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

• ClinicalTrials.gov Identifier: NCT05228730
• Recruitment Status: Completed
• First Posted: February 8, 2022
• Last Update Posted: February 8, 2023
• Sponsor: Murdoch Childrens Research Institute
• Collaborators: Coalition for Epidemic Preparedness Innovations; The Peter Doherty Institute for Infection and Immunity
• Information provided by (Responsible Party): Murdoch Childrens Research Institute

Study Description

Brief Summary:

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

Condition or disease	Intervention/treatment	Phase
COVID-19	Biological: Tozinameran - Standard dose; Biological: Tozinameran - fractional dose; Biological: Elasomeran - standard dose; Biological: Elasomeran - fractional dose	Phase 3

Detailed Description:

As per brief summary

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 13 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Intervention 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 (Participant, Outcomes Assessor)
• Masking Description: The participants and those evaluating reactogenicity will be blinded to the vaccine allocation for the first 28 days following vaccination. After that, both clinical investigators and participants will be aware of their investigational product allocation. Laboratory staff will remain blinded to the investigational product allocation during the immunology testing.
• Primary Purpose: Prevention
• Official Title: 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
• Actual Study Start Date: May 2, 2022
• Actual Primary Completion Date: July 25, 2022
• Actual Study Completion Date: November 30, 2022

Arms and Interventions

Arm	Intervention/treatment
Active Comparator: AstraZeneca (ChAdOx1-S, or Vaxzevria®)-Standard Pfizer-BioNTech booster group; Received two doses of AstraZeneca as primary COVID-19 vaccine	Biological: Tozinameran - Standard dose; 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.; Other Names: BNT162b2; Pfizer-BioNTech; Comirnaty
Experimental: AstraZeneca (ChAdOx1-S, or Vaxzevria®)-Fractional Pfizer-BioNTech booster group; Received two doses of AstraZeneca as primary COVID-19 vaccine	Biological: Tozinameran - fractional dose; 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.; Other Names: BNT162b2; Comirnaty; Pfizer-BioNTech
Active Comparator: AstraZeneca (ChAdOx1-S, or Vaxzevria®) Standard Elasomeran booster group; Received two doses of AstraZeneca as primary COVID-19 vaccine	Biological: Elasomeran - standard dose; 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.; Other Names: mRNA-1273; Spikevax; Moderna
Experimental: AstraZeneca (ChAdOx1-S, or Vaxzevria®)-Fractional Elasomeran booster group; Received two doses of AstraZeneca as primary COVID-19 vaccine	Biological: Elasomeran - fractional dose; 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.; Other Names: mRNA-1273; Spikevax; Moderna
Active Comparator: Pfizer-BioNTech (BNT162b2, or Comirnaty®)-Standard Pfizer-BioNTech booster group; Received two doses of Pfizer-BioNTech as primary COVID-19 vaccine	Biological: Tozinameran - Standard dose; 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.; Other Names: BNT162b2; Pfizer-BioNTech; Comirnaty
Experimental: Pfizer-BioNTech (BNT162b2, or Comirnaty®)-Fractional Pfizer-BioNTech booster group; Received two doses of Pfizer-BioNTech as primary COVID-19 vaccine	Biological: Tozinameran - fractional dose; 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.; Other Names: BNT162b2; Comirnaty; Pfizer-BioNTech
Active Comparator: Pfizer-BioNTech (BNT162b2, or Comirnaty®)-Standard Elasomeran booster group; Received two doses of Pfizer-BioNTech as primary COVID-19 vaccine	Biological: Elasomeran - standard dose; 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.; Other Names: mRNA-1273; Spikevax; Moderna
Experimental: Pfizer-BioNTech (BNT162b2, or Comirnaty®)-Fractional Elasomeran booster group; Received two doses of Pfizer-BioNTech as primary COVID-19 vaccine	Biological: Elasomeran - fractional dose; 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.; Other Names: mRNA-1273; Spikevax; Moderna

Outcome Measures

Primary Outcome Measures :

1. SARS-CoV-2 specific Immunoglobulin (Ig)G antibodies at 28-days post booster vaccination [ Time Frame: 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
2. Total incidence of solicited reactions (systemic and local) [ Time Frame: Total incidence of solicited reactions will be measured for 7 days post booster vaccination ]
   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.

Secondary Outcome Measures :

1. SARS-CoV-2 specific IgG antibodies at baseline (pre booster), and 6-months post booster vaccination. [ Time Frame: 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
2. 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) [ Time Frame: Baseline (pre booster), 28 days and 6 months post booster vaccination ]
   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.
3. 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 [ Time Frame: Baseline (pre booster), 28 days-, and 6-months post booster vaccination ]
   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.
4. Interferon gamma (IFNγ) concentrations in International Units (IU)/mL [ Time Frame: Baseline (pre booster), 28 days-, and 6-months post booster vaccination ]
   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).
5. Number of IFNγ producing cells/million PBMCs [ Time Frame: Baseline (pre booster), 28 days-, and 6-months post booster vaccination ]
   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.
6. Frequency of cytokine-expressing T cells [ Time Frame: Baseline (pre booster), 28 days-, and 6-months post booster vaccination ]
   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.
7. Cytokine concentrations following PBMCs stimulation [ Time Frame: Baseline (pre booster), 28 days-, and 16-months post booster vaccination ]
   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.
8. Incidence of unsolicited adverse events (AE) [ Time Frame: 28 days-post booster vaccination ]
   All unsolicited AE will be collected for 28 days post booster vaccination. Data will be presented as proportion of participants who report unsolicited AE.
9. Incidence of medically attended adverse events (AE) [ Time Frame: 3 months post booster vaccination ]
   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.
10. Incidence of serious adverse events (SAE) [ Time Frame: 6 months post booster vaccination ]
    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.

Eligibility Criteria

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

Criteria

Inclusion Criteria:

1. Have completed two doses of Pfizer-BioNTech or AstraZeneca vaccines with the recommended schedule 6 months prior to the date of enrolment
2. Willing and able to give written informed consent
3. Aged 18 years or above
4. Willing to complete the follow-up requirements of the study

Exclusion Criteria:

1. Received 3 doses of COVID-19 vaccine
2. Received 2 doses of COVID-19 less than 6 months prior to the start of the trial
3. Received a different Covid-19 vaccine not available in Australia
4. Currently on immunosuppressive medication or anti-cancer chemotherapy
5. HIV infection
6. Congenital immune deficiency syndrome
7. Has received immunoglobulin or other blood products in the 3 months prior to vaccination
8. Study staff and their relatives
9. Have a history of a severe allergic reaction to any COVID-19 vaccines or have a medical exception to receiving further COVID-19 vaccines
10. Cannot read or understand English

Contacts and Locations

Locations

Australia, Victoria

Royal Children's Hospital

Melbourne, Victoria, Australia, 3010

Sponsors and Collaborators

Murdoch Childrens Research Institute

Coalition for Epidemic Preparedness Innovations

The Peter Doherty Institute for Infection and Immunity

Investigators

• Principal Investigator: Kim Mulholland, MD; Murdoch Childrens Research Institute

More Information

Additional Information:

Coalition for Epidemic Preparedness Innovations (CEPI). Priority List of Adverse Events of Special Interest 

Indonesia reports record number of doctor deaths from COVID-19 in July 

Quarter-dose of Moderna COVID vaccine still rouses a big immune response 

US Food and Drug Administration (FDA). Moderna COVID-19 Vaccine 

US Food and Drug Administration (FDA). Toxicity Grading Scale for Healthy Adult and Adolescent Volunteers Enrolled in Preventive Vaccine Clinical Trials 2007 

Australian Technical Advisory Group on Immunisation (ATAGI). ATAGI recommendations on the use of a booster dose of COVID-19 vaccine 2021 

Publications:

Munro APS, Janani L, Cornelius V, Aley PK, Babbage G, Baxter D, Bula M, Cathie K, Chatterjee K, Dodd K, Enever Y, Gokani K, Goodman AL, Green CA, Harndahl L, Haughney J, Hicks A, van der Klaauw AA, Kwok J, Lambe T, Libri V, Llewelyn MJ, McGregor AC, Minassian AM, Moore P, Mughal M, Mujadidi YF, Murira J, Osanlou O, Osanlou R, Owens DR, Pacurar M, Palfreeman A, Pan D, Rampling T, Regan K, Saich S, Salkeld J, Saralaya D, Sharma S, Sheridan R, Sturdy A, Thomson EC, Todd S, Twelves C, Read RC, Charlton S, Hallis B, Ramsay M, Andrews N, Nguyen-Van-Tam JS, Snape MD, Liu X, Faust SN; COV-BOOST study group. Safety and immunogenicity of seven COVID-19 vaccines as a third dose (booster) following two doses of ChAdOx1 nCov-19 or BNT162b2 in the UK (COV-BOOST): a blinded, multicentre, randomised, controlled, phase 2 trial. Lancet. 2021 Dec 18;398(10318):2258-2276. doi: 10.1016/S0140-6736(21)02717-3. Epub 2021 Dec 2. Erratum In: Lancet. 2021 Dec 18;398(10318):2246.

• Responsible Party: Murdoch Childrens Research Institute
• ClinicalTrials.gov Identifier: NCT05228730
• Other Study ID Numbers: 81764
• First Posted: February 8, 2022
• Last Update Posted: February 8, 2023
• Last Verified: February 2023

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Yes
• Plan Description: We 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.
• Supporting Materials: Study Protocol; Informed Consent Form (ICF)
• Time Frame: Individual participant data (IPD) sharing plans in development
• Access Criteria: IPD sharing plans in development

• 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

Keywords provided by Murdoch Childrens Research Institute:

Booster dose; Moderna; Pfizer; fractional and standard doses; COVID-19 vaccination; mRNA vaccine

Additional relevant MeSH terms:

COVID-19; Respiratory Tract Infections; Infections; Pneumonia, Viral; Pneumonia; Virus Diseases; Coronavirus Infections; Coronaviridae Infections; Nidovirales Infections; RNA Virus Infections; Lung Diseases; Respiratory Tract Diseases