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

NCT ID: NCT02755948

Last Updated: 2024-12-06

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: NA
• Total Enrollment: 75 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2012-04-30
• Study Completion Date: 2020-02-01

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.

Conditions

Respiratory Syncytial Virus Infections; Influenza, Human

Keywords

Influenza; Respiratory Syncytial Virus Infections; RSV A Memphis 37

Study Design

• Allocation Method: NON_RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: BASIC_SCIENCE
• Blinding Strategy: NONE

Study Groups

RSV A Memphis 37

Participants will be inoculated with RSV Memphis 37 virus.

Group Type: EXPERIMENTAL

RSV A Memphis 37

Intervention Type: BIOLOGICAL

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-like (H1N1)

Participants will be inoculated with Influenza A/California/04/2009-like (H1N1).

Group Type: EXPERIMENTAL

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

Intervention Type: 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)

Participants will be inoculated with Influenza A/Belgium/4217/2015 (H3N2).

Group Type: EXPERIMENTAL

Influenza A/Belgium/4217/2015 (H3N2)

Intervention Type: BIOLOGICAL

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

Interventions

RSV A Memphis 37

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

Intervention Type: BIOLOGICAL

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

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

Intervention Type: BIOLOGICAL

Influenza A/Belgium/4217/2015 (H3N2)

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

Intervention Type: BIOLOGICAL

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 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

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 55 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: Yes

Sponsors

Medical Research Council

OTHER_GOV

Sponsor Role: collaborator

Wellcome Trust

OTHER

Sponsor Role: collaborator

National Institute for Health Research, United Kingdom

OTHER_GOV

Sponsor Role: collaborator

Imperial College London

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Christopher Chiu, BMBCh PhD

Role: PRINCIPAL_INVESTIGATOR

Imperial College London

Locations

National Heart and Lung Institute, Imperial College London

London, , United Kingdom

Countries

United Kingdom

References

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.

Reference Type: RESULT

PMID: 26687547 (View on PubMed)

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.

Reference Type: RESULT

PMID: 26873992 (View on PubMed)

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.

Reference Type: DERIVED

PMID: 34256007 (View on PubMed)

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.

Reference Type: DERIVED

PMID: 31815739 (View on PubMed)

Provided Documents

Document Type: Study Protocol and Statistical Analysis Plan

View Document

Document Type: Informed Consent Form

View Document

Other Identifiers

11/LO/1826

Identifier Type: OTHER

Identifier Source: secondary_id

13SM0365

Identifier Type: -

Identifier Source: org_study_id