Cell Mediated Immunity Against RSV and Influenza in a Human Experimental Challenge

Not Applicable

Completed

• Conditions: Respiratory Syncytial Virus Infections; Influenza, Human
• Interventions: Biological: RSV A Memphis 37; Biological: Influenza A/California/04/2009-likw (H1N1); Biological: Influenza A/Belgium/4217/2015 (H3N2)

• Registration Number: NCT02755948
• Lead Sponsor: Imperial College London

Brief Summary

Respiratory viruses including influenza and respiratory syncytial virus (RSV) are among the most important causes of severe disease globally, infecting everyone repeatedly throughout life. Understanding of how to prevent infection is incomplete but boosting immunity with vaccines remains the best strategy. T cells have been shown in animals to be essential for clearing respiratory viral infection and are likely to be helpful if stimulated by vaccines. However, where these cells originate from and how they develop in the human lung are still unclear. The investigators will inoculate volunteers with influenza or RSV to examine the relationship between T cells in their blood and lungs and the outcome of infection. By tracking these specialised cells, the investigators aim to develop a better understanding of how they are generated in order to harness them with future vaccines.

Detailed Description

Influenza and Respiratory Syncytial Virus (RSV) are the two most common causes of severe viral respiratory tract infection. Seasonal influenza has an overall incidence of 10-20% per annum with frequent complications, and the annual mortality in the USA has been estimated at up to 9.9 deaths per 100,000. According to World Health Organization (WHO) estimates, RSV causes around 64 million infections per annum and 160,000 deaths. It is the leading cause of severe respiratory illness in young children (associated with severe infant wheezing illness) and is also a significant problem in susceptible adults (including the elderly and those with airways disease) in whom RSV is responsible for around 22% of winter respiratory illnesses with a case fatality rate of 2-8%. No vaccines or specific antivirals are available for RSV and those licensed for influenza remain suboptimal. Further understanding of the human immune response to these viruses particularly in the context of the respiratory tract is therefore essential. Experimental human infection studies have the advantage of studying these pathogens in their natural host with the capacity to sample different anatomical sites intensively. Thus the investigators aim to use these models in helping to test vaccines and therapeutics as well as providing critical information on immunity and pathogenesis.

The investigators will use previously characterised Good Manufacturing Practices-certified RSV and influenza viruses derived from recent clinical isolates to investigate the response to infection in healthy adult volunteers. Subjects will be recruited via advertisement and screened at Imperial College London. Healthy individuals will be enrolled in the study and undergo baseline investigations including sampling from blood, upper and lower respiratory tract. They will then be inoculated with RSV or influenza by intranasal drops and quarantined for 10 days. During this time, they will have further blood and respiratory sampling. After the 10 day isolation period, they will be discharged and followed up for up to 6 months post-infection.

These samples will undergo analysis for antibody, B and T cell responses to correlate with outcome of inoculation, which may include no infection, asymptomatic or symptomatic infection. Thus the investigators will infer the role of immune correlates in protection against infection or symptomatic disease.

Basic Information
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Recruitment & Eligibility
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Study & Design
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Trial Locations

Study Timeline

• Study Start: 2012-04
• Study First Submitted: 2016-04-11
• Study First Submitted QC: 2016-04-26
• Study First Posted: 2016-04-29
• Primary Completion: 2020-02-01
• Study Completion: 2020-02-01
• Results First Submitted: 2024-07-12
• Status Verified: 2024-10
• Results First Submitted QC: 2024-10-23
• Last Update Submitted: 2024-10-23
• Results First Posted: 2024-12-06
• Last Update Posted: 2024-12-06

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 75

Inclusion Criteria

• Healthy persons aged 18 to 55 years, able to give informed consent

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Exclusion Criteria

• Chronic respiratory disease (asthma, chronic obstructive pulmonary disease, rhinitis, sinusitis) in adulthood
• Inhaled bronchodilator or steroid use within the last 12 months
• Use of any medication or other product (prescription or over-the-counter) for symptoms of rhinitis or nasal congestion within the last 3 months
• Acute upper respiratory infection (URI or sinusitis) in the past 6 weeks
• Smoking in the past 6 months OR >5 pack-year lifetime history
• Subjects with allergic symptoms present at baseline
• Clinically relevant abnormality on chest X-ray
• Any ECG abnormality
• Those in close domestic contact (i.e. sharing a household with, caring for, or daily face to face contact) with children under 3 years, the elderly (>65 years), immunosuppressed persons, or those with chronic respiratory disease
• Subjects with known or suspected immune deficiency
• Receipt of systemic glucocorticoids (in a dose ≥ 5 mg prednisone daily or equivalent) within one month, or any other cytotoxic or immunosuppressive drug within 6 months prior to challenge
• Known immunoglobulin A deficiency, immotile cilia syndrome, or Kartagener's syndrome
• History of frequent nose bleeds
• Any significant medical condition or prescribed drug deemed by the study doctor to make the participant unsuitable for the study
• Pregnant or breastfeeding women
• Positive urine drug screen
• Detectable baseline haemagglutination inhibition titres against influenza challenge strains
• Influenza arm only: history of hypersensitivity to eggs, egg proteins, gentamicin, gelatin or arginine, or with life-threatening reactions to previous influenza vaccinations

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
RSV A Memphis 37	RSV A Memphis 37	Participants will be inoculated with RSV Memphis 37 virus.
Influenza A/California/04/2009-like (H1N1)	Influenza A/California/04/2009-likw (H1N1)	Participants will be inoculated with Influenza A/California/04/2009-like (H1N1).
Influenza A/Belgium/4217/2015 (H3N2)	Influenza A/Belgium/4217/2015 (H3N2)	Participants will be inoculated with Influenza A/Belgium/4217/2015 (H3N2).

Primary Outcome Measures

Name	Time	Method
Total Symptom Score	14 days	Total Symptom Score in infected versus uninfected participants by Jackson's criteria.; Eight symptoms were evaluated in the symptom diary: nasal discharge, nasal congestion, sneezing, cough, sore throat, headache, feverishness and fatigue. Subjects were asked to score each symptom 0 (absent), 1 (mild), 2 (moderate), 3 (severe). A clinical cold was defined as 2 out of 3 of: a cumulative 14-day symptom score of ≥14; a subjective feeling of a cold; nasal discharge for ≥3 days. Symptoms were evaluated over a longer period than in Jackson's original description to account for an anticipated slower onset and longer duration of illness with RSV compared with rhinovirus. Maximum cumulative symptom score is therefore 336.

Secondary Outcome Measures

Name	Time	Method
Frequency of T Cells in Blood by Flow Cytometry	6 months	Peak Ki-67+ CD38+ CD8+ T cells in the blood by flow cytometry.
Frequency of T Cells in Respiratory Tract by Flow Cytometry	6 months	Peak Ki-67+ CD38+ CD8+ T cells in bronchoalveolar lavage (BAL) by flow cytometry
Viral Load	28 days	Nasal wash viral load by quantitative polymerase chain reaction (qPCR) (Area under curve)
Frequency of T Cells in Blood by Enzyme-linked Immunospot (ELISpot)	6 months	Peak T cells in blood by Enzyme-linked Immunospot (ELISpot). IFNy SFU/million PBMCs (Spot Forming Unit)

Trial Locations

Locations (1)

National Heart and Lung Institute, Imperial College London; 🇬🇧 London, United Kingdom