Utility of animal and in vivo experimental infection of humans with rhinoviruses in the development of therapeutic agents for viral exacerbations of asthma and chronic obstructive pulmonary disease

Vecchio, Alfred M. Del; Branigan, Patrick; Barnathan, Elliot S.; Flavin, Susan; Silkoff, Philip E.; Turner, Ronald B.

doi:10.1016/j.pupt.2014.10.005

Cited by 14 publications

(11 citation statements)

References 214 publications

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“…The human challenge model has been used to investigate the viral pathogenicity [22][23][24][25][26] and recent publications on the asthma challenge model have focused on how the asthmatic host responds to HRV infection. Work is ongoing as to susceptibility to viral induced asthma worsening [27,28] innate immune dysregulation [29] and induction of innate, and type 2 responses in nasal and bronchial epithelial secretions [30].…”

Section: Rhinovirus (The "Common" Cold)mentioning

confidence: 99%

“…A variety of animal models exist to research respiratory viruses such as influenza [124][125][126], RSV [127][128][129][130][131][132][133][134][135][136][137], HRV [22,[138][139][140]. No single animal offers a platform for all respiratory viruses that infect humans, and different animal models exist for the same virus, which can give different, often conflicting results.…”

Section: The History Of the Human Viral Challenge Modelmentioning

confidence: 99%

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The human viral challenge model: accelerating the evaluation of respiratory antivirals, vaccines and novel diagnostics

et al. 2018

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The Human Viral Challenge (HVC) model has, for many decades, helped in the understanding of respiratory viruses and their role in disease pathogenesis. In a controlled setting using small numbers of volunteers removed from community exposure to other infections, this experimental model enables proof of concept work to be undertaken on novel therapeutics, including vaccines, immunomodulators and antivirals, as well as new diagnostics.Crucially, unlike conventional phase 1 studies, challenge studies include evaluable efficacy endpoints that then guide decisions on how to optimise subsequent field studies, as recommended by the FDA and thus licensing studies that follow. Such a strategy optimises the benefit of the studies and identifies possible threats early on, minimising the risk to subsequent volunteers but also maximising the benefit of scarce resources available to the research group investing in the research. Inspired by the principles of the 3Rs (Replacement, Reduction and Refinement) now commonly applied in the preclinical phase, HVC studies allow refinement and reduction of the subsequent development phase, accelerating progress towards further statistically powered phase 2b studies. The breadth of data generated from challenge studies allows for exploration of a wide range of variables and endpoints that can then be taken through to pivotal phase 3 studies.We describe the disease burden for acute respiratory viral infections for which current conventional development strategies have failed to produce therapeutics that meet clinical need. The Authors describe the HVC model’s utility in increasing scientific understanding and in progressing promising therapeutics through development.The contribution of the model to the elucidation of the virus-host interaction, both regarding viral pathogenicity and the body’s immunological response is discussed, along with its utility to assist in the development of novel diagnostics.Future applications of the model are also explored.Electronic supplementary materialThe online version of this article (10.1186/s12931-018-0784-1) contains supplementary material, which is available to authorized users.

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Section: Rhinovirus (The "Common" Cold)mentioning

confidence: 99%

Section: The History Of the Human Viral Challenge Modelmentioning

confidence: 99%

The human viral challenge model: accelerating the evaluation of respiratory antivirals, vaccines and novel diagnostics

et al. 2018

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“…For example, some microbial species are not able to colonize certain animals; therefore, known human pathogens may not cause infection in animals [27,86]. Also, a pre-existing condition, such as diabetes, or preinfection with one microbe, such as a virus, can influence the incidence of infection, virulence and/or colonization of another microbial species.…”

Section: Mammalian Modelsmentioning

confidence: 99%

“…While this is an excellent example of how a pre-existing viral infection can affect bacterial biofilm formation, there are very few animal models used to study viral-bacterial interactions. Presumably this is because of the challenges of infecting nonhuman species with human viruses, many of which do not infect, or do not cause symptoms characteristic of human infection, in animals [86,105,106].…”

Section: Otitis Mediamentioning

confidence: 99%

Biofilm Models of Polymicrobial Infection

2015

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Interactions between microbes are complex and play an important role in the pathogenesis of infections. These interactions can range from fierce competition for nutrients and niches to highly evolved cooperative mechanisms between different species that support their mutual growth. An increasing appreciation for these interactions, and desire to uncover the mechanisms that govern them, has resulted in a shift from monomicrobial to polymicrobial biofilm studies in different disease models. Here we provide an overview of biofilm models used to study select polymicrobial infections and highlight the impact that the interactions between microbes within these biofilms have on disease progression. Notable recent advances in the development of polymicrobial biofilm-associated infection models and challenges facing the study of polymicrobial biofilms are addressed. Polymicrobial interactions in biofilmsOver the past 2 decades there has been a revolutionary paradigm shift in the field of microbiology with the appreciation that bacteria present in most biological systems exist in biofilms, rather than in a free-living state. This understanding has dramatically changed the way we study bacteria in the laboratory and resulted in the development of many new experimental systems that replicate biofilm environments [1][2][3][4][5]. Studies utilizing these systems have demonstrated time and time again that bacteria behave very differently when in a biofilm than during planktonic growth. In many ways, we now have to relearn everything we thought we knew about bacterial behavior through the view of the biofilm lens.Similarly, the recent explosion of metagenomic studies has significantly increased our appreciation of the complexity of the microbial populations present in biofilms [6,7]. This is also true for infections, most of which are thought to be biofilm related and inherently polymicrobial, including various species of bacteria, fungi and viruses [8]. It is thought that microbes act in concert to establish biofilms, which in turn can increase tolerance to antimicrobials, exacerbate of the host's immune response and increase persistence at the infection site [7,[9][10][11].Genetic diversity of microbes within biofilm communities is thought to increase the fitness of the residing community, making them more equipped to survive environmental stresses. In large part, this is due to an expanded gene pool, which can be more easily shared within the confines of a biofilm community [12]. Community composition and interactions within the community can have huge influences on bacterial behavior. Thus, just as the behavior of planktonic versus biofilm-associated bacteria is dramatically different, so is that of bacteria in single species versus multispecies systems.Interactions between microbes are complex and highly dependent on context. They can range from fierce competition for nutrients and niches, manifested by antagonistic behavior, to highly evolved cooperative mechanisms between different species that support their mutual grow...

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“…124 11 AA exposed to allergen 1 placebo, 10 AA exposed to RV, 9 AA exposed to RV and allergen Perhaps the most promising use of the virus challenge model will be to accelerate the process of drug development. 137,138 Virus challenge studies have been used to evaluate the effects of existing asthma therapies on virus-induced exacerbations. 123,125 Recently the first study using viral challenge to evaluate a novel, unlicensed drug in asthma was also published.…”

Section: Future Directions For Human Infection Modelsmentioning

confidence: 99%