ShigellosisPhase 3NCT00368316
Safety, Immunogenicity and Efficacy of Shigella Conjugate Vaccines in 1-4 Year Olds in Israel
A Phase 3 study testing Shigella conjugate vaccines in people with Shigellosis, run by Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) at 2 sites in Israel.
Trial summary
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. Read more about this study
- Who is it for?
- Ages 1 year to 4 years
- Conditions the study is for
- Shigellosis
- What is being tested?
- Shigella conjugate vaccines
- Type of treatment
- Vaccines
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 2,799 participants
- Where
- 2 sitesIsrael
- Study dates
- Jan 2003to Feb 2009
- Phase
- Phase 3
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 1 year to 4 years
- All sexes
- No healthy volunteers
- Child
Who may be able to join
- 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.
Who cannot join
- 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.
Trial locations and contacts
2 sites in 1 country.
Israel2 sites
Schneider Childrens Hospital
Petah Tikva
Chaim Sheba Medical Center
Tel Aviv
About this study
Official title: Phase 3 Study (Safety, Immunogenicity and Efficacy) of Improved Shigella Conjugate Vaccines in 1-4 Year Olds in Israel
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.
Read more
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.
Read the 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.
- Conditions
- Shigellosis
- Being tested
- Shigella conjugate vaccines
- Keywords
- Dysentery, S. sonnei, Antibody Response, Protection
- Medical subject headings
- Dysentery, Bacillary, Dysentery
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Shigella conjugate vaccinesBiological
Also called S. sonnei O-SP-rEPA conjugate., S. flexneri 2a O-SP-rEPA conjugate.
Shigella sonnei-rEPA and Shigella flexneri2a rEPA vaccines
| Study group | Role | What they receive |
|---|---|---|
| S. sonnei conjugate vaccine | Experimental | Shigella sonnei O-specific polysaccharide covalently bound to recombinant exoprotein A of Pseudomonas aeruginosa Receives: Biological: Shigella conjugate vaccines |
| S. flexneri 2a conjugate vaccine | Experimental | Shigella flexneri 2a O-specific polysaccharide covalently bound to recombinant exoprotein A of pseudomonas aeruginosa Receives: Biological: Shigella conjugate vaccines |
What is being measured
The primary outcome is the main question the study is designed to answer.
Number of Participants With Adverse Events
Number of participants with events per vaccine type and dose occuring in >=5% of participants
Measured: 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
Secondary outcomes (2)
Geometric Mean Immunoglobulin G (IgG) Anti-Lipopolysaccharide (LPS) Levels
Age-related homologous IgG anti-LPS levels
Measured: 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
Measured: During 2 years post vaccination
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted24 Aug 2006 (estimated)
- Study startJan 2003
- Primary completionJan 2008
- Study completionFeb 2009
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Publications (7)Papers the sponsor has linked to this study.
- Other trials for ShigellosisStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 3
- Primary purpose
- Prevention
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Quadruple blind
- Who is masked
- Participant, Care provider, Investigator, Outcomes assessor
- Enrolment
- 2,799 participants (actual)
Sponsor and investigators
- Lead sponsor
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
- Sponsor type
- US National Institutes of Health
- Collaborators
- The Chaim Sheba Medical Center, Schneider Children's Medical Center, Israel
- Responsible party
- Sponsor
- Investigators
- Rachel Schneerson, MD, Principal investigator, PDMI, NICHD, NIH
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT00368316
- Sponsor's protocol ID
- 999900003
- Other IDs
- OH00-CH-N003
- Status last verified
- Jun 2012
- First submitted
- 22 Aug 2006
- Last updated
- 22 Jun 2012
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- Yes
Publications
Development of vaccines against shigellosis: memorandum from a WHO meeting. Bull World Health Organ. 1987;65(1):17-25.
PubMed 3495364DuPont HL, Hornick RB, Snyder MJ, Libonati JP, Formal SB, Gangarosa EJ. Immunity in shigellosis. II. Protection induced by oral live vaccine or primary infection. J Infect Dis. 1972 Jan;125(1):12-6. doi: 10.1093/infdis/125.1.12. No abstract available.
PubMed 4550416Taylor DN, Echeverria P, Blaser MJ, Pitarangsi C, Blacklow N, Cross J, Weniger BG. Polymicrobial aetiology of travellers' diarrhoea. Lancet. 1985 Feb 16;1(8425):381-3. doi: 10.1016/s0140-6736(85)91397-2.
PubMed 2857430Hossain MA, Hasan KZ, Albert MJ. Shigella carriers among non-diarrhoeal children in an endemic area of shigellosis in Bangladesh. Trop Geogr Med. 1994;46(1):40-2.
PubMed 8165738Huilan S, Zhen LG, Mathan MM, Mathew MM, Olarte J, Espejo R, Khin Maung U, Ghafoor MA, Khan MA, Sami Z, et al. Etiology of acute diarrhoea among children in developing countries: a multicentre study in five countries. Bull World Health Organ. 1991;69(5):549-55.
PubMed 1659953Struelens MJ, Patte D, Kabir I, Salam A, Nath SK, Butler T. Shigella septicemia: prevalence, presentation, risk factors, and outcome. J Infect Dis. 1985 Oct;152(4):784-90. doi: 10.1093/infdis/152.4.784.
PubMed 4045231Passwell JH, Ashkenazi S, Banet-Levi Y, Ramon-Saraf R, Farzam N, Lerner-Geva L, Even-Nir H, Yerushalmi B, Chu C, Shiloach J, Robbins JB, Schneerson R; Israeli Shigella Study Group. Age-related efficacy of Shigella O-specific polysaccharide conjugates in 1-4-year-old Israeli children. Vaccine. 2010 Mar 2;28(10):2231-2235. doi: 10.1016/j.vaccine.2009.12.050. Epub 2010 Jan 5.
PubMed 20056180
Study at a glance
From the registry record, last updated by the sponsor on 22 Jun 2012. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Phase 3 Study (Safety, Immunogenicity and Efficacy) of Improved Shigella Conjugate Vaccines in 1-4 Year Olds in Israel
- ClinicalTrials.gov ID
- NCT00368316
- Acronym / sponsor ID
- 999900003
- Conditions
- Shigellosis
- Keywords
- Dysentery, S. sonnei, Antibody Response, Protection
- Phase
- Phase 3
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 2,799 participants (actual)
- Lead sponsor
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)US National Institutes of Health
- Collaborators
- The Chaim Sheba Medical Center, Schneider Children's Medical Center, Israel
- Study start
- Jan 2003
- Primary completion
- Jan 2008 (actual)
- Study completion
- Feb 2009 (actual)
- First posted
- 24 Aug 2006 (estimated)
- Results
- Posted 19 Jun 2012
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
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.
Study design
- Primary purpose
- Prevention
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Quadruple blind (participant, care provider, investigator, outcomes assessor)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| S. sonnei conjugate vaccine | Experimental | Biological: Shigella conjugate vaccinesShigella sonnei O-specific polysaccharide covalently bound to recombinant exoprotein A of Pseudomonas aeruginosa |
| S. flexneri 2a conjugate vaccine | Experimental | Biological: Shigella conjugate vaccinesShigella flexneri 2a O-specific polysaccharide covalently bound to recombinant exoprotein A of pseudomonas aeruginosa |
Who may qualify
- Ages
- 1 year to 4 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Child
Key inclusion criteria (1 listed)
- 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.
Key exclusion criteria (4 listed)
- 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.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Shigella conjugate vaccinesAlso: S. sonnei O-SP-rEPA conjugate., S. flexneri 2a O-SP-rEPA conjugate.Shigella sonnei-rEPA and Shigella flexneri2a rEPA vaccines | Biological | S. flexneri 2a conjugate vaccine, S. sonnei conjugate vaccine |
Primary outcome
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
Number of participants with events per vaccine type and dose occuring in >=5% of participants
2 secondary outcomes
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
Percentage of Efficacy
Time frame: During 2 years post vaccination
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 22 Jun 2012.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Background: PubMed 3495364Development of vaccines against shigellosis: memorandum from a WHO meeting. Bull World Health Organ. 1987;65(1):17-25.
- Background: PubMed 4550416DuPont HL, Hornick RB, Snyder MJ, Libonati JP, Formal SB, Gangarosa EJ. Immunity in shigellosis. II. Protection induced by oral live vaccine or primary infection. J Infect Dis. 1972 Jan;125(1):12-6. doi: 10.1093/infdis/125.1.12. No abstract available.
- Background: PubMed 2857430Taylor DN, Echeverria P, Blaser MJ, Pitarangsi C, Blacklow N, Cross J, Weniger BG. Polymicrobial aetiology of travellers' diarrhoea. Lancet. 1985 Feb 16;1(8425):381-3. doi: 10.1016/s0140-6736(85)91397-2.
- Background: PubMed 8165738Hossain MA, Hasan KZ, Albert MJ. Shigella carriers among non-diarrhoeal children in an endemic area of shigellosis in Bangladesh. Trop Geogr Med. 1994;46(1):40-2.
- Background: PubMed 1659953Huilan S, Zhen LG, Mathan MM, Mathew MM, Olarte J, Espejo R, Khin Maung U, Ghafoor MA, Khan MA, Sami Z, et al. Etiology of acute diarrhoea among children in developing countries: a multicentre study in five countries. Bull World Health Organ. 1991;69(5):549-55.
- Background: PubMed 4045231Struelens MJ, Patte D, Kabir I, Salam A, Nath SK, Butler T. Shigella septicemia: prevalence, presentation, risk factors, and outcome. J Infect Dis. 1985 Oct;152(4):784-90. doi: 10.1093/infdis/152.4.784.
- Results publication: PubMed 20056180Passwell JH, Ashkenazi S, Banet-Levi Y, Ramon-Saraf R, Farzam N, Lerner-Geva L, Even-Nir H, Yerushalmi B, Chu C, Shiloach J, Robbins JB, Schneerson R; Israeli Shigella Study Group. Age-related efficacy of Shigella O-specific polysaccharide conjugates in 1-4-year-old Israeli children. Vaccine. 2010 Mar 2;28(10):2231-2235. doi: 10.1016/j.vaccine.2009.12.050. Epub 2010 Jan 5.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Rachel Schneerson, MD principal investigator
PDMI, NICHD, NIH
2 sites in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 3 study testing Shigella conjugate vaccines in people with Shigellosis, run by Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) at 2 sites in Israel.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 1 inclusion and 4 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 22 Jun 2012. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 2 sites in Israel. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 3 studies compare the treatment with the current standard treatment or a placebo in a large group, to confirm how well it works and watch for side effects.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 19 Jun 2012). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
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). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT00368316, which also lists 7 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 22 Jun 2012.