COVID-19 Booster Study in Healthy Adults in Australia

A Randomised Controlled Trial to Assess the Immunogenicity, Safety and Reactogenicity of a Bivalent mRNA Moderna COVID-19 Vaccine or a Protein-based Novavax COVID-19 Vaccine Given as a Fourth Dose in Healthy Adults in Australia

This is a double-blinded, randomised study to determine the safety, reactogenicity, and immunogenicity of a bivalent mRNA Moderna COVID-19 vaccine or a protein-based Novavax COVID-19 vaccine given as a fourth dose in healthy adults in Australia.

Study Overview

• Status: Active, not recruiting
• Conditions: COVID-19
• Intervention / Treatment: Biological: Bivalent Moderna; Biological: Novavax

Detailed Description

This is a blinded, two-arm randomised study to determine the safety, reactogenicity and immunogenicity of a fourth dose of SARS-CoV-2 vaccines in Australia in adults 18 years or older who have received their third dose of COVID-19 vaccine at least six months previously. Participants will be randomised to receive either bivalent Moderna (mRNA-1273.214) or Novavax. A separate non-randomised control arm (no vaccine given), frequency matched by age to the vaccine groups will also be enrolled for comparison. A total of 200 participants per group will be recruited.

• Study Type: Interventional
• Enrollment (Actual): 497
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: Kim Mulholland, MD/Prof; Phone Number: +61 3 993 66771; Email: Kim.Mulholland@lshtm.ac.uk
• Study Contact Backup: Name: Claire Von Mollendorf, MD/PHD; Phone Number: 61 3 993 66771; Email: claire.vonmollendorf@mcri.edu.au

Study Locations

• Australia
  • Victoria
    • Melbourne, Victoria, Australia, 3052
      • Royal Children's Hospital, Murdoch Children's Research Institute

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: Yes

Description

Inclusion Criteria:

1. Have received three doses of COVID-19 vaccines at least 6 months earlier.
2. No confirmed SARS-CoV-2 infection on PCR or RAT within the last 3 months.
3. Willing and able to give written informed consent.
4. Aged 18 years or above.
5. Willing to complete the follow-up requirements of the study.

Exclusion Criteria:

1. Currently receiving immunosuppressive medication or anti-cancer chemotherapy.
2. Known HIV infection.
3. Congenital immune deficiency syndrome.
4. Received immunoglobulin or other blood products in the three months prior to potential study booster vaccination.
5. Study staff and their relatives.
6. Have a history of a severe allergic reaction to any COVID-19 vaccines or have a medical exemption to receiving further COVID-19 vaccines.
7. Cannot read or understand English.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Bivalent Moderna (mRNA-1273.214); Participants who have received three doses of COVID-19 vaccine, with the last dose at least 6 months prior to the study, will receive a booster dose of bivalent mRNA Moderna COVID-19 vaccine (mRNA-1273.214) The mRNA-1273.214 encodes the prefusion stabilized S protein of SARS-CoV-2 formulated in RNA-lipid nanoparticles composed of 4 lipids and 1-monomethoxypolyethyleneglycol-2, 3-dimyristylglycerol with polyethylene glycol. 25μg of each mRNA sequence that encode the prefusion stabilized spike glycoproteins of the ancestral SARS-CoV-2 (Wuhan-Hu-1) and the Omicron variant (B.1.1.529 [BA.1]).	Biological: Bivalent Moderna; A single standard dose of the bivalent Moderna (mRNA-1273.214) COVID-19 vaccine containing equal amounts of mRNAs (25μg of each mRNA sequence) that encode the prefusion stabilized spike glycoproteins of the ancestral SARS-CoV-2 (Wuhan-Hu-1) and the Omicron variant (B.1.1.529 [BA.1]) with mRNAs encapsulated in lipid nanoparticles, will be administered on day 0 of the study.; Other Names: mRNA-1273.214
Active Comparator: Novavax; Participants who have received three doses of COVID-19 vaccine, with the last dose at least 6 months prior to the study, will receive a booster dose of Novavax COVID-19 protein subunit vaccine. Novavax contains 5μg of SARS-CoV-2 spike protein and is adjuvanted with Matrix-M. Adjuvant Matrix-M contains, per 0.5 mL dose: Quillaja saponaria saponins fraction A (42.5 micrograms) and Quillaja saponaria saponins fraction C (7.5 micrograms).	Biological: Novavax; A single dose of Novavax contains 5μg of SARS-CoV-2 spike protein and is adjuvanted with Matrix-M. Adjuvant Matrix-M contains, per 0.5 mL dose: Quillaja saponaria saponins fraction A (42.5 micrograms) and Quillaja saponaria saponins fraction C (7.5 micrograms), will be administered on day 0 of the study.
No Intervention: Control group- no vaccine; Participants who have received three doses of COVID-19 vaccine, with the last dose at least 6 months prior to the study, will be recruited but will not receive any COVID-19 vaccine.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Total incidence of solicited reactions (systemic and local)	Questionnaire to document solicited reactions is developed specifically for this study. Data will be reported as the proportion of participants who report by each intervention arm. Solicited reactions such as pain, tenderness, erythema/redness, induration/swelling, fever, nausea/vomiting, headache, fatigue/malaise, myalgia, arthralgia will be collected from the participants 7 days post-vaccination.	Total incidence of solicited reactions will be measured for 7 days post booster vaccination
SARS-CoV-2 specific Immunoglobulin (Ig)G antibodies at 28-days post booster vaccination	Serum samples collected at 28-days post booster vaccination from the two intervention groups will be evaluated for SARS-CoV-2 specific IgG antibodies using the commercial Euroimmun S1 IgG ELISA. Data will be reported as binding antibody units/mL and presented as geometric mean concentration and 95% confidence intervals	28-days post booster vaccination

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Incidence of unsolicited adverse events (AE)	All unsolicited AE will be collected for 28 days post booster vaccination. Data will be presented as proportion of participants who report unsolicited AE.	28 days-post booster vaccination
Incidence of medically attended adverse events (AE)	Participants with medically attended AE will be collected for 3 months post booster vaccination. Data will be presented as proportion of participants who report unsolicited AE.	3 months post booster vaccination
SARS-CoV-2 specific IgG antibodies at baseline (pre booster), and 6- and 12-months post booster vaccination	Serum samples collected at baseline (pre booster), 6- and 12-months post booster vaccination from the two intervention groups and the control group will be evaluated for SARS-CoV-2 specific IgG antibodies using the commercial Euroimmun S1 IgG ELISA . Data will be reported as binding antibody units/mL and presented as geometric mean concentration and 95% confidence intervals	Baseline (pre booster), 6-months and 12-months post booster vaccination
SARS-CoV-2 specific neutralising antibodies at baseline (pre booster), 28 days, 6- and 12-months post booster vaccination measured by surrogate virus neutralization test (sVNT)	Serum samples collected at baseline (pre booster), 28 days, 6- and 12-months post booster vaccination from all groups will be evaluated for SARS-CoV-2 specific neutralising antibodies using the GenScript® cPass surrogate virus neutralization test (sVNT) for both wild-type and Omicron variant. Neutralising antibody response will be reported as percentage (%) inhibition of receptor binding domain-angiotensin-converting enzyme 2 (RBD-ACE2) binding relative to a positive control.	Baseline (pre booster), 6-months and 12-months post booster vaccination
SARS-CoV-2 specific neutralising antibodies at baseline (pre booster), 28 days and 6- months post booster vaccination measured by SARS-CoV-2 microneutralisation assay	A subset of samples (20%) from all timepoints will be assessed using a SARS-CoV-2 microneutralisation assay to both the wild type (vaccine) strain and for two SARS-CoV-2 Variants of concern. Neutralizing antibody will be reported as endpoint titre.	Baseline (pre booster), 6-months and 12-months post booster vaccination
Interferon gamma (IFNγ) concentrations in International Units (IU)/mL	Interferon gamma (IFNγ) concentrations as a measurement of cellular immunity will be assessed on a subset (50%) of the participants from each group. QuantiFERON Human IFN-γ SARS-CoV-2 (Qiagen) will be used to stimulate IFN-γ production in whole blood and then IFN-γ production will be measured using Enzyme-Linked ImmunoSorbent Assay (ELISA). Data will be presented as geometric mean concentration (GMC) and 95% confidence intervals (CI).	Baseline (pre booster), 6-months and 12-months post booster vaccination
Number of IFNγ producing cells/million PBMCs	IFNγ producing cells as a measurement of cellular immunity will be assessed on a subset (50%) of the participants from each group. IFN-γ Enzyme-Linked ImmunoSpot (Elispot) assay will be performed on isolated peripheral blood mononuclear cells (PBMCs) stimulated with SARS-CoV-2 specific peptides. Data will be reported as number of IFNγ producing cells/million and presented using means and 95% confidence intervals.	Baseline (pre booster), 6-months and 12-months post booster vaccination
Frequency of cytokine-expressing T cells	Frequency of cytokine-expressing T cells will be assessed on a subset (50%) of participants using Flow cytometry (intracellular staining) on PBMCs samples stimulated with SARS-CoV-2 specific peptides. Data will be reported as frequency (%) of cytokine-expressing T cells presented as means and 95% CI.	Baseline (pre booster), 6-months and 12-months post booster vaccination
Cytokine concentrations following PBMCs stimulation	Cytokine concentrations following PBMCs stimulation will be assessed on a subset (50%) of participants using multiplex cytokine assays. Data will be reported as cytokine concentrations in pg/ml and presented as GMC and 95% CI.	Baseline (pre booster), 6-months and 12-months post booster vaccination
Incidence of serious adverse events (SAE)	SAE will be collected throughout the follow-up period of 12 months post booster vaccination. Data will be presented as a proportion of participants who report unsolicited SAE.	12 months post booster vaccination

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
SARS-CoV-2 breakthrough infections	Breakthrough SARS-CoV-2 infections will be recorded during the 12-month study period. Nasal swabs will be collected from all severe breakthrough cases and a subset of mild cases within three days of illness if available. A representative sample of positive samples will be processed for viral load and whole genome sequencing of SARS-CoV-2. Correlation analysis will be performed on virological markers (viral load and viral genome characteristics) and immunological markers (humoral antibody, cell-mediated immunity) among mild and severe breakthrough cases.	12 months post booster vaccination

Collaborators and Investigators

• Sponsor: Murdoch Childrens Research Institute
• Collaborators: Coalition for Epidemic Preparedness Innovations; The Peter Doherty Institute for Infection and Immunity
• Investigators: Principal Investigator: Kim Mulholland, MD/Prof, Murdoch Childrens Research Institute

Publications and helpful links

Helpful Links

• World Health Organization. Interim statement on the use of additional booster doses of Emergency Use Listed mRNA vaccines against COVID-19 2022
• US Food and Drug Administration (FDA). Toxicity Grading Scale for Healthy Adult and Adolescent Volunteers Enrolled in Preventive Vaccine Clinical Trials 2007
• International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use. Addendum on Estimands and Sensitivity Analysis in Clinical Trials to the Guideline on Statistical Principles for Clinical Trials 2019

Study record dates

Study Major Dates

• Study Start (Actual): February 28, 2023
• Primary Completion (Estimated): October 1, 2024
• Study Completion (Estimated): October 1, 2024

Study Registration Dates

• First Submitted: December 19, 2022
• First Submitted That Met QC Criteria: December 19, 2022
• First Posted (Actual): December 20, 2022

Study Record Updates

• Last Update Posted (Actual): November 1, 2023
• Last Update Submitted That Met QC Criteria: October 30, 2023
• Last Verified: October 1, 2023

More Information

Terms related to this study

• Keywords: control group; monovalent, bivalent; Booster dose Moderna and Novavax
• Additional Relevant MeSH Terms: Coronavirus Infections; Coronaviridae Infections; Nidovirales Infections; RNA Virus Infections; Virus Diseases; Infections; Respiratory Tract Infections; Respiratory Tract Diseases; Pneumonia, Viral; Pneumonia; Lung Diseases; COVID-19
• Other Study ID Numbers: 91108

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: The investigators will share de-identified data to ethically approved studies in cases where participants have indicated on the consent form that they consent to the use of their data and where consistent with terms of collaboration agreements.
• IPD Sharing Time Frame: Individual participant data (IPD) sharing plans in development
• IPD Sharing Access Criteria: In development
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; ICF

Drug and device information, study documents

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