Use of qualitative integrative cycler PCR (qicPCR) to identify optimal therapeutic dosing time-points in a Respiratory Syncytial Virus Human Viral Challenge Model (hVCM)

Kelly, Geraldine; Laxton, Carl; Garelnabi, Mariam; Alton, Brian; Addan, Fatima; Catchpole, Andrew; Thomas, E. D.; Borley, Daryl W.; Dee, Kieran; Boyers, Alison; Bringas, Erica; Noulin, Nicolas; Lambkin‐Williams, Robert; Murray, Edward J.

doi:10.1016/j.jviromet.2015.08.019

Cited by 6 publications

(7 citation statements)

References 12 publications

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“…Thus, some technical problems are likely to affect the outcome. Finally, the peak virus load was similar to that observed in nasal wash samples collected from healthy subjects challenged with RSV Memphis 37 strain (Kelly et al, ) or from RSV‐infected infants (DeVincenzo et al, ). However, the viral load was sustained for more than 10 days in ALI epithelium whereas the virus infection resolved in 10 days in healthy subjects in vivo .…”

Section: Discussionsupporting

confidence: 71%

“…The air liquid interface (ALI) culture cellular layer consists of ciliated cells and some goblet cells, and this system shows apical shedding of progeny virions that are subsequently spread by the coordinated motion of the beating cilia, so mimicking human RSV infection. In fact, ALI epithelium was reported to demonstrate robust RSV replication (Villenave et al, ; Pickles, ), and the level of RSV load was similar to that observed in nasal washes from RSV infected infants (DeVincenzo et al, ) or after nasal challenge with RSV Memphis 37 strain to healthy subjects (Kelly et al, ). Thus, ALI epithelium is now being used as a model to study the behaviour of respiratory pathogens in human tissue (Essaidi‐Laziosi et al, ).…”

Section: Introductionmentioning

confidence: 73%

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Late therapeutic intervention with a respiratory syncytial virus L‐protein polymerase inhibitor, PC786, on respiratory syncytial virus infection in human airway epithelium

Brookes¹,

Coates²,

Allen³

et al. 2018

British J Pharmacology

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Background and PurposeEffective anti‐respiratory syncytial virus (RSV) agents are still not available for clinical use. Current major targets are virus surface proteins, such as a fusion protein involved in viral entry, but agents effective after RSV infection is established are required. Here we have investigated the effects of late therapeutic intervention with a novel inhaled RSV polymerase inhibitor, PC786, on RSV infection in human airway epithelium.Experimental ApproachAir liquid interface‐cultured bronchial or small airway epithelium was infected with RSVA2. PC786 was applied apically or basolaterally once daily following peak virus load on Day 3 post inoculation. Apical wash was collected daily for determination of viral burden by PCR and plaque assay (primary endpoints) and biomarker analyses. The effects were compared with those of ALS‐8112, an anti‐RSV nucleoside analogue, and GS‐5806, a fusion‐protein inhibitor, which were treated basolaterally.Key ResultsLate intervention with GS‐5806 did not show significant anti‐viral effects, but PC786 produced potent, concentration‐dependent inhibition of viral replication with viral load falling below detectable limits 3 days after treatment commenced in airway epithelium. These effects were superior to those of ALS‐8112. PC786 showed inhibitory activities against RSV‐induced increases of CCL5, IL‐6, double‐strand DNA and mucin. The effects of PC786 were also confirmed in small airway epithelium.Conclusion and ImplicationsLate therapeutic intervention with the RSV polymerase inhibitor, PC786, reduced the viral burden quickly in human airway epithelium. Thus, PC786 demonstrates the potential to be an effective therapeutic agent to treat active RSV infection.

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Section: Discussionsupporting

confidence: 71%

Section: Introductionmentioning

confidence: 73%

Late therapeutic intervention with a respiratory syncytial virus L‐protein polymerase inhibitor, PC786, on respiratory syncytial virus infection in human airway epithelium

Brookes¹,

Coates²,

Allen³

et al. 2018

British J Pharmacology

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“…An essential element of design in both studies was the timing of the first administration of therapeutic postexperimental virus inoculation; the timing was dependent on the detection of virus in nasal wash samples post inoculation of challenge virus by a rapid PCR assay [163], rather than at an arbitrary time point. Subsequently the therapeutic was administered every 12 hours.…”

Section: The Hvc Model and Rsvmentioning

confidence: 99%

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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“…The US-FDA has licensed Vaxchora based on the data of this challenge trial (14). Other mature models have been developed for viruses, bacteria, and parasites, including norovirus, RSV, Salmonella typhi, Streptococcus, Shigella, malaria, and schistosomiasis (15)(16)(17)(18)(19)(20)(21).…”

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confidence: 99%

Controlled Human Infection to Speed Up SARS-CoV-2 Vaccine Development

Baay¹,

Neels

2021

Front. Immunol.

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Controlled human infection (CHI) studies have been performed previously with a range of virologic, bacteriologic, and parasitic agents, yielding important information on immunopathogenesis, duration of vaccine-induced immunity, and to define correlates of protection in healthy populations (1-3). CHI can also provide key safety, tolerability, immunogenicity, and efficacy data supporting vaccine research. Typically, in a CHI experiment, participants are given a test vaccine and are inoculated 2-4 weeks later with the pathogen of interest via the most physiologically relevant route of administration. Such experiments require only a few months to complete, and the number of participants enrolled is usually rather in the tens than in the hundreds, let alone in the thousands or ten-thousands needed for phase 3 Randomized Controlled Trials (RCTs).The COVID-19 pandemic has a major impact on global health. Currently (February 2021), more than 110 million people have (had) an infection with SARS-CoV-2, and nearly 2.5 million died of COVID-19. 1 Large parts of the world are in the second wave, with no view of imminent solutions, although vaccine development is continuing at unprecedented speed. A number of clinical trials are already ongoing with 73 candidates, including 16 candidates in phase 3 (4). Although the Pfizer/ BioNTech, Moderna and AstraZeneca vaccines have been fully evaluated and licensed for emergency use, a second wave of vaccines is under development and worthwhile to become available, given the global market need to cover immunization of seven billion people. If some of the vaccines need two doses to complete primovaccination, that brings the global need quickly to 10 billion doses or more. Today, we cannot say if this will be a yearly need, since duration of immunity will only be known later on. In addition, it cannot be excluded that mutations require quick adaptation of vaccines to potentially new strains. To mitigate the risks of efficacy and availability, we will have to rely on a range of vaccines.Admittedly, RNA vaccines, nanoparticle vaccines, and virus like particle vaccines (5, 6) can be produced substantially faster compared to conventional expression systems (7), under the assumption that manufacturing facilities are up and running, with sufficient supplies and staffing. For example, in the case of inactivated or live-attenuated viral (such as virus vaccine candidates being produced in cell lines), or recombinant protein vaccine candidate production, product-specific manufacturing

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Use of qualitative integrative cycler PCR (qicPCR) to identify optimal therapeutic dosing time-points in a Respiratory Syncytial Virus Human Viral Challenge Model (hVCM)

Cited by 6 publications

References 12 publications

Late therapeutic intervention with a respiratory syncytial virus L‐protein polymerase inhibitor, PC786, on respiratory syncytial virus infection in human airway epithelium

Late therapeutic intervention with a respiratory syncytial virus L‐protein polymerase inhibitor, PC786, on respiratory syncytial virus infection in human airway epithelium

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

Controlled Human Infection to Speed Up SARS-CoV-2 Vaccine Development

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