Shigellosis Clinical Trial
Official title:
Shigella Sonnei OSPC-rDT Conjugate Vaccine
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 non-toxic recombinant diphtheria toxin
mutant (rDT).
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 to 3 year old children. Higher levels of IgG anti O-SP are expected 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 ug 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 non-toxic recombinant diphtheria toxin mutant. IgG
antibody levels induced in young outbred mice by this new S. sonnei O-SPC conjugate were
significantly higher then those elicited by the O-SP conjugates.
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 non-toxic recombinant diphtheria toxin
mutant (rDT).
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 to 3 year old children. Higher levels of IgG anti O-SP are expected 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 ug 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 non-toxic recombinant diphtheria toxin mutant. IgG
antibody levels induced in young outbred mice by this new S. sonnei O-SPC conjugate were
significantly higher then those elicited by the O-SP conjugates.
;
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