Investigating COVID-19 Vaccine Immunity in Children in the Melbourne Infant Study of BCG for Allergy and Infection Reduction (COSI BAIR)

A Single-arm Clinical Trial to Investigate COVID-19 Specific Vaccine and Heterologous Immunity in the Melbourne Infant Study of BCG for Allergy and Infection Reduction (COSI BAIR)

The COSI BAIR trial will involve approximately 60 children, aged 5 to 8 years old, comprising a subset of participants from the Melbourne Infant Study BCG for Allergy and Infection Reduction (MIS BAIR) randomised controlled trial. The overall aim of this trial is to investigate the specific and heterologous effects of COVID-19 vaccination on immunity in children. COSI BAIR will aim to recruit its participants from the MIS BAIR Bacillus Calmette-Guérin (BCG)-naïve group. These children will be followed up until 28 days after their final Coronavirus Disease 2019 (COVID-19) vaccination.

Venous blood samples will be collected at two study visits, at Murdoch Children's Research Institute (MCRI):

1. Day 0 - baseline (day of COVID-19 vaccination #1), and
2. Day 84 (28 days after COVID-19 vaccination #2).

Study Overview

• Status: Completed
• Conditions: COVID-19; Vaccine Reaction; Immunization; Infection
• Intervention / Treatment: Biological: Tozinameran

• Study Type: Interventional
• Enrollment (Actual): 51
• Phase: Phase 4

Contacts and Locations

Study Locations

• Australia
  • Victoria
    • Parkville, Victoria, Australia, 3052
      • Melbourne Children's campus

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 5 years to 11 years (CHILD)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Age between five and eleven years (i.e. prior to the twelfth birthday) at the time of enrolment,

• Participant who was randomised in the MIS BAIR trial, and

  • Was randomly allocated to receive and received BCG as part of the MIS BAIR trial, OR,
  • Was randomly allocated to not receive and did not receive BCG;
• Is an individual whose parent/legally acceptable representative (LAR) consented to be contacted about future ethically approved research, during the MIS BAIR trial consent process, AND
• Has a parent/LAR capable of understanding the parent/LAR information statement and consent form (PICF) document and providing consent on the participant's behalf.

Exclusion Criteria:

• Has a known hypersensitivity to the active ingredient or any of the excipients in tozinameran,
• Has a prior polymerase chain reaction (PCR)-confirmed diagnosis of COVID-19 whether symptomatic or not,
• Has received a COVID-19 vaccine (approved by the TGA or otherwise) prior to trial enrolment,
• An individual and/or parent/legally acceptable representative who is unwilling or unable to give written informed consent,
• An individual and/or parent/legally acceptable representative who is unwilling or unable to consent to attend all scheduled study visits,
• An individual and/or parent/LAR who is unwilling or unable to give consent for blood samples to be taken from the trial participant at each study visit, and
• Has or has had a clinically significant medical morbidity (e.g. immunocompromised because of congenital or acquired disorders or immunosuppressive medical treatment; a bleeding disorder; a recent history of inflammatory cardiac illness within the past 6 months, e.g., myocarditis, pericarditis, endocarditis, acute rheumatic fever (with active myocardial inflammation) or acute rheumatic heart disease, or acute decompensated heart failure), and
• Has received BCG at any other time than as part of the MIS BAIR trial.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: BASIC_SCIENCE
• Allocation: NA
• Interventional Model: SINGLE_GROUP
• Masking: NONE

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

EXPERIMENTAL: Approved COVID-19 vaccination; The approved COVID-19 vaccination arm will receive the COMIRNATY™ (tozinameran - BNT162b2 [mRNA]) COVID-19 VACCINE. The dose, strength of the dose unit, dosing interval and dosing period of tozinameran used in this trial will be as approved by the Therapeutic Goods Administration (TGA) and recommended by the Australian Technical Advisory Group on Immunisation (ATAGI) for children aged 5 to <12 years of age. The recommended dose of tozinameran for this age group is 10 µg (0.2 mL) and the recommended schedule is 2 doses, 8 weeks apart. Therefore two tozinameran doses of 10µg (0.2 mL) will be administered intramuscularly 8-weeks apart as part of this arm of the trial.

Biological: Tozinameran; Tozinameran is a single-stranded, 5'-capped messenger RNA (mRNA) produced using a cell-free in vitro transcription from the corresponding DNA templates, encoding the viral spike (S) protein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2); Other Names: COMIRNATY; BNT162b2 [mRNA]; Pfizer COVID-19 Vaccine

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Mean change from baseline of in vitro whole blood stimulation cytokine responses to COVID-19 specific and heterologous stimulants	The difference in cytokine concentrations between those measured on the day of first vaccination and 28 days after second vaccination is the primary outcome measure	Day 0 (the day of the first COVID-19 vaccine dose) to day 84 (28 days after the second COVID-19 vaccine dose)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Mean change from baseline of anti-SARS-CoV-2 antibody titres	The difference in anti-SARS-CoV-2 antibody titres between those measured on the day of first vaccination and 28 days after second vaccination is outcome measure 2	Day 0 (the day of the first COVID-19 vaccine dose) to day 84 (28 days after the second COVID-19 vaccine dose)
Mean change from baseline of SARS-CoV-2-reactive T cell responses	The difference in SARS-CoV-2-reactive T cell responses, as measured by interferon-gamma producing units, between those measured on the day of first vaccination and 28 days after second vaccination is outcome measure 3	Day 0 (the day of the first COVID-19 vaccine dose) to day 84 (28 days after the second COVID-19 vaccine dose)
Correlation of serological profiling of previous viral infections and antiviral responses, and post-vaccination anti-SARS-CoV-2 antibody titres	Pearson product-moment correlation coefficient of all trial participants' serological profiling of previous viral infections and antiviral responses on the day of first COVID-19 vaccination and anti-SARS-CoV-2 antibody titres measured at 28 days after second vaccination is outcome measure 4. Previous viral infection organisms considered will include SARS-CoV-1, Middle East Respiratory Syndrome Coronavirus and circulating coronaviruses (eg. human coronavirus HKU1).	Day 0 (the day of the first COVID-19 vaccine dose) to day 84 (28 days after the second COVID-19 vaccine dose)
Correlation of serological profiling of vaccine-preventable disease antibody responses and post-vaccination anti-SARS-CoV-2 antibody titres	Pearson product-moment correlation coefficient of all trial participants' vaccine-preventable disease antibody responses on the day of first COVID-19 vaccination and anti-SARS-CoV-2 antibody titres measured at 28 days after second vaccination is outcome measure 5. Vaccine-preventable disease organisms examined will include Haemophilus influenzae B, Streptococcus pneumoniae and measles.	Day 0 (the day of the first COVID-19 vaccine dose) to day 84 (28 days after the second COVID-19 vaccine dose)
Correlation of whole blood cytokine responses to vaccine-preventable disease antigens and post-vaccination anti-SARS-CoV-2 antibody titres	Pearson product-moment correlation coefficient of all trial participants' whole blood cytokine responses to vaccine-preventable disease antigens on the day of first COVID-19 vaccination and anti-SARS-CoV-2 antibody titres measured at 28 days after second vaccination is outcome measure 6. Vaccine-preventable disease organisms examined will include Haemophilus influenzae B, Streptococcus pneumoniae and measles.	Day 0 (the day of the first COVID-19 vaccine dose) to day 84 (28 days after the second COVID-19 vaccine dose)
Mean change from baseline of vaccine-preventable disease antibody titres	The difference in vaccine-preventable disease antibody titres between those measured on the day of first vaccination and 28 days after second vaccination is outcome measure 7. Vaccine-preventable disease organisms examined will include Haemophilus influenzae B, Streptococcus pneumoniae and measles.	Day 0 (the day of the first COVID-19 vaccine dose) to day 84 (28 days after the second COVID-19 vaccine dose)

Collaborators and Investigators

• Sponsor: Murdoch Childrens Research Institute

Publications and helpful links

General Publications

• Freyne B, Messina NL, Donath S, Germano S, Bonnici R, Gardiner K, Casalaz D, Robins-Browne RM, Netea MG, Flanagan KL, Kollmann T, Curtis N; Melbourne Infant Study: BCG for Allergy and Infection Reduction (MIS BAIR) Group. Neonatal BCG Vaccination Reduces Interferon-gamma Responsiveness to Heterologous Pathogens in Infants From a Randomized Controlled Trial. J Infect Dis. 2020 Jun 11;221(12):1999-2009. doi: 10.1093/infdis/jiaa030.
• Freyne B, Donath S, Germano S, Gardiner K, Casalaz D, Robins-Browne RM, Amenyogbe N, Messina NL, Netea MG, Flanagan KL, Kollmann T, Curtis N. Neonatal BCG Vaccination Influences Cytokine Responses to Toll-like Receptor Ligands and Heterologous Antigens. J Infect Dis. 2018 May 5;217(11):1798-1808. doi: 10.1093/infdis/jiy069.
• Messina NL, Pittet LF, Gardiner K, Freyne B, Francis KL, Zufferey C, Abruzzo V, Morrison C, Allen KJ, Flanagan KL, Ponsonby AL, Robins-Browne R, Shann F, South M, Vuillermin P, Donath S, Casalaz D, Curtis N. Neonatal Bacille Calmette-Guerin Vaccination and Infections in the First Year of Life: The MIS BAIR Randomized Controlled Trial. J Infect Dis. 2021 Oct 13;224(7):1115-1127. doi: 10.1093/infdis/jiab306.
• Messina NL, Gardiner K, Donath S, Flanagan K, Ponsonby AL, Shann F, Robins-Browne R, Freyne B, Abruzzo V, Morison C, Cox L, Germano S, Zufferey C, Zimmermann P, Allen KJ, Vuillermin P, South M, Casalaz D, Curtis N. Study protocol for the Melbourne Infant Study: BCG for Allergy and Infection Reduction (MIS BAIR), a randomised controlled trial to determine the non-specific effects of neonatal BCG vaccination in a low-mortality setting. BMJ Open. 2019 Dec 15;9(12):e032844. doi: 10.1136/bmjopen-2019-032844.
• Zimmermann P, Donath S, Perrett KP, Messina NL, Ritz N, Netea MG, Flanagan KL, van der Klis FRM, Curtis N; MIS BAIR group. The influence of neonatal Bacille Calmette-Guerin (BCG) immunisation on heterologous vaccine responses in infants. Vaccine. 2019 Jun 19;37(28):3735-3744. doi: 10.1016/j.vaccine.2019.03.016. Epub 2019 May 29.
• Pittet LF, Messina NL, Gardiner K, Freyne B, Abruzzo V, Francis KL, Morrison C, Zufferey C, Vuillermin P, Allen KJ, Ponsonby AL, Robins-Browne R, Shann F, Flanagan KL, Phillips R, Donath S, Casalaz D, Curtis N. Prevention of infant eczema by neonatal Bacillus Calmette-Guerin vaccination: The MIS BAIR randomized controlled trial. Allergy. 2022 Mar;77(3):956-965. doi: 10.1111/all.15022. Epub 2021 Aug 9.

Helpful Links

• MIS BAIR trial website. Participants for COSI BAIR will be recruited from this trial population.

Study record dates

Study Major Dates

• Study Start (ACTUAL): January 20, 2022
• Primary Completion (ACTUAL): September 29, 2022
• Study Completion (ACTUAL): September 29, 2022

Study Registration Dates

• First Submitted: December 22, 2021
• First Submitted That Met QC Criteria: December 22, 2021
• First Posted (ACTUAL): December 23, 2021

Study Record Updates

• Last Update Posted (ESTIMATE): February 9, 2023
• Last Update Submitted That Met QC Criteria: February 7, 2023
• Last Verified: February 1, 2023

More Information

Terms related to this study

• Keywords: mRNA vaccine; Non-specific effects; COVID-19 vaccination; paediatric vaccination; heterologous immunity
• Additional Relevant MeSH Terms: Pathologic Processes; Coronavirus Infections; Coronaviridae Infections; Nidovirales Infections; RNA Virus Infections; Virus Diseases; Respiratory Tract Infections; Respiratory Tract Diseases; Pneumonia, Viral; Pneumonia; Lung Diseases; Disease Attributes; COVID-19; Infections; Communicable Diseases; Physiological Effects of Drugs; Immunologic Factors; Vaccines
• Other Study ID Numbers: 81771

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES

IPD Plan Description

At the time of article publication, the following will be made available long-term for use by future researchers from a recognised research institution whose proposed use of the data has been ethically reviewed and approved by an independent committee and who accept MCRI's conditions for access:

• Individual participant data that underlie the results reported in this article after deidentification (text, tables, figures and appendices), and
• Trial protocol, PICF, analytic code

We may share the information and samples we collect with other researchers within Australia and/or overseas to increase our understanding of COVID-19 and COVID-19 vaccination and other infections. The location of data/samples sent overseas is not yet determined. Data and samples would be sent identifiable only by a study number so that the child's identity is not disclosed to these researchers. Any data or samples sent to researchers outside of Australia will not be covered by Australian regulations.

• IPD Sharing Time Frame: Following the completion and analysis of the trial, the data will be retained long-term following the mandatory archive period for use in future research projects. The retention period will be for at least 15 years post-trial completion or until the child is aged 25 years (whichever is later). The Sponsor-Investigator and/or delegate will be the custodians during the archive period. Following the end of the archival period, the data will be disposed of.
• IPD Sharing Access Criteria: Must pertain to ethically approved research; Must be from a recognised institution; Must be willing to share the aims, outcomes and outcomes measures of the secondary analyses; Must ask for consent from the COSI BAIR principal investigators; Must be approved by the COSI BAIR Sponsor-Investigator
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; ICF; ANALYTIC_CODE

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: Yes