A Tool for Investigating Asthma and COPD Exacerbations: A Newly Manufactured and Well Characterised GMP Wild-Type Human Rhinovirus for Use in the Human Viral Challenge Model

Abstract

Background: Human Rhinovirus infection is an important precursor to asthma and chronic obstructive pulmonary disease exacerbations and the Human Viral Challenge model may provide a powerful tool in studying these and other chronic respiratory diseases. In this study we have reported the production and human characterisation of a new Wild-Type HRV-16 challenge virus produced specifically for this purpose.

Methods and stock development: A HRV-16 isolate from an 18 year old experimentally infected healthy female volunteer (University of Virginia Children's Hospital, USA) was obtained with appropriate medical history and consent. We manufactured a new HRV-16 stock by minimal passage in a WI-38 cell line under Good Manufacturing Practice conditions. Having first subjected the stock to rigorous adventitious agent testing and determining the virus suitability for human use, we conducted an initial safety and pathogenicity clinical study in adult volunteers in our dedicated clinical quarantine facility in London.

Human challenge and conclusions: In this study we have demonstrated the new Wild-Type HRV-16 Challenge Virus to be both safe and pathogenic, causing an appropriate level of disease in experimentally inoculated healthy adult volunteers. Furthermore, by inoculating volunteers with a range of different inoculum titres, we have established the minimum inoculum titre required to achieve reproducible disease. We have demonstrated that although inoculation titres as low as 1 TCID50 can produce relatively high infection rates, the optimal titre for progression with future HRV challenge model development with this virus stock was 10 TCID50. Studies currently underway are evaluating the use of this virus as a challenge agent in asthmatics.

Trial registration: ClinicalTrials.gov NCT02522832.

Conflict of interest statement

We have the following interests. The study was funded by hVIVO Services Limited, the employer of all authors. There are no patents, products in development or marketed products to declare. This does not alter our adherence to all the PLOS ONE policies on sharing data and materials, as detailed online in the guide for authors.

Figures

Fig 1. A Summary of the Clinical Trial Design.

Fig 2. Summary of passages for production of the master virus seed stock.

Fig 3. Mean Viral Load Titres (TCID50 Nasal Wash Samples), Mean Total Symptom Score and Mean Mucus Weight in Laboratory Confirmed Infected Volunteers from Day 1 to Day 8 in the 1 TCID50 Virus Titre Group.

(Error Bars SEM)

Fig 4. Mean Viral Load Titres (TCID50 Nasal Wash Samples), Mean Total Symptom Score and Mean mucus weight in Laboratory Confirmed Infected Volunteers from Day 1 to Day 8 in the 10 TCID50 Virus Titre Group.

(Error Bars SEM)

Fig 5. Mean Viral Load Titres (TCID50 Nasal Wash Samples), Mean Total Symptom Score and Mean Mucus Weight in Laboratory Confirmed Infected Volunteers from Day 1 to Day 8 in the 100 TCID50 Virus Titre Group.

(Error Bars SEM)

Fig 6. AUC of Total Symptoms, Viral Shedding (TCID50 Nasal Wash Samples) and Mucus Weight.