Shigella Sonnel O-SPC/rBRU Conjugate Vaccine
Condition: Immunogenicity; Shigellosis
MeSH terms: Dysentery, Bacillary
Study type: Interventional
Phase: Phase 1

Summary: 
      The active ingredient of this Shigella sonnei O-SP-core conjugate vaccine is a
      saccharide-protein conjugate composed of a fragment of S. sonnei LPS. The saccharide
      component consists of an average of 3.5 repeat units of the O-SP plus the core region of the
      LPS (O-SPC). The O-SPC is covalently bound to the recombinant non-toxic exoprotein B of
      Clostridium difficile.

      The objective of this phase of the study is to determine if this vaccine is safe and can
      induce IgG antibody type-specific immunity to shigellosis in adults. The overall objective is
      to determine if this vaccine can elicit higher levels of IgG antibody than the previous
      experimental vaccines made with the full length O-SP, shown to be >70% efficacious in greater
      than or equal to3 year old children, to induce type-specific immunity to shigellosis in
      younger children.

      Sixty 18-49 years-old healthy adults will be recruited in Israel. Volunteers will be
      vaccinated on a random basis with one i.m. injection of 10 or 25 micrograms of the
      investigational conjugate vaccine. Local and systemic reactions will be observed at 30
      minutes, and the volunteers will be instructed to take their temperature and examine the
      injection site for redness and swelling and fill out a questionnaire at 6, hours and daily
      for 7 days after vaccination. The volunteers will visit the clinic at 24 or 48 hours
      following the injection and any time they request it. The study will commence with 5
      volunteers injected with the 10ug dose to be followed, if no severe adverse reactions occur,
      by 5 volunteers injected with the 25ug dose. If a severe adverse reaction occurs on 1 of the
      5 volunteers in either group, 5 more will be injected with that dose. If there are no severe
      adverse reactions the study will proceed. If there is one more severe reaction the study will
      be halted and re-evaluated by the IRB and the FDA.

      Vaccine-induced antibodies will be measured at 1 and 6 months after immunization, and
      compared to those elicited by our previous S. sonnei conjugate vaccines.

      There is a body of evidence that a critical level of serum IgG antibody to the O-specific
      polysaccharide domain of LPS confers type-specific immunity to S. sonnei as well as to other
      Shigella:

        1. Shigellosis is rarely observed in infants up to the age of 4-6 months. The most obvious
           explanation for this is that maternally-derived serum IgG provides this immunity;

        2. There is an age-related development of IgG anti-LPS antibodies that, in many instances,
           is not induced by the homologous bacteria but by non-pathogenic cross-reacting enteric
           bacteria;

        3. The highest incidence, morbidity, and mortality occur during 6 months to 6 years of age
           when the maternally-derived serum anti-O-SP has waned and the naturally-derived
           antibodies have not yet appeared;

        4. One injection of a S. sonnei-rEPA conjugate showed significant protection against
           shigellosis in Israeli Defense Force soldiers. Vaccinees who developed shigellosis
           showed significantly lower serum IgG responses to the homologous LPS than those did
           not.The high antibody level induced by the conjugate vaccine indicates the positive
           correlation between the serum IgG anti-LPS levels and immunity to S. sonnei infection;

        5. Following Phase 1 and Phase 2 studies that showed safety and age-related immunogenicity,
           a double-blinded randomized and vaccine-controlled Phase 3 evaluation of S. sonnei and
           S. flexneri type 2a O-specific polysaccharide (O-SP) protein conjugates was conducted
           among 1-4 year-olds in Israel.

      For recipients of the S. sonnei conjugate 71.1% efficacy was shown among 3-4 year-old
      recipients, no efficacy was shown for recipients of S. flexneri 2a. There was no
      statistically significant efficacy for either vaccine in the 1-3 year-olds. Levels of serum
      IgG anti-O-SP were elevated according to the vaccine the children received but G.M. levels
      declined rapidly several months after the last injection. Our interpretation is that the
      age-related efficacy of the Shigella conjugates was due to the conjugate-induced O-SP
      antibody levels. Accordingly, we have developed a method to increase the immunogenicity of
      the conjugates to approach the antibody levels of Israeli soldiers shown to be protected by
      our S. sonnei O-SP.

      Low-molecular-mass O-SP-core (O-SPC) fragments were isolated from S. sonnei LPS, and bound by
      their reducing ends to the carrier protein. The O-SPC conjugates used oxime linkages between
      the terminal Kdo residues at the reducing ends of the S. sonnei saccharides and aminooxy
      linkers bound to the carrier. The coupling reaction was carried out at a neutral pH and room
      temperature. The carrier protein was a mutant non-toxic Clostridium difficile exotoxin B. IgG
      antibody levels induced in young outbred mice by this new S. sonnei O-SPC conjugate were
      significantly higher than those elicited by the O-SP conjugates.
    

Detailed description: 
      The active ingredient of this Shigella sonnei O-SP-core conjugate vaccine is a
      saccharide-protein conjugate composed of a fragment of S. sonnei LPS. The saccharide
      component consists of an average of 3.5 repeat units of the O-SP plus the core region of the
      LPS (O-SPC). The O-SPC is covalently bound to the recombinant non-toxic exoprotein B of
      Clostridium difficile.

      The objective of this phase of the study is to determine if this vaccine is safe and can
      induce IgG antibody type-specific immunity to shigellosis in adults. The overall objective is
      to determine if this vaccine can elicit higher levels of IgG antibody than the previous
      experimental vaccines made with the full length O-SP, shown to be >70% efficacious in greater
      than or equal to3 year old children, to induce type-specific immunity to shigellosis in
      younger children.

      Sixty 18-49 years-old healthy adults will be recruited in Israel. Volunteers will be
      vaccinated on a random basis with one i.m. injection of 10 or 25 micrograms of the
      investigational conjugate vaccine. Local and systemic reactions will be observed at 30
      minutes, and the volunteers will be instructed to take their temperature and examine the
      injection site for redness and swelling and fill out a questionnaire at 6, hours and daily
      for 7 days after vaccination. The volunteers will visit the clinic at 24 or 48 hours
      following the injection and any time they request it. The study will commence with 5
      volunteers injected with the 10ug dose to be followed, if no severe adverse reactions occur,
      by 5 volunteers injected with the 25ug dose. If a severe adverse reaction occurs on 1 of the
      5 volunteers in either group, 5 more will be injected with that dose. If there are no severe
      adverse reactions the study will proceed. If there is one more severe reaction the study will
      be halted and re-evaluated by the IRB and the FDA.

      Vaccine-induced antibodies will be measured at 1 and 6 months after immunization, and
      compared to those elicited by our previous S. sonnei conjugate vaccines.

      There is a body of evidence that a critical level of serum IgG antibody to the O-specific
      polysaccharide domain of LPS confers type-specific immunity to S. sonnei as well as to other
      Shigella:

        1. Shigellosis is rarely observed in infants up to the age of 4-6 months. The most obvious
           explanation for this is that maternally-derived serum IgG provides this immunity;

        2. There is an age-related development of IgG anti-LPS antibodies that, in many instances,
           is not induced by the homologous bacteria but by non-pathogenic cross-reacting enteric
           bacteria;

        3. The highest incidence, morbidity, and mortality occur during 6 months to 6 years of age
           when the maternally-derived serum anti-O-SP has waned and the naturally-derived
           antibodies have not yet appeared;

        4. One injection of a S. sonnei-rEPA conjugate showed significant protection against
           shigellosis in Israeli Defense Force soldiers. Vaccinees who developed shigellosis
           showed significantly lower serum IgG responses to the homologous LPS than those did
           not.The high antibody level induced by the conjugate vaccine indicates the positive
           correlation between the serum IgG anti-LPS levels and immunity to S. sonnei infection;

        5. Following Phase 1 and Phase 2 studies that showed safety and age-related immunogenicity,
           a double-blinded randomized and vaccine-controlled Phase 3 evaluation of S. sonnei and
           S. flexneri type 2a O-specific polysaccharide (O-SP) protein conjugates was conducted
           among 1-4 year-olds in Israel.

      For recipients of the S. sonnei conjugate 71.1% efficacy was shown among 3-4 year-old
      recipients, no efficacy was shown for recipients of S. flexneri 2a. There was no
      statistically significant efficacy for either vaccine in the 1-3 year-olds. Levels of serum
      IgG anti-O-SP were elevated according to the vaccine the children received but G.M. levels
      declined rapidly several months after the last injection. Our interpretation is that the
      age-related efficacy of the Shigella conjugates was due to the conjugate-induced O-SP
      antibody levels. Accordingly, we have developed a method to increase the immunogenicity of
      the conjugates to approach the antibody levels of Israeli soldiers shown to be protected by
      our S. sonnei O-SP.

      Low-molecular-mass O-SP-core (O-SPC) fragments were isolated from S. sonnei LPS, and bound by
      their reducing ends to the carrier protein. The O-SPC conjugates used oxime linkages between
      the terminal Kdo residues at the reducing ends of the S. sonnei saccharides and aminooxy
      linkers bound to the carrier. The coupling reaction was carried out at a neutral pH and room
      temperature. The carrier protein was a mutant non-toxic Clostridium difficile exotoxin B. IgG
      antibody levels induced in young outbred mice by this new S. sonnei O-SPC conjugate were
      significantly higher than those elicited by the O-SP conjugates.
    

Intervention name(s): Shigella Sonnei O-SPC/rBRU
Intervention type(s): Biological
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Double (Participant, Investigator)
Primary purpose: Prevention
Keywords: Shigellosis; Safety and Immunogenicity; Conjugate Vaccine