similar in the children, the level of anti-LPS elicited by the conjugates was lower than in adults. We improved the immunogenicity of Shigella conjugates as shown in mice and then in adult humans. Now we apply to evaluate the safety, immunogenicity and efficacy of these improved conjugates in 1 to 4 years-old children in Israel. In addition to monitoring the safety and immunogenicity of the two investigational Shigella vaccines, active surveillance of the vaccines for enteric infections wil be maintained for at lest 2 years to evaluate the effect of vaccination.

  Eligibility

Ages Eligible for Study:   1 Year to 4 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria
  • INCLUSION CRITERIA:

Volunteers who are healthy 1-4 year old children whose parents/guardians have read the Information Sheet provided by the Principal Investigator and signed the consent form, and who will be available for follow up.

EXCLUSION CRITERIA: Children with

  • chronic diseases receiving medication;
  • who have received systemic steroids during the month preceding Shigella vaccination;
  • who had severe side effects following vaccinations; and
  • those not available for follow up.
  Contacts and Locations
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Please refer to this study by its ClinicalTrials.gov identifier: NCT00368316

Locations
Israel
Schneider Childrens Hospital
Petach Tikva, Israel
Chaim Sheba Medical Center
Tel Aviv, Israel
Sponsors and Collaborators
The Chaim Sheba Medical Center
Schneider Children's Medical Center, Israel
Investigators
Principal Investigator: Rachel Schneerson, MD PDMI, NICHD, NIH
  More Information

Publications:
Responsible Party: National Institutes of Health Clinical Center (CC) ( Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) )
ClinicalTrials.gov Identifier: NCT00368316     History of Changes
Other Study ID Numbers: 999900003, OH00-CH-N003
Study First Received: August 22, 2006
Results First Received: May 9, 2012
Last Updated: June 21, 2012
Health Authority: United States: Food and Drug Administration

Keywords provided by National Institutes of Health Clinical Center (CC):
Dysentery
S. sonnei
Antibody Response
Protection

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

ClinicalTrials.gov processed this record on July 24, 2014