COVID-19 Booster Study in Healthy Adults in Australia

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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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

Conditions
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COVID-19

Intervention / Treatment
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* Biological: Bivalent Moderna
* Biological: Novavax


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Have received three doses of COVID-19 vaccines at least 6 months earlier. No confirmed SARS-CoV-2 infection on PCR or RAT within the last 3 months. Willing and able to give written informed consent. Aged 18 years or above. Willing to complete the follow-up requirements of the study. Exclusion Criteria: Currently receiving immunosuppressive medication or anti-cancer chemotherapy. Known HIV infection. Congenital immune deficiency syndrome. Received immunoglobulin or other blood products in the three months prior to potential study booster vaccination. Study staff and their relatives. Have a history of a severe allergic reaction to any COVID-19 vaccines or have a medical exemption to receiving further COVID-19 vaccines. Cannot read or understand English.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Study participants who have previously received 3 COVID-19 vaccines will be either randomised into one of two vaccine groups or be part of a self-selected control group. Randomised participants will receive a standard dose of either the bivalent Moderna or the protein-based Novavax vaccine. 200 non-randomised participants will be part of a control group and will not receive any COVID-19 vaccine.
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Bivalent Moderna (mRNA-1273.214)<br>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<br>* 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.<br>* Other names: mRNA-1273.214;|
| Active Comparator: Novavax<br>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<br>* 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.<br>|
| No Intervention: Control group- no vaccine<br>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?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 | 
| 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 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 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 | 
| 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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Booster dose Moderna and Novavax, control group, monovalent, bivalent