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"human challenge"

Stephanie Fresnay, Monica A McArthur, Laurence S Magder, Thomas C Darton, Claire Jones, Claire S Waddington, Christoph J Blohmke, Brian Angus, Myron M Levine, Andrew J Pollard, Marcelo B Sztein
Typhoid fever, caused by the human-restricted organism Salmonella enterica serovar Typhi (S. Typhi), constitutes a major global health problem. The development of improved attenuated vaccines is pressing, but delayed by the lack of appropriate preclinical models. Herein, we report that high levels of S. Typhi-responsive CD8+ T cells at baseline significantly correlate with an increased risk of disease in humans challenged with a high dose (~10(4) CFU) wild-type S. Typhi. Typhoid fever development was associated with higher multifunctional S...
2017: Frontiers in Immunology
Hazel C Dobinson, Malick M Gibani, Claire Jones, Helena B Thomaides-Brears, Merryn Voysey, Thomas C Darton, Claire S Waddington, Danielle Campbell, Iain Milligan, Liqing Zhou, Sonu Shrestha, Simon A Kerridge, Anna Peters, Zoe Stevens, Audino Podda, Laura B Martin, Flavia D'Alessio, Duy Pham Thanh, Buddha Basnyat, Stephen Baker, Brian Angus, Myron M Levine, Christoph J Blohmke, Andrew J Pollard
Background.: To expedite the evaluation of vaccines against paratyphoid fever, we aimed to develop the first human challenge model of Salmonella enterica serovar Paratyphi A infection. Methods.: Two groups of 20 participants underwent oral challenge with S. Paratyphi A following sodium bicarbonate pretreatment at 1 of 2 dose levels (group 1: 1-5 × 103 colony-forming units [CFU] and group 2: 0.5-1 × 103 CFU). Participants were monitored in an outpatient setting with daily clinical review and collection of blood and stool cultures...
April 15, 2017: Clinical Infectious Diseases: An Official Publication of the Infectious Diseases Society of America
Alba Grifoni, Michael Angelo, John Sidney, Sinu Paul, Bjoern Peters, Aruna D de Silva, Elizabeth Phillips, Simon Mallal, Sean A Diehl, Jason Botten, Jonathan Boyson, Beth D Kirkpatrick, Stephen S Whitehead, Anna P Durbin, Alessandro Sette, Daniela Weiskopf
A deletion variant of the dengue virus (DENV) serotype 2 (DENV2) Tonga/74 strain lacking 30 nucleotides from its 3' untranslated region (rDEN2Δ30) has previously been established for use in a controlled human DENV challenge model. To evaluate if this model is appropriate for the derivation of correlates of protection for DENV vaccines on the basis of cellular immunity, we wanted to compare the cellular immune response to this challenge strain to the response induced by natural infection. To achieve this, we predicted HLA class I- and class II-restricted peptides from rDEN2Δ30 and used them in a gamma interferon enzyme-linked immunosorbent spot assay to interrogate CD8(+) and CD4(+) T cell responses in healthy volunteers infected with rDEN2Δ30...
April 15, 2017: Journal of Virology
Marina Alberti, Cristian Correa, John M Marzluff, Andrew P Hendry, Eric P Palkovacs, Kiyoko M Gotanda, Victoria M Hunt, Travis M Apgar, Yuyu Zhou
Humans challenge the phenotypic, genetic, and cultural makeup of species by affecting the fitness landscapes on which they evolve. Recent studies show that cities might play a major role in contemporary evolution by accelerating phenotypic changes in wildlife, including animals, plants, fungi, and other organisms. Many studies of ecoevolutionary change have focused on anthropogenic drivers, but none of these studies has specifically examined the role that urbanization plays in ecoevolution or explicitly examined its mechanisms...
January 3, 2017: Proceedings of the National Academy of Sciences of the United States of America
Avital A Shimanovich, Amanda D Buskirk, Shannon J Heine, William C Blackwelder, Rezwanul Wahid, Karen L Kotloff, Marcela F Pasetti
Shigella is an important cause of diarrheal disease in young children living in developing countries. No approved vaccines are available, and the development of vaccine candidates has been hindered by the lack of firm immunological correlates of protection, among other reasons. To address this gap in knowledge, we established quantitative assays to measure Shigella-specific serum bactericidal antibody (SBA) and opsonophagocytic killing antibody (OPKA) activities and investigated their potential association with protection against disease in humans...
February 2017: Clinical and Vaccine Immunology: CVI
Maximillian S Habibi, Christopher Chiu
Despite the recent explosion in RSV vaccine development, there remain substantial hurdles to overcome before licensing of effective vaccines will allow widespread use, particularly in high-risk populations. Incomplete understanding of mechanisms and correlates of protection against RSV mean that, for the time being, successful RSV vaccines must directly demonstrate efficacy, which necessitates large and costly clinical trials in naturally infected patients. To mitigate the risks inherent in progressing to these late-stage trials, experimental human RSV infection studies have recently been re-established, representing the interface between pre-clinical models and observational studies of patients...
January 11, 2017: Vaccine
Cyril Carfantan, Yvain Goudard, Christophe Butin, Sandrine Duron-Martinaud, Jean-Philippe Even, Anthony Anselme, Erwan Dulaurent, Mélanie Géhant, Vicky Vitalis, Christian Bay, Jérôme Bancarel, Julien Bordes
INTRODUCTION: The French army has been deployed in Mali since January 2013 with the Serval Operation and since July 2014 in the Sahel-Saharan Strip (SSS) with the Barkhane Operation where the distances (up to 1100km) can be very long. French Military Medical Service deploys an inclusive chain from the point of injury (POI) to hospital in France. A patient evacuation coordination cell (PECC) has been deployed since February 2013 to organise forward medical evacuation (MEDEVAC) in the area between the POI and three forward surgical units...
January 2017: Injury
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 E Wentworth, Rebecca A Halpin, Xudong Lin, Amy Ransier, Timothy B Stockwell, Suman R Das, Anthony S Gilbert, Robert Lambkin-Williams, Geoffrey S Ginsburg, Christopher W Woods, Katia Koelle
Knowledge of influenza virus evolution at the point of transmission and at the intrahost level remains limited, particularly for human hosts. Here, we analyze a unique viral data set of next-generation sequencing (NGS) samples generated from a human influenza challenge study wherein 17 healthy subjects were inoculated with cell- and 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...
December 15, 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...
March 2017: 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...
June 8, 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...
April 19, 2016: MBio
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