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A Study of Protective Immunity Against RSV and Influenza in Experimental Human Challenge of Volunteers

Primary Purpose

Respiratory Syncytial Virus Infections, Influenza, Human

Status
Terminated
Phase
Not Applicable
Locations
United Kingdom
Study Type
Interventional
Intervention
RSV A Memphis 37
Influenza A/California/04/2009
Sponsored by
Imperial College London
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional basic science trial for Respiratory Syncytial Virus Infections focused on measuring Influenza, Respiratory Syncytial Virus Infections, RSV A Memphis 37

Eligibility Criteria

18 Years - 55 Years (Adult)All SexesAccepts Healthy Volunteers

Inclusion Criteria:

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

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 6 months
  • Acute upper respiratory infection 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
  • 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

Sites / Locations

  • National Heart and Lung Institute, Imperial College London

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Experimental

Arm Label

RSV A Memphis 37

Influenza A/California/04/2009

Arm Description

Half the participants will be inoculated with RSV Memphis 37 10(4) plaque forming units (PFU) in 1 milliliter (mL) 25% sucrose/Dulbecco's Modification of Eagle's Medium (DMEM) delivered by intranasal drops. They will then be monitored as in-patients for 10 days with daily clinical assessment and blood and respiratory tract sampling. Following discharge, they will be followed up for up to 6 months post-inoculation.

Half the participants will be inoculated with Influenza A/California/04/09 3.5x10(4) tissue culture infective dose 50% (TCID50) in 1 mL in Dulbecco's phosphate buffered saline (DPBS) delivered by intranasal drops. They will then be monitored as in-patients for 10 days with daily clinical assessment and blood and respiratory tract sampling. Following discharge, they will be followed up for up to 6 months post-inoculation.

Outcomes

Primary Outcome Measures

Symptoms
Self-reported upper and lower respiratory and systemic symptoms by diary card

Secondary Outcome Measures

Frequency of T cells in blood and respiratory tract by flow cytometry
Frequency of T cells in blood and respiratory tract by flow cytometry as a proportion of live lymphocytes
Frequency of T cells in blood and respiratory tract by enzyme-linked immunospot (ELISpot)
Frequency of antigen-specific T cells in blood and respiratory tract by enzyme-linked immunospot (ELISpot) as a proportion of mononuclear cells
Virus-specific serum plaque reduction neutralization titer
Antibody responses to infection in blood and respiratory tract by plaque reduction neutralisation assay
Virus-specific antibody geometric mean titer
Antibody responses to infection in blood and respiratory tract by enzyme-linked immunoassay (ELISA) as a proportion of mononuclear cells
Frequency of B cells in blood and respiratory tract by flow cytometry
Frequency of virus-specific B cells by flow cytometry as a proportion of live lymphocytes
Frequency of B cells in blood and respiratory tract by ELISpot
Frequency of virus-specific B cells by ELISpot
Viral load
Nasal wash viral load by quantitative polymerase chain reaction (qPCR)

Full Information

First Posted
April 11, 2016
Last Updated
June 23, 2022
Sponsor
Imperial College London
Collaborators
Medical Research Council, Wellcome Trust, National Institute for Health Research, United Kingdom
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1. Study Identification

Unique Protocol Identification Number
NCT02755948
Brief Title
A Study of Protective Immunity Against RSV and Influenza in Experimental Human Challenge of Volunteers
Official Title
Cell Mediated Immunity Against RSV and Influenza in a Human Experimental Challenge
Study Type
Interventional

2. Study Status

Record Verification Date
June 2022
Overall Recruitment Status
Terminated
Why Stopped
Study objectives have been met.
Study Start Date
April 2012 (Actual)
Primary Completion Date
February 1, 2020 (Actual)
Study Completion Date
February 1, 2020 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Imperial College London
Collaborators
Medical Research Council, Wellcome Trust, National Institute for Health Research, United Kingdom

4. Oversight

Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Respiratory Syncytial Virus Infections, Influenza, Human
Keywords
Influenza, Respiratory Syncytial Virus Infections, RSV A Memphis 37

7. Study Design

Primary Purpose
Basic Science
Study Phase
Not Applicable
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Allocation
Non-Randomized
Enrollment
95 (Actual)

8. Arms, Groups, and Interventions

Arm Title
RSV A Memphis 37
Arm Type
Experimental
Arm Description
Half the participants will be inoculated with RSV Memphis 37 10(4) plaque forming units (PFU) in 1 milliliter (mL) 25% sucrose/Dulbecco's Modification of Eagle's Medium (DMEM) delivered by intranasal drops. They will then be monitored as in-patients for 10 days with daily clinical assessment and blood and respiratory tract sampling. Following discharge, they will be followed up for up to 6 months post-inoculation.
Arm Title
Influenza A/California/04/2009
Arm Type
Experimental
Arm Description
Half the participants will be inoculated with Influenza A/California/04/09 3.5x10(4) tissue culture infective dose 50% (TCID50) in 1 mL in Dulbecco's phosphate buffered saline (DPBS) delivered by intranasal drops. They will then be monitored as in-patients for 10 days with daily clinical assessment and blood and respiratory tract sampling. Following discharge, they will be followed up for up to 6 months post-inoculation.
Intervention Type
Biological
Intervention Name(s)
RSV A Memphis 37
Intervention Description
Good Manufacturing Practices-certified RSV Memphis 37 10(4) PFU in 1 mL 25% sucrose/DMEM delivered by intranasal drops
Intervention Type
Biological
Intervention Name(s)
Influenza A/California/04/2009
Intervention Description
Good Manufacturing Practices-certified Influenza A/California/04/09 3.5x10(4) TCID50 in 1 mL in DPBS delivered by intranasal drops
Primary Outcome Measure Information:
Title
Symptoms
Description
Self-reported upper and lower respiratory and systemic symptoms by diary card
Time Frame
28 days
Secondary Outcome Measure Information:
Title
Frequency of T cells in blood and respiratory tract by flow cytometry
Description
Frequency of T cells in blood and respiratory tract by flow cytometry as a proportion of live lymphocytes
Time Frame
6 months
Title
Frequency of T cells in blood and respiratory tract by enzyme-linked immunospot (ELISpot)
Description
Frequency of antigen-specific T cells in blood and respiratory tract by enzyme-linked immunospot (ELISpot) as a proportion of mononuclear cells
Time Frame
6 months
Title
Virus-specific serum plaque reduction neutralization titer
Description
Antibody responses to infection in blood and respiratory tract by plaque reduction neutralisation assay
Time Frame
6 months
Title
Virus-specific antibody geometric mean titer
Description
Antibody responses to infection in blood and respiratory tract by enzyme-linked immunoassay (ELISA) as a proportion of mononuclear cells
Time Frame
6 months
Title
Frequency of B cells in blood and respiratory tract by flow cytometry
Description
Frequency of virus-specific B cells by flow cytometry as a proportion of live lymphocytes
Time Frame
6 months
Title
Frequency of B cells in blood and respiratory tract by ELISpot
Description
Frequency of virus-specific B cells by ELISpot
Time Frame
6 months
Title
Viral load
Description
Nasal wash viral load by quantitative polymerase chain reaction (qPCR)
Time Frame
28 days

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
55 Years
Accepts Healthy Volunteers
Accepts Healthy Volunteers
Eligibility Criteria
Inclusion Criteria: - Healthy persons aged 18 to 55 years, able to give informed consent 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 6 months Acute upper respiratory infection 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 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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Christopher Chiu, BMBCh PhD
Organizational Affiliation
Imperial College London
Official's Role
Principal Investigator
Facility Information:
Facility Name
National Heart and Lung Institute, Imperial College London
City
London
ZIP/Postal Code
W2 1PG
Country
United Kingdom

12. IPD Sharing Statement

Plan to Share IPD
No
Citations:
PubMed Identifier
26687547
Citation
Jozwik A, Habibi MS, Paras A, Zhu J, Guvenel A, Dhariwal J, Almond M, Wong EHC, Sykes A, Maybeno M, Del Rosario J, Trujillo-Torralbo MB, Mallia P, Sidney J, Peters B, Kon OM, Sette A, Johnston SL, Openshaw PJ, Chiu C. RSV-specific airway resident memory CD8+ T cells and differential disease severity after experimental human infection. Nat Commun. 2015 Dec 21;6:10224. doi: 10.1038/ncomms10224. Erratum In: Nat Commun. 2016;7:11011.
Results Reference
result
PubMed Identifier
26873992
Citation
Currie SM, Gwyer Findlay E, McFarlane AJ, Fitch PM, Bottcher B, Colegrave N, Paras A, Jozwik A, Chiu C, Schwarze J, Davidson DJ. Cathelicidins Have Direct Antiviral Activity against Respiratory Syncytial Virus In Vitro and Protective Function In Vivo in Mice and Humans. J Immunol. 2016 Mar 15;196(6):2699-710. doi: 10.4049/jimmunol.1502478. Epub 2016 Feb 12.
Results Reference
result
PubMed Identifier
34256007
Citation
Paterson S, Kar S, Ung SK, Gardener Z, Bergstrom E, Ascough S, Kalyan M, Zyla J, Maertzdorf J, Mollenkopf HJ, Weiner J, Jozwik A, Jarvis H, Jha A, Nicholson BP, Veldman T, Woods CW, Mallia P, Kon OM, Kaufmann SHE, Openshaw PJ, Chiu C. Innate-like Gene Expression of Lung-Resident Memory CD8+ T Cells during Experimental Human Influenza: A Clinical Study. Am J Respir Crit Care Med. 2021 Oct 1;204(7):826-841. doi: 10.1164/rccm.202103-0620OC.
Results Reference
derived
PubMed Identifier
31815739
Citation
Guvenel A, Jozwik A, Ascough S, Ung SK, Paterson S, Kalyan M, Gardener Z, Bergstrom E, Kar S, Habibi MS, Paras A, Zhu J, Park M, Dhariwal J, Almond M, Wong EH, Sykes A, Del Rosario J, Trujillo-Torralbo MB, Mallia P, Sidney J, Peters B, Kon OM, Sette A, Johnston SL, Openshaw PJ, Chiu C. Epitope-specific airway-resident CD4+ T cell dynamics during experimental human RSV infection. J Clin Invest. 2020 Jan 2;130(1):523-538. doi: 10.1172/JCI131696.
Results Reference
derived

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A Study of Protective Immunity Against RSV and Influenza in Experimental Human Challenge of Volunteers

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