<clinical_study>
  <!-- This xml conforms to an XML Schema at:
    https://clinicaltrials.gov/ct2/html/images/info/public.xsd -->
  <required_header>
    <download_date>ClinicalTrials.gov processed this data on September 20, 2023</download_date>
    <link_text>Link to the current ClinicalTrials.gov record.</link_text>
    <url>https://clinicaltrials.gov/ct2/show/NCT04401488</url>
  </required_header>
  <id_info>
    <org_study_id>RHM CHI0678</org_study_id>
    <nct_id>NCT04401488</nct_id>
  </id_info>
  <brief_title>Paediatric Post Pneumococcal Conjugate Vaccine Nasopharyngeal Carriage Study</brief_title>
  <official_title>Paediatric Post Pneumococcal Conjugate Vaccine Nasopharyngeal Carriage Study</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>University Hospital Southampton NHS Foundation Trust</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Solent NHS Trust</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>University Hospital Southampton NHS Foundation Trust</source>
  <oversight_info>
    <is_fda_regulated_drug>Yes</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
    <is_us_export>No</is_us_export>
  </oversight_info>
  <brief_summary>
    <textblock>
      The investigators intend to investigate the carriage of pneumococci and other respiratory&#xD;
      microbes since the introduction of pneumococcal conjugate vaccines (Prevenar 7 and Prevenar&#xD;
      13). The principal aim is to gain a collection of samples that can be used to help&#xD;
      investigate any changes that might occur in the epidemiology of microbes that are carried in&#xD;
      the upper respiratory tract and which may cause respiratory disease, sepsis or meningitis&#xD;
      after the introduction of Prevenar.&#xD;
&#xD;
      Nasopharyngeal and nasal swabs will be taken from up to 2,000 children aged 4 years and under&#xD;
      in each year of the study. Swabs will be processed using traditional microbiology and&#xD;
      molecular diagnostic techniques and isolated microbes such as S. pneumoniae further&#xD;
      characterised using molecular methods. The investigators will also ask parents to complete a&#xD;
      short questionnaire requesting: basic demographic data; vaccine history; recent illness;&#xD;
      overseas travel and antibiotic usage.&#xD;
&#xD;
      The study will contribute to the success of the introduction of pneumococcal conjugate&#xD;
      vaccines and will play a central role in maintaining confidence. The study will also help&#xD;
      provide information for future vaccine policy as further vaccines are developed against&#xD;
      microbes which cause respiratory disease, sepsis and meningitis.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Streptococcus pneumoniae (the pneumococcus) is an important cause of pneumonia, meningitis&#xD;
      and bacteraemia worldwide. The prevention of invasive pneumococcal disease (IPD) by&#xD;
      immunisation has been a key public health priority. Conjugate vaccines have a good record of&#xD;
      eradicating carriage of bacteria as well as protecting against disease because they evoke a&#xD;
      T-cell dependent response. For this reason, they are also efficacious in children less than 2&#xD;
      years of age. The first pneumococcal conjugate vaccine, Prevenar 7, was licensed in the UK in&#xD;
      2001 and was added to the routine UK childhood immunisation schedule on 4th September 2006.&#xD;
      Prevenar 13 replaced Prevenar 7 from 1st April 2010.&#xD;
&#xD;
      In the US Prevenar 7 was a successful intervention, resulting in decreases of childhood IPD&#xD;
      by 69%, which was unsurprising considering that serotypes included in the vaccine (4, 6B, 9V,&#xD;
      14, 18C, 19F and 23F) had been reported to cause 70% of all IPD in young children. Decreases&#xD;
      in IPD amongst the adult population were higher than predicted which is thought to have been&#xD;
      due to herd immunity. Unfortunately this was also paralleled by an increase in disease caused&#xD;
      by non-vaccine types or vaccine-related serotypes which had changed their protective capsule&#xD;
      (undergone capsule switching) such as the acquisition of 19A capsular locus by a previously&#xD;
      serotype 4 clone .&#xD;
&#xD;
      The introduction of Prevenar 7 into the UK childhood immunisation schedule led to a&#xD;
      significant reduction in pneumococcal disease amongst children in the UK and early data after&#xD;
      the introduction of Prevenar 13 suggests a further decline in pneumococcal carriage and&#xD;
      disease due to the additional six serotypes contained within the vaccine. Recent studies in&#xD;
      the UK have characterised collections of pneumococci in an attempt to better understand the&#xD;
      clonal distribution of serotypes and sequence types. Such studies are important since&#xD;
      pneumococci are highly transformable, with there being ample evidence of capsule switching&#xD;
      and serotype replacement amongst pneumococci.&#xD;
&#xD;
      Although Prevenar 7 and 13 have been successful interventions in the UK and elsewhere,&#xD;
      improved vaccines will be required to further control pneumococcal disease. Public Health&#xD;
      England (previously Health Protection Agency) surveillance data of invasive pneumococcal&#xD;
      disease has already indicated that serotype replacement has occurred after the implementation&#xD;
      of Prevenar. The investigator's previous study, referred to here as the Southampton&#xD;
      pneumococcal carriage study (Full name 'Understanding changes in the molecular epidemiology&#xD;
      of pneumococci carried in the nasopharynx amongst children after the introduction of&#xD;
      pneumococcal conjugate vaccines', REC No. 06/Q1704/105), also showed serotype replacement&#xD;
      during the first three years of Prevenar 7 introduction. The serotypes seen during the&#xD;
      investigator's SMART study (full name 'Analysis of the microbial community of the upper&#xD;
      respiratory tract to support the development of effective vaccine policy', REC No.&#xD;
      11/SC/0518) similarly suggest the occurrence of serotype replacement in those who have had&#xD;
      the Prevenar vaccine due to the low level of vaccine types found within the investigator's&#xD;
      data set (data not yet published). There is currently insufficient evidence for the wider use&#xD;
      of Prevenar 13 in teenagers and younger adults.&#xD;
&#xD;
      The introduction of vaccines that contain only selected serotypes, as is the case with&#xD;
      Prevenar 7 and Prevenar 13, have been shown to promote S. pneumoniae capsule switching or&#xD;
      capsule replacement which allows for the evasion of vaccine induced host immunity. It is&#xD;
      therefore important to monitor which serotypes of S. pneumoniae are commonly causing disease.&#xD;
      It is also important to analyse the nasopharynx as an ecological niche because a reduction in&#xD;
      the carriage of pneumococci, due to Prevenar, could lead to a replacement effect such that&#xD;
      pneumococci of serotypes not covered by the vaccine or other bacterial/microbe species may&#xD;
      fill the niche. It is therefore also important to gain information on the carriage of other&#xD;
      bacteria/microbes such as Haemophilus influenzae, Staphylococcus aureus and Neisseria&#xD;
      meningitidis.&#xD;
&#xD;
      Many studies have been largely limited to studying disease-causing pneumococci and needed to&#xD;
      be supplemented by pneumococcal carriage studies such as the investigator's Southampton&#xD;
      pneumococcal carriage study. The Southampton pneumococcal carriage study started immediately&#xD;
      before the implementation of pneumococcal conjugate vaccines in the UK and completed its&#xD;
      eighth swabbing time-point during winter 2013/14. It was the only longitudinal pneumococcal&#xD;
      carriage study of its kind in the UK and is, to the investigators knowledge, one of only two&#xD;
      longitudinal carriage studies globally that began as Prevenar was being introduced, the other&#xD;
      being in Massachusetts, USA. The investigator's SMART study gives a unique snapshot of&#xD;
      bacterial carriage in the community in all age groups and has provided information which will&#xD;
      enable us to better understand bacterial carriage. The investigators believe that such&#xD;
      studies are of high importance in understanding the carriage of microbes, in particular&#xD;
      pneumococcal carriage, during the implementation of pneumococcal conjugate vaccines.&#xD;
&#xD;
      The paediatric post pneumococcal conjugate vaccine nasopharyngeal carriage study is a&#xD;
      development of the Southampton pneumococcal carriage study which proposes to continue to&#xD;
      contribute to the success of the introduction of pneumococcal conjugate vaccines and,&#xD;
      depending on the biological consequences of on-going vaccine use, play a central role in&#xD;
      maintaining confidence. The study will also help provide information for future vaccine&#xD;
      policy and vaccine development as further pneumococcal conjugate vaccines, and indeed other&#xD;
      vaccines such as the meningococcal B vaccine, are introduced. Although Prevenar vaccines have&#xD;
      been successful interventions, reducing pneumococcal deaths for children under 5 years of age&#xD;
      globally by an estimated 250,000 between 2000 and 2008, there were still a reported 485,000&#xD;
      pneumococcal deaths in children of this age range in 2008 alone. Conjugate vaccines will need&#xD;
      to be continuously redesigned in order to maintain suppression of pneumococcal disease. It is&#xD;
      therefore important to continue gaining information on circulating serotypes and sequence&#xD;
      types from carriage and compare these to disease-causing pneumococci since the implementation&#xD;
      of Prevenar and relate this to the potential development and introduction of new vaccines.&#xD;
&#xD;
      Hypothesis The circulating pneumococcal population of the nasopharynx has implications for&#xD;
      pneumococcal disease in children.&#xD;
&#xD;
      Aims&#xD;
&#xD;
        -  to gain a collection of pneumococci and other microbes of related importance that can be&#xD;
           used to help investigate any changes that occur in the epidemiology of pneumococcal&#xD;
           disease since the introduction of Prevenar 13.&#xD;
&#xD;
        -  to use microbes isolated from the respiratory tract during the investigator's previous&#xD;
           studies (the Southampton pneumococcal carriage study and the SMART study) to further&#xD;
           investigate the carriage of microbes including S. pneumoniae and the effects of&#xD;
           Prevenar.&#xD;
&#xD;
        -  to use all isolated strains to help understand changes in the molecular epidemiology of&#xD;
           pneumococci, and other relevant microbe species of the upper respiratory tract.&#xD;
&#xD;
      Research questions&#xD;
&#xD;
      This study aims to provide key data that will continue to support the implementation of&#xD;
      pneumococcal vaccines. The key outcomes from this study are:&#xD;
&#xD;
        -  To contribute to understanding any changes that may take place in the frequency of&#xD;
           nasopharyngeal carriage of the pneumococcus and microbes of related importance and, at a&#xD;
           molecular level, how these changes may have occurred.&#xD;
&#xD;
        -  To continue providing data on the molecular epidemiology of carried pneumococci in young&#xD;
           children.&#xD;
&#xD;
        -  To describe the indirect impact of Prevenar 13 on pneumococcal carriage in young&#xD;
           children.&#xD;
&#xD;
        -  To compare the genomic epidemiology of serotype 3 pneumococci in carriage and disease&#xD;
           with the aim of identifying reasons for the ineffectiveness of Prevenar-13 against this&#xD;
           serotype.&#xD;
&#xD;
        -  To compare the genomic epidemiology of non-Prevenar 13 serotypes from carriage and&#xD;
           disease with Prevenar 13 serotypes with the aim of identifying differences in their&#xD;
           virulence potential.&#xD;
&#xD;
      Methods Recruitment for the paediatric post pneumococcal conjugate vaccine nasopharyngeal&#xD;
      carriage study will take place year-round. The investigators aim to recruit children aged 4&#xD;
      years and under who are visiting either the Paediatric Outpatients department at University&#xD;
      Hospital Southampton NHS Foundation Trust or Solent NHS Trust sites and sites working in&#xD;
      partnership with the Solent NHS Trust. By analysing pneumococci and other microbes of&#xD;
      importance collected from the Southampton pneumococcal carriage study, the SMART study and&#xD;
      the paediatric post pneumococcal conjugate vaccine nasopharyngeal carriage study, it will be&#xD;
      possible to examine the impact of immunisation on the pneumococcal population and overall&#xD;
      carriage of microbes of interest in an age group at high risk of acquisition and carriage.&#xD;
      Swabs and/or swab contents from participants and the microbes isolated from swabs from the&#xD;
      above studies will be stored for the duration on this project. The current study is&#xD;
      cross-sectional in order to gain a 'snapshot' of the frequency and types of pneumococci and&#xD;
      other microbes of importance being carried amongst young children.&#xD;
&#xD;
      During the paediatric post pneumococcal conjugate vaccine nasopharyngeal carriage study,&#xD;
      swabs from the back of the nose (Nasopharyngeal swabs) will be taken from up to 2,000&#xD;
      children aged 4 years and under in each year of the study. The investigators will also ask to&#xD;
      take nasal swabs, but these will be optional. Swabs will be taken from children who are&#xD;
      already attending/visiting the Paediatric Outpatients department at University Hospital&#xD;
      Southampton NHS Foundation Trust or Solent NHS Trust sites and sites working in partnership&#xD;
      with the Solent NHS Trust. Swabbing will be performed following a modified World Health&#xD;
      Organisation (WHO) protocol. Swabs will be collected by either a trained healthcare&#xD;
      professional (i.e. a research nurse, health care assistant, medical student, doctor) or a&#xD;
      trained member of the study team (i.e. clinical trials assistants) and submitted to the&#xD;
      project research team for selective bacterial isolation and testing such as molecular&#xD;
      analysis. As was the practice for the Southampton pneumococcal carriage study and the SMART&#xD;
      study, swabs will be taken solely for research purposes and will be anonymised immediately;&#xD;
      there will be no patient identifier on the swabs. Swabs will be taken to the research team at&#xD;
      University Hospital Southampton NHS Foundation Trust and processed within 48 hours of being&#xD;
      taken. The remaining contents of new swabs collected as part of the study will be stored in&#xD;
      microbial storage media for the future analysis of microbe DNA only - no human DNA will be&#xD;
      analysed at any time. At this stage the swabs will be disposed of using the normal practices&#xD;
      of University Hospital Southampton NHS Foundation Trust. The selective media plates will be&#xD;
      examined after incubation for the presence of Streptococcus pneumoniae, Staphylococcus&#xD;
      aureus, Haemophilus influenzae, α haemolytic Streptococcus, Neisseria meningitidis and&#xD;
      Moraxella catarrhalis. If a plate shows growth of any of these bacteria, individual colonies&#xD;
      will be sub-cultured and subsequently frozen for future analysis e.g. to determine the&#xD;
      frequency of carriage of multiple serotypes and sequence types. Any bacteria/microbes&#xD;
      isolated will be deemed a gift to the research study. This information is given on the&#xD;
      patient information sheet. If a participant withdraws from the study the bacteria isolated&#xD;
      from their swab will be destroyed.&#xD;
&#xD;
      The investigators will also ask parents/ guardians to complete a short questionnaire&#xD;
      requesting basic demographic data, vaccine history, information regarding recent illness and&#xD;
      recent antibiotic usage. This is to help allow us to understand the impact of age,&#xD;
      demographic data and/or vaccine and antibiotic history on the carriage of specific&#xD;
      respiratory microbes.&#xD;
&#xD;
      Analysis will be done using the bacteria isolated and swab contents stored in microbial&#xD;
      storage media as part of this paediatric post pneumococcal conjugate vaccine nasopharyngeal&#xD;
      carriage study, as well as bacteria isolated and stored during the Southampton pneumococcal&#xD;
      carriage study and the SMART study to investigate carriage of microbes including S.&#xD;
      pneumoniae and the effects of Prevenar.&#xD;
&#xD;
      Sampling and statistical power The study design is cross-sectional. Children aged 4 years and&#xD;
      under will be sampled. Up to 1,000 participants will be recruited each winter (October to&#xD;
      March), until winter 2019/2020, at which point year-round recruitment will be undertaken and&#xD;
      up to 2000 participants will be recruited each year. The parents of potential participants&#xD;
      will be approached by a trained healthcare professional or member of the study team in the&#xD;
      reception/waiting room of the Paediatric Outpatients Department of University Hospital&#xD;
      Southampton NHS Foundation Trust or Solent NHS Trust sites and sites working in partnership&#xD;
      with the Solent NHS Trust. All participants will be aged 4 years and under; therefore, the&#xD;
      parents or legal guardian will be asked to provide informed consent for their child's&#xD;
      participation in the study. Informed consent will be taken after having time to read the&#xD;
      information sheet provided and will therefore be based on information provided in in the&#xD;
      information sheet and the opportunity to question study personnel. Entry to the study will be&#xD;
      voluntary.&#xD;
&#xD;
      The investigator's previous pneumococcal carriage studies have found an average carriage rate&#xD;
      of approximately 30%. The investigators had previously assumed that the introduction of&#xD;
      pneumococcal conjugate vaccines would lead to a reduction in the pneumococcal carriage rate&#xD;
      due to a reduction in serotypes included in the vaccines. Although there was a reduction in&#xD;
      these serotypes, a concomitant increase of non-vaccine serotypes occurred. For the present&#xD;
      study, the investigators have therefore assumed that the overall pneumococcal carriage rate&#xD;
      will remain at 30%. In order to detect a carriage rate of 30% (with 95% CI width of 5% on&#xD;
      both side of the carriage rate) the investigators will require at least 340 participants per&#xD;
      winter (allowing an error rate of 5% to occur during culturing). To detect rare serotypes&#xD;
      with a carriage rate as low as 2% (with 95% CI width of 1% on both side of the carriage rate)&#xD;
      the investigators will require at least 793 participants per winter allowing an error rate of&#xD;
      5% to occur during culturing). However, since this is a pragmatic study whereby the future&#xD;
      epidemiology of pneumococcal carriage is unknown, with or without further novel vaccine&#xD;
      implementation, the investigators anticipate that up to 1,000 participants per winter will be&#xD;
      required to detect significant changes the pre-specified precision in the overall&#xD;
      pneumococcal carriage rate and/or specific serotype carriage rate. This will then enable us&#xD;
      to detect an overall carriage rate as low as 3% (with 95% CI width of 1% on both side of the&#xD;
      carriage rate). Increased recruitment of 2000 participants per year allows for the detection&#xD;
      of carriage prevalence of 30% (with 95% CI width of 2% on both side of the carriage rate&#xD;
      allowing an error rate of 5% to occur during culturing).&#xD;
&#xD;
      A power calculation was performed by a statistician at the University of Southampton.&#xD;
&#xD;
      Timetable The study started on the 10th November 2014 and will recruit/swab for 8 years (as a&#xD;
      result of an extension given REC approval 22nd March 2016 and an extension given REC approval&#xD;
      2nd September 2019 and HRA approval 23rd August 2019). Recruitment and swabbing took place&#xD;
      during the winters (October to March) of 2014/15, 2015/16, 2016/17, 2017/18, 2018/19 and then&#xD;
      year-round from October 2019 to March 2022 (as per the amendment submitted March 2020). This&#xD;
      extended recruitment allows the year-round surveillance of S. pneumoniae to detect&#xD;
      fluctuation of carriage. In response to the COVID-19 outbreak, it also allows the detection&#xD;
      of circulating microbes of outbreak, epidemic and pandemic potential. The study will end 31st&#xD;
      March 2027 to allow enough time for analysis.&#xD;
&#xD;
      All sampling will take place within the Outpatients Department of University Hospital&#xD;
      Southampton Foundation NHS Trust (or the NIHR Clinical Research Facility if there are no&#xD;
      rooms available in the Outpatients Department) or at Solent NHS Trust sites and sites working&#xD;
      in partnership with the Solent NHS Trust. Academic work will take place within the Faculty of&#xD;
      Medicine, University of Southampton and at collaborating centres such as the Wellcome Trust&#xD;
      Sanger Institute, Cambridge.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Unknown status</overall_status>
  <last_known_status>Recruiting</last_known_status>
  <start_date type="Actual">October 1, 2014</start_date>
  <completion_date type="Anticipated">March 31, 2022</completion_date>
  <primary_completion_date type="Anticipated">March 31, 2022</primary_completion_date>
  <study_type>Observational</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <observational_model>Ecologic or Community</observational_model>
    <time_perspective>Cross-Sectional</time_perspective>
  </study_design_info>
  <primary_outcome>
    <measure>Collection of pneumococci</measure>
    <time_frame>By the end of the study (31/03/2027)</time_frame>
    <description>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</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Understand changes in the molecular epidemiology of pneumococci</measure>
    <time_frame>By the end of the study (31/03/2027)</time_frame>
    <description>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.</description>
  </secondary_outcome>
  <enrollment type="Anticipated">4000</enrollment>
  <condition>S. Pneumoniae</condition>
  <condition>Pneumococcal Conjugate Vaccine</condition>
  <intervention>
    <intervention_type>Biological</intervention_type>
    <intervention_name>Prevenar 7 and Prevenar 13</intervention_name>
    <description>pneumococcal conjugate vaccines</description>
  </intervention>
  <eligibility>
    <study_pop>
      <textblock>
        Children aged 4 years and under.&#xD;
      </textblock>
    </study_pop>
    <sampling_method>Non-Probability Sample</sampling_method>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  All children aged 4 years or under, attending the recruitment sites during the&#xD;
             recruitment period will be invited to participate through their parents or legal&#xD;
             guardian.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  One child per family&#xD;
&#xD;
          -  Children with obstructed nasal passages&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>N/A</minimum_age>
    <maximum_age>4 Years</maximum_age>
    <healthy_volunteers>Accepts Healthy Volunteers</healthy_volunteers>
  </eligibility>
  <overall_contact>
    <last_name>Denise Morris</last_name>
    <phone>02381208895</phone>
    <email>d.e.morris@soaoton.ac.uk</email>
  </overall_contact>
  <overall_contact_backup>
    <last_name>Stuart Clarke</last_name>
    <phone>02381208895</phone>
    <email>S.C.Clarke@soton.ac.uk</email>
  </overall_contact_backup>
  <location>
    <facility>
      <name>University Hospital Southampton Foundation NHS Trust</name>
      <address>
        <city>Southampton</city>
        <state>Hampshire</state>
        <zip>SO16 6YD</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Denise Morris</last_name>
      <phone>02381208895</phone>
      <email>d.e.morris@soton.ac.uk</email>
    </contact>
    <investigator>
      <last_name>Saul Faust</last_name>
      <role>Principal Investigator</role>
    </investigator>
    <investigator>
      <last_name>Stuart Clarke</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location_countries>
    <country>United Kingdom</country>
  </location_countries>
  <verification_date>May 2020</verification_date>
  <study_first_submitted>May 20, 2020</study_first_submitted>
  <study_first_submitted_qc>May 20, 2020</study_first_submitted_qc>
  <study_first_posted type="Actual">May 26, 2020</study_first_posted>
  <last_update_submitted>May 27, 2020</last_update_submitted>
  <last_update_submitted_qc>May 27, 2020</last_update_submitted_qc>
  <last_update_posted type="Actual">May 29, 2020</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Pneumonia</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Heptavalent Pneumococcal Conjugate Vaccine</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
  </patient_data>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT04401488
org study id: RHM CHI0678
nct id: NCT04401488
lead sponsor: 
collaborator: 
is fda regulated drug: Yes
is fda regulated device: No
is us export: No
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.
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.
observational model: Ecologic or Community
time perspective: Cross-Sectional
measure: Collection of pneumococci
time frame: By the end of the study (31/03/2027)
description: 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
measure: Understand changes in the molecular epidemiology of pneumococci
time frame: By the end of the study (31/03/2027)
description: 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.
intervention type: Biological
intervention name: Prevenar 7 and Prevenar 13
description: pneumococcal conjugate vaccines
study pop: 
sampling method: Non-Probability Sample
criteria: 
gender: All
minimum age: N/A
maximum age: 4 Years
healthy volunteers: Accepts Healthy Volunteers
last name: Denise Morris
phone: 02381208895
email: d.e.morris@soaoton.ac.uk
last name: Stuart Clarke
phone: 02381208895
email: S.C.Clarke@soton.ac.uk
facility: 
status: Recruiting
contact: 
investigator: 
investigator: 
country: United Kingdom
responsible party type: Sponsor
mesh term: Pneumonia
mesh term: Heptavalent Pneumococcal Conjugate Vaccine
sharing ipd: No