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Respiratory Syncytial Virus InfectionsNCT02755948

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

A study testing RSV A Memphis 37, Influenza A/California/04/2009-likw (H1N1) and Influenza A/Belgium/4217/2015 (H3N2) in people with Respiratory Syncytial Virus Infections and Influenza, Human, run by Imperial College London at 1 site in United Kingdom.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
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Trial 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. Read more about this study

Who is it for?
Ages 18 to 55 yearsHealthy volunteers can take part
What is being tested?
RSV A Memphis 37, Influenza A/California/04/2009-likw (H1N1) and Influenza A/Belgium/4217/2015 (H3N2)
Could I receive a placebo?
No, everyone receives an active treatment
How many people
75 participants
Where
1 siteUnited Kingdom
Study dates
Apr 2012to 1 Feb 2020
Phase
Interventional
Are there results?
Yes, posted in the registrySummary in the doctors' view

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 to 55 years
  • All sexes
  • Healthy volunteers accepted
  • Adult

Who may be able to join

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

Who cannot join

  • 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
Show all 18Show fewer
  • 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

Trial locations and contacts

1 site in 1 country.

United Kingdom1 site
  • National Heart and Lung Institute, Imperial College London

    London, W2 1PG

Other trials in United Kingdom

About this study

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.

Read the 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.

Being tested
RSV A Memphis 37, Influenza A/California/04/2009-likw (H1N1), Influenza A/Belgium/4217/2015 (H3N2)
Keywords
Influenza, Respiratory Syncytial Virus Infections, RSV A Memphis 37
Medical subject headings
Respiratory Syncytial Virus Infections, Influenza, Human

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • RSV A Memphis 37Biological

    Good Manufacturing Practices-certified RSV Memphis 37 10(4) PFU in 1 mL 25% sucrose/DMEM delivered by intranasal drops

  • Influenza A/California/04/2009-likw (H1N1)Biological

    Good Manufacturing Practices-certified Influenza A/California/04/09 3.5x10^6 TCID50 in 1 mL in DPBS delivered by intranasal drops

  • Influenza A/Belgium/4217/2015 (H3N2)Biological

    Good Manufacturing Practices-certified Influenza A/Belgium/4217/2015 (H3N2) 3.5x10^6 TCID50 in 1 mL in DPBS delivered by intranasal drops

Study groups in NCT02755948
Study groupRoleWhat they receive
RSV A Memphis 37ExperimentalParticipants will be inoculated with RSV Memphis 37 virus.
Receives: Biological: RSV A Memphis 37
Influenza A/California/04/2009-like (H1N1)ExperimentalParticipants will be inoculated with Influenza A/California/04/2009-like (H1N1).
Receives: Biological: Influenza A/California/04/2009-likw (H1N1)
Influenza A/Belgium/4217/2015 (H3N2)ExperimentalParticipants will be inoculated with Influenza A/Belgium/4217/2015 (H3N2).
Receives: Biological: Influenza A/Belgium/4217/2015 (H3N2)

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. Total Symptom Score

    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.

    Measured: 14 days

Secondary outcomes (4)
  1. Frequency of T Cells in Blood by Flow Cytometry

    Peak Ki-67+ CD38+ CD8+ T cells in the blood by flow cytometry.

    Measured: 6 months

  2. Frequency of T Cells in Respiratory Tract by Flow Cytometry

    Peak Ki-67+ CD38+ CD8+ T cells in bronchoalveolar lavage (BAL) by flow cytometry

    Measured: 6 months

  3. Viral Load

    Nasal wash viral load by quantitative polymerase chain reaction (qPCR) (Area under curve)

    Measured: 28 days

  4. Frequency of T Cells in Blood by Enzyme-linked Immunospot (ELISpot)

    Peak T cells in blood by Enzyme-linked Immunospot (ELISpot). IFNy SFU/million PBMCs (Spot Forming Unit)

    Measured: 6 months

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted29 Apr 2016 (estimated)
  2. Study startApr 2012
  3. Primary completion1 Feb 2020
  4. Study completion1 Feb 2020

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase N/A
Primary purpose
Basic science
Allocation
Non-randomised
Intervention model
Parallel groups
Model description
GMP influenza A/California/04/2009-like (H1N1); influenza A/Belgium/4217/2015 (H3N2); or RSV Memphis 37 virus strains will be used for experimental infection of volunteers.
Masking
None (open label)
Enrolment
75 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT02755948
Sponsor's protocol ID
13SM0365
Other IDs
11/LO/1826
Status last verified
Oct 2024
First submitted
11 Apr 2016
Last updated
6 Dec 2024
Data monitoring committee
Yes
FDA-regulated drug
No
FDA-regulated device
No
Individual data sharing
No

Publications

  • 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.

    PubMed 26687547
  • 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.

    PubMed 26873992
  • 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.

    PubMed 34256007
  • 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.

    PubMed 31815739

Questions about this trial

What is this clinical trial studying?

A study testing RSV A Memphis 37, Influenza A/California/04/2009-likw (H1N1) and Influenza A/Belgium/4217/2015 (H3N2) in people with Respiratory Syncytial Virus Infections and Influenza, Human, run by Imperial College London at 1 site in United Kingdom.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 1 inclusion and 18 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 6 Dec 2024. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 1 site in United Kingdom. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

Are results available for this study?

Yes. Results are posted in the registry (first posted 6 Dec 2024). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Total Symptom Score (time frame: 14 days). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT02755948, which also lists 4 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 6 Dec 2024.

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