Safety, Immunogenicity and Efficacy of Shigella Conjugate Vaccines in 1-4 Year Olds in Israel
Condition: Shigellosis
MeSH terms: Dysentery, Bacillary
Study type: Interventional
Phase: Phase 3

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.
    

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.
    

Intervention name(s): Shigella conjugate vaccines
Intervention type(s): Biological
Intervention description(s): Shigella sonnei-rEPA and Shigella flexneri2a rEPA vaccines
Other intervention name(s): S. sonnei O-SP-rEPA conjugate.; S. flexneri 2a O-SP-rEPA conjugate.
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Prevention
Keywords: Dysentery; S. sonnei; Antibody Response; Protection