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Trial registered on ANZCTR


Registration number
ACTRN12621000110886
Ethics application status
Approved
Date submitted
18/10/2020
Date registered
4/02/2021
Date last updated
4/02/2021
Date data sharing statement initially provided
4/02/2021
Date results information initially provided
4/02/2021
Type of registration
Retrospectively registered

Titles & IDs
Public title
Effect of recent prior infection on influenza vaccine immunogenicty
Scientific title
Immune responses induced by Trivalent Inactivated Influenza Vaccine, comparing antibody titres and B cell responses of participants who had or lacked recent prior influenza A(H3N2) virus infection.
Secondary ID [1] 302549 0
NIL
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Influenza 319420 0
Inflammatory and immune system 319758 0
Condition category
Condition code
Infection 317394 317394 0 0
Studies of infection and infectious agents
Inflammatory and Immune System 317693 317693 0 0
Normal development and function of the immune system

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
A single 0.5 ml dose of commercially available trivalent inactivated seasonal influenza vaccine, administered via intramuscular injection by health care staff of the Ha Nam Preventive Medicine Centre, a division of the Ministry of Health, Viet Nam. The vaccine contains 15 micrograms of hemagglutinin of each of three component strains belonging to A(H1N1), A(H3N2) and B (sub)types. Vaccine will be administered to adults participants with and without prior A(H3N2) virus infection since 2007, detected through active monitoring of the Ha Nam Household Cohort.
Intervention code [1] 318836 0
Prevention
Intervention code [2] 319078 0
Treatment: Drugs
Comparator / control treatment
All participants received vaccine. Participants who had infection recently prior to vaccination were compared with particpants who lakced recent infection.
Control group
Active

Outcomes
Primary outcome [1] 325428 0
Geometric mean ratio of serum hemagglutination inhibition (HI) antibody titres against vaccine virus. The Geometric mean ratio is calculated as the mean of the differences in log 2 titres in post- minus pre-vaccination sera.
Timepoint [1] 325428 0
Day 14 post-vaccination
Primary outcome [2] 325735 0
Geometric mean titre of hemagglutination inhibition (HI) antibodies against vaccine virus in post-vaccination sera
Timepoint [2] 325735 0
Day 14 post-vaccination
Primary outcome [3] 325736 0
Proportion who seroconvert, defined as a 4-fold or greater rise in titre of serum HI antibodies against vaccine virus.
Timepoint [3] 325736 0
Day 14 post vaccination
Secondary outcome [1] 387917 0
Strain coverage of antibodies induced by vaccination, measured by titrating sera against up to 40 A(H3N2) strains in HI assay. Generalized additive models (GAMs) and lowess models are then used to fit and compare Log2 titre landscapes acoss virus strains arranged temporally or by antigenic distance. Similarly, differences in log2 titres at post- minus pre-vaccination time-points are fitted against temporally or antigenically arranged strains to determine how recent prior A(H3N2) infection affects the production of antibodies that cross-recognize strains circulating before, with and after the vaccine strain.
Timepoint [1] 387917 0
Pre-vaccination, and days 7, 14, 21 and 280 post-vaccination
Secondary outcome [2] 388931 0
Influenza hemagglutinin reactive B cell frequency and phenotype will be determined by flow cytometry and ELISPOT. The magnitude of the response to vaccination will be determined by subtraction of frequencies in pre-vaccination samples.
Timepoint [2] 388931 0
Days 7, 14, and 21 post-vaccination.

Eligibility
Key inclusion criteria
Aged > 18 years; Continual participant in the Ha Nam cohort since 2007 with complete sampling and documentation of A(H3N2) influenza virus infection history
Minimum age
18 Years
Maximum age
No limit
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
History of allergic reactions to vaccines

Study design
Purpose of the study
Prevention
Allocation to intervention
Non-randomised trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
All participants were vaccinated
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Other
Other design features
The study is designed to investigate the effect of A(H3N2) influenza virus infection history on vaccine immunogenicity. Participants who had and lacked A(H3N2) infection since 2007 were purposefully selected to study vaccine immunogenicity in 2016. Participants were selected to obtain similar age and sex distributions in each group.
Phase
Not Applicable
Type of endpoint(s)
Statistical methods / analysis
Geometric mean titres and titre rises are adjusted for baseline titres and compared using linear regression. Generalized addition and lowess models are used to fit titres and titres rises across temporally arranged virus strains to compare the strain coverage of vaccine induced antibodies.

Recruitment
Recruitment status
Completed
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 outside Australia
Country [1] 23063 0
Viet Nam
State/province [1] 23063 0
Ha Nam

Funding & Sponsors
Funding source category [1] 306985 0
Government body
Name [1] 306985 0
National Health and Medical Research Council
Address [1] 306985 0
16 Marcus Clarke St,
Canberra ACT 2601
Country [1] 306985 0
Australia
Primary sponsor type
University
Name
The University of Melbourne
Address
Grattan Street, Parkville, Victoria, 3010
Country
Australia
Secondary sponsor category [1] 307549 0
None
Name [1] 307549 0
Address [1] 307549 0
Country [1] 307549 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 307116 0
University of Melbourne Human Research Etrrhics Committee
Ethics committee address [1] 307116 0
Office of Research Ethics and Integrity
Research Innovation and Commercialization
The University of Melbourne
Grattan Street, Parkville, Victoria, 3010
Ethics committee country [1] 307116 0
Australia
Date submitted for ethics approval [1] 307116 0
Approval date [1] 307116 0
20/07/2016
Ethics approval number [1] 307116 0
1646470.1
Ethics committee name [2] 307117 0
Oxford Tropical Research Ethics Committe
Ethics committee address [2] 307117 0
University of Oxford
Research Services, University Offices
Wellington Square, Oxford OX1 2JD
Ethics committee country [2] 307117 0
United Kingdom
Date submitted for ethics approval [2] 307117 0
Approval date [2] 307117 0
19/07/2016
Ethics approval number [2] 307117 0
30-16
Ethics committee name [3] 307118 0
National Institute of Hygiene and Epidemiology Viet Nam Institutional Review Board
Ethics committee address [3] 307118 0
National Institute of Hygiene and Epidemiology, Viet Nam
1 Yersin St
Hai Ba Trung
Ha Noi
(post codes are not applicable in this location)
Ethics committee country [3] 307118 0
Viet Nam
Date submitted for ethics approval [3] 307118 0
Approval date [3] 307118 0
04/05/2016
Ethics approval number [3] 307118 0
IRB-VN01057-08/2016

Summary
Brief summary
A) Aims and Objectives
The primary aim is to determine the impact of prior influenza infection and cross-reactive memory B cells on neutralizing antibody titers to the prevailing infecting or vaccine strain. We hypothesize that responses dominated by cross-reactive memory B cells are inferior to responses with less memory cell involvement.
B) Key Question(s)
1) Does influenza infection history affect prevailing strain titer?
2) Are prevailing strain titers related to the magnitude of memory-type humoral responses, defined as early, cross-reactive IgG responses?
3) What proportion of acutely responding B cells (plasmablasts) are memory-derived, what proportion adapt to the prevailing strain, and how do these relate to titers to the prevailing strain?
C) Research Design
This prospective study will investigate immune responses to influenza vaccination and infection in an existing cohort. The Ha Nam cohort includes 270 households, and is unique in that participants have been actively monitored for influenza illness or infection defined by seroconversion, since 2007, a period including eleven influenza seasons. This provides a rare opportunity to understand how prior influenza infections and immune memory influence antibody responses to new strains, and the protection that is generated. Responses to influenza vaccine will be compared between participants with divergent influenza infection histories. Responses to vaccination and natural infection will also be compared. Blood samples will be collected before and after vaccination or infection to determine peak and sustained levels of protective antibodies to the prevailing strain, to compare the evolution of antibody responses to prevailing and past strains in the two groups, and to characterize antibody producing B cells. We have developed key resources to facilitate these analyses including a computational tool (antibody landscapes) to analyse titers in the context of antigenic difference between strains; and high throughput BCR sequencing and analysis that can indicate whether acutely responding cells are naïve- or memory-B cell derived.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 106090 0
Dr Annette Fox
Address 106090 0
Peter Doherty Institute
792 Elizabeth St
Melbourne
Victoria, 3000
Country 106090 0
Australia
Phone 106090 0
+61 3 93429313
Fax 106090 0
Email 106090 0
annette.fox@unimelb.edu.au
Contact person for public queries
Name 106091 0
Dr Annette Fox
Address 106091 0
Peter Doherty Institute
792 Elizabeth St
Melbourne
Victoria, 3000
Country 106091 0
Australia
Phone 106091 0
+61 3 93429313
Fax 106091 0
Email 106091 0
annette.fox@unimelb.edu.au
Contact person for scientific queries
Name 106092 0
Dr Annette Fox
Address 106092 0
Peter Doherty Institute
792 Elizabeth St
Melbourne
Victoria, 3000
Country 106092 0
Australia
Phone 106092 0
+61 3 93429313
Fax 106092 0
Email 106092 0
annette.fox@unimelb.edu.au

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
Yes
What data in particular will be shared?
Vaccine titres
When will data be available (start and end dates)?
Data will be available for 5 years after publication.
Available to whom?
Researchers
Available for what types of analyses?
Research
How or where can data be obtained?
on request by emailing the principle investigator at annette.fox@unimelb.edu.au
What supporting documents are/will be available?
Study protocol
Informed consent form
Ethical approval
How or where can supporting documents be obtained?
Type [1] 9468 0
Study protocol
Citation [1] 9468 0
Link [1] 9468 0
Email [1] 9468 0
Other [1] 9468 0
Attached
Type [2] 9469 0
Informed consent form
Citation [2] 9469 0
Link [2] 9469 0
Email [2] 9469 0
Other [2] 9469 0
Attached
Type [3] 9470 0
Ethical approval
Citation [3] 9470 0
Link [3] 9470 0
Email [3] 9470 0
Other [3] 9470 0
Attached
Summary results
Have study results been published in a peer-reviewed journal?
No
Other publications
Have study results been made publicly available in another format?
No
Results – basic reporting
Results – plain English summary