ImMUnologiCal memOry to reSpirAtory viraL infection in the airways

ISRCTN	ISRCTN69859970
DOI	https://doi.org/10.1186/ISRCTN69859970
IRAS number	342829
Secondary identifying numbers	CPMS 63937, Wellcome Trust Grant Ref: 226131/Z/22/Z

Submission date: 12/11/2024
Registration date: 16/01/2025
Last edited: 16/01/2025

Recruitment status: Recruiting
Overall study status: Ongoing
Condition category: Infections and Infestations

Prospectively registered

Protocol

Statistical analysis plan

Results

Individual participant data

Record updated in last year

Plain English summary of protocol

Background and study aims
Respiratory infections are commonly caused by bacteria and viruses. Lower respiratory tract infections caused by influenza, respiratory syncytial virus (RSV), SARS-CoV-2 and human metapneumovirus (hMPV) are common in young children and older adults and the leading causes of hospitalisation. They can exacerbate morbidity, presenting an especially burdensome challenge to the quality of life and healthcare systems overall. The burden of respiratory infections, particularly in older populations, was highlighted during the COVID-19 pandemic, with increased age proving to be the biggest risk factor for morbidity and mortality. Whilst respiratory vaccines exist, they may not provide optimal immunity. In the case of COVID-19, recent data suggest that local airway adaptive immune responses could be critical in the defence against symptomatic infection in humans. In a recent study, this team demonstrated the presence of an enriched SARS-CoV-2 specific B and T cell population in BAL compared to blood. Particularly, antigen-specific T-cell responses persist in the lung mucosa for up to 7 months after infection. Data on whether such antigen-specific tissue-resident T and B cells are present in human airways after other respiratory infections are currently scanty but could be important in the rational design of new mucosal vaccines. Mucosal vaccines could provide broader and long-term protection at the site of infection to allow more efficient clearance of infection and reduce onward virus transmission. For instance, live attenuated vaccines, such as in live-attenuated influenza vaccine (LAIV) and the recent candidate pertussis-attenuated vaccine, BPZE1, have shown induction of mucosal immunity but their ability to confer long-protection is not well understood. This study aims to improve our understanding of tissue-resident immunity by collecting samples from participants who have had a recent respiratory infection, assessing breadth, longevity and cross-reactive ability. This is vital for predicting host susceptibility to future infections, and importantly, for decerning the potential target opportunities for a mucosal-delivered next-generation vaccine.

Who can participate?
Adults aged 18-85 years old with a confirmed respiratory viral infection of interest who are in good health

What does the study involve?
The study will include three groups, depending on the number of visits and subsequent viral infection incidence. All participants will undergo a research bronchoscopy, including nasal sampling and blood collection at 35 days (± 21 days) post-confirmed respiratory viral infection with either SARS-CoV-2, hCoV RSV, influenza, rhinovirus or HMPV. Nasal samples and blood will also be collected from these participants at 126 days (±14days) post-infection. Post completion of Group A, participants will be invited to continue in the study and move into Group B for long-term assessment (a second bronchoscopy over the 9-12 months of follow-up) as well as to Group C in case a new respiratory viral infection ensues (a second bronchoscopy in case they acquire a new confirmed spontaneous infection). The total duration of the study will be approximately 5 months for participants in Group A, and up to 12 months for participants in Group B and C from the day of enrolment for each volunteer.

What are the possible benefits and risks of participating?
Participants will be helping research to understand the differences between blood and lung/nose immune responses to respiratory viral infections and how these responses behave over time. Participation will also help the research team compare these responses across different age groups in the study. Finally, they will also be helping in the development of new vaccines that can provide better and longer protection against COVID and other respiratory infections.

During the bronchoscopy, there may be some mild discomfort. After the procedure, participants may more commonly experience a sore nose/throat, cough or mild chest/back ache.

Where is the study run from?
Oxford Vaccine Group, University of Oxford, UK
Liverpool Vaccine Group, Liverpool School of Tropical Medicine, UK

When is the study starting and how long is it expected to run for?
October 2024 to December 2026

Who is funding the study?
Wellcome Trust

Who is the main contact?
Dr Carla Solórzano Gonzalez, carla.solorzanogonzalez@paediatrics.ox.ac.uk
Reyna Sara Quintero Barceinas, sara.quinterobarceinas@paediatrics.ox.ac.uk

Contact information

Dr Carla Solorzano-Gonzalez
Scientific

Senior Program Manager, Oxford Vaccine Group
University of Oxford
Department of Paediatrics
IDRM, Old Road Campus
Headington
Oxford
OX3 7TY
United Kingdom

Phone	+44 (0)186511400
Email	Carla.SolorzanoGonzalez@paediatrics.ox.ac.uk

Dr Reyna Sara Quintero Barceinas
Public, Scientific

Project Manager
Oxford Vaccine Group
Department of Paediatrics
Centre for Clinical Vaccinology & Tropical Medicine
Churchill Hospital, Old Road, Headington
Oxford
OX3 7LE
United Kingdom

Email	sara.quinterobarceinas@paediatrics.ox.ac.uk

Study information

Study design	Observational longitudinal cohort study
Primary study design	Observational
Secondary study design	Longitudinal study
Study setting(s)	Other
Study type	Treatment
Participant information sheet	Not available in web format, please use the contact details below to request a patient information sheet
Scientific title	A longitudinal cohort study to better understand the Immunological memory to respiratory viral infection in the upper and lower airways
Study acronym	IMUCOSAL
Study objectives	This study aims to provide a better understanding of how the immune system at the nose and airways respond to various viruses, such as SARS-CoV-2, RSV, influenza etc, how long natural/hybrid immunity can last and how likely it is to confer protection against repeat respiratory viral infections.
Ethics approval(s)	Submitted 31/10/2024, Northwest - Greater Manchester East Research Ethics Committee (-, -, -, United Kingdom; +44 (0)207 104 8290; gmeast.rec@hra.nhs.uk), ref: 24/NW/0353
Health condition(s) or problem(s) studied	Duration of natural and hybrid immunity in response to various viruses, including SARS-CoV-2, RSV, and influenza in the nose and airways
Intervention	This study will recruit up to 200 adults (aged 18 to 85 years) within 8 weeks following a laboratory-confirmed respiratory infection and consent them into the study. The study will include three (3) groups, depending on the number of visits and subsequent rates of respiratory infections. Group A: All participants will undergo a research bronchoscopy, nasal sampling and blood donation between 4-6 weeks (±2 weeks) post-confirmed respiratory infection with a follow-up visit including nasal sampling and blood 4 months (±2 weeks) post-infection. Group B: A subset of study participants from group A will be followed up to 12 months post-infection (PI). This will include an additional bronchoscopy procedure, nasal sampling and blood collection. Group C:  Any participant from group A who experiences a new respiratory infection at any time during the study, caused by the same or a new respiratory pathogen, will be invited to have another bronchoscopy 4-6 weeks (±2 weeks) post the new infection.  In a subset of study participants, nasal tissue biopsy will be collected. This procedure will be performed close to the bronchoscopy date but on a separate date and participants will be specifically consented to it. Age and other demographics will be captured in RedCap.
Intervention type	Other
Primary outcome measure	Frequency and breadth of antigen-specific T and B cell responses in the respiratory mucosa and blood after re-stimulation measured using flow cytometry and ELISPOTs at 35 days post infections
Secondary outcome measures	1. Sustainability of T and B cells in the respiratory mucosa and blood measured using flow cytometry and ELISPOTs for 12 months post-infection at 35,126 and 322 days post-infection 2. Assess the cross-reactive potential of T and B cells in respiratory mucosa and blood after stimulation with heterologous antigens measured using flow cytometry at 35-126 post-infection 3. Quantify antibody levels (IgA, IgG, IgM) in respiratory mucosa and blood using MSD/ELISA assays and describe their time kinetics at 35, 126 and 322 days post-infection 4. Frequency of antigen-specific T cells and antibody titres measured using flow cytometry assays, ELISA, and MSD (comparison of generated data primary and secondary objectives 1 and 2) at 35, 126 and 322 days post-infection 5. Levels and type of immunity in individuals with recurrent infection and those with only one infection within the period of participation in the study measured using flow cytometry assays, ELISA, and MSD at 35, 126 and 322 days post-infection 6. Participants age stratification in 2 groups (15-60 years of age and >60 years) measured using data collected in study records and comparison of cellular and humoral immune responses using flow cytometry assays, ELISA, and MSD at 35, 126 and 322 days post-infection
Overall study start date	31/10/2024
Completion date	15/12/2026

Eligibility

Participant type(s)	Patient
Age group	Mixed
Lower age limit	18 Years
Upper age limit	85 Years
Sex	Both
Target number of participants	200; UK Sample Size: 200
Key inclusion criteria	1. Adults aged 18-85 years of age (inclusive, at the time of consent) 2. Medically healthy, such that according to the investigator's judgement, hospitalisation within the study period is not anticipated, and the participant appears likely to be able to remain a study participant through the end of protocol-specified follow-up. Planned elective procedures for pre-existing conditions are allowable. 3. Fluent in English, ability to understand the procedures and convey any adverse events effectively to the research team 4. Willing and able to provide written informed consent before any study procedures are performed and can understand and comply with the requirements of the study 5. Willing to provide their national insurance number or passport number to be registered on The Over-Volunteering Prevention System (TOPS) 6. Agree to allow study staff to contact his or her GP or equivalent NHS databases to access the participant’s vaccination records, medical history 7. Willing to allow their GP and/or consultant, if appropriate, to be notified of participation in the study 8. Individuals with laboratory-confirmed respiratory viral infection of interest (swabs to be provided to volunteers by the corresponding site). The viral infections of interest are SARS-CoV-2, hCOV, RSV, Influenza, Rhinovirus and HMPV 9. Agreement to refrain from blood donation during the study 10. For participants of childbearing potential only : willing to use effective contraception* for the duration of the study AND to have a pregnancy test at screening and bronchoscopy visits
Key exclusion criteria	1. Currently involved in another study unless observational or non-interventional. Exceptions may be applied at the discretion of the Chief Investigator to ensure no harm comes to the participants (e.g. excessive blood sampling or nasal sampling. 2. Participants with uncontrolled medical or surgical conditions that may preclude nasal or oral intubation with a bronchoscope or the bronchoscopy itself, in the opinion of the investigator. 3. Participants who have received anti-viral medication or convalescent plasma to treat their respiratory viral infection. 4. Any confirmed or suspected immunosuppressive or immunodeficient state, including HIV infection; asplenia; severe infection(s); receipt of immunosuppressive therapy such as anti-cancer chemotherapy or radiation therapy within the preceding 12 months, or long-term systemic corticosteroid therapy (including for more than 7 consecutive days within the previous 3 months. 5. History of hereditary angioedema, acquired angioedema, or idiopathic angioedema. 6. History of any serious psychiatric condition likely to affect participation in the study. 7. Participants who have had previous adverse reactions to benzodiazepines or anaesthetic agents (lidocaine) including reversal agents such as flumazenil. 8. Participants with a full blood count, clotting or renal function level outside of local laboratory reference ranges and deemed as clinically significant by the investigator. 9. Any medication that may affect the coagulation system in the last 7 days (excluding low dose 75 mg aspirin). 10. Participants with very poor venous access. 11. Receipt of blood products or immunoglobulins within 3 months prior to screening. 12. Participants who, in the opinion of the Investigator (or designee), should not participate in this study. 13. Participants with asthma, medicated with steroid inhalers. 14. On long term oxygen therapy (LTOT). 15. Oxygen saturations on screening of <92% on air. 16. For participants requiring spirometry^: If FEV1 is less than 50% predicted or <1 litre absolute or not able to perform the procedure. This will be assessed following spirometry on the day of the bronchoscopy. 17. Any uncontrolled medical or surgical condition as deemed clinically significant by the CI 18. For participants of childbearing potential only: participants who are pregnant, breastfeeding or lactating, or are planning pregnancy during the study. 19. Detectable circulating hepatitis B surface antigen (HBsAg). 20. Seropositive for hepatitis C virus (antibodies to HCV). 21. Seropositive for HIV (antibodies to HIV). 22. Study site staff or a partner of study site staff. 23. For nasal biopsy participants, history of a bleeding disorder (e.g factor deficiency, coagulopathy, or platelet disorder), or prior history of significant unexplained bleeding or bruising following surgical or dental procedures. 24. For nasal biopsy participants, allergy to Lidocaine local anaesthetic. 25. ^ Criteria for participants requiring spirometry 26. Medical Research Council (MRC) score >1. 27. Participants with a >20-year smoking pack history. 28. Diagnosis of chronic respiratory disease.
Date of first enrolment	15/12/2024
Date of final enrolment	31/03/2026

Locations

Countries of recruitment

United Kingdom

Study participating centres

Liverpool School of Tropical Medicine

Clinical Sciences, 1 Daulby Street
Liverpool
L7 8XZ
United Kingdom

University of Oxford

Department of Paediatrics, Oxford Vaccine Group, Headington
Oxford
OX3 7LE
United Kingdom

John Radcliffe Hospital

Headley Way
Headington
Oxford
OX3 9DU
United Kingdom

Sponsor information

University of Oxford
Hospital/treatment centre

Research Governance, Ethics & Assurance Team (RGEA)
Joint Research Office, 1st Floor, Boundary Brook House
Churchill Drive, Headington
Oxford
OX3 7GB
England
United Kingdom

Email	RGEA.Sponsor@admin.ox.ac.uk
Website	https://www.ox.ac.uk
"ROR"	https://ror.org/052gg0110

Funders

Funder type

Government

Wellcome Trust
Private sector organisation / Trusts, charities, foundations (both public and private)

Alternative name(s): Wellcome, WT
Location: United Kingdom

Results and Publications

Intention to publish date	15/12/2027
Individual participant data (IPD) Intention to share	No
IPD sharing plan summary	Data sharing statement to be made available at a later date
Publication and dissemination plan	1. Peer-reviewed scientific journals 2. Conference presentation 3. Publication on website 4. Other publication 5. Submission to regulatory authorities Participants will not be identifiable from shared or published data. De-identified participant data will be made available upon requests directed to the chief investigator. Proposals will be reviewed and approved by the sponsor, chief investigator, and collaborators on the basis of scientific merit. After approval of a proposal, data can be shared through a secure online platform after signing a data access agreement.
IPD sharing plan	The current data sharing plans for this study are unknown and will be available at a later date.

Editorial Notes

12/11/2024: Study's existence confirmed by National Institute for Health and Care Research (NIHR) (UK).