View clinical trials related to Shigellosis.
Filter by:This study is an open-label, dose-escalating Phase 1 investigation of S. flexneri 2a InvaplexAR vaccine. A total of up to 40 subjects will receive one of four S. flexneri 2a InvaplexAR vaccine doses. The vaccine will be administered intranasally (without adjuvant).
This is a phase I, single-blind, randomized, placebo-controlled, single-center study in healthy subjects using a staggered approach to dosing. 30 subjects will be randomized to receive 10 μg Flexyn2a candidate vaccine with or without adjuvant or placebo.
NIDIAG is an international collaboration on integrated diagnosis-treatment platforms, funded by the European Commission (EC). NIDIAG aims to develop an improved, patient-centred system for delivering primary health care in resource-constrained settings. NIDIAG will investigate three clinical syndromes, namely (i) persistent digestive disorders, (ii) persistent fever and (iii) neurological disorders, due to neglected tropical diseases (NTDs). The current study focuses on persistent digestive disorders, which are defined as diarrhoea or abdominal pain that last for at least 2 weeks. While acute diarrhoea has been studied globally, few research activities have focused on the epidemiology, diagnosis and treatment of long-lasting diarrhoeal episodes (2 weeks and longer) in the tropics. The spectrum of possibly involved pathogens includes more than 30 bacterial, parasitic and viral infectious agents. This lack of data may be explained by the fact that people suffering from NTDs might only seek care at a late stage of the disease. Furthermore, health systems in affected regions are often weak and their primary health-care centres are often under-staffed and lack essential diagnostic equipment. The hypothesis of this study is that development of an evidence-based syndromic approach can lead to better diagnosis and management of NTDs in patients with persistent digestive disorders. The study will be carried out in two West African countries (Côte d'Ivoire and Mali) and in two Asian countries (Indonesia and Nepal). The study will follow a "case-control" design and patients and controls will be prospectively enrolled. In order to address the knowledge gaps, three specific objectives will be pursued. First, the contribution of NTDs to the 'persistent digestive disorders syndrome' will be assessed. Second, the value of clinical features and rapid diagnostic tests (RDTs) for the diagnosis of target NTDs that give rise to persistent digestive disorders will be determined. Third, the clinical response to standard empiric and targeted treatment of several NTDs in patients with persistent digestive disorders will be evaluated. These objectives will provide a long-term benefit for the communities by improving the clinical decision-making process for the target NTDs and thus, better diagnostic work-up and patient management can be achieved in the study countries and other similar resource-constrained countries
This Phase 1 clinical trial is aimed to evaluate the safety and immunogenicity of 3 doses of a candidate vaccine against Shigella sonnei (1790GAHB vaccine) when administered at different dosages by different routes (intradermally, intranasally or intramuscularly) in healthy adults (18 to 45 years of age at enrollment). The safety profile of the 1790GAHB vaccine is evaluated in comparison to that of placebo (GAHB-Placebo), constituted by an aluminum hydroxide suspension having the same concentration as study vaccine formulations. A total of 52 eligible subjects will be assigned to one of three sequential cohorts as follows: Cohort A) 0.1 μg ID and 5 μg IN Cohort B) 1 μg ID and 20 μg IN Cohort C) 10 μg ID, 80 μg IN and 5 μg IM Within each cohort, in an observer-blind fashion, subjects will be randomized to receive three vaccinations, four weeks apart, of either 1790GAHB vaccine (at five antigen concentrations) or GAHB placebo. Specifically for IN and ID administration routes, a Data Safety Monitoring Board will be in place to receive a summary of all safety data obtained during one week follow-up post-first vaccination with the lower dose. Based on evaluation of the safety data, the Data Safety Monitoring Board will make a recommendation, as to whether the next cohort should be vaccinated with higher antigen concentration or not. Expected duration of the study for an individual subject is 9 months. Each subject will be followed-up for 6 months after the 3rd vaccination
This Phase 1 clinical trial is aimed to evaluate the safety and immunogenicity of 3 doses of 5 sequentially escalating dosages of a candidate vaccine against Shigella sonnei (1790GAHB vaccine) administered by intramuscular route in healthy adults (18 to 45 years of age at enrollment). The safety profile of the 1790GAHB vaccine is evaluated in comparison to that of placebo (GAHB-Placebo), constituted by an aluminum hydroxide suspension having the same concentration as study vaccine formulations. A total of 50 eligible subjects will be assigned to one of five sequential cohorts of 10 subjects each. Within each cohort, in an observer-blind fashion, subjects will be randomized to receive three vaccinations, four weeks apart, of either 1790GAHB vaccine (at five antigen concentrations) or GAHB placebo. A Data Safety Monitoring Board will be in place to receive a summary of all safety data obtained during one week follow-up post-first vaccination with the lower dose. Based on evaluation of the safety data, the Data Safety Monitoring Board will make a recommendation, as to whether the next cohort should be vaccinated with higher antigen concentration or not. Expected duration of the study for an individual subject is 9 months. Each subject will be followed-up for 6 months after the 3rd vaccination.
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 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 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.