PneumoniaPhase 4LAIV/EHPCNCT03502291
The Effect of Live Attenuated Inactivated Influenza Vaccine on Experimental Human Pneumococcal Carriage Study
A Phase 4 study testing Study one: LAIV + Inoculation and Study two: Inoculation + LAIV in people with Pneumonia and Influenza, Human, run by Liverpool University Hospitals NHS Foundation Trust at 1 site in United Kingdom.
Trial summary
The investigators are interested in examining the effect of the Live Attenuated Influenza (flu) Vaccine (LAIV) upon nasal carriage of bacteria called Streptococcus pneumoniae (also known as pneumococcus). The nasal spray is a live attenuated vaccine which means that it has weakened virus that does not cause disease. Read more about this study
- Who is it for?
- Ages 18 to 50 yearsHealthy volunteers can take part
- Conditions the study is for
- Pneumonia, Influenza, Human
- What is being tested?
- Study one: LAIV + Inoculation and Study two: Inoculation + LAIV
- Type of treatment
- Vaccines, Injection or infusion
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 324 participants
- Where
- 1 siteUnited Kingdom
- Study dates
- Aug 2015to May 2017
- Phase
- Phase 4
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 50 years
- All sexes
- Healthy volunteers accepted
- Adult
Who may be able to join
- have capacity to give informed consent
- aged 18-50 yrs - ages chosen to minimise the risk of pneumococcal infection
- 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.
Who cannot join
- currently involved in another study unless observational or in follow-up phase (non-interventional)
- received any influenza vaccine in the last 2 years
Trial locations and contacts
1 site in 1 country.
United Kingdom1 site
Royal Liverpool Hospital
Liverpool, Merseyside, L7 8XP
About this study
The investigators are interested in examining the effect of the Live Attenuated Influenza (flu) Vaccine (LAIV) upon nasal carriage of bacteria called Streptococcus pneumoniae (also known as pneumococcus). The nasal spray is a live attenuated vaccine which means that it has weakened virus that does not cause disease. This vaccine is licenced in the United Kingdom for children and adolescents from 2 to 18 years of age.
Pneumococcus can commonly be found harmlessly inhabiting the nose where it does not cause any problem (pneumococcal colonisation). About 10% of adults carry pneumococcus at any one time, and almost all adults experience an episode of carriage at least once per year. Carriage acts as a natural vaccine, boosting immunity against pneumococcal infection in adults and children.
Read more
During influenza there is an increase in the burden of pneumococcal pneumonia. We have studied the effects of pneumococcus for many years and have developed a programme in which we can nasally inoculate healthy participants with a dose of pneumococcus and achieve a reproducible carriage rate. The investigators would now like to use this model to investigate the effects of the nasal influenza vaccine upon pneumococcal carriage and to better understand how influenza infections lead to increased susceptibility to pneumonia.
Pneumococcal disease in young adults is rare - less than 10 cases per 100,000 people per year. When pneumococcus does cause problems, usually in young children or elderly people, it can be very serious as it is responsible for diseases such as pneumonia, sepsis and meningitis, which kill millions of children around the world each year.
Read the detailed description
Secondary bacterial infections such as pneumococcal pneumonia are a leading cause of death during influenza endemics. Individuals recently infected with influenza become more susceptible to pneumonia, an effect associated with increased density of pneumococcal carriage in the nose and uncontrolled inflammatory immunological responses. The interaction of influenza virus and pneumococcus has been known and well documented. Recent works have shown that the Live Attenuated Influenza Vaccine (LAIV) enhances pneumococcal carriage in murine models. 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 LAIV-vaccinated individuals 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. There is an urgent need for a clinical trial that will determine the effect of LAIV on pneumococcal carriage dynamics.
The investigators have developed a safe and reproducible experimental human pneumococcal carriage (EHPC) model. The investigators will use EHPC to define the effect of antecedent and concurrent LAIV on pneumococcal carriage acquisition, density and duration. The investigators will perform two double - blinded Randomised Controlled Trials (RCT) to compare LAIV with Quadrivalent Inactivated Influenza Vaccine (QIV). The investigators will compare clinical symptoms, pneumococcal carriage density and duration associated with both vaccines administered antecedent to or concurrently with EHPC inoculation. Changes in the nasopharyngeal microbiome, inflammatory responses in the nasal mucosal and lung cellular immunity associated with influenza virus and pneumococcus interaction will be investigated. This project may provide some reassurance regarding the impact of mass immunization with LAIV on carriage or, if carriage is increased, will provide knowledge of how a natural carriage episode might develop into pneumonia in susceptible subjects during pandemic influenza.
- Conditions
- Pneumonia, Influenza, Human
- Being tested
- Study one: LAIV + Inoculation, Study one: Placebo + Inoculation, Study two: Inoculation + LAIV, Study two: Inoculation + placebo
- Keywords
- Human challenge models, Immunity, Streptococcus pneumoniae, Live Attenuated Influenza Vaccine
- Medical subject headings
- Pneumonia, Influenza, Human
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Study one: LAIV + InoculationBiological
Also called FLUMIST or FLUENZ AstraZeneca
Pneumococci bacteria nasal inoculation following vaccination with LAIV and intramuscular placebo
Study one: Placebo + InoculationBiological
Also called Fluarix Tetra GlaxoSmithKline
Pneumococci bacteria nasal inoculation following vaccination QIV with nasal placebo spray
Study two: Inoculation + LAIVBiological
Also called FLUMIST or FLUENZ AstraZeneca
Pneumococci bacteria nasal inoculation prior to vaccination with LAIV and intramuscular placebo
Study two: Inoculation + placeboBiological
Also called Fluarix Tetra GlaxoSmithKline
Pneumococci bacteria nasal inoculation prior to vaccination QIV with nasal placebo
| Study group | Role | What they receive |
|---|---|---|
| Study One: LAIV + Inoculation | Active comparator | LAIV Nasal Spray: Inoculation (FLUMIST or FLUENZ) plus intramuscular placebo then inoculation with pneumococci bacteria Receives: Biological: Study one: LAIV + Inoculation |
| Study One: Placebo + inoculation | Placebo comparator | Quadrivalent Inactivated Influenza Vaccine Intramuscular (Fluarix Tetra) plus nasal placebo then inoculation with pneumococci bacterial Receives: Biological: Study one: Placebo + Inoculation |
| Study Two: Inoculation + LAIV | Active comparator | Inoculation with pneumococci bacteria then Live attenuated Influenza Vaccine Nasal Spray (FLUMIST or FLUENZ) plus intramuscular placebo Receives: Biological: Study two: Inoculation + LAIV |
| Study Two: Inoculation + placebo | Placebo comparator | Inoculation with pneumococci bacteria then Quadrivalent Inactivated Influenza Vaccine Intramuscular (Fluarix Tetra) plus nasal placebo Receives: Biological: Study two: Inoculation + placebo |
What is being measured
The primary outcome is the main question the study is designed to answer.
Detection of pneumococcal bacteria in the nasal wash sample
Primary outcome: detection of pneumococcal bacteria in the nasal wash sample at any time point after inoculation by classical microbiology. 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
Measured: within 6 weeks of inoculation per patient
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted18 Apr 2018
- Study startAug 2015
- Primary completionMay 2017
- Study completionMay 2017
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (1)Papers the sponsor has linked to this study.
- Other trials for PneumoniaStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 4
- Primary purpose
- Health services research
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Model description
- DBRCT performed as two studies over two flu seasons. 2 arms to each study.
- Masking
- Double blind
- Who is masked
- Participant, Investigator
- Enrolment
- 324 participants (actual)
Sponsor and investigators
- Lead sponsor
- Liverpool University Hospitals NHS Foundation Trust
- Sponsor type
- Other government
- Collaborators
- Sponsor GmbH, Liverpool School of Tropical Medicine
- Responsible party
- Sponsor
- Investigators
- Jamie Rylance, Principal investigator, Liverpool School of Tropical Medicine
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT03502291
- Sponsor's protocol ID
- 4896
- Acronym
- LAIV/EHPC
- Status last verified
- May 2016
- First submitted
- 18 Oct 2016
- Last updated
- 18 Apr 2018
- Results posted
- No
- Data monitoring committee
- Yes
- Individual data sharing
- No
Publications
Mitsi E, Reine J, Urban BC, Solorzano C, Nikolaou E, Hyder-Wright AD, Pojar S, Howard A, Hitchins L, Glynn S, Farrar MC, Liatsikos K, Collins AM, Walker NF, Hill HC, German EL, Cheliotis KS, Byrne RL, Williams CT, Cubas-Atienzar AI, Fletcher TE, Adams ER, Draper SJ, Pulido D, Beavon R, Theilacker C, Begier E, Jodar L, Gessner BD, Ferreira DM. Streptococcus pneumoniae colonization associates with impaired adaptive immune responses against SARS-CoV-2. J Clin Invest. 2022 Apr 1;132(7):e157124. doi: 10.1172/JCI157124.
PubMed 35139037
Study at a glance
From the registry record, last updated by the sponsor on 18 Apr 2018. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- The Effect of Live Attenuated Inactivated Influenza Vaccine on Experimental Human Pneumococcal Carriage Study
- ClinicalTrials.gov ID
- NCT03502291
- Acronym / sponsor ID
- LAIV/EHPC / 4896
- Conditions
- Pneumonia, Influenza, Human
- Keywords
- Human challenge models, Immunity, Streptococcus pneumoniae, Live Attenuated Influenza Vaccine
- Phase
- Phase 4
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 324 participants (actual)
- Lead sponsor
- Liverpool University Hospitals NHS Foundation TrustOther government
- Collaborators
- Sponsor GmbH, Liverpool School of Tropical Medicine
- Study start
- Aug 2015
- Primary completion
- May 2017 (actual)
- Study completion
- May 2017 (actual)
- First posted
- 18 Apr 2018 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
The investigators are interested in examining the effect of the Live Attenuated Influenza (flu) Vaccine (LAIV) upon nasal carriage of bacteria called Streptococcus pneumoniae (also known as pneumococcus). The nasal spray is a live attenuated vaccine which means that it has weakened virus that does not cause disease. This vaccine is licenced in the United Kingdom for children and adolescents from 2 to 18 years of age.
Pneumococcus can commonly be found harmlessly inhabiting the nose where it does not cause any problem (pneumococcal colonisation). About 10% of adults carry pneumococcus at any one time, and almost all adults experience an episode of carriage at least once per year. Carriage acts as a natural vaccine, boosting immunity against pneumococcal infection in adults and children.
During influenza there is an increase in the burden of pneumococcal pneumonia. We have studied the effects of pneumococcus for many years and have developed a programme in which we can nasally inoculate healthy participants with a dose of pneumococcus and achieve a reproducible carriage rate. The investigators would now like to use this model to investigate the effects of the nasal influenza vaccine upon pneumococcal carriage and to better understand how influenza infections lead to increased susceptibility to pneumonia.
Pneumococcal disease in young adults is rare - less than 10 cases per 100,000 people per year. When pneumococcus does cause problems, usually in young children or elderly people, it can be very serious as it is responsible for diseases such as pneumonia, sepsis and meningitis, which kill millions of children around the world each year.
Detailed description
Secondary bacterial infections such as pneumococcal pneumonia are a leading cause of death during influenza endemics. Individuals recently infected with influenza become more susceptible to pneumonia, an effect associated with increased density of pneumococcal carriage in the nose and uncontrolled inflammatory immunological responses. The interaction of influenza virus and pneumococcus has been known and well documented. Recent works have shown that the Live Attenuated Influenza Vaccine (LAIV) enhances pneumococcal carriage in murine models. 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 LAIV-vaccinated individuals 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. There is an urgent need for a clinical trial that will determine the effect of LAIV on pneumococcal carriage dynamics.
The investigators have developed a safe and reproducible experimental human pneumococcal carriage (EHPC) model. The investigators will use EHPC to define the effect of antecedent and concurrent LAIV on pneumococcal carriage acquisition, density and duration. The investigators will perform two double - blinded Randomised Controlled Trials (RCT) to compare LAIV with Quadrivalent Inactivated Influenza Vaccine (QIV). The investigators will compare clinical symptoms, pneumococcal carriage density and duration associated with both vaccines administered antecedent to or concurrently with EHPC inoculation. Changes in the nasopharyngeal microbiome, inflammatory responses in the nasal mucosal and lung cellular immunity associated with influenza virus and pneumococcus interaction will be investigated. This project may provide some reassurance regarding the impact of mass immunization with LAIV on carriage or, if carriage is increased, will provide knowledge of how a natural carriage episode might develop into pneumonia in susceptible subjects during pandemic influenza.
Study design
- Primary purpose
- Health services research
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Double blind (participant, investigator)
- Number of arms
- 4
- Model description
- DBRCT performed as two studies over two flu seasons. 2 arms to each study.
| Arm | Type | Receives |
|---|---|---|
| Study One: LAIV + Inoculation | Active comparator | Biological: Study one: LAIV + InoculationLAIV Nasal Spray: Inoculation (FLUMIST or FLUENZ) plus intramuscular placebo then inoculation with pneumococci bacteria |
| Study One: Placebo + inoculation | Placebo comparator | Biological: Study one: Placebo + InoculationQuadrivalent Inactivated Influenza Vaccine Intramuscular (Fluarix Tetra) plus nasal placebo then inoculation with pneumococci bacterial |
| Study Two: Inoculation + LAIV | Active comparator | Biological: Study two: Inoculation + LAIVInoculation with pneumococci bacteria then Live attenuated Influenza Vaccine Nasal Spray (FLUMIST or FLUENZ) plus intramuscular placebo |
| Study Two: Inoculation + placebo | Placebo comparator | Biological: Study two: Inoculation + placeboInoculation with pneumococci bacteria then Quadrivalent Inactivated Influenza Vaccine Intramuscular (Fluarix Tetra) plus nasal placebo |
Who may qualify
- Ages
- 18 to 50 years
- Sex
- All
- Healthy volunteers
- Accepted
- Age groups
- Adult
Key inclusion criteria (3 listed)
- have capacity to give informed consent
- aged 18-50 yrs - ages chosen to minimise the risk of pneumococcal infection
- 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.
Key exclusion criteria (2 listed)
- currently involved in another study unless observational or in follow-up phase (non-interventional)
- received any influenza vaccine in the last 2 years
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Study one: LAIV + InoculationAlso: FLUMIST or FLUENZ AstraZenecaPneumococci bacteria nasal inoculation following vaccination with LAIV and intramuscular placebo | Biological | Study One: LAIV + Inoculation |
| Study one: Placebo + InoculationAlso: Fluarix Tetra GlaxoSmithKlinePneumococci bacteria nasal inoculation following vaccination QIV with nasal placebo spray | Biological | Study One: Placebo + inoculation |
| Study two: Inoculation + LAIVAlso: FLUMIST or FLUENZ AstraZenecaPneumococci bacteria nasal inoculation prior to vaccination with LAIV and intramuscular placebo | Biological | Study Two: Inoculation + LAIV |
| Study two: Inoculation + placeboAlso: Fluarix Tetra GlaxoSmithKlinePneumococci bacteria nasal inoculation prior to vaccination QIV with nasal placebo | Biological | Study Two: Inoculation + placebo |
Primary outcome
Detection of pneumococcal bacteria in the nasal wash sample
Time frame: within 6 weeks of inoculation per patient
Primary outcome: detection of pneumococcal bacteria in the nasal wash sample at any time point after inoculation by classical microbiology. 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
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 18 Apr 2018.
- Derived from this study: PubMed 35139037Mitsi E, Reine J, Urban BC, Solorzano C, Nikolaou E, Hyder-Wright AD, Pojar S, Howard A, Hitchins L, Glynn S, Farrar MC, Liatsikos K, Collins AM, Walker NF, Hill HC, German EL, Cheliotis KS, Byrne RL, Williams CT, Cubas-Atienzar AI, Fletcher TE, Adams ER, Draper SJ, Pulido D, Beavon R, Theilacker C, Begier E, Jodar L, Gessner BD, Ferreira DM. Streptococcus pneumoniae colonization associates with impaired adaptive immune responses against SARS-CoV-2. J Clin Invest. 2022 Apr 1;132(7):e157124. doi: 10.1172/JCI157124.
- Individual participant dataSharing planned: No
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Jamie Rylance principal investigator
Liverpool School of Tropical Medicine
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 4 study testing Study one: LAIV + Inoculation and Study two: Inoculation + LAIV in people with Pneumonia and Influenza, Human, run by Liverpool University Hospitals NHS Foundation Trust at 1 site in United Kingdom.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 3 inclusion and 2 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 18 Apr 2018. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in United Kingdom. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 4 studies take place after a treatment is approved, to learn more about its long-term benefits and risks in everyday use.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Detection of pneumococcal bacteria in the nasal wash sample (time frame: within 6 weeks of inoculation per patient). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT03502291, which also lists 1 linked publication.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 18 Apr 2018.