View clinical trials related to Shigellosis.
Filter by:This is a research study about an experimental (investigational) oral inactivated whole cell Shigella flexneri 2a killed vaccine (Sf2aWC). Sf2aWC is a killed vaccine that is being made to prevent disease from Shigella., which causes bloody, watery diarrhea. Infants and children living in developing countries experience the greatest consequences of this disease. The purpose of this study is to find a dose of the vaccine that is safe, tolerable, and develops an immune response. About 82 healthy adults, ages 18-45, will participate in this study. This study will require volunteers to stay in the research facility for several nights for the first dose. Participants in Cohorts 2, 3, and 4 will not be required to stay overnight for the second and third doses. Participants will be assigned to receive 1 of 4 vaccine doses by mouth. Study procedures include: stool samples, blood samples and documenting side effects. Participants will be involved in study related procedures for about 8 months.
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.
Healthy volunteers will receive a 2-dose vaccination with Shigella dysenteriae candidate vaccine spaced 8 weeks apart. The objective is to demonstrate the safety and reactogenicity of the Shigella dysenteriae bioconjugate vaccine (GVXN SD133) alone or in combination with an adjuvant (Aluminium Hydroxide). The safety and reactogenicity of the GVXN SD133 vaccine will be also evaluated at two different concentrations of antigen, Shigella polysaccharide O1. Blood samples will be collected at intervals to examine systemic vaccine antigen-specific immune responses.
Shigellosis is one of the major causes of morbidity and mortality in many developing countries. The continued emergence of antibiotic resistant strains has complicated the treatment of shigellosis and has increased the cost of treatment markedly. Antimicrobial peptides are considered as endogenous antibiotic. A mixture of these antimicrobial peptides (LL-37 and beta-defensin) drenches the mucosal epithelial surfaces forming a barrier for invading microorganisms. Recently, we found that Shigella down-regulates the expression of LL-37 and beta-defensin 1 (HBD-1) in the colon of patients during acute shigellosis thereby facilitating bacterial invasion. Both LL-37 and HBD-1 could inhibit the growth of various microbes e.g. S. dysenteriae type 1, S. flexneri, and S. boydii. Our study indicated that bacterial DNA might be a potential mediator for the down- regulation in vitro. Down-regulation of LL-37 and HBD-1 was also seen in watery diarrhea caused by other pathogens. Thus, bacteria-mediated down-regulation of our front line defenses could be one strategy evolved by the pathogens to subvert this host-defense mechanism. gene encoding LL-37 in cultured epithelial cell lines were up-regulated when treated with butyrate; butyrate decreased the severity of Shigella infections in rabbit model. We could reproduce our findings from human i.e. downregulation of CAP-18 (the rabbit homologue to human LL-37) in colon epithelia after infection with Shigella flexneri. CAP-18 reappeared after treatment of the infected rabbits with sodium butyrate. Thus, the rabbit model demonstrated the proof of principal. In this study, we aim to assess the efficacy of sodium butyrate enema in reduction of clinical symptoms and / severity, reduction of inflammatory responses and induction of endogenous antibiotic activity in the rectum in adult patients with shigellosis.
The purpose of this study is to select a safe and immunogenic dose of Invaplex 50 intranasal vaccine, and to assess protection of Invaplex 50 intranasal vaccine against diarrhea, dysentery, and fever following challenge with the Shigella flexneri 2a 2457T strain.
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.