Why the development of effective typhoid control measures requires the use of human challenge studies

Jones, Claire; Darton, Thomas C.; Pollard, Andrew J.

doi:10.3389/fmicb.2014.00707

Cited by 8 publications

(5 citation statements)

References 45 publications

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“…These mice have been referred to as ''Human Immune System'' (HIS) mice and have become an attractive tool for studying infectious diseases specific to humans. For example, Salmonella enterica serovar typhi (S. typhi), the causative agent of typhoid fever in humans, is entirely hostadapted to humans and does not cause typhoid disease in mice [12,13]. However, HIS mice are permissive to lethal S. typhi infection, suggesting that HIS mice can serve as a model to identify the mechanism of protection against typhoid in humans [14][15][16][17].…”

Section: Introductionmentioning

confidence: 99%

Humoral Immunity in Mice Transplanted with Hematopoietic Stem Cells Derived from Human Umbilical Cord Blood Recapitulates That of Human Infants

Walker

Vuyyuru

Manser

et al. 2017

Stem Cells and Development

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Immunodeficient mice transplanted with human hematopoietic stem cells (HSCs) have been referred to as "Human Immune System" (HIS) mice and are a translational platform for studying human immune responses in vivo. Human HSC sources used in generating HIS mice include fetal liver (FL), umbilical cord blood (CB), and adult bone marrow (BM). Since HSCs from FL, CB, and BM are produced at various stages of human development, we tested whether mice transplanted with these three HSCs differ in their immune responses. We found that compared with CB HSCs or FL HSCs, adult BM HSCs reconstitute the immune system poorly. The resulting HIS mice do not mount an antibody response to Borrelia hermsii infection and as a consequence suffer persistently high levels of bacteremia. While both CB and FL HSCs yield comparable levels of immune reconstitution of HIS mice resulting in robust anti-B. hermsii immune responses, FL HSC-transplanted mice exhibited a discernable difference in their human B cell maturity as identified by an increased frequency of CD10 immature B cells and relatively smaller lymphoid follicles compared with CB HSC-transplanted mice. Although CB HSC-transplanted mice generated robust antibody responses to B. hermsii and specific protein antigens of B. hermsii, they failed to respond to Salmonella typhi Vi polysaccharide, a classical T cell-independent antigen. This situation resembles that seen in human infants and young children. Therefore, CB HSC-transplanted mice may serve as a translation platform to explore approaches to overcome the impaired antipolysaccharide responses characteristic of human infants.

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Section: Introductionmentioning

confidence: 99%

Humoral Immunity in Mice Transplanted with Hematopoietic Stem Cells Derived from Human Umbilical Cord Blood Recapitulates That of Human Infants

Walker

Vuyyuru

Manser

et al. 2017

Stem Cells and Development

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“…Vaccine and drug development efforts for malaria, diarrheal diseases, and influenza have benefitted from the availability of safe and consistently performing human infection models [114][115][116][117][118]. The ability to produce human infection and well-characterized disease phenotypes with a standardized and controlled pathogen exposure is a powerful tool for evaluating drug and vaccine candidates.…”

Section: Dengue Human Infection Model (Dhim)mentioning

confidence: 99%

Trials and tribulations on the path to developing a dengue vaccine

Thomas

Rothman

2015

Vaccine

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Dengue is a rapidly expanding global health problem. Development of a safe and efficacious tetravalent vaccine along with strategic application of vector control activities represents a promising approach to reducing the global disease burden. Although many vaccine development challenges exist, numerous candidates are in clinical development and one has been tested in three clinical endpoint studies. The results of these studies have raised numerous questions about how we measure vaccine immunogenicity and how these readouts are associated with clinical outcomes in vaccine recipients who experience natural infection. In this review the authors discuss the dengue vaccine pipeline, development challenges, the dengue vaccine-immunologic profiling intersection, and research gaps.

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“…Moreover, it has been suggested that without directly challenging healthy volunteers, we cannot fully understand the complex pathways associated with infection. 16 Of course, our intention is not to suggest challenge research can replace RCTs or phase 3 clinical studies. This comparison is only meant to illustrate the key advantages offered by challenge research and thus its importance.…”

Section: Vaccine Challenge Researchmentioning

confidence: 99%

The challenge of human challenge research models: A Canadian perspective

Murdoch¹,

Caulfield

2017

Medical Law International

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Research in which healthy volunteers are exposed to pathogens or other aetiologic agents that may cause disease remains controversial. Proponents suggest such work is key to understanding pathways of infection and the efficacy of vaccines and treatments. Yet, this research creates ethical and legal issues surrounding consent, participant vulnerability and the potential for harm. Moreover, public trust in research could be compromised if avoidable, serious harm occurs, making challenge research risky. Among Canadian research ethics guidelines, overarching messages are that participant interests cannot be subservient to those of research and that risks must be proportional to likely benefits. Moreover, common law fiduciary obligations to clinical research participants and the deterrent effect of potential tortious or criminal negligence act to reinforce the idea that challenge protocols should be a strategy of last resort. Researchers could benefit from clear guidance directly addressing the unique issues with challenge research.

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Why the development of effective typhoid control measures requires the use of human challenge studies

Cited by 8 publications

References 45 publications

Humoral Immunity in Mice Transplanted with Hematopoietic Stem Cells Derived from Human Umbilical Cord Blood Recapitulates That of Human Infants

Humoral Immunity in Mice Transplanted with Hematopoietic Stem Cells Derived from Human Umbilical Cord Blood Recapitulates That of Human Infants

Trials and tribulations on the path to developing a dengue vaccine

The challenge of human challenge research models: A Canadian perspective

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