Clinical Trial Details
— Status: Recruiting
Administrative data
| NCT number |
NCT04401488 |
| Other study ID # |
RHM CHI0678 |
| Secondary ID |
|
| Status |
Recruiting |
| Phase |
|
| First received |
|
| Last updated |
|
| Start date |
October 1, 2014 |
| Est. completion date |
March 31, 2022 |
Study information
| Verified date |
May 2020 |
| Source |
University Hospital Southampton NHS Foundation Trust |
| Contact |
Denise Morris |
| Phone |
02381208895 |
| Email |
d.e.morris[@]soaoton.ac.uk |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Observational
|
Clinical Trial Summary
The investigators intend to investigate the carriage of pneumococci and other respiratory
microbes since the introduction of pneumococcal conjugate vaccines (Prevenar 7 and Prevenar
13). The principal aim is to gain a collection of samples that can be used to help
investigate any changes that might occur in the epidemiology of microbes that are carried in
the upper respiratory tract and which may cause respiratory disease, sepsis or meningitis
after the introduction of Prevenar.
Nasopharyngeal and nasal swabs will be taken from up to 2,000 children aged 4 years and under
in each year of the study. Swabs will be processed using traditional microbiology and
molecular diagnostic techniques and isolated microbes such as S. pneumoniae further
characterised using molecular methods. The investigators will also ask parents to complete a
short questionnaire requesting: basic demographic data; vaccine history; recent illness;
overseas travel and antibiotic usage.
The study will contribute to the success of the introduction of pneumococcal conjugate
vaccines and will play a central role in maintaining confidence. The study will also help
provide information for future vaccine policy as further vaccines are developed against
microbes which cause respiratory disease, sepsis and meningitis.
Description:
Streptococcus pneumoniae (the pneumococcus) is an important cause of pneumonia, meningitis
and bacteraemia worldwide. The prevention of invasive pneumococcal disease (IPD) by
immunisation has been a key public health priority. Conjugate vaccines have a good record of
eradicating carriage of bacteria as well as protecting against disease because they evoke a
T-cell dependent response. For this reason, they are also efficacious in children less than 2
years of age. The first pneumococcal conjugate vaccine, Prevenar 7, was licensed in the UK in
2001 and was added to the routine UK childhood immunisation schedule on 4th September 2006.
Prevenar 13 replaced Prevenar 7 from 1st April 2010.
In the US Prevenar 7 was a successful intervention, resulting in decreases of childhood IPD
by 69%, which was unsurprising considering that serotypes included in the vaccine (4, 6B, 9V,
14, 18C, 19F and 23F) had been reported to cause 70% of all IPD in young children. Decreases
in IPD amongst the adult population were higher than predicted which is thought to have been
due to herd immunity. Unfortunately this was also paralleled by an increase in disease caused
by non-vaccine types or vaccine-related serotypes which had changed their protective capsule
(undergone capsule switching) such as the acquisition of 19A capsular locus by a previously
serotype 4 clone .
The introduction of Prevenar 7 into the UK childhood immunisation schedule led to a
significant reduction in pneumococcal disease amongst children in the UK and early data after
the introduction of Prevenar 13 suggests a further decline in pneumococcal carriage and
disease due to the additional six serotypes contained within the vaccine. Recent studies in
the UK have characterised collections of pneumococci in an attempt to better understand the
clonal distribution of serotypes and sequence types. Such studies are important since
pneumococci are highly transformable, with there being ample evidence of capsule switching
and serotype replacement amongst pneumococci.
Although Prevenar 7 and 13 have been successful interventions in the UK and elsewhere,
improved vaccines will be required to further control pneumococcal disease. Public Health
England (previously Health Protection Agency) surveillance data of invasive pneumococcal
disease has already indicated that serotype replacement has occurred after the implementation
of Prevenar. The investigator's previous study, referred to here as the Southampton
pneumococcal carriage study (Full name 'Understanding changes in the molecular epidemiology
of pneumococci carried in the nasopharynx amongst children after the introduction of
pneumococcal conjugate vaccines', REC No. 06/Q1704/105), also showed serotype replacement
during the first three years of Prevenar 7 introduction. The serotypes seen during the
investigator's SMART study (full name 'Analysis of the microbial community of the upper
respiratory tract to support the development of effective vaccine policy', REC No.
11/SC/0518) similarly suggest the occurrence of serotype replacement in those who have had
the Prevenar vaccine due to the low level of vaccine types found within the investigator's
data set (data not yet published). There is currently insufficient evidence for the wider use
of Prevenar 13 in teenagers and younger adults.
The introduction of vaccines that contain only selected serotypes, as is the case with
Prevenar 7 and Prevenar 13, have been shown to promote S. pneumoniae capsule switching or
capsule replacement which allows for the evasion of vaccine induced host immunity. It is
therefore important to monitor which serotypes of S. pneumoniae are commonly causing disease.
It is also important to analyse the nasopharynx as an ecological niche because a reduction in
the carriage of pneumococci, due to Prevenar, could lead to a replacement effect such that
pneumococci of serotypes not covered by the vaccine or other bacterial/microbe species may
fill the niche. It is therefore also important to gain information on the carriage of other
bacteria/microbes such as Haemophilus influenzae, Staphylococcus aureus and Neisseria
meningitidis.
Many studies have been largely limited to studying disease-causing pneumococci and needed to
be supplemented by pneumococcal carriage studies such as the investigator's Southampton
pneumococcal carriage study. The Southampton pneumococcal carriage study started immediately
before the implementation of pneumococcal conjugate vaccines in the UK and completed its
eighth swabbing time-point during winter 2013/14. It was the only longitudinal pneumococcal
carriage study of its kind in the UK and is, to the investigators knowledge, one of only two
longitudinal carriage studies globally that began as Prevenar was being introduced, the other
being in Massachusetts, USA. The investigator's SMART study gives a unique snapshot of
bacterial carriage in the community in all age groups and has provided information which will
enable us to better understand bacterial carriage. The investigators believe that such
studies are of high importance in understanding the carriage of microbes, in particular
pneumococcal carriage, during the implementation of pneumococcal conjugate vaccines.
The paediatric post pneumococcal conjugate vaccine nasopharyngeal carriage study is a
development of the Southampton pneumococcal carriage study which proposes to continue to
contribute to the success of the introduction of pneumococcal conjugate vaccines and,
depending on the biological consequences of on-going vaccine use, play a central role in
maintaining confidence. The study will also help provide information for future vaccine
policy and vaccine development as further pneumococcal conjugate vaccines, and indeed other
vaccines such as the meningococcal B vaccine, are introduced. Although Prevenar vaccines have
been successful interventions, reducing pneumococcal deaths for children under 5 years of age
globally by an estimated 250,000 between 2000 and 2008, there were still a reported 485,000
pneumococcal deaths in children of this age range in 2008 alone. Conjugate vaccines will need
to be continuously redesigned in order to maintain suppression of pneumococcal disease. It is
therefore important to continue gaining information on circulating serotypes and sequence
types from carriage and compare these to disease-causing pneumococci since the implementation
of Prevenar and relate this to the potential development and introduction of new vaccines.
Hypothesis The circulating pneumococcal population of the nasopharynx has implications for
pneumococcal disease in children.
Aims
- to gain a collection of pneumococci and other microbes of related importance that can be
used to help investigate any changes that occur in the epidemiology of pneumococcal
disease since the introduction of Prevenar 13.
- to use microbes isolated from the respiratory tract during the investigator's previous
studies (the Southampton pneumococcal carriage study and the SMART study) to further
investigate the carriage of microbes including S. pneumoniae and the effects of
Prevenar.
- to use all isolated strains to help understand changes in the molecular epidemiology of
pneumococci, and other relevant microbe species of the upper respiratory tract.
Research questions
This study aims to provide key data that will continue to support the implementation of
pneumococcal vaccines. The key outcomes from this study are:
- To contribute to understanding any changes that may take place in the frequency of
nasopharyngeal carriage of the pneumococcus and microbes of related importance and, at a
molecular level, how these changes may have occurred.
- To continue providing data on the molecular epidemiology of carried pneumococci in young
children.
- To describe the indirect impact of Prevenar 13 on pneumococcal carriage in young
children.
- To compare the genomic epidemiology of serotype 3 pneumococci in carriage and disease
with the aim of identifying reasons for the ineffectiveness of Prevenar-13 against this
serotype.
- To compare the genomic epidemiology of non-Prevenar 13 serotypes from carriage and
disease with Prevenar 13 serotypes with the aim of identifying differences in their
virulence potential.
Methods Recruitment for the paediatric post pneumococcal conjugate vaccine nasopharyngeal
carriage study will take place year-round. The investigators aim to recruit children aged 4
years and under who are visiting either the Paediatric Outpatients department at University
Hospital Southampton NHS Foundation Trust or Solent NHS Trust sites and sites working in
partnership with the Solent NHS Trust. By analysing pneumococci and other microbes of
importance collected from the Southampton pneumococcal carriage study, the SMART study and
the paediatric post pneumococcal conjugate vaccine nasopharyngeal carriage study, it will be
possible to examine the impact of immunisation on the pneumococcal population and overall
carriage of microbes of interest in an age group at high risk of acquisition and carriage.
Swabs and/or swab contents from participants and the microbes isolated from swabs from the
above studies will be stored for the duration on this project. The current study is
cross-sectional in order to gain a 'snapshot' of the frequency and types of pneumococci and
other microbes of importance being carried amongst young children.
During the paediatric post pneumococcal conjugate vaccine nasopharyngeal carriage study,
swabs from the back of the nose (Nasopharyngeal swabs) will be taken from up to 2,000
children aged 4 years and under in each year of the study. The investigators will also ask to
take nasal swabs, but these will be optional. Swabs will be taken from children who are
already attending/visiting the Paediatric Outpatients department at University Hospital
Southampton NHS Foundation Trust or Solent NHS Trust sites and sites working in partnership
with the Solent NHS Trust. Swabbing will be performed following a modified World Health
Organisation (WHO) protocol. Swabs will be collected by either a trained healthcare
professional (i.e. a research nurse, health care assistant, medical student, doctor) or a
trained member of the study team (i.e. clinical trials assistants) and submitted to the
project research team for selective bacterial isolation and testing such as molecular
analysis. As was the practice for the Southampton pneumococcal carriage study and the SMART
study, swabs will be taken solely for research purposes and will be anonymised immediately;
there will be no patient identifier on the swabs. Swabs will be taken to the research team at
University Hospital Southampton NHS Foundation Trust and processed within 48 hours of being
taken. The remaining contents of new swabs collected as part of the study will be stored in
microbial storage media for the future analysis of microbe DNA only - no human DNA will be
analysed at any time. At this stage the swabs will be disposed of using the normal practices
of University Hospital Southampton NHS Foundation Trust. The selective media plates will be
examined after incubation for the presence of Streptococcus pneumoniae, Staphylococcus
aureus, Haemophilus influenzae, α haemolytic Streptococcus, Neisseria meningitidis and
Moraxella catarrhalis. If a plate shows growth of any of these bacteria, individual colonies
will be sub-cultured and subsequently frozen for future analysis e.g. to determine the
frequency of carriage of multiple serotypes and sequence types. Any bacteria/microbes
isolated will be deemed a gift to the research study. This information is given on the
patient information sheet. If a participant withdraws from the study the bacteria isolated
from their swab will be destroyed.
The investigators will also ask parents/ guardians to complete a short questionnaire
requesting basic demographic data, vaccine history, information regarding recent illness and
recent antibiotic usage. This is to help allow us to understand the impact of age,
demographic data and/or vaccine and antibiotic history on the carriage of specific
respiratory microbes.
Analysis will be done using the bacteria isolated and swab contents stored in microbial
storage media as part of this paediatric post pneumococcal conjugate vaccine nasopharyngeal
carriage study, as well as bacteria isolated and stored during the Southampton pneumococcal
carriage study and the SMART study to investigate carriage of microbes including S.
pneumoniae and the effects of Prevenar.
Sampling and statistical power The study design is cross-sectional. Children aged 4 years and
under will be sampled. Up to 1,000 participants will be recruited each winter (October to
March), until winter 2019/2020, at which point year-round recruitment will be undertaken and
up to 2000 participants will be recruited each year. The parents of potential participants
will be approached by a trained healthcare professional or member of the study team in the
reception/waiting room of the Paediatric Outpatients Department of University Hospital
Southampton NHS Foundation Trust or Solent NHS Trust sites and sites working in partnership
with the Solent NHS Trust. All participants will be aged 4 years and under; therefore, the
parents or legal guardian will be asked to provide informed consent for their child's
participation in the study. Informed consent will be taken after having time to read the
information sheet provided and will therefore be based on information provided in in the
information sheet and the opportunity to question study personnel. Entry to the study will be
voluntary.
The investigator's previous pneumococcal carriage studies have found an average carriage rate
of approximately 30%. The investigators had previously assumed that the introduction of
pneumococcal conjugate vaccines would lead to a reduction in the pneumococcal carriage rate
due to a reduction in serotypes included in the vaccines. Although there was a reduction in
these serotypes, a concomitant increase of non-vaccine serotypes occurred. For the present
study, the investigators have therefore assumed that the overall pneumococcal carriage rate
will remain at 30%. In order to detect a carriage rate of 30% (with 95% CI width of 5% on
both side of the carriage rate) the investigators will require at least 340 participants per
winter (allowing an error rate of 5% to occur during culturing). To detect rare serotypes
with a carriage rate as low as 2% (with 95% CI width of 1% on both side of the carriage rate)
the investigators will require at least 793 participants per winter allowing an error rate of
5% to occur during culturing). However, since this is a pragmatic study whereby the future
epidemiology of pneumococcal carriage is unknown, with or without further novel vaccine
implementation, the investigators anticipate that up to 1,000 participants per winter will be
required to detect significant changes the pre-specified precision in the overall
pneumococcal carriage rate and/or specific serotype carriage rate. This will then enable us
to detect an overall carriage rate as low as 3% (with 95% CI width of 1% on both side of the
carriage rate). Increased recruitment of 2000 participants per year allows for the detection
of carriage prevalence of 30% (with 95% CI width of 2% on both side of the carriage rate
allowing an error rate of 5% to occur during culturing).
A power calculation was performed by a statistician at the University of Southampton.
Timetable The study started on the 10th November 2014 and will recruit/swab for 8 years (as a
result of an extension given REC approval 22nd March 2016 and an extension given REC approval
2nd September 2019 and HRA approval 23rd August 2019). Recruitment and swabbing took place
during the winters (October to March) of 2014/15, 2015/16, 2016/17, 2017/18, 2018/19 and then
year-round from October 2019 to March 2022 (as per the amendment submitted March 2020). This
extended recruitment allows the year-round surveillance of S. pneumoniae to detect
fluctuation of carriage. In response to the COVID-19 outbreak, it also allows the detection
of circulating microbes of outbreak, epidemic and pandemic potential. The study will end 31st
March 2027 to allow enough time for analysis.
All sampling will take place within the Outpatients Department of University Hospital
Southampton Foundation NHS Trust (or the NIHR Clinical Research Facility if there are no
rooms available in the Outpatients Department) or at Solent NHS Trust sites and sites working
in partnership with the Solent NHS Trust. Academic work will take place within the Faculty of
Medicine, University of Southampton and at collaborating centres such as the Wellcome Trust
Sanger Institute, Cambridge.
