Characterisation of a New Wild-Type H3N2 Virus for the Human Viral Challenge Model

Study Overview
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Brief Summary
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The study will characterise Influenza A/Perth/16/2009(H3N2) virus in healthy participants using the viral challenge model. The study includes two cohorts. Cohort 1: A randomised, double-blind study of 4 titres of Challenge Virus to determine the optimum titre. Cohort 2: An open-label extension arm in which all participants will receive the 'optimum' titre as identified from Cohort 1.

Detailed Description
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Influenza and its associated diseases are a major cause of morbidity and mortality. The United States Advisory Committee on Immunization Practices recommends influenza vaccination for everyone over 6 months of age. The failure of the flu vaccine in 2014-2015 demonstrates the need for a model that allows the rapid development of novel antivirals, universal/intra-seasonal vaccines, immunomodulators, monoclonal antibodies and other novel treatments. Studies using experimental influenza virus infection in human participants have demonstrated that adult volunteers can be infected by nasal inoculation, and experimental infection is safe and not associated with transmission to contacts. The experimental virus is manufactured in compliance with Good Manufacturing Practice for use in the Human Viral Challenge Model. The investigators chose an H3N2 influenza subtype given that this strain has the most substantial impact in terms of morbidity or mortality annually as described by the Centre for Disease Control . The investigators first subjected the virus batch to rigorous adventitious agent testing, then confirmed the virus to be wild-type by Sanger sequencing and finally determined the virus titres appropriate for human use via the established ferret model. hVIVO team built on its previous experience with other H3N2 and H1N1 viruses to develop this unique model. The first part of study (Cohort 1) was to determine the safety and optimal virus titre in healthy adult volunteers using our unique clinical quarantine facility in London, UK. After the first part of the study was completed, the study was amended to add an older population group (45-64 years old) in order to characterise the course of infection in an age group better representing the at-risk population.

Official Title
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A Randomised, Double Blind Study To Characterise Influenza A/Perth/16/2009(H3N2) Virus

Conditions
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Influenza

Intervention / Treatment
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* Other: Infectious titre 1 (H3N2)
* Other: Infectious titre 2 (H3N2)
* Other: Infectious titre 3 (H3N2)
* Other: Infectious titre 4 (H3N2)
* Other: Infectious titre 5 (H3N2) (Subjects aged 18 to 45 years old)
* Other: Infectious titre 5 (H3N2) (Subjects aged 46 to 64 years old)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: In good health with no history of major medical conditions. A total body weight ≥ 50 kg and a BMI of >18. Acceptable forms of effective contraception. An informed consent document signed and dated by the subject and Investigator. Sero-suitable for Challenge Virus. Exclusion Criteria: Subjects who have a significant history of any tobacco use at any time (≥ total 10 pack year history, e.g. one pack a day for 10 years). Subjects who have been pregnant within six months prior to the study, or who have a positive pregnancy test at any point in the study. Any history or evidence of any clinically significant medical conditions (cardiovascular, gastrointestinal, endocrinological, haematological, hepatic, immunological, metabolic, urological, neurological, psychotic, renal, and/or other major disease or malignancy). History or evidence of autoimmune disease or known immunodeficiency of any cause. Subjects with any history of asthma, COPD, pulmonary hypertension, reactive airway disease, or chronic lung condition of any aetiology. Positive human immunodeficiency virus (HIV), Hepatitis A (HAV), B (HBV), or C (HCV) test. Any significant abnormality altering the anatomy of the nose or nasopharynx. Any clinically significant history of epistaxis (nose bleeds). Any nasal or sinus surgery within six months of inoculation. Recurrent history of clinically significant autonomic dysfunction. Any abnormal laboratory test or ECG. Confirmed positive test for drugs of abuse. Venous access deemed inadequate for the phlebotomy and cannulation. Any known allergies to the excipients in the Challenge Virus inoculums. Health care workers who work in units with severely immuno-compromised patients. Evidence of vaccinations within the four weeks prior to Human Viral Challenge or intention to receive travel vaccination before the last study visit. Receipt of blood or blood products, or loss (including blood donations) of 450 mL or more of blood, during the 3 months prior to inoculations. Presence of significant respiratory symptoms existing on the day of challenge or between admission to the unit and inoculation with virus. History suggestive of respiratory infection within 14 days prior to admission to the unit. Use within 28 days prior to Human Viral Challenge (Day 0) of nasal steroids * Use within seven days of any other medication or product (prescription or over-the-counter), for symptoms of hay fever, rhinitis, nasal congestion or respiratory tract infection. Receipt of systemic: glucocorticoids, antiviral drugs, or immunoglobulins (Igs) or any other cytotoxic or immunosuppressive drug. Receipt of any systemic chemotherapy agent at any time.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 64 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Basic Science
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Infectious titre 1<br>6 participants aged 18 to 45 were inoculated with 1mL containing 2.8 x 10*3 TCID50 of virus | Other: Infectious titre 1 (H3N2)<br>* Infectious titre 1: 2.8 x 10*3 TCID50/mL<br>|
| Experimental: Infectious titre 2<br>6 participants aged 18 to 45 were inoculated with 1mL containing 2.5 x 10*4 TCID50 of virus | Other: Infectious titre 2 (H3N2)<br>* Infectious titre 2: 2.5 x 10*4 TCID50/mL<br>|
| Experimental: Infectious titre 3<br>6 participants aged 18 to 45 were inoculated with 1mL containing 3.6 x 10*5 TCID50 of virus | Other: Infectious titre 3 (H3N2)<br>* Infectious titre 3: 3.6 x 10*5 TCID50/mL<br>|
| Experimental: Infectious titre 4<br>6 participants aged 18 to 45 were inoculated with 1mL containing 4.7 x 10*6 TCID50 of virus | Other: Infectious titre 4 (H3N2)<br>* Infectious titre 4: 4.7 x 10*6 TCID50/mL<br>|
| Experimental: Infectious titre 5 (age 18 to 45 y)<br>6 participants aged 18 to 45 were inoculated with 1mL containing 3.5 x 10*5 TCID50 of virus. | Other: Infectious titre 5 (H3N2) (Subjects aged 18 to 45 years old)<br>* Infectious titre 5: 3.5 x 10*5 TCID50/mL<br>|
| Experimental: Infectious titre 5 (age 46 to 64 y)<br>16 participants aged 46 to 64 were inoculated with 1mL containing 3.5 x 10*5 TCID50 of virus. | Other: Infectious titre 5 (H3N2) (Subjects aged 46 to 64 years old)<br>* Infectious titre 5: 3.5 x 10*5 TCID50/mL<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Area Under the Curve of Virus Load | Area under the curve (AUC) of the Challenge Viral load, measured by nasopharyngeal swab quantitative polymerase chain reaction [qPCR], from Day 1 to Day 8 post-Viral Challenge. Nasopharyngeal swabs are collected up to 3 times per day ( every 8 hours +/- 30mins) | 8 days | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Flu, Influenza, Human Viral Challenge Model, Wild-Type, H3N2, Universal Influenza Vaccine, Intra-seasonal vaccines, Antiviral