scholarly journals Consensus Report on Shigella Controlled Human Infection Model: Immunological Assays

2019 ◽  
Vol 69 (Supplement_8) ◽  
pp. S596-S601 ◽  
Author(s):  
Robert W Kaminski ◽  
Marcela F Pasetti ◽  
Ana Older Aguilar ◽  
Kristen A Clarkson ◽  
Sjoerd Rijpkema ◽  
...  
Keyword(s):  
Vaccine Development ◽  
Human Infection ◽  
Health Concern ◽  
Substantial Contribution ◽  
Enzyme Linked Immunosorbent Assay ◽  
Infection Model ◽  
Middle Income ◽  
Severe Diarrhea ◽  
Vaccine Type ◽  
Immunological Assays

Abstract Moderate to severe diarrhea caused by Shigella is a global health concern due to its substantial contribution to morbidity and mortality in children aged <5 years in low- and middle-income countries. Although antibiotic treatment can be effective, emerging antimicrobial resistance, limited access, and cost affirm the role of vaccines as the most attractive countermeasure. Controlled human infection models (CHIMs) represent a valuable tool for assessing vaccine efficacy and potentially accelerating licensure. Currently, immunological analysis during CHIM studies is customized based on vaccine type, regimen, and administration route. Additionally, differences in type of immunoassays and procedures used limit comparisons across studies. In November 2017, an expert working group reviewed Shigella CHIM studies performed to date and developed consensus guidelines on prioritization of immunoassays, specimens, and collection time points. Immunoassays were ranked into 3 tiers, with antibodies to Shigella lipopolysaccharide (LPS) being the highest priority. To facilitate comparisons across clinical studies, a second workshop was conducted in December 2017, which focused on the pathway toward a recognized enzyme-linked immunosorbent assay (ELISA) to determine serum immunoglobulin G titers against Shigella LPS. The consensus of the meeting was to establish a consortium of international institutions with expertise in Shigella immunology that would work with the National Institute for Biological Standards and Control to establish a harmonized ELISA, produce a reference sera, and identify a reliable source of Shigella LPS for global utilization. Herein we describe efforts toward establishing common procedures to advance Shigella vaccine development, support licensure, and ultimately facilitate vaccine deployment and uptake.

scholarly journals A framework for Controlled Human Infection Model (CHIM) studies in Malawi: Report of a Wellcome Trust workshop on CHIM in Low Income Countries held in Blantyre, Malawi

2017 ◽  
Vol 2 ◽  
pp. 70 ◽  
Author(s):  
Stephen B Gordon ◽  
Jamie Rylance ◽  
Amy Luck ◽  
Kondwani Jambo ◽  
Daniela M Ferreira ◽  
...  
Keyword(s):  
Low Income ◽  
Vaccine Development ◽  
Clinical Laboratory ◽  
Human Infection ◽  
Low Income Countries ◽  
Infection Model ◽  
Proof Of Concept ◽  
Middle Income ◽  
Regulatory Issues ◽  
Middle Income Countries

Controlled human infection model (CHIM) studies have pivotal importance in vaccine development, being useful for proof of concept, pathogenesis, down-selection and immunogenicity studies.  To date, however, they have seldom been carried out in low and middle income countries (LMIC), which is where the greatest burden of vaccine preventable illness is found.  This workshop discussed the benefits and barriers to CHIM studies in Malawi.  Benefits include improved vaccine effectiveness and host country capacity development in clinical, laboratory and governance domains.  Barriers include acceptability, safety and regulatory issues. The report suggests a framework by which ethical, laboratory, scientific and governance issues may be addressed by investigators considering or planning CHIM in LMIC.

scholarly journals Stakeholder views on the acceptability of Human Infection Studies in Malawi

2019 ◽  
Author(s):  
Blessings M. Kapumba ◽  
Kondwani Jambo ◽  
Jamie Rylance ◽  
Markus Gmeiner ◽  
Rodrick Sambakunsi ◽  
...  
Keyword(s):  
Vaccine Development ◽  
Human Infection ◽  
Stakeholder Perceptions ◽  
Ethical Challenges ◽  
Inclusion Criteria ◽  
Government Officials ◽  
District Health ◽  
Middle Income ◽  
Rural And Urban ◽  
Ongoing Assessment

Abstract Background: Human infection studies (HIS) are valuable in vaccine development. Deliberate infection, however, creates challenging questions, particularly in low and middle-income countries (LMIC) where HIS are new and ethical challenges may be heightened. Consultation with stakeholders is needed to support contextually appropriate and acceptable study design. We examined stakeholder perceptions about the acceptability and ethics of HIS in Malawi, to inform decisions about planned pneumococcal challenge research and wider understanding of HIS ethics in LMIC. Methods: We conducted 6 deliberative focus groups and 15 follow-up interviews with research staff, medical students, and community representatives from rural and urban Blantyre. We also conducted 5 key informant interviews with clinicians, ethics committee members and district health government officials. Findings: Stakeholders perceived HIS research to have potential population health benefits, but they also had concerns, particularly related to safety of volunteers and negative community reactions. Acceptability depended on a range of conditions related to procedures for voluntary and informed consent, inclusion criteria, medical care or support, compensation, regulation, and robust community engagement. These conditions largely mirror those in existing guidelines for HIS and biomedical research in LMICs. Stakeholder perceptions pointed to potential tensions, for example balancing equity, safety and relevance in inclusion criteria. Conclusions: Our findings suggest HIS research could be acceptable in Malawi, provided certain conditions are in place. Ongoing assessment of participant experiences and stakeholder perceptions will be required to strengthen HIS research during development and roll-out. Key words: Human Infection Studies, pneumococcal, Malawi, acceptability, ethics

scholarly journals Advances in Diagnostic Methods for Zika Virus Infection

2018 ◽  
Vol 12 (4) ◽  
Author(s):  
Carlos A. Herrada ◽  
Md. Alamgir Kabir ◽  
Rommel Altamirano ◽  
Waseem Asghar
Keyword(s):  
Reverse Transcription ◽  
Zika Virus ◽  
Vaccine Development ◽  
Genome Structure ◽  
Diagnostic Methods ◽  
World Health ◽  
Health Concern ◽  
Localized Surface Plasmon ◽  
Enzyme Linked Immunosorbent Assay ◽  
Health Organization

The Zika virus (ZIKV) is one of the most infamous mosquito-borne flavivirus on recent memory due to its potential association with high mortality rates in fetuses, microcephaly and neurological impairments in neonates, and autoimmune disorders. The severity of the disease, as well as its fast spread over several continents, has urged the World Health Organization (WHO) to declare ZIKV a global health concern. In consequence, over the past couple of years, there has been a significant effort for the development of ZIKV diagnostic methods, vaccine development, and prevention strategies. This review focuses on the most recent aspects of ZIKV research which includes the outbreaks, genome structure, multiplication and propagation of the virus, and more importantly, the development of serological and molecular detection tools such as Zika IgM antibody capture enzyme-linked immunosorbent assay (Zika MAC-ELISA), plaque reduction neutralization test (PRNT), reverse transcription quantitative real-time polymerase chain reaction (qRT-PCR), reverse transcription-loop mediated isothermal amplification (RT-LAMP), localized surface plasmon resonance (LSPR) biosensors, nucleic acid sequence-based amplification (NASBA), and recombinase polymerase amplification (RPA). Additionally, we discuss the limitations of currently available diagnostic methods, the potential of newly developed sensing technologies, and also provide insight into future areas of research.

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 Risk assessment for the implementation of controlled human Schistosoma mansoni infection trials in Uganda

2019 ◽  
Vol 2 ◽  
pp. 17 ◽  
Author(s):  
Jan Pieter Koopman ◽  
Moses Egesa ◽  
Anne Wajja ◽  
Moses Adriko ◽  
Jacent Nassuuna ◽  
...  
Keyword(s):  
Risk Assessment ◽  
The Netherlands ◽  
Schistosoma Mansoni ◽  
Vaccine Development ◽  
Natural Infection ◽  
Parasitic Infection ◽  
Human Infection ◽  
Sub Saharan Africa ◽  
Infection Model ◽  
Road Map

Schistosomiasis is a parasitic infection highly prevalent in sub-Saharan Africa, and a significant cause of morbidity; it is a priority for vaccine development. A controlled human infection model for Schistosoma mansoni (CHI-S) with potential to accelerate vaccine development has been developed among naïve volunteers in the Netherlands. Because responses both to infections and candidate vaccines are likely to differ between endemic and non-endemic settings, we propose to establish a CHI-S in Uganda where Schistosoma mansoni is endemic. As part of a “road-map” to this goal, we have undertaken a risk assessment. We identified risks related to importing of laboratory vector snails and schistosome strains from the Netherlands to Uganda; exposure to natural infection in endemic settings concurrently with CHI-S studies, and unfamiliarity of the community with the nature, risks and rationale for CHI. Mitigating strategies are proposed. With careful implementation of the latter, we believe that CHI-S can be implemented safely in Uganda. Our reflections are presented here to promote feedback and discussion.

scholarly journals Contribution of noncanonical antigens to virulence and adaptive immunity in human infection with enterotoxigenic E. coli

2020 ◽  
Author(s):  
FM Kuhlmann ◽  
RO Laine ◽  
S Afrin ◽  
R Nakajima ◽  
M Akhtar ◽  
...  
Keyword(s):  
Immune Responses ◽  
Vaccine Development ◽  
Human Infection ◽  
Middle Income ◽  
Symptomatic Disease ◽  
E Coli ◽  
Middle Income Countries ◽  
Colonization Factor ◽  
Specific Antigens ◽  
Colonization Factors

AbstractEnterotoxigenic E. coli (ETEC) contribute significantly to the substantial burden of infectious diarrhea among children living in low and middle income countries. In the absence of a vaccine for ETEC, children succumb to acute dehydration as well as non-diarrheal sequelae related to these infections including malnutrition. The considerable diversity of ETEC genomes has complicated canonical vaccine development approaches focused on a subset of antigens known as colonization factors (CFs). To identify additional conserved immunogens, we mined genomic sequences of 89 ETEC isolates, bioinformatically selected potential surface-exposed pathovar-specific antigens conserved in more than 40% of the genomes (n=118), and assembled the representative proteins onto microarrays, complemented with known or putative colonization factor subunit molecules (n=52), and toxin subunits to interrogate samples from individuals with acute symptomatic ETEC infections. Surprisingly, in this open-aperture approach, we found that immune responses were largely constrained to a small number of antigens including individual colonization factor antigens and EtpA, an extracellular adhesin. In a Bangladeshi cohort of naturally infected children < 2 years of age, both EtpA and a second noncanonical antigen, EatA, elicited significant serologic responses that were associated with protection from symptomatic illness. In addition, children infected with ETEC isolates bearing either etpA or eatA genes were significantly more likely to develop symptomatic disease. These studies support a role for more recently discovered noncanonical antigens in virulence and the development of adaptive immune responses during ETEC infections, findings that may inform vaccine design efforts to complement existing approaches.

scholarly journals A Controlled Human Infection Model of Group AStreptococcusPharyngitis: Which Strain and Why?

mSphere ◽  
2019 ◽  
Vol 4 (1) ◽  
Author(s):  
Joshua Osowicki ◽  
Kristy I. Azzopardi ◽  
Liam McIntyre ◽  
Tania Rivera-Hernandez ◽  
Cheryl-lynn Y. Ong ◽  
...  
Keyword(s):  
Animal Model ◽  
Molecular Epidemiology ◽  
Virulence Factors ◽  
Healthy Adult ◽  
Vaccine Development ◽  
Human Infection ◽  
Infection Model ◽  
Vaccine Antigens ◽  
Adult Volunteers

ABSTRACTGroup AStreptococcus(GAS) is a major cause of global infection-related morbidity and mortality. A modern controlled human infection model (CHIM) of GAS pharyngitis can accelerate vaccine development and pathogenesis research. A robust rationale for strain selection is central to meeting ethical, scientific, and regulatory requirements. Multifaceted characterization studies were done to compare a preferred candidateemm75 (M75) GAS strain to three other strains: an alternative candidateemm12 (M12) strain, an M1 strain used in 1970s pharyngitis CHIM studies (SS-496), and a representative (5448) of the globally disseminated M1T1 clone. A range of approaches were used to explore strain growth, adherence, invasion, delivery characteristics, short- and long-term viability, phylogeny, virulence factors, vaccine antigens, resistance to killing by human neutrophils, and lethality in a murine invasive model. The strains grew reliably in a medium without animal-derived components, were consistently transferred using a swab method simulating the CHIM protocol, remained viable at −80°C, and carried genes for most candidate vaccine antigens. Considering GAS molecular epidemiology, virulence factors,in vitroassays, and results from the murine model, the contemporary strains show a spectrum of virulence, with M75 appearing the least virulent and 5448 the most. The virulence profile of SS-496, used safely in 1970s CHIM studies, was similar to that of 5448 in the animal model and virulence gene carriage. The results of this multifaceted characterization confirm the M75 strain as an appropriate choice for initial deployment in the CHIM, with the aim of safely and successfully causing pharyngitis in healthy adult volunteers.IMPORTANCEGAS (Streptococcus pyogenes) is a leading global cause of infection-related morbidity and mortality. A modern CHIM of GAS pharyngitis could help to accelerate vaccine development and drive pathogenesis research. Challenge strain selection is critical to the safety and success of any CHIM and especially so for an organism such as GAS, with its wide strain diversity and potential to cause severe life-threatening acute infections (e.g., toxic shock syndrome and necrotizing fasciitis) and postinfectious complications (e.g., acute rheumatic fever, rheumatic heart disease, and acute poststreptococcal glomerulonephritis). In this paper, we outline the rationale for selecting anemm75 strain for initial use in a GAS pharyngitis CHIM in healthy adult volunteers, drawing on the findings of a broad characterization effort spanning molecular epidemiology,in vitroassays, whole-genome sequencing, and animal model studies.

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 Consensus Report on Shigella Controlled Human Infection Model: Clinical Endpoints

2019 ◽  
Vol 69 (Supplement_8) ◽  
pp. S591-S595 ◽  
Author(s):  
Calman A MacLennan ◽  
Mark S Riddle ◽  
Wilbur H Chen ◽  
Kawsar R Talaat ◽  
Varsha Jain ◽  
...  
Keyword(s):  
Primary Endpoint ◽  
Working Group ◽  
Shigella Flexneri ◽  
The United States ◽  
Human Infection ◽  
Watery Diarrhea ◽  
Infection Model ◽  
Antibiotic Administration ◽  
Severe Diarrhea ◽  
Clinical Endpoints

Abstract The Shigella controlled human infection model (CHIM) is valuable for assessing candidate Shigella vaccine efficacy and potentially accelerating regulatory approval. The Shigella CHIM is currently being conducted at 3 sites in the United States using Shigella flexneri 2a strain 2457T and Shigella sonnei strain 53G. Shigellosis can present variably as watery diarrhea alone or with dysentery, and can be accompanied by manifestations including fever, abdominal cramps, tenesmus, and malaise. For comparability, it is important to harmonize the primary clinical endpoint. An expert working group was convened on 2 February 2018 to review clinical data from Shigella CHIM studies performed to date and to develop a consensus primary endpoint. The consensus endpoint enabled “shigellosis” to present as severe diarrhea or moderate diarrhea or dysentery. The latter 2 criteria are met when concurrent with fever of 38.0°C and/or vomiting, and/or a constitutional/enteric symptom graded at least as “moderate” severity. The use of a blinded independent committee to adjudicate the primary endpoint by subject was also regarded as important. As safety of volunteers in challenge studies is of paramount importance and treatment timing can affect primary outcomes, a standard for early antibiotic administration was established as follows: (1) when the primary endpoint is met; (2) if a fever of ≥39.0°C develops; or (3) if the study physician deems it appropriate. Otherwise, antibiotics are given at 120 hours postinfectious challenge. The working group agreed on objective and subjective symptoms to be solicited, and standardized methods for assessing subject-reported severity of symptoms.

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