Safety, Immunogenicity and Efficacy of Shigella Conjugate Vaccines in 1-4 Year Olds in Israel
Phase 3 Study (Safety, Immunogenicity and Efficacy) of Improved Shigella Conjugate Vaccines in 1-4 Year Olds in Israel
2 other identifiers
interventional
2,799
1 country
2
Brief 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. 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.
Trial Health
Trial Health Score
Automated assessment based on enrollment pace, timeline, and geographic reach
participants targeted
Target at P75+ for phase_3
Started Jan 2003
Longer than P75 for phase_3
2 active sites
Health score is calculated from publicly available data and should be used for screening purposes only.
Trial Relationships
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Study Timeline
Key milestones and dates
Study Start
First participant enrolled
January 1, 2003
CompletedFirst Submitted
Initial submission to the registry
August 22, 2006
CompletedFirst Posted
Study publicly available on registry
August 24, 2006
CompletedPrimary Completion
Last participant's last visit for primary outcome
January 1, 2008
CompletedStudy Completion
Last participant's last visit for all outcomes
February 1, 2009
CompletedResults Posted
Study results publicly available
June 19, 2012
CompletedJune 22, 2012
June 1, 2012
5 years
August 22, 2006
May 9, 2012
June 21, 2012
Conditions
Keywords
Outcome Measures
Primary Outcomes (1)
Number of Participants With Adverse Events
Number of participants with events per vaccine type and dose occuring in \>=5% of participants
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
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
During 2 years post vaccination
Study Arms (2)
S. sonnei conjugate vaccine
EXPERIMENTALShigella sonnei O-specific polysaccharide covalently bound to recombinant exoprotein A of Pseudomonas aeruginosa
S. flexneri 2a conjugate vaccine
EXPERIMENTALShigella flexneri 2a O-specific polysaccharide covalently bound to recombinant exoprotein A of pseudomonas aeruginosa
Interventions
Shigella sonnei-rEPA and Shigella flexneri2a rEPA vaccines
Eligibility Criteria
You may qualify if:
- 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.
You may not qualify if:
- 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.
Contact the study team to confirm eligibility.
Sponsors & Collaborators
Study Sites (2)
Schneider Childrens Hospital
Petah Tikva, Israel
Chaim Sheba Medical Center
Tel Aviv, Israel
Related Publications (7)
Development of vaccines against shigellosis: memorandum from a WHO meeting. Bull World Health Organ. 1987;65(1):17-25.
PMID: 3495364BACKGROUNDDuPont 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.
PMID: 4550416BACKGROUNDTaylor 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.
PMID: 2857430BACKGROUNDHossain 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.
PMID: 8165738BACKGROUNDHuilan 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.
PMID: 1659953BACKGROUNDStruelens 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.
PMID: 4045231BACKGROUNDPasswell 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.
PMID: 20056180RESULT
MeSH Terms
Conditions
Condition Hierarchy (Ancestors)
Limitations and Caveats
No efficacy could be assessed after 2nd injection of S. sonnei conjugate due to the small number of positive isolates at that time. There were too few cases of S. flexneri 2a infection for evaluation of vaccine B efficacy.
Results Point of Contact
- Title
- Dr. Rachel Schneerson, Co-Director
- Organization
- PDMI, NICHD, NIH
Study Officials
- PRINCIPAL INVESTIGATOR
Rachel Schneerson, MD
PDMI, NICHD, NIH
Publication Agreements
- PI is Sponsor Employee
- No
- Restrictive Agreement
- No
Study Design
- Study Type
- interventional
- Phase
- phase 3
- Allocation
- RANDOMIZED
- Masking
- QUADRUPLE
- Who Masked
- PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
- Purpose
- PREVENTION
- Intervention Model
- PARALLEL
- Sponsor Type
- NIH
- Responsible Party
- SPONSOR
Study Record Dates
First Submitted
August 22, 2006
First Posted
August 24, 2006
Study Start
January 1, 2003
Primary Completion
January 1, 2008
Study Completion
February 1, 2009
Last Updated
June 22, 2012
Results First Posted
June 19, 2012
Record last verified: 2012-06