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

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

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.

Study Overview

• Status: Terminated
• Conditions: Influenza, Human; Respiratory Syncytial Virus Infections
• Intervention / Treatment: Biological: RSV A Memphis 37; Biological: Influenza A/California/04/2009

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.

• Study Type: Interventional
• Enrollment (Actual): 95
• Phase: Not Applicable

Contacts and Locations

Study Locations

• United Kingdom
  • London, United Kingdom, W2 1PG
    • National Heart and Lung Institute, Imperial College London

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 55 years (Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / 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

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Symptoms	Self-reported upper and lower respiratory and systemic symptoms by diary card	28 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Viral load	Nasal wash viral load by quantitative polymerase chain reaction (qPCR)	28 days
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	6 months
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	6 months
Virus-specific serum plaque reduction neutralization titer	Antibody responses to infection in blood and respiratory tract by plaque reduction neutralisation assay	6 months
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	6 months
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	6 months
Frequency of B cells in blood and respiratory tract by ELISpot	Frequency of virus-specific B cells by ELISpot	6 months

Collaborators and Investigators

• Sponsor: Imperial College London
• Collaborators: Medical Research Council; Wellcome Trust; National Institute for Health Research, United Kingdom
• Investigators: Principal Investigator: Christopher Chiu, BMBCh PhD, Imperial College London

Publications and helpful links

General 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. Erratum In: Nat Commun. 2016;7:11011.
• 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.
• 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.
• 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.

Study record dates

Study Major Dates

• Study Start (Actual): April 1, 2012
• Primary Completion (Actual): February 1, 2020
• Study Completion (Actual): February 1, 2020

Study Registration Dates

• First Submitted: April 11, 2016
• First Submitted That Met QC Criteria: April 26, 2016
• First Posted (Estimate): April 29, 2016

Study Record Updates

• Last Update Posted (Actual): June 29, 2022
• Last Update Submitted That Met QC Criteria: June 23, 2022
• Last Verified: June 1, 2022

More Information

Terms related to this study

• Keywords: Influenza; Respiratory Syncytial Virus Infections; RSV A Memphis 37
• Additional Relevant MeSH Terms: RNA Virus Infections; Infections; Respiratory Tract Infections; Respiratory Tract Diseases; Paramyxoviridae Infections; Mononegavirales Infections; Orthomyxoviridae Infections; Pneumovirus Infections; Virus Diseases; Influenza, Human; Respiratory Syncytial Virus Infections
• Other Study ID Numbers: 13SM0365; 11/LO/1826 (Other Identifier: London-Fulham Research Ethics Committee)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No