Evaluation of Full Versus Fractional Doses of COVID-19 Vaccines Given as a Booster in Adults in Australia - Mongolia, Indonesia, Australia Coronavirus (MIACoV).

Study Overview
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Brief Summary
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This is a single-blind, randomised controlled clinical trial to determine the reactogenicity and immunogenicity of severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) vaccines (Pfizer-BioNTech or Moderna) as booster dose in adults, who have previously received either Pfizer-BioNTech or AstraZeneca as their primary doses. Both fractional and standard doses of Pfizer-BioNTech or Moderna will be tested. The trial intervention will be given in line with Australian Technical Advisory Group on Immunisation (ATAGI) recommendations for booster vaccine doses which allows booster doses from 5 months onwards . There will be a total of 8 groups, with 100 individuals of even spread of participants above and below 50 years in each group. The trial will be single site, based at Royal Children's Hospital, Melbourne, Australia

Detailed Description
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As per brief summary

Official Title
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A Randomised Controlled Trial to Assess the Immunogenicity, Safety, and Reactogenicity of Standard-dose Versus Fractional Doses of COVID-19 Vaccines (Pfizer-BioNTech or Moderna) Given as an Additional Dose After Priming With Pfizer-BioNTech or AstraZeneca in Healthy Adults in Australia-MIACoV

Conditions
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COVID-19

Intervention / Treatment
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* Biological: Tozinameran - Standard dose
* Biological: Tozinameran - fractional dose
* Biological: Elasomeran - standard dose
* Biological: Elasomeran - fractional dose


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Have completed two doses of Pfizer-BioNTech or AstraZeneca vaccines with the recommended schedule 6 months prior to the date of enrolment 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: Received 3 doses of COVID-19 vaccine Received 2 doses of COVID-19 less than 6 months prior to the start of the trial Received a different Covid-19 vaccine not available in Australia Currently on immunosuppressive medication or anti-cancer chemotherapy HIV infection Congenital immune deficiency syndrome Has received immunoglobulin or other blood products in the 3 months prior to vaccination Study staff and their relatives Have a history of a severe allergic reaction to any COVID-19 vaccines or have a medical exception 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 will be randomised into one of four groups. The four groups consists of a standard or fractional dose of either Pfizer or Moderna vaccine.
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: AstraZeneca (ChAdOx1-S, or Vaxzevria®)-Standard Pfizer-BioNTech booster group<br>Received two doses of AstraZeneca as primary COVID-19 vaccine | Biological: Tozinameran - Standard dose<br>* 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). A standard dose will be administered on day 0 of the study.<br>* Other names: Comirnaty;|
| Experimental: AstraZeneca (ChAdOx1-S, or Vaxzevria®)-Fractional Pfizer-BioNTech booster group<br>Received two doses of AstraZeneca as primary COVID-19 vaccine | Biological: Tozinameran - fractional dose<br>* 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). A fractional dose (15mcg) of the intervention will be administered on day 0 of the study.<br>* Other names: Pfizer-BioNTech;|
| Active Comparator: AstraZeneca (ChAdOx1-S, or Vaxzevria®) Standard Elasomeran booster group<br>Received two doses of AstraZeneca as primary COVID-19 vaccine | Biological: Elasomeran - standard dose<br>* 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). A single standard dose (50mcg) of the intervention will be administered on day 0 of the study.<br>* Other names: Moderna;|
| Experimental: AstraZeneca (ChAdOx1-S, or Vaxzevria®)-Fractional Elasomeran booster group<br>Received two doses of AstraZeneca as primary COVID-19 vaccine | Biological: Elasomeran - fractional dose<br>* 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). A fractional dose (20mcg) of the intervention will be administered on day 0 of the study.<br>* Other names: Moderna;|
| Active Comparator: Pfizer-BioNTech (BNT162b2, or Comirnaty®)-Standard Pfizer-BioNTech booster group<br>Received two doses of Pfizer-BioNTech as primary COVID-19 vaccine | Biological: Tozinameran - Standard dose<br>* 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). A standard dose will be administered on day 0 of the study.<br>* Other names: Comirnaty;|
| Experimental: Pfizer-BioNTech (BNT162b2, or Comirnaty®)-Fractional Pfizer-BioNTech booster group<br>Received two doses of Pfizer-BioNTech as primary COVID-19 vaccine | Biological: Tozinameran - fractional dose<br>* 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). A fractional dose (15mcg) of the intervention will be administered on day 0 of the study.<br>* Other names: Pfizer-BioNTech;|
| Active Comparator: Pfizer-BioNTech (BNT162b2, or Comirnaty®)-Standard Elasomeran booster group<br>Received two doses of Pfizer-BioNTech as primary COVID-19 vaccine | Biological: Elasomeran - standard dose<br>* 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). A single standard dose (50mcg) of the intervention will be administered on day 0 of the study.<br>* Other names: Moderna;|
| Experimental: Pfizer-BioNTech (BNT162b2, or Comirnaty®)-Fractional Elasomeran booster group<br>Received two doses of Pfizer-BioNTech as primary COVID-19 vaccine | Biological: Elasomeran - fractional dose<br>* 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). A fractional dose (20mcg) of the intervention will be administered on day 0 of the study.<br>* Other names: Moderna;|

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 Delta 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 four 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 16-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, Pfizer, fractional and standard doses, COVID-19 vaccination, mRNA vaccine