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"human challenge"

Peter Teunis, Maria J Figueras
Cases of Aeromonas diarrhea have been described all over the world. The genus Aeromonas includes ca. 30 species, of which 10 have been isolated in association with gastroenteritis. The dominating species that account for ca. 96% of the identified strains are Aeromonas caviae, A. veronii, A. dhakensis, and A. hydrophila. However, the role of Aeromonas as a true enteropathogen has been questioned on the basis of the lack of outbreaks, the non-fulfillment of Koch's postulates and the low numbers of acute illnesses in the only existing human challenge study...
2016: Frontiers in Microbiology
Ashley Sobel Leonard, Micah T McClain, Gavin J D Smith, David Wentworth, Rebecca A Halpin, Xudong Lin, Amy Ransier, Timothy B Stockwell, Suman Das, Anthony S Gilbert, Robert Lambkin-Williams, Geoffrey S Ginsburg, Christopher W Woods, Katia Koelle
: Knowledge of influenza evolution at the point of transmission and at the intra-host level remains limited, particularly for human hosts. Here, we analyze a unique viral dataset of next-generation sequencing (NGS) samples generated from a human influenza challenge study wherein 17 healthy subjects were inoculated with egg-passaged virus. Nasal wash samples collected from 7 of these subjects were successfully deep sequenced. From these, we characterized changes in the subjects' viral populations during infection and identified differences between the virus in these samples and the viral stock used to inoculate the subjects...
October 5, 2016: Journal of Virology
E Mitsi, A M Roche, J Reiné, T Zangari, J T Owugha, S H Pennington, J F Gritzfeld, A D Wright, A M Collins, S van Selm, M I de Jonge, S B Gordon, J N Weiser, D M Ferreira
The ability of pneumococcal conjugate vaccine (PCV) to decrease transmission by blocking the acquisition of colonization has been attributed to herd immunity. We describe the role of mucosal immunoglobulin G (IgG) to capsular polysaccharide (CPS) in mediating protection from carriage, translating our findings from a murine model to humans. We used a flow cytometric assay to quantify antibody-mediated agglutination demonstrating that hyperimmune sera generated against an unencapsulated mutant was poorly agglutinating...
August 31, 2016: Mucosal Immunology
Rachel Fearns, Jerome Deval
Worldwide, respiratory syncytial virus (RSV) causes severe disease in infants, the elderly, and immunocompromised people. No vaccine or effective antiviral treatment is available. RSV is a member of the non-segmented, negative-strand (NNS) group of RNA viruses and relies on its RNA-dependent RNA polymerase to transcribe and replicate its genome. Because of its essential nature and unique properties, the RSV polymerase has proven to be a good target for antiviral drugs, with one compound, ALS-8176, having already achieved clinical proof-of-concept efficacy in a human challenge study...
October 2016: Antiviral Research
P Teunis, J Schijven, S Rutjes
Adenoviruses are found everywhere in the environment, and cause various health problems including symptoms of enteric illness, and respiratory illness. Despite their significance to public health, few studies have addressed the health risks associated with exposure to adenovirus. Human challenge studies have been published for a few adenoviruses, which involved exposure through oral ingestion, inhalation, intranasal and intraocular droplet inoculation. Nothwithstanding the different symptoms resulting from such exposures, infection can be defined as colonization of a corresponding mucosa...
August 30, 2016: Epidemiology and Infection
Thomas C Darton, Claire Jones, Christoph J Blohmke, Claire S Waddington, Liqing Zhou, Anna Peters, Kathryn Haworth, Rebecca Sie, Christopher A Green, Catherine A Jeppesen, Maria Moore, Ben A V Thompson, Tessa John, Robert A Kingsley, Ly-Mee Yu, Merryn Voysey, Zoe Hindle, Stephen Lockhart, Marcelo B Sztein, Gordon Dougan, Brian Angus, Myron M Levine, Andrew J Pollard
BACKGROUND: Typhoid persists as a major cause of global morbidity. While several licensed vaccines to prevent typhoid are available, they are of only moderate efficacy and unsuitable for use in children less than two years of age. Development of new efficacious vaccines is complicated by the human host-restriction of Salmonella enterica serovar Typhi (S. Typhi) and lack of clear correlates of protection. In this study, we aimed to evaluate the protective efficacy of a single dose of the oral vaccine candidate, M01ZH09, in susceptible volunteers by direct typhoid challenge...
August 2016: PLoS Neglected Tropical Diseases
Stefan H E Kaufmann, Sarah Fortune, Ilaria Pepponi, Morten Ruhwald, Lewis K Schrager, Tom H M Ottenhoff
The 4th Global Forum on TB Vaccines, convened in Shanghai, China, from 21 - 24 April 2015, brought together a wide and diverse community involved in tuberculosis vaccine research and development to discuss the current status of, and future directions for this critical effort. This paper summarizes the sessions on Biomarkers and Correlates, and Human Challenge Models. Summaries of all sessions from the 4th Global Forum are compiled in a special supplement of Tuberculosis. [August 2016, Vol 99, Supp S1, S1-S30]...
August 2016: Tuberculosis
Mihai Pop, Joseph N Paulson, Subhra Chakraborty, Irina Astrovskaya, Brianna R Lindsay, Shan Li, Héctor Corrada Bravo, Clayton Harro, Julian Parkhill, Alan W Walker, Richard I Walker, David A Sack, O Colin Stine
BACKGROUND: Enterotoxigenic Escherichia coli (ETEC) is a major cause of diarrhea in inhabitants from low-income countries and in visitors to these countries. The impact of the human intestinal microbiota on the initiation and progression of ETEC diarrhea is not yet well understood. RESULTS: We used 16S rRNA (ribosomal RNA) gene sequencing to study changes in the fecal microbiota of 12 volunteers during a human challenge study with ETEC (H10407) and subsequent treatment with ciprofloxacin...
2016: BMC Genomics
Saranya Sridhar
Influenza A virus (IAV) remains a significant global health issue causing annual epidemics, pandemics, and sporadic human infections with highly pathogenic avian or swine influenza viruses. Current inactivated and live vaccines are the mainstay of the public health response to influenza, although vaccine efficacy is lower against antigenically distinct viral strains. The first pandemic of the twenty-first century underlined the urgent need to develop new vaccines capable of protecting against a broad range of influenza strains...
2016: Frontiers in Immunology
Shobana Balasingam, Annelies Wilder-Smith
OBJECTIVES: Controlled human infection, the intentional infection of healthy volunteers, allows disease pathogenesis to be studied and vaccines and therapeutic interventions to be evaluated in a controlled setting. A systematic review of randomized controlled trials of countermeasures for influenza that used the experimental human infection platform was performed. The primary objective was to document the scope of trials performed to date and the main efficacy outcome in the trials. The secondary objective was to assess safety and identify serious adverse events...
August 2016: International Journal of Infectious Diseases: IJID
Amy E Kirby, Ashleigh Streby, Christine L Moe
BACKGROUND: In the US, noroviruses are estimated to cause 21 million cases annually with economic losses reaching $2 billion. Outbreak investigations frequently implicate vomiting as a major transmission risk. However, little is known about the characteristics of vomiting as a symptom or the amount of virus present in emesis. METHODOLOGY AND PRINCIPAL FINDINGS: Emesis samples and symptomology data were obtained from previous norovirus human challenge studies with GI...
2016: PloS One
Nan Zhang, Zhenghui Liu, Longbiao Yao, Padmaja Mehta-D'souza, Rodger P McEver
OBJECTIVE: During inflammation, P-selectin expressed on activated endothelial cells and platelets mediates rolling adhesion of leukocytes. Atherosclerosis-prone mice crossed with P-selectin-deficient (Selp(-/-)) mice develop smaller lesions. Cytokines, such as tumor necrosis factor-α, increase Selp transcripts and augment atherosclerosis in mice. However, they decrease SELP transcripts in humans, challenging assumptions that human P-selectin is atherogenic. We used mice expressing a human SELP transgene to examine the atherogenic role of P-selectin...
June 2016: Arteriosclerosis, Thrombosis, and Vascular Biology
Matthew J Memoli, Pamela A Shaw, Alison Han, Lindsay Czajkowski, Susan Reed, Rani Athota, Tyler Bristol, Sarah Fargis, Kyle Risos, John H Powers, Richard T Davey, Jeffery K Taubenberger
UNLABELLED: Despite long-term investment, influenza continues to be a significant worldwide problem. The cornerstone of protection remains vaccination, and approved vaccines seek to elicit a hemagglutination inhibition (HAI) titer of ≥1:40 as the primary correlate of protection. However, recent poor vaccine performance raises questions regarding the protection afforded and whether other correlates of protection should be targeted. A healthy volunteer challenge study was performed with a wild-type 2009 A(H1N1)pdm influenza A challenge virus at the NIH Clinical Center to evaluate two groups of participants with HAI titers of ≥1:40 and <1:40...
2016: MBio
Beth D Kirkpatrick, Stephen S Whitehead, Kristen K Pierce, Cecilia M Tibery, Palmtama L Grier, Noreen A Hynes, Catherine J Larsson, Beulah P Sabundayo, Kawsar R Talaat, Anna Janiak, Marya P Carmolli, Catherine J Luke, Sean A Diehl, Anna P Durbin
A dengue human challenge model can be an important tool to identify candidate dengue vaccines that should be further evaluated in large efficacy trials in endemic areas. Dengue is responsible for about 390 million infections annually. Protective efficacy results for the most advanced dengue vaccine candidate (CYD) were disappointing despite its ability to induce neutralizing antibodies against all four dengue virus (DENV) serotypes. TV003 is a live attenuated tetravalent DENV vaccine currently in phase 2 evaluation...
March 16, 2016: Science Translational Medicine
James S McCarthy, Louise Marquart, Silvana Sekuloski, Katharine Trenholme, Suzanne Elliott, Paul Griffin, Rebecca Rockett, Peter O'Rourke, Theo Sloots, Iñigo Angulo-Barturen, Santiago Ferrer, María Belén Jiménez-Díaz, María-Santos Martínez, Rob Hooft van Huijsduijnen, Stephan Duparc, Didier Leroy, Timothy N C Wells, Mark Baker, Jörg J Möhrle
Effective progression of candidate antimalarials is dependent on optimal dosing in clinical studies, which is determined by a sound understanding of pharmacokinetics and pharmacodynamics (PK/PD). Recently, two important translational models for antimalarials have been developed: the NOD/SCID/IL2Rγ(-/-) (NSG) model, whereby mice are engrafted with noninfected and Plasmodium falciparum-infected human erythrocytes, and the induced blood-stage malaria (IBSM) model in human volunteers. The antimalarial mefloquine was used to directly measure the PK/PD in both models, which were compared to previously published trial data for malaria patients...
June 2016: Antimicrobial Agents and Chemotherapy
Mark S Riddle, Richard I Walker
The global health community is beginning to gain an understanding of the global burden of norovirus-associated disease, which appears to have significant burden in both developed- and developing-country populations. Of particular importance is the growing recognition of norovirus as a leading cause of gastroenteritis and diarrhea in countries where rotavirus vaccine has been introduced. While not as severe as rotavirus disease, the sheer number of norovirus infections not limited to early childhood makes norovirus a formidable global health problem...
June 3, 2016: Vaccine
Chad K Porter, Mark S Riddle, Ashley N Alcala, David A Sack, Clayton Harro, Subhra Chakraborty, Ramiro L Gutierrez, Stephen J Savarino, Michael Darsley, Robin McKenzie, Barbara DeNearing, Hans Steinsland, David R Tribble, A Louis Bourgeois
BACKGROUND: Experimental human challenge models have played a major role in enhancing our understanding of infectious diseases. Primary outcomes have typically utilized overly simplistic outcomes that fail to entirely account for complex illness syndromes. We sought to characterize clinical outcomes associated with experimental infection with enterotoxigenic Escherichia coli (ETEC) and to develop a disease score. METHODS: Data were obtained from prior controlled human ETEC infection studies...
2016: PloS One
Sharon M Tennant, A Duncan Steele, Marcela F Pasetti
Infectious diarrhea is a leading cause of morbidity and of mortality; the burden of disease affects individuals of all ages but particularly young children, especially those living in poor regions where the disease is endemic. It is also a health concern for international travelers to these areas. Experts on vaccines and enteric infections and advocates for global health improvement gathered in Scotland from 8 to 10 July 2015 to discuss recent advances in the assessment and understanding of the burden of enteric diseases and progress in the development and implementation of strategies to prevent these infections...
April 2016: Clinical and Vaccine Immunology: CVI
Stephanie Fresnay, Monica A McArthur, Laurence Magder, Thomas C Darton, Claire Jones, Claire S Waddington, Christoph J Blohmke, Brian Angus, Myron M Levine, Andrew J Pollard, Marcelo B Sztein
BACKGROUND: Typhoid fever, caused by the human-restricted organism Salmonella Typhi (S. Typhi), is a major public health problem worldwide. Development of novel vaccines remains imperative, but is hampered by an incomplete understanding of the immune responses that correlate with protection. METHODS: Recently, a controlled human infection model was re-established in which volunteers received ~10(3) cfu wild-type S. Typhi (Quailes strain) orally. Twenty-one volunteers were evaluated for their cell-mediated immune (CMI) responses...
2016: Journal of Translational Medicine
Subhra Chakraborty, Clayton Harro, Barbara DeNearing, Jay Bream, Nicole Bauers, Len Dally, Jorge Flores, Lillian Van de Verg, David A Sack, Richard Walker
Shigella causes high morbidity and mortality worldwide, but there is no licensed vaccine for shigellosis yet. We evaluated the safety and immunogenicity of a formalin-inactivated whole-cell Shigella flexneri2a vaccine, Sf2aWC, given orally to adult volunteers. In a double-blind, placebo-controlled trial, 82 subjects were randomized to receive three doses of vaccine in dose escalation (2.6 ± 0.8 × 10(8), × 10(9), × 10(10), and × 10(11)vaccine particles/ml). Vaccine safety was actively monitored, and antigen-specific systemic and mucosal immune responses were determined in serum, antibody in lymphocyte supernatant (ALS), and fecal samples...
April 2016: Clinical and Vaccine Immunology: CVI
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