A site assessment tool for inpatient controlled human infection models for enteric disease pathogens

2021 ◽  
pp. 174077452110524
Author(s):  
Chad K Porter ◽  
Katherine J Detizio ◽  
Nicole Maier ◽  
Kayla J Testa ◽  
Kawsar R Talaat ◽  
...  
Keyword(s):  
Assessment Tool ◽  
Human Infection ◽  
Infection Model ◽  
Enteric Disease ◽  
Ethical Considerations ◽  
Site Assessment ◽  
Susceptible Host ◽  
Infection Models ◽  
A Site ◽  
Ongoing Evaluation

The use of the controlled human infection model to facilitate product development and to advance understanding of host-pathogen interactions is of increasing interest. While administering a virulent (or infective) organism to a susceptible host necessitates an ongoing evaluation of safety and ethical considerations, a central theme in conducting these studies in a safe and ethical manner that yields actionable data is their conduct in facilities well-suited to address their unique attributes. To that end, we have developed a framework for evaluating potential sites in which to conduct inpatient enteric controlled human infection model to ensure consistency and increase the likelihood of success.

scholarly journals Consensus Report on Shigella Controlled Human Infection Model: Introduction and Overview

2019 ◽  
Vol 69 (Supplement_8) ◽  
pp. S577-S579 ◽  
Author(s):  
Calman A MacLennan ◽  
Anastazia Older Aguilar ◽  
A Duncan Steele
Keyword(s):  
Best Practices ◽  
Vaccine Development ◽  
Disease Process ◽  
The United States ◽  
Human Infection ◽  
Infection Model ◽  
Infectious Agents ◽  
Vaccine Candidates ◽  
Infection Models ◽  
Consensus Report

Abstract In recent years, controlled human infection models (CHIMs) have become available for a range of infectious agents and have proved invaluable for understanding the disease process, pathogenesis, and mechanisms of immunity. CHIM studies have also contributed significantly to advancing development of a number of vaccines by providing an indication of vaccine efficacy. The Shigella CHIM has been established in 3 sites in the United States, and it is likely that the CHIM will play an important regulatory role for advancing the range of Shigella vaccine candidates that are currently in development. This supplement describes the harmonization of best practices across sites, with a view to maximizing the contribution that CHIM studies can make to Shigella vaccine development.

scholarly journals Establishment of a Controlled Human Infection Model with a Lyophilized Strain of Shigella sonnei 53G

mSphere ◽  
2020 ◽  
Vol 5 (5) ◽  
Author(s):  
Robert W. Frenck ◽  
Michelle Dickey ◽  
Akamol E. Suvarnapunya ◽  
Lakshmi Chandrasekaran ◽  
Robert W. Kaminski ◽  
...  
Keyword(s):  
Vaccine Development ◽  
Human Infection ◽  
Shigella Sonnei ◽  
World Health ◽  
Infection Model ◽  
Sample Collection ◽  
Open Label ◽  
Content Type ◽  
Infection Models ◽  
Study Results

ABSTRACT Controlled human infection models (CHIMs) are useful for vaccine development. To improve on existing models, we developed a CHIM using a lyophilized preparation of Shigella sonnei strain 53G produced using current good manufacturing practice (cGMP). Healthy adults were enrolled in an open-label dose-ranging study. Following administration of a dose of rehydrated S. sonnei strain 53G, subjects were monitored for development of disease. The first cohort received 500 CFU of 53G, and dosing of subsequent cohorts was based on results from the previous cohort. Subjects were administered ciprofloxacin on day 5 and discharged home on day 8. Subjects returned as outpatients for clinical checks and sample collection. Attack rates increased as the dose of S. sonnei was increased. Among those receiving the highest dose (1,760 CFU), 70% developed moderate to severe diarrhea, 50% had dysentery, and 40% had fever. Antilipopolysaccharide responses were observed across all cohorts. An S. sonnei CHIM using a lyophilized lot of strain 53G was established. A dose in the range of 1,500 to 2,000 CFU of 53G was selected as the dose for future challenge studies using this product. This model will enable direct comparison of study results between institutions and ensure better consistency over time in the challenge inoculum. IMPORTANCE Controlled human infection models (CHIMs) are invaluable tools utilized to understand the human response to infection, potentially leading to protective immune mechanisms and allowing efficacy testing of enteric countermeasures, including vaccines, antibiotics, and other products. The development of an improved Shigella CHIM for both Shigella sonnei and Shigella flexneri is consistent with international efforts, supported by international donors and the World Health Organization, focused on standardizing Shigella CHIMs and using them to accelerate Shigella vaccine development. The use of lyophilized Shigella challenge strains rather than plate-grown inoculum preparations is considered an important step forward in the standardization process. Furthermore, the results of studies such as this justify the development of lyophilized preparations for additional epidemiologically important S. flexneri serotypes, including S. flexneri 3a and S. flexneri 6.

scholarly journals Urban Blue Acupuncture: A Protocol for Evaluating a Complex Landscape Design Intervention to Improve Health and Wellbeing in a Coastal Community

2020 ◽  
Vol 12 (10) ◽  
pp. 4084 ◽  
Author(s):  
Simon Bell ◽  
Himansu Sekhar Mishra ◽  
Lewis R. Elliott ◽  
Rebecca Shellock ◽  
Peeter Vassiljev ◽  
...  
Keyword(s):  
Assessment Tool ◽  
Qualitative Interviews ◽  
Complex Interventions ◽  
Research Strategy ◽  
Site Assessment ◽  
Horizon 2020 ◽  
Before And After ◽  
Complex Landscape ◽  
The Uk ◽  
A Site

Within the BlueHealth project, funded under the Horizon 2020 European Union research framework, a number of targeted experimental design interventions were used to test the effect and impact of planning and design on encouraging people to use various blue spaces. Complex interventions were implemented and evaluations before and after each were made using a set of tools which triangulate with each other—a site assessment tool, a behaviour observation tool, a questionnaire survey (including an economic evaluation) and qualitative interviews. The theoretical basis for the research is that of affordances, and the projects each involved modest changes to the landscape using the approach of “urban acupuncture” where a small intervention can potentially have an effect out of all proportion to the investment. This paper is a protocol paper and describes the research strategy and methodology in detail for one of the intervention sites, located in Plymouth in the UK. The aim is to present the methodology as a whole so as to act as (a) a reference framework for the results of all the projects which will be reported separately in a series of research articles once all the results are in and analysed and (b) a useful reference for other researchers wishing to carry out such complex projects and where a comprehensive presentation of the strategy and methodology is unavailable. We offer this protocol for reference, for critique and for inspiration to those following us.

scholarly journals 1028 Sleep and Enteric Disease: Sleep Now for Less Diarrhea Later

SLEEP ◽  
2020 ◽  
Vol 43 (Supplement_1) ◽  
pp. A390-A391
Author(s):  
J Mantua ◽  
R L Gutierrez ◽  
S D Isidean ◽  
A N Alaca ◽  
K J Testa ◽  
...  
Keyword(s):  
Research Program ◽  
Sleep Time ◽  
Human Infection ◽  
Enterotoxigenic Escherichia Coli ◽  
Infection Model ◽  
Enteric Disease ◽  
Us Army ◽  
Medicine Research ◽  
Severe Diarrhea ◽  
The Us

Abstract Introduction The bi-directional relationship between sleep and immune function is well-established. Sufficient sleep supports immune health and can increase vaccine efficacy. Conversely, sickness can disturb sleep quality, which can delay recovery and waking functioning. However, the bidirectional relationship between sleep and infectious diarrhea, the leading infectious disease threat to deployed military populations, has not been studied. We assessed the bi-directional relationship between sleep and enteric disease utilizing data from a recently-completed controlled human infection model (CHIM) with enterotoxigenic Escherichia coli (ETEC). Methods During a CHIM to assess the efficacy of an immunoprophylactic targeting ETEC (NCT03040687), we measured sleep via actigraphy over an 8-day inpatient period. Participants ingested prophylaxis 3 times/day during days -2 and -1 and ingested ETEC on day 0. The primary outcome was moderate-severe diarrhea following the ETEC challenge. We hypothesized better sleep pre-challenge would reduce risk of disease after the challenge (assessed using linear regression). We also hypothesized total sleep time (TST) and sleep efficiency (SE) after the challenge would be lower/poorer than baseline (assessed using paired t-test). Results Among 59 participants (aged 34.4±8.1yrs, 64% female), longer TST the night preceding ETEC challenge was associated with lower total diarrhea volume (B=-3.13,p=.001). SE was slightly but significantly poorer after the challenge (78 vs. 76%; t(55)=2.2,p=.03), but there was no significant change in TST, potentially due to low TST pre-challenge (316 vs. 329 minutes; p=0.12). Conclusion These results - in aggregation with previous work on sleep and vaccines - suggest military sleep regulations should be put in place to increase sleep prior to traveling to an area of responsibility with high risk for enteric disease. These minor behavioral changes could provide lasting benefits to readiness of military servicemembers. Support This work was supported by Joint Warfighter Medical Research Program (JWMRP) and the Military Operational Medicine Research Program (MOMRP). The opinions and assertions contained herein are the private views of the authors and are not to be construed as official or as reflecting the views of the US Army or of the US Department of Defense. This abstract has been approved for public release with unlimited distribution.

scholarly journals Characterization of a new Leishmania major isolate for use in a controlled human infection model

2020 ◽  
Author(s):  
Helen Ashwin ◽  
Jovana Sadlova ◽  
Barbora Vojtkova ◽  
Tomas Becvar ◽  
Patrick Lypaczewski ◽  
...  
Keyword(s):  
Leishmania Major ◽  
Vaccine Development ◽  
Human Infection ◽  
Sand Fly ◽  
Infection Model ◽  
Phase 3 ◽  
Pivotal Phase ◽  
Infection Models

AbstractLeishmaniasis is widely regarded as a vaccine-preventable disease, but the costs required to reach pivotal Phase 3 studies and uncertainty about which candidate vaccines should be progressed into human studies significantly limits progress in vaccine development for this neglected tropical disease. Controlled human infection models (CHIM) provide a pathway for accelerating vaccine development and to more fully understand disease pathogenesis and correlates of protection. Here, we describe the isolation, characterization and GMP manufacture of a new clinical isolate of Leishmania major. Two fresh isolates of L. major from Israel were initially compared by genome sequencing, in vivo infectivity and drug sensitivity in mice, and development and transmission competence in sand flies, allowing one (L. major_MRC-02) to be selected for GMP production. This study addresses a major roadblock in the development of vaccines for leishmaniasis, providing a key resource for CHIM studies of sand fly transmitted cutaneous leishmaniasis.

scholarly journals Consensus Report on Shigella Controlled Human Infection Model: Conduct of Studies

2019 ◽  
Vol 69 (Supplement_8) ◽  
pp. S580-S590 ◽  
Author(s):  
Kawsar R Talaat ◽  
A Louis Bourgeois ◽  
Robert W Frenck ◽  
Wilbur H Chen ◽  
Calman A MacLennan ◽  
...  
Keyword(s):  
District Of Columbia ◽  
Human Infection ◽  
Morbidity And Mortality ◽  
World Health ◽  
Infection Model ◽  
Shared Experiences ◽  
Infection Models ◽  
Health Organization ◽  
Consensus Report ◽  
Selection Of

Abstract 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, and is a priority organism for the World Health Organization. A Shigella vaccine would decrease the morbidity and mortality associated with shigellosis, improve child health, and decrease the need for antibiotics. Controlled human infection models (CHIMs) are useful tools in vaccine evaluation for early up- or down-selection of vaccine candidates and potentially useful in support of licensure. Over time, the methods employed in these models have become more uniform across sites performing CHIM trials, although some differences in conduct persist. In November 2017, a Shigella CHIM workshop was convened in Washington, District of Columbia. Investigators met to discuss multiple aspects of these studies, including study procedures, clinical and immunological endpoints, and shared experiences. This article serves as a uniform procedure by which to conduct Shigella CHIM studies.

scholarly journals Phage Resistance Is Associated with Decreased Virulence in KPC-Producing Klebsiella pneumoniae of the Clonal Group 258 Clade II Lineage

2021 ◽  
Vol 9 (4) ◽  
pp. 762
Author(s):  
Lucia Henrici De Angelis ◽  
Noemi Poerio ◽  
Vincenzo Di Pilato ◽  
Federica De Santis ◽  
Alberto Antonelli ◽  
...  
Keyword(s):  
Klebsiella Pneumoniae ◽  
Parental Strain ◽  
Bacterial Infections ◽  
Capsular Polysaccharide ◽  
Galleria Mellonella ◽  
Bacterial Pathogen ◽  
Phage Resistance ◽  
Infection Model ◽  
Lytic Phage ◽  
Susceptible Host

Phage therapy is now reconsidered with interest in the treatment of bacterial infections. A major piece of information for this application is the definition of the molecular targets exploited by phages to infect bacteria. Here, the genetic basis of resistance to the lytic phage φBO1E by its susceptible host Klebsiella pneumoniae KKBO-1 has been investigated. KKBO-1 phage-resistant mutants were obtained by infection at high multiplicity. One mutant, designated BO-FR-1, was selected for subsequent experiments, including virulence assessment in a Galleria mellonella infection model and characterization by whole-genome sequencing. Infection with BO-FR-1 was associated with a significantly lower mortality when compared to that of the parental strain. The BO-FR-1 genome differed from KKBO-1 by a single nonsense mutation into the wbaP gene, which encodes a glycosyltransferase involved in the first step of the biosynthesis of the capsular polysaccharide (CPS). Phage susceptibility was restored when BO-FR-1 was complemented with the constitutive wbaP gene. Our results demonstrated that φBO1E infects KKBO-1 targeting the bacterial CPS. Interestingly, BO-FR-1 was less virulent than the parental strain, suggesting that in the context of the interplay among phage, bacterial pathogen and host, the emergence of phage resistance may be beneficial for the host.

scholarly journals Rhinovirus induces MUC5AC in a human infection model and in vitro via NF- B and EGFR pathways

2010 ◽  
Vol 36 (6) ◽  
pp. 1425-1435 ◽  
Author(s):  
C. A. Hewson ◽  
J. J. Haas ◽  
N. W. Bartlett ◽  
S. D. Message ◽  
V. Laza-Stanca ◽  
...  
Keyword(s):  
Human Infection ◽  
Infection Model

scholarly journals A pneumococcal controlled human infection model in Malawi: Transfer of an established pneumococcal carriage model from Liverpool, UK to Blantyre, Malawi – A feasibility study

2020 ◽  
Vol 5 ◽  
pp. 25
Author(s):  
Ben Morton ◽  
Sarah Burr ◽  
Kondwani Jambo ◽  
Jamie Rylance ◽  
Marc Y.R. Henrion ◽  
...  
Keyword(s):  
Streptococcus Pneumoniae ◽  
Feasibility Study ◽  
Invasive Disease ◽  
Community Acquired Pneumonia ◽  
Human Infection ◽  
Infection Model ◽  
Endpoint Detection ◽  
Pneumococcal Carriage ◽  
Sampling Protocols ◽  
Classical Culture

Streptococcus pneumoniae is the leading cause of morbidity and mortality due to community acquired pneumonia, bacterial meningitis and bacteraemia worldwide. Pneumococcal conjugate vaccines protect against invasive disease, but are expensive to manufacture, limited in serotype coverage, associated with serotype replacement and demonstrate reduced effectiveness against mucosal colonisation.  As asymptomatic colonisation of the human nasopharynx is a prerequisite for pneumococcal disease, this is proposed as a marker for novel vaccine efficacy. Our team established a safe and reproducible pneumococcal controlled human infection model at Liverpool School of Tropical Medicine (LSTM). This has been used to test vaccine induced protection against nasopharyngeal carriage for ten years in over 1000 participants. We will transfer established standardised operating procedures from LSTM to Malawi and test in up to 36 healthy participants. Primary endpoint: detection of the inoculated pneumococci by classical culture from nasal wash recovered from the participants after pneumococcal challenge. Secondary endpoints: confirmation of robust clinical and laboratory methods for sample capture and processing. Tertiary endpoints: participant acceptability of study and methods. We will test three doses of pneumococcal inoculation (20,000, 80,000 and 160,000 colony forming units [CFUs] per naris) using a parsimonious study design intended to reduce unnecessary exposure to participants. We hypothesise that 80,000 CFUs will induce nasal colonisation in approximately half of participants per established LSTM practice. The aims of the feasibility study are: 1) Establish Streptococcus pneumoniae experimental human pneumococcal carriage in Malawi; 2) Confirm optimal nasopharyngeal pneumococcal challenge dose; 3) Confirm safety and measure potential symptoms; 4) Confirm sampling protocols and laboratory assays; 5) Assess feasibility and acceptability of consent and study procedures. Confirmation of pneumococcal controlled human infection model feasibility in Malawi will enable us to target pneumococcal vaccine candidates for an at-risk population who stand the most to gain from new and improved vaccine strategies.

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