Evaluation of COVID-19 Vaccines Given as a Booster in Healthy Adults in Indonesia (MIACoV Indonesia)

Study Overview
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Brief Summary
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This is a randomised controlled clinical trial to determine the reactogenicity and immunogenicity of booster doses of SARS-CoV-2 vaccines (Pfizer-BioNTech, AstraZeneca or Moderna) in adults who have previously received either AstraZeneca or Coronavac as their primary doses. Both fractional and standard doses of Pfizer-BioNTech, AstraZeneca and Moderna will be tested.

Detailed Description
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There will be a total of 800 participants in the study, to be randomised and administered booster doses in this study. The study will be conducted at 3 clinics in Bandung. Participants will have previously received primary doses of Coronavac or Astranzeneca, with the second dose administered at least 6 months previously. Participants will be followed for 12 months following the booster vaccine adminstration, with blood samples drawn at baseline, 28 days, 6 months and 12 months following booster vaccine administration.

Official Title
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A Randomised Controlled Trial to Assess the Immunogenicity, Safety & Reactogenicity of Standard Dose Versus Fractional Doses of COVID-19 Vaccines (Pfizer-BioNTech, AstraZeneca or Moderna) Given as a Booster Dose After Priming With Coronavac or AstraZeneca in Healthy Adults in Indonesia

Conditions
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COVID-19

Intervention / Treatment
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* Biological: Pfizer-BioNTech Standard dose
* Biological: AstraZeneca Standard dose
* Biological: Pfizer-BioNTech Fractional dose
* Biological: AstraZeneca Fractional dose
* Biological: Moderna Standard dose
* Biological: Moderna Fractional dose


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Clinically healthy adults aged 18 years and above who had completed the primary series of COVID-19 vaccine with CoronaVac or AstraZeneca more than 6 months prior to enrolment to the study. Signed written informed consent form and willing to comply with the instructions of the investigator and the schedule of the trial. Exclusion Criteria: Those who have already received a third dose of SARS-CoV-2 vaccine Concomitantly enrolled or scheduled to be enrolled in another trial. Those with fever (temperature ˃ 37.5℃, measured with infrared thermometer/thermal gun), upper respiratory tract infection symptoms such as sneezing, nasal congestion, runny nose, cough, sore throat, loss of taste, chills and shortness of breath within 72 hours before enrolment. Blood pressure ˃ 180/110 mmHg. History of confirmed COVID-19 within one month prior to study enrolment. History of allergy to vaccines or vaccine ingredients, and severe adverse reactions to vaccines, such as urticaria, dyspnoea, and angioneurotic oedema. Those with uncontrolled autoimmune disease such as systemic lupus erythematosis. History of uncontrolled coagulopathy or blood disorders, immune deficiency. History of having received blood derived product/transfusion within 3 months prior to enrolment. Those who received immunosuppressant therapy such as high-dose corticosteroid or cancer chemotherapy Those with uncontrolled chronic disease, such as severe heart disease, asthma exacerbation Those who have history of uncontrolled epilepsy (within the last 2 years) or other progressive neurological disorders, such as Guillain-Barre Syndrome Those who have receive any vaccination within 2 weeks before study vaccine administration for this protocol, or intended to receive any vaccination within 2 weeks after study vaccine administration. Pregnant woman Those aged ≥60 years old with difficulty in climbing 10 steps of stairs, frequently experiencing fatigue, difficulty in walking 100-200 m, or having at least 5 comorbidities (hypertension, diabetes, cancer, chronic lung disease, heart attack, congestive heart failure, chest pain, asthma, joint pain, stroke, and kidney disease). Those who are study staff working on the study or the immediate family of study investigators

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
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Pfizer-BioNTech Standard dose after CoronaVac priming<br>Pfizer-BioNTech (BNT162b2, or Comirnaty®) Dose: 30ug in 0.3ml The 50 participants in this arm received second CoronaVac priming dose at least 6 months prior to randomisation. | Biological: Pfizer-BioNTech Standard dose<br>* Standard Dose - (30ug in 0.3ml) 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).<br>* Other names: Comirnaty;|
| Experimental: Pfizer-BioNTech Fractional dose after CoronaVac priming<br>Pfizer-BioNTech (BNT162b2, or Comirnaty®) Dose: 15ug in 0.15ml The 50 participants in this arm received second CoronaVac priming dose at least 6 months prior to randomisation. | Biological: Pfizer-BioNTech Fractional dose<br>* Fractional Dose - (15ug in 0.15ml) 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).<br>* Other names: Comirnaty;|
| Experimental: AstraZeneca Standard dose after CoronaVac priming<br>AstraZeneca (ChAdOx1-S, Vaxzevria®). Dose: 0.5ml The 50 participants in this arm received second CoronaVac priming dose at least 6 months prior to randomisation. | Biological: AstraZeneca Standard dose<br>* Standard Dose (5xE10vp in 0.5ml) ChAdOx1 nCoV-19 is a recombinant replication-defective chimpanzee adenovirus expressing the SARS-CoV-2 spike (S) surface glycoprotein<br>* Other names: Vaxzevria;|
| Experimental: AstraZeneca Fractional dose after CoronaVac priming<br>AstraZeneca (ChAdOx1-S, Vaxzevria®). Dose: 0.25ml The 50 participants in this arm received second CoronaVac priming dose at least 6 months prior to randomisation. | Biological: AstraZeneca Fractional dose<br>* Fractional Dose (2.5E10vp in 0.25ml) ChAdOx1 nCoV-19 is a recombinant replication-defective chimpanzee adenovirus expressing the SARS-CoV-2 spike (S) surface glycoprotein<br>* Other names: Vaxzevria;|
| Experimental: Moderna Standard Dose after CoronaVac priming<br>Moderna (mRNA-1273 or Spikevax®) Dose: 50ug in 0.25ml The 100 participants in this arm received second CoronaVac priming dose at least 6 months prior to randomisation. | Biological: Moderna Standard dose<br>* Standard dose (50ug in 0.25ml)<br>* Other names: Spikevax®;|
| Experimental: Moderna Fractional Dose after CoronaVac priming<br>Moderna (mRNA-1273 or Spikevax®) Dose: 20ug in 0.1ml The 100 participants in this arm received second CoronaVac priming dose at least 6 months prior to randomisation. | Biological: Moderna Fractional dose<br>* Fractional dose (20ug in 0.1ml)<br>* Other names: Spikevax®;|
| Experimental: Pfizer-BioNTech Standard dose after AstraZeneca priming<br>Pfizer-BioNTech (BNT162b2, or Comirnaty®) Dose: 30ug in 0.3ml The 50 participants in this arm received second AstraZeneca priming dose at least 6 months prior to randomisation. | Biological: Pfizer-BioNTech Standard dose<br>* Standard Dose - (30ug in 0.3ml) 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).<br>* Other names: Comirnaty;|
| Experimental: Pfizer-BioNTech Fractional dose after AstraZeneca priming<br>Pfizer-BioNTech (BNT162b2, or Comirnaty®) Dose: 15ug in 0.15ml The 50 participants in this arm received second AstraZeneca priming dose at least 6 months prior to randomisation. | Biological: Pfizer-BioNTech Fractional dose<br>* Fractional Dose - (15ug in 0.15ml) 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).<br>* Other names: Comirnaty;|
| Experimental: AstraZeneca Standard dose after AstraZeneca priming<br>AstraZeneca (ChAdOx1-S, Vaxzevria®). Dose: 0.5ml The 50 participants in this arm received second AstraZeneca priming dose at least 6 months prior to randomisation. | Biological: AstraZeneca Standard dose<br>* Standard Dose (5xE10vp in 0.5ml) ChAdOx1 nCoV-19 is a recombinant replication-defective chimpanzee adenovirus expressing the SARS-CoV-2 spike (S) surface glycoprotein<br>* Other names: Vaxzevria;|
| Experimental: AstraZeneca Fractional dose after AstraZeneca priming<br>AstraZeneca (ChAdOx1-S, Vaxzevria®). Dose: 0.25ml The 50 participants in this arm received second AstraZeneca priming dose at least 6 months prior to randomisation. | Biological: AstraZeneca Fractional dose<br>* Fractional Dose (2.5E10vp in 0.25ml) ChAdOx1 nCoV-19 is a recombinant replication-defective chimpanzee adenovirus expressing the SARS-CoV-2 spike (S) surface glycoprotein<br>* Other names: Vaxzevria;|
| Experimental: Moderna Standard Dose after AstraZeneca priming<br>Moderna (mRNA-1273 or Spikevax®) Dose: 50ug in 0.25ml The 100 participants in this arm received second AstraZeneca priming dose at least 6 months prior to randomisation. | Biological: Moderna Standard dose<br>* Standard dose (50ug in 0.25ml)<br>* Other names: Spikevax®;|
| Experimental: Moderna Fractional Dose afterAstraZeneca priming<br>Moderna (mRNA-1273 or Spikevax®) Dose: 20ug in 0.1 The 100 participants in this arm received second AstraZeneca priming dose at least 6 months prior to randomisation. | Biological: Moderna Fractional dose<br>* Fractional dose (20ug in 0.1ml)<br>* Other names: Spikevax®;|

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 IgG CMIA. The primary endpoint is the seroresponse rate at the Day-28 visit. The Seroresponse rate at the individual level is defined as either a ≥4-fold rise in binding antibodies at the Day-28 visit compared to baseline (pre-vaccination) with a titre of <200 BAU/ml, a ≥2-fold rise among participants with a baseline (pre-vaccination) titre of >≥200 BAU/ml, or ≥4 times the lower limit of detection if baseline levels are lower than the limit of detection. | Assessed at 28 days | 
| Incidence of solicited systemic and local reactions (reactogenicity) | Questionnaire to document solicited reactions is developed specifically for this study. Data will be reported as the proportion of participants who report grade 3 or 4 reactions by each intervention arm. Solicited reactions such as pain, tenderness, erythema/redness, induration, swelling, fever, nausea, vomiting, headache, fatigue/malaise, myalgia, arthralgia, diarrhea, enlarged lymph nodes will be collected from the participants 7 days post-vaccination. | Assessed for 7 days post-vaccination | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| SARS-CoV-2 specific IgG antibodies at baseline (pre booster), 6- and 12-months post booster vaccination. | Serum samples collected at baseline (pre booster), 28 days, and 6- and 12-months post booster vaccination from all groups will be evaluated for SARS-CoV-2 specific IgG antibodies using IgG CMIA. Data will be reported as binding antibody units (BAU)/mL and presented as geometric mean concentration (GMC) and 95% confidence intervals (CI) | Assessed at time-points: baseline, 28 days, 6 months, and 12 months). | 
| 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. | Assessed at 4 time-points (baseline, 28 days, 6 months, and 12 months). | 
| SARS-CoV-2 specific neutralising antibodies at baseline (pre booster), 28 days-, 6- and 12-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. | Assessed at 4 time-points (baseline, 28 days, 6 months, and 12 months). | 
| Interferon gamma (IFNγ) concentrations in International Units (IU)/mL | Applicable to the subset participants with additional blood collection. Interferon gamma (IFNγ) concentrations as a measurement of cellular immunity will be assessed on a subset 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 (enzyme-linked immunosorbent assay). Data will be presented as geometric mean concentration (GMC) and 95% confidence intervals (CI). | Assessed at 4 time-points (baseline, 28 days, 6 months, and 12 months). | 
| Number of IFNγ producing cells/million PBMCs | Applicable to the subset participants with additional blood collection. IFNγ producing cells as a measurement of cellular immunity will be assessed on a subset 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. | Assessed at 4 time-points (baseline, 28 days, 6 months, and 12 months). | 
| Frequency of cytokine-expressing T cells | Applicable to the subset participants with additional blood collection. Frequency of cytokine-expressing T cells will be assessed on a subset 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. | Assessed at 4 time-points (baseline, 28 days, 6 months, and 12 months). | 
| Cytokine concentrations following PBMCs stimulation | Applicable to the subset participants with additional blood collection. 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.IFN-γ Elispot, intracellular cytokine assays (flow cytometry) and multiplex cytokine assays will be performed on isolated peripheral blood mononuclear cells (PBMCs) | Assessed at 4 time-points (baseline, 28 days, 6 months, and 12 months). | 
| 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 for all AE | 
| Incidence of medically attended adverse events | 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 for medically attended AE | 
| Incidence of serious adverse events (SAE) | SAE will be collected throughout the follow up period of 12 months. Data will be presented as a proportion of participants who report SAE. | 12 months post booster vaccination for SAE | 
| Incidence of confirmed COVID-19 infection | Confirmed (Polymerase Chain Reaction [PCR] or rapid antigen test) COVID-19 infections will be documented throughout the follow-up period, by clinical severity | Throughout the follow up period of 12 months. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Booster, fractional and standard doses, Pfizer, Astrazeneca, Moderna, COVID-19 vaccination, mRNA vaccine