A5009523661- Viral gastroenteritis research and epidemiology
- Escherichia coli research studies
- Clostridium difficile and Clostridium perfringens research
- Salmonella and Campylobacter epidemiology
- Vaccine Coverage and Hesitancy
- Antibiotic Resistance in Bacteria
- Vibrio bacteria research studies
- Peptidase Inhibition and Analysis
- Legionella and Acanthamoeba research
- Gut microbiota and health
- Biochemical and Molecular Research
- Ubiquitin and proteasome pathways
- Bacteriophages and microbial interactions
- Bacterial Genetics and Biotechnology
Walter Reed Army Institute of Research
2009-2025
University of Vermont
2003-2005
Shigella infections remain endemic in places with poor sanitation and are a leading cause of diarrheal mortality globally, as well major contributor to gut enteropathy stunting. There currently no licensed vaccines for shigellosis but it has been estimated that an effective vaccine could avert 590,000 deaths over 20-year period. A challenge development the low immunogenicity protective efficacy candidate infants young children. Additionally, new might be less immunogenic highly setting...
Shigellosis accounts for substantial morbidity and mortality worldwide is the second most common cause of moderate severe diarrhoea in children.This phase 2b study (NCT03527173), conducted between August 2018 November 2019, evaluated vaccine efficacy (VE), safety, immunogenicity a Shigella sonnei GMMA candidate (1790GAHB) adults, using S. 53 G controlled human infection model. Participants (randomized 1:1) received two doses 1790GAHB or placebo (GAHB-Placebo), at day (D) 1 D29, an oral...
Shigella is a major cause of moderate to severe diarrhea largely affecting children (<5 years old) living in low- and middle-income countries. Several vaccine candidates are development, controlled human infection models (CHIMs) can be useful tools provide an early assessment efficacy potentially support licensure. A lyophilized strain S. sonnei 53G was manufactured evaluated establish dose that safely reproducibly induced ≥60% attack rate. Samples were collected pre- postchallenge assess...
ABSTRACT Shigella is a significant cause of diarrhea, predominantly affecting children in low- and middle-income countries, as well international travelers. Not all individuals exposed to or other enteropathogens have symptomatic responses, investigating the differences between asymptomatic can further our understanding enteropathogen proliferation responses. Here, we profiled fecal microbiomes 45 infected with sonnei strain 53G through 16S rRNA sequencing controlled human infection model...
Invasive nontyphoidal Salmonella (iNTS) disease remains a major public health challenge in sub-Saharan Africa. Typhimurium (STm) is responsible for the majority of cases, with specific lineages being associated increased risk bloodstream infection. We have recently developed STm controlled human infection model (CHIM) to better understand pathogenesis and provide platform test candidate vaccines. Selecting appropriate strains central design consideration developing protocols. describe...
Shigella sonnei live vaccine candidate, WRSS1, which was previously evaluated in US, Israeli and Thai volunteers, administered orally to Bangladeshi adults children assess its safety, clinical tolerability immunogenicity. In a randomized, placebo-controlled, dose-escalation, age-descending study, 39 (18–39 years) 64 (5–9 were enrolled. Each adult cohort (n = 13) received one dose of 3x104, or three doses 3 × 105 106 colony forming unit (CFU) WRSS1 10) placebo 3). child 16) 3x103, 3x105, CFU...
Shigella causes morbidity and mortality worldwide, primarily affecting young children living in low-resource settings. It is also of great concern due to increasing antibiotic resistance, a priority organism for the World Health Organization. A vaccine would decrease associated with shigellosis, improve child health, need antibiotics. Controlled human infection models (CHIMs) are useful tools evaluation early up- or down-selection candidates potentially support licensure. Over time, methods...
Summary The intracellular pathogen, Salmonella enterica serovar Typhimurium, is able to proliferate in phagocytes, although reactive oxygen and nitrogen intermediates are lethal most phagocytosed bacteria. To determine whether repair of oxidatively damaged DNA involved S. typhimurium intramacrophage proliferation, null mutants the base excision (BER) system were generated. These deficient discrete enzymes ( Δnth , Δnei Δxth Δnfo ) or defined glycosylase Δnth/nei endonuclease Δxth/nfo steps....
Controlled human infection models (CHIMs) are useful for vaccine development. To improve on existing models, we developed a CHIM using lyophilized preparation of Shigella sonnei strain 53G produced current good manufacturing practice (cGMP). Healthy adults were enrolled in an open-label dose-ranging study. Following administration dose rehydrated S. 53G, subjects monitored development disease. The first cohort received 500 CFU and dosing subsequent cohorts was based results from the previous...
Reactive oxidants are a primary weapon of the macrophage antibacterial arsenal. The ability virulent Salmonella to repair oxidative DNA lesions via base-excision system (BER) enables its survival and replication within macrophage, but is not required for extracellular growth. also inhibits targeting oxidant generators Salmonella-containing vacuole (SCV) Pathogenicity Island 2 (SPI2). Accordingly, relative contributions these two discrete systems resistance both mutagenesis lethality RAW...
Shigella sonnei live vaccine candidates WRSs2 and WRSs3 are principally attenuated by the loss of virG(icsA) gene that prevents bacterial spread. In addition both strains lack enterotoxin SenA a paralog SenB. also has deletion in encoding MsbB2. Both these expected to be improved safer versions WRSS1 only lacked was reactogenic volunteer trials. During construction WRSs3, segments virulence plasmid spanning two FRT sites were found inverted orientation. These inversions have been analysed...
Several animal models exist to evaluate the immunogenicity and protective efficacy of candidate Shigella vaccines. The two most widely used nonprimate for vaccine development include a murine pulmonary challenge model guinea pig keratoconjunctivitis model. Nonhuman primate exhibit clinical features gross microscopic colonic lesions that mimic those induced in human shigellosis. Challenge enterotoxigenic Escherichia coli (ETEC) Campylobacter spp. have been successfully developed with Aotus...
There is an increasing need to establish quality principles for designing, developing and manufacturing challenge agents as currently these are classified differently by various jurisdictions. Indeed, considerations agent vary between countries due differences in regulatory oversight, the categorization of incorporation into medicinal/vaccine development processes. To this end, a whitepaper on guidance has been produced disseminated consultation researchers, experts or advisory bodies. This...
ABSTRACT Three Mu d J prototrophs demonstrated that intracellular replication is a Salmonella virulence trait (K. Y. Leung and B. Finlay, Proc. Natl. Acad. Sci. USA, 88: 11470-11474, 1991). mutS mutH are disrupted in mutants 3-11 12-23, ssaQ mutant 17-21. Further analysis revealed loss of pathogenicity island 2 function underlies the defect
Background: Shigellosis accounts for substantial morbidity and mortality worldwide is the second most common cause of moderate severe diarrhoea in children, after rotavirus.Methods: This phase 2b study (NCT03527173) evaluated vaccine efficacy (VE) against shigellosis, safety, immunogenicity a Shigella sonnei GMMA candidate (1790GAHB) adults, using S. 53G controlled human infection model (CHIM). Participants (randomized 1:1) received two doses 1790GAHB or placebo (GAHB-Placebo), at day (D) 1...