Plain English Summary
Background and study aims
Secondary bacterial infections such as pneumococcal pneumonia are a leading cause of death during influenza epidemics. Individuals recently infected with influenza become more susceptible to pneumonia, an effect associated with an increased number of pneumococcus (bacteria causing pneumonia) in the nose (pneumococcal carriage) and uncontrolled inflammatory immunological responses. The interaction between influenza virus and pneumococcus has been known and well documented. Recent works have shown that the Live Attenuated Influenza Vaccine (LAIV) increases pneumococcal carriage in murine models (mice/rats). These results highlighted the potential effect of mass immunization of children with LAIV on pneumococcal carriage. Increased carriage could lead to increased pneumococcal disease in people vaccinated with LAIV as well as increased bacterial transmission within the population. LAIV has been licensed for use in children since 2011 in Europe, and has been increasingly administered in children and adults in the USA. This study looks at the effect of LAIV on pneumococcal carriage and compares it with the Quadrivalent Inactivated Influenza Vaccine (QIV).
Who can participate?
Adults aged 18-50, able to speak fluent English and able to give informed consent.
What does the study involve?
Participants are randomly allocated into one of two groups. Those in group 1 are given Fluenz nasal vaccine (LAIV) and a placebo injection. Those in group 2 are given Fluarix vaccination (QIV) as an injection and a placebo nasal spray. All participants are inoculated with pneumococcal bacteria in the nose. Clinical symptoms and pneumococcal carriage between the two groups are then compared.
What are the possible benefits and risks of participating?
The benefit to volunteers when taking part in this study will be that they will all receive a flu vaccination. The risks associated with taking part in the study relate to the vaccination, inoculation with pneumococcus, blood sampling and nasal cell sampling. Risks associated with the influenza/ placebo vaccinations include: Pain and tenderness at the site of injection; Muscle aches; Fatigue; Nausea; Diarrhoea; Tiredness; Swelling at injection site; Headache; Runny, stuffy nose; Anaphylaxis (very rare 1: 1000000). Risks associated with blood sampling: feeling faint, bruising
Risks associated with pneumococcal inoculation: pneumococcal infection however this very unloikely, we have experienced inoculating over 400 volunteers and we have not had one case of pneumococcal infection. Risks associated with nasal cell sampling: minor temporary discomfort, irritation, eyes watering and minor bleeding.
Where is the study run from?
Royal Liverpool University Hospital (UK)
When is the study starting and how long is it expected to run for?
August 2015 to November 2017
Who is funding the study?
Bill and Melinda Gates Foundation (USA)
Who is the main contact?
Miss Angela Wright
Trial website
Additional identifiers
EudraCT number
2014-004634-26
ClinicalTrials.gov number
NCT03502291
Protocol/serial number
18994
Study information
Scientific title
The effect of live attenuated inactivated influenza vaccine on experimental human pneumococcal carriage: a randomised controlled trial
Acronym
LAIV and EHPC
Study hypothesis
This study looks at the effect of live attenuated inactivated influenza vaccine (LAIV) on pneumococcal carriage dynamics and compares it with the Quadrivalent Inactivated Influenza Vaccine (QIV).
Ethics approval
NRES Northwest- Liverpool East REC, ref: 14/NW/1460
Study design
Randomised; Observational; Design type: Clinical Laboratory Study
Primary study design
Interventional
Secondary study design
Randomised controlled trial
Trial setting
Other
Trial type
Treatment
Patient information sheet
Not available in web format, please use contact details to request a participant information sheet
Condition
Topic: Infectious diseases and microbiology; Subtopic: Infection (all Subtopics); Disease: Infectious diseases and microbiology
Intervention
1. Influenza Vaccination: Volunteers are randomised to receive Fluenz nasal vaccine (LAIV) plus placebo injection OR Fluarix vaccination (QIV) via injection and placebo nasal spray
2. Pneumococcal Inoculation: All volunteers are inoculated with pneumococcal bacteria in the nose
Study Entry : Single Randomisation only
Intervention type
Other
Phase
Drug names
Primary outcome measure
1. We will define the effect of LAIV on pneumococcal colonisation using the EHPC model in order to assess the potential effects of mass influenza vaccination. We will measure colonisation acquisition, density and duration.
2. Pneumococcal colonisation will be monitored using microbiological cultures of nasal wash samples. Nasal wash samples will be taken at pre-vaccination/ preinoculation*, day 2, 6*/7, 9, 14, 21*/22 and 27*/29 post inoculation in study one and study two*.
Secondary outcome measures
1. To evaluate changes in commensal and potential pathogenic species in nasopharyngeal microbiome associated with influenza vaccination
2. To evaluate inflammatory responses at the nasal mucosa using mucosal nanosampling method (lining fluid and cells)
3. To evaluate cellular responses in the lung after LAIV and EHPC co-infection
4. To evaluate symptoms associated with influenza vaccination and EHPC
Overall trial start date
01/10/2014
Overall trial end date
14/11/2017
Reason abandoned (if study stopped)
Eligibility
Participant inclusion criteria
Participants will be eligible to participate in this study provided they:
1. Have capacity to give informed consent
2. Aged 18-50 yrs - ages chosen to minimise the risk of pneumococcal infection
3. Speak fluent English to ensure a comprehensive understanding of the research project and their proposed involvement, in order to minimise any communication issues to maximise participant safety
Participant type
Patient
Age group
Adult
Gender
Both
Target number of participants
Planned Sample Size: 314; UK Sample Size: 314; Description: To allow for a dropout rate of 10%, up to 146 participants will be initially recruited for study 1 and up to 168 participants will be initially recruited for study 2.130 participants will complete the study (65 in each arm) to achieve 80% power to detect 50% increase in colonisation rates induced by antecedent LAIV compared to control 150 participants will complete the study (100 in LAIV arm and 50 in QIV arm) to achieve 99% power to detect a 2-fold increase in pneumococcal density induce
Participant exclusion criteria
1. Currently involved in another study unless observational or in follow-up phase (noninterventional)
2. Received any influenza vaccine in the last 2 years
3. Egg allergy (as per influenza vaccines patient leaflet)
4. Previous significant adverse reaction to any vaccination/immunisation
5. Close contact with at risk individuals (children under 5 years, immunosuppressed adults, elderly, chronic ill health) – to minimise risk of pneumococcal transmission and transmission of virus for those receiving the LAIV
6. Current regular smoker (smokes daily)
7. Significant smoking history [defined as someone who has previously smoked more than 20 cigarettes per day for 10 years or the equivalent (>10 pack yrs)] – to minimise risk of bronchoscopy or pneumococcal disease
8. Asthma (on regular medication) or respiratory disease – to minimise risk of bronchoscopy or pneumococcal disease
9. Pregnant to minimise the risk of pneumococcal disease
10. Women of childbearing potential (WOCBP) who are not deemed to have sufficient, effective birth control in place for 1 month prior to vaccination and 1 month after the final vaccination
11. Allergic to penicillin/amoxicillin/ gentamicin
12. On medication that may affect the immune system in any way e.g. steroids, steroid nasal spray
13. Are regularly taking acetylsalicylic acid (aspirin) – as per LAIV guidance to reduce the risk of Reye’s syndrome
14. Been involved in a clinical trial involving EHPC over the last 3 years
15. Unable to give fully informed consent
16. Current acute severe febrile illness - to avoid vaccination and inoculation in participants that may have current infection
Recruitment start date
26/08/2015
Recruitment end date
30/04/2017
Locations
Countries of recruitment
United Kingdom
Trial participating centre
Royal Liverpool University Hospital
Research & Development
4th Floor, Linda McCartney Centre
Prescot Street
Liverpool, Merseyside
L7 8XP
United Kingdom
Funders
Funder type
Government
Funder name
Bill and Melinda Gates Foundation
Alternative name(s)
Bill & Melinda Gates Foundation, BMGF
Funding Body Type
private sector organisation
Funding Body Subtype
Trusts, charities, foundations (both publically funded and privately funded)
Location
United States of America
Results and Publications
Publication and dissemination plan
We plan to publish the results in peer reviewed journals and at International conferences. We will aim to publish the results from study one and study two at the end of study two. We will make the publication available to participants at the end of the study. We will also disseminate research findings to the participants at the end of the study in the form of a newsletter.
Intention to publish date
Participant level data
To be made available at a later date
Basic results (scientific)
https://www.clinicaltrialsregister.eu/ctr-search/trial/2014-004634-26/results
Publication list