A Phase 3 interventional study of Shigella conjugate vaccines in Shigellosis, sponsored by Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD). Completed at 2 sites in Israel. Open to participants aged 1 Year to 4 Years. Per ClinicalTrials.gov, last updated 2012-06-22.
Sponsored by Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) · Phase 3, Interventional, and Prevention
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.
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.
56 studies on the registry are indexed under Dysentery, Bacillary; 6 are open to participants now.
This study's enrollment of 2,799 is above the median of 73 across 48 interventional studies indexed under Dysentery, Bacillary.
Browse Dysentery, Bacillary studies →Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) is the lead sponsor of 416 studies on the registry; 25 are open to participants now.
Of its 13 completed or terminated interventional studies of FDA-regulated products, 10 (77%) have results posted.
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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
Shigella sonnei O-specific polysaccharide covalently bound to recombinant exoprotein A of Pseudomonas aeruginosa
Biological: Shigella conjugate vaccines
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
Also known as: S. sonnei O-SP-rEPA conjugate., S. flexneri 2a O-SP-rEPA conjugate.
Number of Participants With Adverse Events
Number of participants with events per vaccine type and dose occuring in \>=5% of participants
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
Geometric Mean Immunoglobulin G (IgG) Anti-Lipopolysaccharide (LPS) Levels
Age-related homologous IgG anti-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
Percentage of Efficacy
Percent efficacy is defined as ((disease rate of controls minus disease rate of vaccinees) divided by disease rate of controls) times 100
Time frame: During 2 years post vaccination
Enrollment period: May 1, 2003 to January 31 3006. Surveillance period: May 1, 2003 to January 31 2008. Children were recruited from day care centers and health clinics in Israel
| Milestone | S. Sonnei Conjugate Vaccine | S. Flexneri 2a Conjugate Vaccine |
|---|---|---|
| Started | 1434 | 1365 |
| Completed | 1392 | 1319 |
| Not completed | 42 | 46 |
Number of participants with events per vaccine type and dose occuring in \>=5% of participants
| participants | S. Sonnei Conjugate Vaccine | S. Flexneri 2a Conjugate Vaccine |
|---|---|---|
| local pain, dose 1 | 82 | 61 |
| local pain, dose 2 | 79 | 64 |
| fever, dose 1 | 56 | 72 |
| fever, dose 2 | 36 | 51 |
Age-related homologous IgG anti-LPS levels
| ELISA units | S. Sonnei Conjugate Vaccine | S. Flexneri 2a Conjugate Vaccine |
|---|---|---|
| Age 1-2 years | 1.40 (NA to NA) | 18.98 (NA to NA) |
| Age >2-3 years | 3.71 (NA to NA) | 26.96 (NA to NA) |
| Age >3-4 years | 6.38 (NA to NA) | 43.86 (NA to NA) |
Percent efficacy is defined as ((disease rate of controls minus disease rate of vaccinees) divided by disease rate of controls) times 100
| Percent efficacy | S. Sonnei Conjugate Vaccine | S. Flexneri 2a Conjugate Vaccine |
|---|---|---|
| Participants aged 1-2 years | 3.8 (-101.1 to 46.5) | -8.4 (-434.5 to 78.0) |
| Participants aged >2-3 years | 35.5 (-56.4 to 73.4) | 22.5 (-244.4 to 82.6) |
| Participants aged >3-4 years | 71.1 (-4.43 to 92.0) | -3.6 (-1550 to 93.5) |
Collected over Local and systemic reactions were sought at 30 minutes, 6, 24 and 48 hours after vaccination by a structured questionnaire.. Non-serious events are listed at a 5% frequency threshold.
| Group | Deaths | Serious | Other |
|---|---|---|---|
| S. Sonnei Conjugate Vaccine | — | 0/1,434 (0%) | 217/1,434 (15.1%) |
| S. Flexneri 2a Conjugate Vaccine | — | 0/1,365 (0%) | 197/1,365 (14.4%) |
| Event | S. Sonnei Conjugate Vaccine | S. Flexneri 2a Conjugate Vaccine |
|---|---|---|
| local pain, dose 1Musculoskeletal and connective tissue disorders | 82/1434 | 61/1365 |
| local pain, dose 2Musculoskeletal and connective tissue disorders | 79/1434 | 64/1365 |
| fever, dose 1Investigations | 56/1434 | 72/1365 |
| fever, dose 2General disorders | 36/1434 | 72/1365 |
| Age, Categorical(Participants) | S. Sonnei Conjugate Vaccine | S. Flexneri 2a Conjugate Vaccine | Total |
|---|---|---|---|
| <=18 years | 1434 | 1365 | 2799 |
| Between 18 and 65 years | 0 | 0 | 0 |
| >=65 years | 0 | 0 | 0 |
| Sex: Female, Male(Participants) | S. Sonnei Conjugate Vaccine | S. Flexneri 2a Conjugate Vaccine | Total |
|---|---|---|---|
| Female | 702 | 642 | 1344 |
| Male | 732 | 723 | 1455 |
| Region of Enrollment(participants) | S. Sonnei Conjugate Vaccine | S. Flexneri 2a Conjugate Vaccine | Total |
|---|---|---|---|
| Israel | 1434 | 1365 | 2799 |
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Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)