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Trial registered on ANZCTR


Registration number
ACTRN12620000644965
Ethics application status
Approved
Date submitted
15/05/2020
Date registered
3/06/2020
Date last updated
20/01/2023
Date data sharing statement initially provided
3/06/2020
Type of registration
Prospectively registered

Titles & IDs
Public title
FluBub Study: Early influenza vaccination in infants
Scientific title
Safety and Immunogenicity of Early Quadrivalent Influenza Vaccine (FluBub Study)
Secondary ID [1] 301237 0
Nil known
Universal Trial Number (UTN)
Trial acronym
FluBub
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Influenza 317405 0
Condition category
Condition code
Infection 315503 315503 0 0
Other infectious diseases

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Young children, particularly those younger than six (6) months are at increased risk of severe influenza infection. Influenza vaccination is recommended for all children 6 months of age or older, but not for younger children. This is despite their risk of severe disease. The safety and immune response to previously available trivalent influenza vaccines (TIV; conferring protection against three influenza strains) has already been demonstrated in infants under 6 months of age, yet these reassuring data have not translated into routine use. There are no data on the safety and immune response in infants under 6 months of age to quadrivalent influenza vaccines (QIV; conferring protection against four strains; routinely used in Australia since 2016), nor is anything known about the impact of the now recommended maternal influenza vaccination on vaccine responses in infants under 6 months of age.
We will conduct a phase 2, prospective randomised open-label feasibility study to assess both the safety of early (under 6 months) influenza vaccination in healthy young infants and its ability to generate a protective immune response via antibody production (immunogenicity). This will be compared with infants vaccinated according to the currently recommended schedule. Approximately 160 infants will be randomised to a vaccination strategy which will either have an early start to the schedule or commence according to the currently recommended schedule.
Arm 1: Early vaccination and booster (receipt of QIV at 6 to <12 weeks; booster at least 4 weeks later);
Arm 3: [Control] Standard vaccination (QIV at 6-7 months of age; booster at least 4 weeks later);
Solicited and unsolicited adverse events will be monitored. Antibody responses will be assessed using the standard haemagglutination inhibition and focal reduction assays. The strength of immune responses will be assessed across the different arms, and impact of amount of maternal antibody present will be considered in the analyses. Additional testing using a systems serological approach will be performed on remaining samples to generate new knowledge on the mechanisms determining vaccine efficacy. Surveillance for influenza infection will occur during the influenza season with episodes of acute respiratory infection confirmed through nasopharyngeal samples.
This is a pilot study that will tell us whether a larger, more informative study will be worthwhile.
Intervention code [1] 317537 0
Prevention
Comparator / control treatment
Arm 3 of the study will serve as the control Arm. Infants in Arm 3 of the study will receive standard QIV vaccination following the timing currently recommended on the Australian National Immunisation Program.
Control group
Active

Outcomes
Primary outcome [1] 323747 0
Frequency of solicited local reactions (pain, redness, or swelling at the vaccination site)
or systemic reactions (fever, nausea and/or vomiting, diarrhoea; loss of appetite, irritability, sleepiness, unusual crying).
Timepoint [1] 323747 0
The first week following vaccination, using parental assessment data entered daily into electronic diaries for 7 consecutive days beginning on the day of vaccination.
Primary outcome [2] 323748 0
Severity of solicited local reactions (pain, redness, or swelling at the vaccination site)
or systemic reactions (fever, nausea and/or vomiting, diarrhoea; loss of appetite, irritability, sleepiness, unusual crying).
Timepoint [2] 323748 0
The first week following vaccination, using parental assessment data entered daily into electronic diaries for 7 consecutive days beginning on the day of vaccination.
Primary outcome [3] 323991 0
Proportion of infants in each study arm with potential seroprotection against the four strains included in the vaccine, assessed using haemagglutination inhibition (HI) and micro-neutralization (MN) assays. HI titre above 1:40 and/or MN titre above 1:160 will be considered positive.
Timepoint [3] 323991 0
Assessed from blood collected 4 weeks after the second QIV dose.
Secondary outcome [1] 382781 0
Frequency of unsolicited adverse events, using parental assessment data entered into electronic diaries.
Timepoint [1] 382781 0
Within 28 days of QIV receipt.
Secondary outcome [2] 382782 0
Frequency of unsolicited severe adverse events, using parental assessment data entered into electronic diaries.
Timepoint [2] 382782 0
Within 28 days of QIV receipt.
Secondary outcome [3] 383514 0
Frequency of medically-attended adverse events, using parental assessment data entered into electronic diaries.
Timepoint [3] 383514 0
Within 28 days of QIV receipt.
Secondary outcome [4] 383515 0
Proportion of infants in each study arm with seroconversion, assessed using haemagglutination inhibition (HI) and micro-neutralization (MN) assays. Seroconversion will be defined as a switch from below to above detection threshold for those with no detectable antibodies pre-vaccination, or a 4-fold increase in HI or MN titres in those with detectable antibody prior to vaccination.
Timepoint [4] 383515 0
Four weeks following the second dose of QIV.
Secondary outcome [5] 383516 0
Post-vaccination geometric mean titre increase, measured using haemagglutination inhibition and micro-neutralization assays.
Timepoint [5] 383516 0
Baseline compared with results 4 weeks after the first and the second QIV doses.

Eligibility
Key inclusion criteria
The age of infants was made consistent throughout the protocol at 6 to <12 weeks as the inclusion criteria. This change occurred in Protocol v7.1 dated 10 November 2020.

The mothers' year of birth was removed. to address obstacles to eligibility without compromising the study outcomes. This change occurred in Protocol v4.0 dated 21 April 2020.

Infants will be enrolled in the study only if, in the opinion of the investigator, they and their mothers are considered able and likely to comply with the requirements of the research protocol.

Arm 4, infants born to mothers with confirmed influenza infection was removed from Protocol v11 dated 17 October 2022 due to the low incidence of influenza cases and low recruitment numbers. Removal of this exploratory Arm will not compromise the study endpoints.
Minimum age
6 Weeks
Maximum age
12 Weeks
Sex
Both males and females
Can healthy volunteers participate?
Yes
Key exclusion criteria
1) Infants born <37 weeks or >42 weeks gestation;
2) Infants with congenital malformations, immunodeficiency or receiving immunosuppressive therapy
3) Infants born to mothers with immunodeficiency or receiving immunosuppressive therapy;
4) Infants previously receiving any monoclonal or polyclonal antibody (e.g, IV immunoglobulin);
5) Infants currently enrolled in a clinical trial for a drug or vaccine.
6) Any condition that, in the opinion of the investigator, would interfere with evaluation of the investigational product or interpretation of subject safety or study results;
7) infants whose parents/guardians are unwilling to comply with study requirements and follow-up until at least 8 months of age;
8) Children of employees of the clinical study site, or any other individuals involved with the conduct of the study, or immediate family members of such individuals.

Study design
Purpose of the study
Prevention
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Central randomisation by computers.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Randomisation will remain 1:1 to Arm 1 and 3. This randomisation plan was confirmed with removal of Arms 2 and 4 in Protocol v11 dated 17 October 2022.
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Parallel
Other design features
Laboratory assays will be performed in a blinded fashion; blinding will be subsequently removed to enable statistical analysis and comparison between outcomes.
Phase
Phase 2
Type of endpoint/s
Safety/efficacy
Statistical methods / analysis
The study is descriptive and not intended to test statistical hypotheses nor designed to detect significant differences between vaccine schedules.

Demographics :
Demographic characteristics will be summarised by group using descriptive statistics. Frequency tables will be generated for categorical variables. Mean, median, standard deviation and range will be provided for continuous data.

A number of key safety endpoints will be assessed:
1) Solicited adverse events: The number and percentage with exact 95% confidence intervals (CI) of infants with reported solicited local and systemic adverse event (AE) during the 7 day follow up period after vaccination will be tabulated for each study arm.
2) Unsolicited adverse events: The number and percentage with exact 95%CI of infants with unsolicited AE during the 28 day follow up period after vaccination will be tabulated for each study arm.
3) For fever during the 7 day follow up period after vaccination, the number and percentage of infants with reported fever with exact 95%CI, fever by predetermined increments and any grade 3 fevers will be reported with exact 95%CI

The proportions of infants with reported AE will be presented for varying time points and considered relative to the standard schedule arm using confidence intervals and application of the Chi-squared test.

Immunogenicity endpoints
Arms 3 and 4 will initially be combined to quantify impact of varying vaccination schedules. Logistic regression will be utilized to further explore differences in seroprotection and seroconversion rates across schedules and assess the impact of maternal vaccination/HAI status. Linear regression of log-transformed GMT ratios will be utilised to explore differences across schedules and assess the impact of maternal vaccination/HAI status on this measure of immunogenicity.

1) Seroprotection: The primary immunogenicity endpoint will be the proportion of vaccine recipients with potential seroprotection to the four viral strains measured at least 4 weeks after a second dose of QIV. The proportions of infants who achieve seroprotection will be presented across schedules as percentages with 95% CIs.
2) Seroconversion: a further immunogenicity endpoint will be the proportion of vaccine recipients with seroconversion, measured at least 4 weeks after a second dose of QIV. For each strain the proportions of infants who achieved seroconversion will be presented across schedules as percentages with 95% CIs.
3) Geometric mean titre (GMT) ratios, calculated as ratios of post-vaccination titres to pre-vaccination titres using a geometric mean scale, will be tabulated with 95% CIs (derived using a natural logarithmic transformation).

Immunogenicity endpoints:
Immunogenicity endpoints will be primarily assessed 4 weeks after the second dose of QIV (approximately 4 months of age in Arm 1; approximately 8 months of age in arms 2,3 and 4). Given the difference in age and potential impact on immunogenicity, further assessments will occur using the samples collected at approximately 8 months of age (4th bleed in Arm 1; 3rd bleed in Arm 2,3 and 4; Figure 1).

Arm 3 and 4 will initially be combined to assessment of impact of varying vaccination schedules. To further assess the impact of clinically relevant predictors on vaccine response (e.g. maternal vaccination status; maternal antibody levels), linear regression models with change in log antibody level as the dependent variable will be constructed. These will be constructed incorporating data from all arms and separately by individual vaccine schedules.

Recruitment
Recruitment status
Recruiting
Date of first participant enrolment
Anticipated
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
WA
Recruitment hospital [1] 16636 0
Perth Children's Hospital - Nedlands
Recruitment hospital [2] 23860 0
King Edward Memorial Hospital - Subiaco
Recruitment hospital [3] 23861 0
Fiona Stanley Hospital - Murdoch
Recruitment hospital [4] 23862 0
St John of God Hospital, Subiaco - Subiaco
Recruitment hospital [5] 23863 0
St John of God Hospital, Mt Lawtley - Mt Lawley
Recruitment hospital [6] 23864 0
St John of God Hospital, Murdoch - Murdoch
Recruitment hospital [7] 23865 0
Womens and Childrens Hospital - North Adelaide
Recruitment hospital [8] 23866 0
Monash Children’s Hospital - Clayton
Recruitment postcode(s) [1] 39323 0
3168 - Clayton
Recruitment postcode(s) [2] 39322 0
5006 - North Adelaide
Recruitment postcode(s) [3] 39319 0
6008 - Subiaco
Recruitment postcode(s) [4] 30231 0
6009 - Nedlands
Recruitment postcode(s) [5] 39321 0
6050 - Mt Lawley
Recruitment postcode(s) [6] 39320 0
6150 - Murdoch

Funding & Sponsors
Funding source category [1] 305686 0
Charities/Societies/Foundations
Name [1] 305686 0
Telethon Kids Institute
Country [1] 305686 0
Australia
Primary sponsor type
Charities/Societies/Foundations
Name
Telethon Kids Institute
Address
Telethon Kids Institute
North Entrance, Perth Children's Hospital
15 Hospital Avenue
Nedlands W.A. 6000
Country
Australia
Secondary sponsor category [1] 306097 0
None
Name [1] 306097 0
Address [1] 306097 0
Country [1] 306097 0
Other collaborator category [1] 282527 0
Government body
Name [1] 282527 0
PathWest Laboratory Medicine QEII
Address [1] 282527 0
PathWest Laboratory Medicine
QEII Medical Centre
Hospital Avenue
Nedlands WA 6009
Country [1] 282527 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 305966 0
Child and Adolescent Health Service Human Research Ethics Committee (EC00268)
Ethics committee address [1] 305966 0
CAHS
Perth Children's Hospital
15 Hospital Avenue
Nedlands W.A. 6000
Ethics committee country [1] 305966 0
Australia
Date submitted for ethics approval [1] 305966 0
20/01/2020
Approval date [1] 305966 0
19/03/2020
Ethics approval number [1] 305966 0
RGS0000003848

Summary
Brief summary
Young children, particularly those younger than six (6) months are at increased risk of severe influenza infection. Influenza vaccination is recommended for all children 6 months of age or older, but not for younger children. This is despite their risk of severe disease. The safety and immune response to previously available trivalent influenza vaccines (TIV; conferring protection against three influenza strains) has already been demonstrated in infants under 6 months of age, yet these reassuring data have not translated into routine use. There are no data on the safety and immune response in infants under 6 months of age to quadrivalent influenza vaccines (QIV; conferring protection against four strains; routinely used in Australia since 2016), nor is anything known about the impact of the now recommended maternal influenza vaccination on vaccine responses in infants under 6 months of age.

We will conduct a phase 2, prospective randomised open-label feasibility study to assess both the safety of early (under 6 months) influenza vaccination in healthy young infants and its ability to generate a protective immune response via antibody production (immunogenicity). This will be compared with infants vaccinated according to the currently recommended schedule. Approximately 160 infants will be randomised to a vaccination strategy which will either have an early start to the schedule or commence according to the currently recommended schedule.

Arm 1: Early vaccination and booster (receipt of QIV at 6 to <12 weeks; booster at least 4 weeks later);
Arm 3: [Control] Standard vaccination (QIV at 6-7 months of age; booster at least 4 weeks later);

Solicited and unsolicited adverse events will be monitored. Antibody responses will be assessed using the standard haemagglutination inhibition and focal reduction assays. The strength of immune responses will be assessed across the different arms, and impact of amount of maternal antibody present will be considered in the analyses. Additional testing using a systems serological approach will be performed on remaining samples to generate new knowledge on the mechanisms determining vaccine efficacy.

Surveillance for influenza infection will occur during the influenza season with episodes of acute respiratory infection confirmed through nasopharyngeal samples.

This is a pilot study that will tell us whether a larger, more informative study will be worthwhile.

Trial website
https://infectiousdiseases.telethonkids.org.au/our-research/vaccine-trials-group/current-studies/flubub/
Trial related presentations / publications
Public notes
Influenza is the most common vaccine- preventable disease and young babies are at high risk of a severe infection. Influenza vaccinations are currently licensed for babies six months or older, leaving young babies unprotected when they are most vulnerable.
The FluBub Study aims to learn more about
the safety and effectiveness of giving the influenza vaccine to younger babies and providing them with much-needed protection earlier in life.
Researchers will evaluate the baby’s immune response to the seasonal flu vaccine when it is given at around two months of age in comparison to six months as per the current National Immunisation Program.
This information may help find a better way to protect newborn babies from influenza and guide policy changes to the recommended vaccination program.


Contacts
Principal investigator
Name 102242 0
Prof Christopher Blyth
Address 102242 0
Telethon Kids Institute
North Entrance, Perth Children's Hospital
15 Hospital Ave
Nedlands W.A. 6009
Country 102242 0
Australia
Phone 102242 0
+61 8 6456 5614
Fax 102242 0
Email 102242 0
christopher.blyth@uwa.edu.au
Contact person for public queries
Name 102243 0
Christopher Blyth
Address 102243 0
Telethon Kids Institute
North Entrance, Perth Children's Hospital
15 Hospital Ave
Nedlands W.A. 6009
Country 102243 0
Australia
Phone 102243 0
+61 8 6456 5614
Fax 102243 0
Email 102243 0
christopher.blyth@uwa.edu.au
Contact person for scientific queries
Name 102244 0
Christopher Blyth
Address 102244 0
Telethon Kids Institute
North Entrance, Perth Children's Hospital
15 Hospital Ave
Nedlands W.A. 6009
Country 102244 0
Australia
Phone 102244 0
+61 8 6456 5614
Fax 102244 0
Email 102244 0
christopher.blyth@uwa.edu.au

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment


What supporting documents are/will be available?

No Supporting Document Provided


Results publications and other study-related documents

Documents added manually
No documents have been uploaded by study researchers.

Documents added automatically
No additional documents have been identified.