ANZCTR - Registration

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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

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]

NIL

Universal Trial Number (UTN)

Trial acronym

Linked study record

Health condition

Health condition(s) or problem(s) studied:

Influenza

Inflammatory and immune system

Condition category

Condition code

Infection

Studies of infection and infectious agents

Inflammatory and Immune System

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]

Prevention

Intervention code [2]

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]

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]

Day 14 post-vaccination

Primary outcome [2]

Geometric mean titre of hemagglutination inhibition (HI) antibodies against vaccine virus in post-vaccination sera

Timepoint [2]

Day 14 post-vaccination

Primary outcome [3]

Proportion who seroconvert, defined as a 4-fold or greater rise in titre of serum HI antibodies against vaccine virus.

Timepoint [3]

Day 14 post vaccination

Secondary outcome [1]

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]

Pre-vaccination, and days 7, 14, 21 and 280 post-vaccination

Secondary outcome [2]

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]

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

Sex

Both males and females

Can healthy volunteers participate?

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

1/11/2016

Date of last participant enrolment

Anticipated

Actual

3/11/2016

Date of last data collection

Anticipated

Actual

19/10/2017

Sample size

Target

100

Accrual to date

Final

100

Recruitment outside Australia

Country [1]

Viet Nam

State/province [1]

Ha Nam

Funding & Sponsors

Funding source category [1]

Government body

Name [1]

National Health and Medical Research Council

Address [1]

16 Marcus Clarke St,
Canberra ACT 2601

Country [1]

Australia

Primary sponsor type

University

Name

The University of Melbourne

Address

Grattan Street, Parkville, Victoria, 3010

Country

Australia

Secondary sponsor category [1]

None

Name [1]

Address [1]

Country [1]

Ethics approval

Ethics application status

Approved

Ethics committee name [1]

University of Melbourne Human Research Etrrhics Committee

Ethics committee address [1]

Office of  Research Ethics and  Integrity
Research Innovation and Commercialization
The University of Melbourne
Grattan Street, Parkville, Victoria, 3010

Ethics committee country [1]

Australia

Date submitted for ethics approval [1]

Approval date [1]

20/07/2016

Ethics approval number [1]

1646470.1

Ethics committee name [2]

Oxford Tropical Research Ethics Committe

Ethics committee address [2]

University of Oxford
Research Services, University Offices
Wellington Square, Oxford OX1 2JD

Ethics committee country [2]

United Kingdom

Date submitted for ethics approval [2]

Approval date [2]

19/07/2016

Ethics approval number [2]

30-16

Ethics committee name [3]

National Institute of Hygiene and Epidemiology Viet Nam Institutional Review Board

Ethics committee address [3]

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]

Viet Nam

Date submitted for ethics approval [3]

Approval date [3]

04/05/2016

Ethics approval number [3]

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

Dr Annette Fox

Address

Peter Doherty Institute
792 Elizabeth St
Melbourne
Victoria, 3000

Country

Australia

Phone

+61 3 93429313

Fax

annette.fox@unimelb.edu.au

Contact person for public queries

Name

Annette Fox

Address

Peter Doherty Institute
792 Elizabeth St
Melbourne
Victoria, 3000

Country

Australia

Phone

+61 3 93429313

Fax

annette.fox@unimelb.edu.au

Contact person for scientific queries

Name

Annette Fox

Address

Peter Doherty Institute
792 Elizabeth St
Melbourne
Victoria, 3000

Country

Australia

Phone

+61 3 93429313

Fax

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?

Doc. No.	Type	Other Details	Attachment
9468	Study protocol	Attached	380758-(Uploaded-18-10-2020-18-33-32)-Study-related document.pdf
9469	Informed consent form	Attached	380758-(Uploaded-18-10-2020-18-37-46)-Study-related document.pdf
9470	Ethical approval	Attached	380758-(Uploaded-18-10-2020-18-38-24)-Study-related document.pdf

Results publications and other study-related documents

Documents added manually

No documents have been uploaded by study researchers.

Documents added automatically

Source	Title	Year of Publication	DOI
Embase	Influenza virus infection history shapes antibody responses to influenza vaccination.	2022	https://dx.doi.org/10.1038/s41591-022-01690-w

N.B. These documents automatically identified may not have been verified by the study sponsor.

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Documents added automatically