COVID-19 Fourth Dose Study in Australia

Study Overview
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Brief Summary
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This clinical trial will be a blinded, randomised study to determine the safety, reactogenicity, and immunogenicity of a second booster dose of SARS-CoV-2 vaccines in adults enrolled over two consecutive stages. Stage 1 will commence at the time of study approval and transition to stage 2 once bivalent vaccines are approved and available in Australia.

Detailed Description
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Participants will be adults aged 18 years or older who have been previously primed with two doses of either Pfizer-BioNTech (BNT162b2, or Comirnaty®) or AstraZeneca (ChAdOx1-S, or Vaxzevria®) and boosted at least 3 months earlier with Pfizer BioNTech vaccine (30µg). There will be no upper age limit. Participants will be recruited from the Murdoch Children's Research Institute, the Royal Children's Hospital (RCH), the Peter Doherty Research Institute, and, if necessary, the greater Melbourne area. Ideally, 100 participants will be recruited per group unless bivalent Omicron-specific vaccines are introduced before this target is reached for monovalent ancestral vaccines. There will be 800 participants in total. Procedures will be implemented to ensure participants of all ages (aged 18 and above) are included and that there is an even age distribution in each group (<50 and ≥50 years).

Official Title
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A Randomised Controlled Trial to Assess the Immunogenicity, Safety and Reactogenicity of a Second Standard Monovalent (Ancestral) or Bivalent Omicron-specific COVID-19 Vaccine Booster Dose (Pfizer-BioNTech or Moderna) in Healthy Adults in Australia.

Conditions
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COVID-19

Intervention / Treatment
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* Biological: Tozinameran
* Biological: Elasomeran
* Biological: Tozinameran
* Biological: Elasomeran
* Biological: Bivalent Pfizer-BioNTech
* Biological: Bivalent Moderna
* Biological: Bivalent Pfizer-BioNTech
* Biological: Bivalent Moderna


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Have completed a primary schedule of two doses of Pfizer-BioNTech or AstraZeneca vaccines and received a booster of Pfizer-BioNTech vaccine (30µg) at least 3 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 received two doses of either Pfizer or Astrazena vaccine as their primary vaccine and a standard dose of Pfizer for their booster will be randomised into one of four groups. The four groups consist of a standard dose of either the monovalent or bivalent Pfizer or Moderna vaccine.
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Monovalent Pfizer-BioNTech(BNT162b2): Pfizer-BioNTech(BNT162b2)-Pfizer-BioNTech(BNT162b2)<br>Participants who received Pfizer-BioNTech(BNT162b2) as primary series and Pfizer-BioNTech(BNT162b2) as first booster will receive a second booster dose of: Biological/Vaccine: Tozinameran - Monovalent Tozinamrean 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). | Biological: Tozinameran<br>* A single standard dose (30mcg) will be administered on day 0 of the study.<br>* Other names: BNT162b2, Pfizer-BioNTech, Comirnaty;|
| Active Comparator: Monovalent Moderna(mRNA-1273, Spikevax®): Pfizer-BioNTech(BNT162b2)-Pfizer-BioNTech(BNT162b2)<br>Participants who received Pfizer-BioNTech(BNT162b2) as primary series and Pfizer-BioNTech(BNT162b2) as first booster will receive a second booster dose of: Biological/Vaccine: Elasomeran - Monovalent Elasomeran 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 SARS-CoV-2). | Biological: Elasomeran<br>* A single standard dose (50mcg) of the intervention will be administered on day 0 of the study.<br>* Other names: mRNA-1273, Spikevax, Moderna;|
| Active Comparator: Monovalent Pfizer-BioNTech(BNT162b2): AstraZeneca(ChAdOx1, Vaxzevria®)-Pfizer-BioNTech(BNT162b2)<br>Participants who received AstraZeneca (ChAdOx1, or Vaxzevria®) as primary series and Pfizer-BioNTech (BNT162b2) as first booster will received a second booster dose of: Biological/Vaccine: Tozinameran - Monovalent Tozinamrean 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). | Biological: Tozinameran<br>* A single standard dose (30mcg) will be administered on day 0 of the study.<br>* Other names: BNT162b2, Pfizer-BioNTech, Comirnaty;|
| Active Comparator: Monovalent Moderna(mRNA-1273, Spikevax®):AstraZeneca(ChAdOx1, Vaxzevria®)-Pfizer-BioNTech(BNT162b2)<br>Participants who received AstraZeneca (ChAdOx1, or Vaxzevria®) as primary series and Pfizer-BioNTech (BNT162b2) as first booster will received a second booster dose of: Biological/Vaccine: Elasomeran - Monovalent Elasomeran 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 SARS-CoV-2). | Biological: Elasomeran<br>* A single standard dose (50mcg) of the intervention will be administered on day 0 of the study.<br>* Other names: mRNA-1273, Spikevax, Moderna;|
| Active Comparator: Bivalent Pfizer-BioNTech (BNT162b2 OMI): Pfizer-BioNTech(BNT162b2)-Pfizer-BioNTech(BNT162b2)<br>Participants who received Pfizer-BioNTech(BNT162b2) as primary series and Pfizer-BioNTech(BNT162b2) as first booster will receive a second booster dose of: Biological/Vaccine: Pfizer-BioNTech, BNT162b2 OMI - bivalent Pfizer-BioNTech bivalent COVID-19 vaccine contains ancestral BNT162b2 and Omicron variant BNT162b2 Omi (BA.1). The Pfizer-BioNTech COVID-19 vaccine, BNT162b2, encodes a P2 mutant spike protein and is formulated as an RNA-lipid nanoparticle (LNP) of nucleoside-modified mRNA (modRNA). | Biological: Bivalent Pfizer-BioNTech<br>* A single standard dose (BNT162b2 15μg +BNT162b2 OMI 15μg) will be administered on day 0 of the study.<br>* Other names: BNT162b2 + BNT162b2 OMI;|
| Active Comparator: Bivalent Moderna (mRNA-1273.214): Pfizer-BioNTech(BNT162b2)-Pfizer-BioNTech(BNT162b2)<br>Participants who received Pfizer-BioNTech(BNT162b2) as primary series and Pfizer-BioNTech(BNT162b2) as first booster will receive a second booster dose of: Biological/Vaccine: Moderna, mRNA-1273.214 - bivalent The Moderna bivalent vaccine (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 (BNT162b2 15μg + BNT162b2 OMI 15μg)will be administered on day 0 of the study.<br>* Other names: mRNA-1273.214 +B.1.1.529 OMI;|
| Active Comparator: Bivalent Pfizer-BioNTech (BNT162b2): AstraZeneca(ChAdOx1, Vaxzevria®)-Pfizer-BioNTech(BNT162b2)<br>Participants who received AstraZeneca (ChAdOx1-S, or Vaxzevria®) as primary series and Pfizer-BioNTech (BNT162b2) as first booster will received a second booster dose of: Biological/Vaccine: Pfizer-BioNTech, BNT162b2 OMI - bivalent Pfizer-BioNTech bivalent COVID-19 vaccine contains ancestral BNT162b2 and Omicron variant BNT162b2 Omi (BA.1). The Pfizer-BioNTech COVID-19 vaccine, BNT162b2, encodes a P2 mutant spike protein and is formulated as an RNA-lipid nanoparticle of nucleoside-modified mRNA. | Biological: Bivalent Pfizer-BioNTech<br>* A single standard dose (BNT162b2 15μg + BNT162b2 OMI 15μg) will be administered on day 0 of the study.<br>* Other names: BNT162b2 + BNT162b2 OMI;|
| Active Comparator: Bivalent Moderna (mRNA-1273.214): AstraZeneca(ChAdOx1, Vaxzevria®)-Pfizer-BioNTech(BNT162b2)<br>Participants who received AstraZeneca (ChAdOx1-S, or Vaxzevria®) as primary series and Pfizer-BioNTech (BNT162b2) as first booster will received a second booster dose of: Biological/Vaccine: Moderna, mRNA-1273.214 - bivalent The Moderna bivalent vaccine (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 (BNT162b2 15μg +BNT162b2 OMI 15μg) will be administered on day 0 of the study.<br>* Other names: mRNA-1273.214 +B.1.1.529 OMI;|

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 all 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-months post booster vaccination | Serum samples collected at baseline (pre booster), and 6-months post booster vaccination from all 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 | Baseline (pre booster), and 6-months post booster vaccination | 
| SARS-CoV-2 specific neutralising antibodies at baseline (pre booster), 28 days and 6-months post booster vaccination measured by surrogate virus neutralization test (sVNT) | Serum samples collected at baseline (pre booster), 28 days- and 6-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), 28 days and 6 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 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), 28 days-, and 6-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 (40%) of the participants from each group. QuantiFERON Human IFN-γ SARS-CoV-2 (Qiagen) will be used to stimulate IFN-γ production in peripheral blood mononuclear cells (PBMCs) and then IFN-γ production will be measured using ELISA. Data will be presented as geometric mean concentration (GMC) and 95% confidence intervals (CI). | Baseline (pre booster), 28 days-, and 6-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 (40%) of the participants from each group. IFN-γ Enzyme-Linked ImmunoSpot (Elispot) assay will be performed on isolated peripheral blood mononuclear cells (PBMCs). Data will be reported as number of IFNγ producing cells/million and presented using means and 95% confidence intervals. | Baseline (pre booster), 28 days-, and 6-months post booster vaccination | 
| Frequency of cytokine-expressing T cells | Frequency of cytokine-expressing T cells will be assessed on a subset (40%) of participants using Flow cytometry (intracellular staining) on PBMCs samples. Data will be reported as frequency (%) of cytokine-expressing T cells presented as means and 95% CI. | Baseline (pre booster), 28 days-, and 6-months post booster vaccination | 
| Cytokine concentrations following PBMCs stimulation | Cytokine concentrations following PBMCs stimulation will be assessed on a subset (40%) 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), 28 days and 6-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 6 months post booster vaccination. Data will be presented as a proportion of participants who report unsolicited SAE. | 6 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 Pfizer, mRNA vaccine, monovalent, bivalent