Condition category
Infections and Infestations
Date applied
04/11/2019
Date assigned
25/11/2019
Last edited
25/11/2019
Prospective/Retrospective
Retrospectively registered
Overall trial status
Ongoing
Recruitment status
No longer recruiting

Plain English Summary

Interruption of transmission of vaccine serotypes underlies the effectiveness of pneumococcal conjugate vaccine programmes at the population level. Nasal colonisation is common in young children. Density varies widely between individuals and over time but its relationship to infectiousness is unknown. In a multi-centre prospective randomised stepped-wedge trial, the live attenuated influenza vaccine (LAIV) is being used as a probe to increase the density of pneumococcal nasal carriage in LAIV-naive 2-year-olds and assess the effect of density change on carriage in household contacts. Families with an eligible 2-year-old index child were recruited across 10 UK sites over 2 seasons (September - December 2017 and 2018); serial saliva and nasopharyngeal swabs taken every two weeks over an 8 week period will be analysed for Streptococcus pneumoniae using real-time PCR. Standard statistical methods including generalised linear mixed models and individual-based mathematical modelling of transmission dynamics will be used for analysis. Understanding the biology of transmission will provide new tools for evaluation of indirect effects of existing and developmental paediatric vaccines.

Background and study aims
Pneumococcus is a bacterium that frequently lives in the noses of young children without causing any illness. Occasionally, it causes disease like ear infections and pneumonia (chest infection) and very rarely meningitis (infection around the surface of the brain). Viral infections, like influenza (flu), seem to help pneumococcus to spread from one person to another and may contribute to these diseases. Flu is a common viral illness spread by coughing, sneezing and direct contact that causes sore throat, cough, fever, runny nose and muscle aches.
The nasal flu vaccine is the licensed vaccine that all 2- to 10-year-old children are routinely offered in the UK every autumn which is known to be safe and effective. The vaccine causes a very mild flu infection and so protects against real flu but the mild infection can change the numbers of other bugs in the nose too without causing any illness. We are conducting this study to find out whether those changes result in those bugs being passed around within the family differently. Nothing in the study changes anything that would be happening anyway, it just tracks what is going on. By understanding how these bugs are spread, we will be able to plan more effective strategies to prevent infections in the future.

Who can participate?
To take part, a family must live near to the study centre, have a healthy child who has turned 2 years of age between January 1st and August 31st (2017 if participating in season 1 or 2018 if participating in season 2) who is eligible to receive their first nasal flu vaccine during the study period and have 2 other household members (adults and/or children) that are willing and able to take part in the study. All those taking part in the study must be willing and able to provide nasal and saliva samples and complete a survey about their recent contacts with household members and other people on five occasions over about 2 months (about every 2 weeks).

What does the study involve?
The 2-year-old child in each family enrolled receives one dose of the flu vaccine that is routinely offered to children aged 2-10 years of age in the UK. Saliva samples and nose swabs are taken from the 2-year-old and all participating family members at each of 5 study visits between September and December to track the spread of bacteria within the family. Participants are also asked to complete a contact survey at each visit. Each family is involved in the study for about 3 months, and visits are carried out as home visits.

What are the possible benefits and risks of participating?
Children participating in the study who are eligible for the nasal flu vaccine receive it at home which may be more convenient and receiving the nasal flu vaccine is the best way to protect them against flu.
Participation will help further understanding in how viruses interact with bacteria that normally live in children’s noses and how these bacteria are transferred from one person to another. This will be useful in developing more effective ways to prevent infections.
There is a reimbursement of £15 per family for each of 5 sampling visits (£75 in total) in the form of vouchers to compensate for the time and trouble in participating in the study.
The most common mild symptoms that a minority of children may develop after nasal flu vaccination are runny nose/nasal congestion, cough, wheezing, fever, headaches and malaise, abdominal pain, vomiting and diarrhoea which may last for 1-2 days and are self-limiting. The vaccine has not been related to severe side effects but, as with all vaccines and medications, severe allergic reactions may occur very rarely. The study staff are trained to manage such a reaction in the unlikely event that it should occur.
Participants may feel mild discomfort for a few seconds while nasal swabs are taken. Saliva samples are easy to get and the process does not have any risks.

Where is the study run from?
Bristol Children’s Vaccine Centre at the University of Bristol (UK)

When is the study starting and how long is it expected to run for?
August 2017 to March 2021

Who is funding the study?
Pfizer (USA) and the Bill and Melinda Gates Foundation (USA)

Who is the main contact?
1. Dr Jennifer Oliver, jennifer.oliver@bristol.ac.uk
2. Dr Jane Metz, jane.metz@bristol.ac.uk

Trial website

Contact information

Type

Public

Primary contact

Dr Jennifer Oliver

ORCID ID

Contact details

Population Health Sciences
Bristol Medical School
University of Bristol
Level 6
UH Bristol Education and Research Centre
Upper Maudlin Street
Bristol
BS2 8AE
United Kingdom
+44 (0)1173420160
jennifer.oliver@bristol.ac.uk

Type

Scientific

Additional contact

Dr Jane Metz

ORCID ID

http://orcid.org/0000-0003-2064-8675

Contact details

Population Health Sciences
Bristol Medical School
University of Bristol
Level 6
UH Bristol Education and Research Centre
Upper Maudlin Street
Bristol
BS2 8AE
United Kingdom
+44 (0)7773883154
jane.metz@bristol.ac.uk

Type

Scientific

Additional contact

Prof Adam Finn

ORCID ID

http://orcid.org/0000-0003-1756-5668

Contact details

UHB Education and Research Centre
Upper Maudlin Street
Bristol
BS2 8AE
United Kingdom
+44 (0)1173420172
adam.finn@bristol.ac.uk

Additional identifiers

EudraCT number

Nil known

ClinicalTrials.gov number

Nil known

Protocol/serial number

CPMS: 35674

Study information

Scientific title

Evaluation of the relationship between pneumococcal colonisation density in 2-year-old children and rates of transmission to family contacts using live attenuated intranasal influenza vaccine as a probe. A randomised prospective step-wedge multicentre study

Acronym

TOP

Study hypothesis

Increased carriage density of Streptococcus pneumoniae (Sp) in the upper respiratory tract of young children following the live attenuated influenzae vaccine (LAIV) will lead to increased rates of Sp transmission to close household contacts.

Ethics approval

Approved 06/09/2017, West - Cornwall & Plymouth Research Ethics Committee (Level 3, Block B, Whitefriars, Lewins Mead, Bristol BS1 2NT; +44 (0)207 104 8059; nrescommittee.southwest-cornwall-plymouth@nhs.net), ref: 17/SW/0190

Study design

Multi-centre prospective randomised stepped-wedge trial

Primary study design

Interventional

Secondary study design

Randomised controlled trial

Trial setting

Community

Trial type

Other

Patient information sheet

As we are enrolling families, there are information sheets for the index child, children and adults.

Condition

Streptococcus pneumoniae (Sp), Haemophilus influenzae (Hi) and Moraxella catarrhalis (Mc)

Intervention

This is a step-wedge design so that both index children of group 1 and group 2 (randomly allocated at a 1:1 ratio) receive the standard dose of LAIV but at different times. The group number determines whether the two-year-old (index) child receives LAIV at the first study visit (Group 1) or at the third study visit, 4 weeks later (Group 2). Serial saliva and nasopharyngeal swabs taken every 2 weeks over an 8-week period will be analysed for Streptococcus pneumoniae using real-time PCR. Standard statistical methods including generalised linear mixed models and individual-based mathematical modelling of transmission dynamics will be used for analysis.

Intervention type

Biological/Vaccine

Phase

Not Applicable

Drug names

Primary outcome measure

Streptococcus pneumoniae carriage and transmission events in family units measured using real-time PCR on serial nasopharyngeal and saliva samples taken every 2 weeks over an 8-week period

Secondary outcome measures

1. Haemophilus influenzae carriage and transmission events in family units measured using real-time PCR on serial nasopharyngeal and saliva samples taken every 2 weeks over an 8-week period.
2. Moraxella catarrhalis carriage and transmission events in family units measured using real-time PCR on serial nasopharyngeal and saliva samples taken every 2 weeks over an 8-week period

Overall trial start date

22/08/2017

Overall trial end date

31/03/2021

Reason abandoned (if study stopped)

Eligibility

Participant inclusion criteria

1. Healthy male or female child
2. Who will be 2 years of age between 1st January and 31st August of the year of recruitment
3. Who is resident near the recruiting centres
4. Who have at least two other people, either adults or children, resident in the house where they live that are willing and able to take part

Participant type

Healthy volunteer

Age group

Mixed

Gender

Both

Target number of participants

500 families

Participant exclusion criteria

Exclusion criteria include all contra-indications in the vaccine licence, in addition:
1. Children currently enrolled in another clinical trial or study which, in the opinion of the investigator might interfere with their likelihood of completing either or both studies or which might confound outcomes of either study. Families participating in the first year of the study who have another child of the right age and are otherwise eligible and who wish to participate again in the second year will be permitted to do so
2. Confirmed or suspected primary or secondary immunodeficiency OR known to be severely immunosuppressed due to any condition or recent (in the last 6 months) therapy (eg leukaemia, HIV infection, organ or bone marrow transplant)
3. Severely immunocompromised household member or close contact (because of potential for transmission of live attenuated virus)
4. Receipt of immunosuppressants or immune modifying drugs including oral or parenteral steroids (at a dose equivalent of prednisolone >0.5mg/kg/day for more than 1 week within the 3 months prior to enrolment). Inhaled steroids are not a contraindication (although see below re asthma and wheezing)
5. Current hospital-based management of asthma
6. Previous receipt of, or intended immunisation with any other influenza vaccine(s)
7. Children who are in risk groups for severe influenza (e.g. chronic respiratory (but for severe asthma see above), cardiac, renal, hepatic or neurological diseases and diabetes) can be enrolled and immunized in the study provided they are eligible to receive LAIV following the guidance published in the Green Book (ref: www.gov.uk/government/uploads/system/uploads/attachment_data/file/456568/2904394_Green_Book_Chapter_19_v10_0.pdf)
8. Children with other chronic, stable medical illnesses that do not result in immunosuppression and are not risk groups indicating receipt of seasonal flu vaccine (e.g. epilepsy, metabolic disorders) may participate in the study, unless their condition or circumstances will in some way interfere with the completion of study procedures
9. Children receiving salicylate therapy (Aspirin)
10. Previous anaphylactic reaction to any component of the nasal flu vaccine (including gelatine or gentamicin), or to eggs or egg proteins (eg ovalbumin)
11. Any other condition or circumstances which, in the opinion of the investigator, might put the index subject or family members or research team members at risk or which might interfere with the likelihood of successful of study procedures and sampling per protocol or which might prevent the results obtained from contributing in any way with successful achievement of the study objectives

Recruitment start date

04/10/2017

Recruitment end date

31/12/2018

Locations

Countries of recruitment

United Kingdom

Trial participating centre

Bristol Children's Vaccine Centre
University Hospitals Bristol NHS Foundation Trust Level 6, UH Bristol Education and Research Centre Upper Maudlin Street
Bristol
BS2 8AE
United Kingdom

Trial participating centre

St Georges Hospital, University of London
Paediatric Infectious Diseases Research Group Jenner Wing, Level 2, Room 2.216F, Mail Point J2C
London
SW17 0RE
United Kingdom

Trial participating centre

University of Oxford
Oxford Vaccine Group Department of Paediatrics Centre for Clinical Vaccinology and Tropical Medicine (CCVTM) Churchill Hospital
Oxford
OX3 7LE
United Kingdom

Trial participating centre

Southampton General Hospital
Southampton National Institute for Health Research Clinical Research Facility University Hospital Southampton NHS Foundation Trust Mailpoint 218 Tremona Road
Southampton
SO16 6YD
United Kingdom

Trial participating centre

Royal Manchester Children's Hospital
Paediatric Research Team Clinical Trial Management Office (ICON Building) Manchester University Hospitals NHS Foundation Trust North Road
Manchester
M13 9WL
United Kingdom

Trial participating centre

Royal United Hospital
Paediatric Clinical Research Team Children’s Centre Outpatient’s Department B11 Royal United Hospital Bath NHS Foundation Trust Combe Park
Bath
BA1 3NG
United Kingdom

Trial participating centre

Musgrove Park Hospital
Department of Clinical Research Starling Clinic Musgrove Park Hospital
Taunton
TA1 5DA
United Kingdom

Trial participating centre

NIHR Clinical Research Network: South West Peninsula
Room F7 Child Health Building Barrack Road
Exeter
EX2 5DW
United Kingdom

Trial participating centre

Sheffield Children's Hospital
Children's Clinical Research Facility D Floor, Stephenson Wing Sheffield Children's Hospital Western Bank
Sheffield
S10 2TH
United Kingdom

Trial participating centre

Gloucester Royal Hospital
Gloucestershire Research Office Leadon House Great Western Road
Gloucester
GL1 3NN
United Kingdom

Sponsor information

Organisation

University of Bristol

Sponsor details

Senate House
Tyndall Avenue
Bristol
BS8 1TH
United Kingdom
+44 (0)117 342 0160
jennifer.oliver@bristol.ac.uk

Sponsor type

University/education

Website

Funders

Funder type

Industry

Funder name

Pfizer

Alternative name(s)

Pfizer Inc., Pfizer Consumer Healthcare

Funding Body Type

private sector organisation

Funding Body Subtype

For-profit companies (industry)

Location

United States of America

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

The researchers intend to present data at conferences over the next 2 years including at the 2020 International Symposium on Pneumococci and Pneumococcal Diseases (ISPPD) and the 2020 and 2021 European Society of Paediatric Infectious Diseases (ESPID).
Written publications are intended when all results are available (from June 2021 onwards).

IPD sharing statement:
The data sharing plans for the current study are unknown and will be made available at a later date.

Intention to publish date

01/06/2021

Participant level data

To be made available at a later date

Basic results (scientific)

Publication list

Publication citations

Additional files

Editorial Notes

05/11/2019: Trial's existence confirmed by the NIHR.