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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT02755948
Recruitment Status : Terminated (Study objectives have been met.)
First Posted : April 29, 2016
Last Update Posted : June 29, 2022
Sponsor:
Collaborators:
Medical Research Council
Wellcome Trust
National Institute for Health Research, United Kingdom
Information provided by (Responsible Party):
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.

Condition or disease Intervention/treatment Phase
Respiratory Syncytial Virus Infections Influenza, Human Biological: RSV A Memphis 37 Biological: Influenza A/California/04/2009 Not Applicable

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.

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 95 participants
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Basic Science
Official Title: Cell Mediated Immunity Against RSV and Influenza in a Human Experimental Challenge
Actual Study Start Date : April 2012
Actual Primary Completion Date : February 1, 2020
Actual Study Completion Date : February 1, 2020

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: RSV A Memphis 37
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.
Biological: RSV A Memphis 37
Good Manufacturing Practices-certified RSV Memphis 37 10(4) PFU in 1 mL 25% sucrose/DMEM delivered by intranasal drops

Experimental: Influenza A/California/04/2009
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.
Biological: Influenza A/California/04/2009
Good Manufacturing Practices-certified Influenza A/California/04/09 3.5x10(4) TCID50 in 1 mL in DPBS delivered by intranasal drops




Primary Outcome Measures :
  1. Symptoms [ Time Frame: 28 days ]
    Self-reported upper and lower respiratory and systemic symptoms by diary card


Secondary Outcome Measures :
  1. Frequency of T cells in blood and respiratory tract by flow cytometry [ Time Frame: 6 months ]
    Frequency of T cells in blood and respiratory tract by flow cytometry as a proportion of live lymphocytes

  2. Frequency of T cells in blood and respiratory tract by enzyme-linked immunospot (ELISpot) [ Time Frame: 6 months ]
    Frequency of antigen-specific T cells in blood and respiratory tract by enzyme-linked immunospot (ELISpot) as a proportion of mononuclear cells

  3. Virus-specific serum plaque reduction neutralization titer [ Time Frame: 6 months ]
    Antibody responses to infection in blood and respiratory tract by plaque reduction neutralisation assay

  4. Virus-specific antibody geometric mean titer [ Time Frame: 6 months ]
    Antibody responses to infection in blood and respiratory tract by enzyme-linked immunoassay (ELISA) as a proportion of mononuclear cells

  5. Frequency of B cells in blood and respiratory tract by flow cytometry [ Time Frame: 6 months ]
    Frequency of virus-specific B cells by flow cytometry as a proportion of live lymphocytes

  6. Frequency of B cells in blood and respiratory tract by ELISpot [ Time Frame: 6 months ]
    Frequency of virus-specific B cells by ELISpot

  7. Viral load [ Time Frame: 28 days ]
    Nasal wash viral load by quantitative polymerase chain reaction (qPCR)



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 55 Years   (Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02755948


Locations
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United Kingdom
National Heart and Lung Institute, Imperial College London
London, United Kingdom, W2 1PG
Sponsors and Collaborators
Imperial College London
Medical Research Council
Wellcome Trust
National Institute for Health Research, United Kingdom
Investigators
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Principal Investigator: Christopher Chiu, BMBCh PhD Imperial College London
Publications of Results:
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
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Responsible Party: Imperial College London
ClinicalTrials.gov Identifier: NCT02755948    
Other Study ID Numbers: 13SM0365
11/LO/1826 ( Other Identifier: London-Fulham Research Ethics Committee )
First Posted: April 29, 2016    Key Record Dates
Last Update Posted: June 29, 2022
Last Verified: June 2022
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Imperial College London:
Influenza
Respiratory Syncytial Virus Infections
RSV A Memphis 37
Additional relevant MeSH terms:
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Influenza, Human
Virus Diseases
Respiratory Syncytial Virus Infections
Infections
Respiratory Tract Infections
Orthomyxoviridae Infections
RNA Virus Infections
Respiratory Tract Diseases
Pneumovirus Infections
Paramyxoviridae Infections
Mononegavirales Infections