Mix and Match of the COVID-19 Vaccine for Safety and Immunogenicity

Study Overview
=================
Brief Summary
-----------------
The main goals of this study are to assess the immune response and safety of two different vaccines for first, second, third and fourth doses as well as for differing intervals between the first and second dose of two-dose vaccines.

Detailed Description
-----------------
For dose 1 and 2, the currently available mRNA vaccines (Pfizer-BioNTech BNT162b2 and Moderna mRNA-1273) are two dose vaccines which were studied in schedules of either 0 and 21 days or 0 and 28 days, respectively. The ChAdOx1 nCOV-19 (Astra-Zeneca) adenovirus-vectored vaccine is authorized to be given in two doses one month to 12 weeks apart. We will compare the interval 0, 28 days to a 0, 112 days (16 weeks) schedule, and assess the immunogenicity of both heterogeneous and heterologous second doses using the Canadian schedule. For dose 3, the currently available mRNA vaccines (Pfizer-BioNTech BNT162b2 and Moderna mRNA-1273) and plant-based virus-like particle (Medicago Covifenz) are anticipated to be administered 6 months apart. We will assess the immunogenicity of both heterogeneous and heterologous third doses using the Canadian schedule. For dose 4, the currently available mRNA vaccines (Pfizer-BioNTech BNT162b2 and Moderna mRNA-1273) and plant-based virus-like particle (Medicago Covifenz) are anticipated to be administered 3 months apart. We will assess the immunogenicity of both heterogeneous and heterologous third doses using the Canadian schedule.

Official Title
-----------------
Immunogenicity and Adverse Events Following Immunization (AEFI) With Alternate Schedules of COVID-19 Vaccines in Canada: is Mix and Match of the Second Dose (MOSAIC-1;CT24a) and Additional Doses (MOSAIC-2 and MOSAIC-3;CT24b and CT24c) Safe and Immunogenic?

Conditions
-----------------
COVID-19

Intervention / Treatment
-----------------
* Biological: mRNA-1273 SARS-CoV-2 vaccine
* Biological: BNT162b2
* Biological: ChAdOx1-S [recombinant]
* Other: 0, 28 day schedule
* Other: 0, 112 day schedule
* Biological: Covifenz


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Participant is willing and able to give written informed consent to participate in the study Age 18 years of age or older in good health or with mild or moderate stable co-morbidities at the time of enrolment Able and willing to complete all the scheduled study procedures during the whole study follow-up period If female of child-bearing potential and heterosexually active, has practiced adequate contraception for 30 days prior to injection, has a negative pregnancy test on the day of injection, and has agreed to continue adequate contraception until 3 months after the final dose of study vaccine (Please refer to the definition section for a description of child-bearing potential and adequate contraception) MOSAIC-1 Vaccine-exposed subgroups: have received or are booked to receive the first dose of an authorized COVID-19 vaccine in the 55 days prior to Visit 1 (documentation of receipt required) MOSAIC -1 Vaccine naïve subgroups: have not received an authorized COVID-19 vaccine at any time MOSAIC-2 participants have received two doses of COVID-19 vaccines authorized in Canada ≥6 months prior to study vaccine administration (documentation of receipt required) MOSAIC-3 participants have received three doses of COVID-19 vaccines authorized in Canada ≥3 months prior to study vaccine administration (documentation of receipt required) Exclusion Criteria: Inability or unwillingness of participant or legally acceptable representative to give written informed consent Any confirmed or suspected immunosuppressive or immunodeficient state; asplenia, or immunosuppressant medication within the past 6 months except short term oral steroids (≤14 days duration) or topical steroids Current diagnosis or treatment for cancer (except basal cell carcinoma of the skin) Administration of immunoglobulins and/or any blood products within 3 months preceding the first dose of study vaccine and for one month after the last dose of study vaccine Allergy to any study vaccine or any active substance in a study vaccine Bleeding disorder or history of significant bleeding following IM injections or venipuncture Continuous use of anticoagulants A history of anaphylaxis to a previous vaccine Pregnancy or intent to become pregnant during the study or within 3 months of the last dose of study vaccine MOSAIC-1: History of laboratory-confirmed COVID-19 disease prior to enrolment by participant report Administration of a live virus vaccine within 4 weeks prior to study vaccine receipt.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 99 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
Accepts Healthy Volunteers

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: M=Moderna SpikeVax mRNA; P=Pfizer/BioNTech Comirnaty mRNA; A=AstraZeneca Vaxzervia; C=Medicago Covifenz VLP MOSAIC 1: Group 1 - M, M - 28 days Group 2 - M, M - 112 days Group 3 - M, P - 28 days Group 4 - M, P - 112 days Group 5 - P, P - 28 days Group 6 - P, P - 112 days Group 7 - P, M - 28 days Group 8 - P, M - 112 days Group 9 - A, M - 28 days Group 10 - A, M - 112 days Group 11 - A, P - 28 days Group 12 - A, P - 112 days MOSAIC 2: Group 1b - P, P, P Group 2b - P, P, M Group 3b - M, M, M Group 4b - M, M, P Group 5b - P and M in any order, M Group 6b - P and M in any order, P Group 7b - A, P or M, P Group 8b - A, P or M, M Group 9b - Any vaccine in any order, C (open-label) MOSAIC 3: Group 1c - P, P, P, P Group 2c - P, P, P, C Group 3c - M, M, M, M Group 4c - M, M, M, C Group 5c - Any 3 in any order, P or M Group 6c - Any 3 in any order, C Group 7c - Any 3 in any order, C (open-label)
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Group 1: Moderna, Moderna - 28 Days apart<br>Participants will be blinded and receive two doses (0.20 mg/mL each) of mRNA-1273 SARS-CoV-2 vaccine via intramuscular injection in the deltoid muscle 28 days apart. Vaccine-exposed participants will only be blinded to, and receive, the second injection. | Biological: mRNA-1273 SARS-CoV-2 vaccine<br>* Contains 1.26 mg of CX-024414 mRNA and 24.38 mg of SM-102 LNP as a white to off-white dispersion in preservative-free diluent buffer at pH 7.5.<br>* Other names: Spikevax;Other: 0, 28 day schedule<br>* Second injection administered 28 days post first injection<br>|
| Active Comparator: Group 2: Moderna, Moderna - 112 days apart<br>Participants will be blinded and receive two doses (0.20 mg/mL each) of mRNA-1273 SARS-CoV-2 vaccine at 0.20 mg/mL via intramuscular injection in the deltoid muscle 112 days apart. Vaccine-exposed participants will only be blinded to, and receive, the second injection. | Biological: mRNA-1273 SARS-CoV-2 vaccine<br>* Contains 1.26 mg of CX-024414 mRNA and 24.38 mg of SM-102 LNP as a white to off-white dispersion in preservative-free diluent buffer at pH 7.5.<br>* Other names: Spikevax;Other: 0, 112 day schedule<br>* Second injection administered 112 days post first injection<br>|
| Active Comparator: Group 3: Moderna, Pfizer/BioNTech - 28 days apart<br>Participants will be blinded and receive one dose (0.20 mg/mL) of mRNA-1273 SARS-CoV-2 vaccine via intramuscular injection in the deltoid muscle followed by one dose (0.3mL) of BNT162b2 vaccine after 28 days. Vaccine-exposed participants will only be blinded to, and receive, the second injection. | Biological: mRNA-1273 SARS-CoV-2 vaccine<br>* Contains 1.26 mg of CX-024414 mRNA and 24.38 mg of SM-102 LNP as a white to off-white dispersion in preservative-free diluent buffer at pH 7.5.<br>* Other names: Spikevax;Biological: BNT162b2<br>* A white to off-white, sterile, preservative-free, frozen suspension for intramuscular injection, supplied with 0.9% sodium chloride diluent for injection plastic ampoules.<br>* Other names: Comirnaty;Other: 0, 28 day schedule<br>* Second injection administered 28 days post first injection<br>|
| Active Comparator: Group 4: Moderna, Pfizer/BioNTech - 112 days apart<br>Participants will be blinded and receive one dose (0.20 mg/mL) of mRNA-1273 SARS-CoV-2 vaccine via intramuscular injection in the deltoid muscle followed by one dose (0.3mL) of BNT162b2 vaccine after 112 days. Vaccine-exposed participants will only be blinded to, and receive, the second injection. | Biological: mRNA-1273 SARS-CoV-2 vaccine<br>* Contains 1.26 mg of CX-024414 mRNA and 24.38 mg of SM-102 LNP as a white to off-white dispersion in preservative-free diluent buffer at pH 7.5.<br>* Other names: Spikevax;Biological: BNT162b2<br>* A white to off-white, sterile, preservative-free, frozen suspension for intramuscular injection, supplied with 0.9% sodium chloride diluent for injection plastic ampoules.<br>* Other names: Comirnaty;Other: 0, 112 day schedule<br>* Second injection administered 112 days post first injection<br>|
| Active Comparator: Group 5: Pfizer/BioNTech, Pfizer/BioNTech - 28 days apart<br>Participants will be blinded and receive two doses (0.3mL each) of BNT162b2 vaccine via intramuscular injection in the deltoid muscle 28 days apart. Vaccine-exposed participants will only be blinded to, and receive, the second injection. | Biological: BNT162b2<br>* A white to off-white, sterile, preservative-free, frozen suspension for intramuscular injection, supplied with 0.9% sodium chloride diluent for injection plastic ampoules.<br>* Other names: Comirnaty;Other: 0, 28 day schedule<br>* Second injection administered 28 days post first injection<br>|
| Active Comparator: Group 6: Pfizer/BioNTech, Pfizer/BioNTech - 112 days apart<br>Participants will be blinded and receive two doses (0.3mL each) of BNT162b2 vaccine via intramuscular injection in the deltoid muscle 112 days apart. Vaccine-exposed participants will only be blinded to, and receive, the second injection. | Biological: BNT162b2<br>* A white to off-white, sterile, preservative-free, frozen suspension for intramuscular injection, supplied with 0.9% sodium chloride diluent for injection plastic ampoules.<br>* Other names: Comirnaty;Other: 0, 112 day schedule<br>* Second injection administered 112 days post first injection<br>|
| Active Comparator: Group 7: Pfizer/BioNTech, Moderna - 28 days apart<br>Participants will be blinded and receive one dose (0.3mL) of BNT162b2 vaccine via intramuscular injection in the deltoid muscle followed by one dose (0.20 mg/mL) of mRNA-1273 SARS-CoV-2 vaccine after 28 days. Vaccine-exposed participants will only be blinded to, and receive, the second injection. | Biological: mRNA-1273 SARS-CoV-2 vaccine<br>* Contains 1.26 mg of CX-024414 mRNA and 24.38 mg of SM-102 LNP as a white to off-white dispersion in preservative-free diluent buffer at pH 7.5.<br>* Other names: Spikevax;Biological: BNT162b2<br>* A white to off-white, sterile, preservative-free, frozen suspension for intramuscular injection, supplied with 0.9% sodium chloride diluent for injection plastic ampoules.<br>* Other names: Comirnaty;Other: 0, 28 day schedule<br>* Second injection administered 28 days post first injection<br>|
| Active Comparator: Group 8: Pfizer/BioNTech, Moderna - 112 days apart<br>Participants will be blinded and receive one dose (0.3mL) of BNT162b2 vaccine via intramuscular injection in the deltoid muscle followed by one dose (0.20 mg/mL) of mRNA-1273 SARS-CoV-2 vaccine after 112 days. Vaccine-exposed participants will only be blinded to, and receive, the second injection. | Biological: mRNA-1273 SARS-CoV-2 vaccine<br>* Contains 1.26 mg of CX-024414 mRNA and 24.38 mg of SM-102 LNP as a white to off-white dispersion in preservative-free diluent buffer at pH 7.5.<br>* Other names: Spikevax;Biological: BNT162b2<br>* A white to off-white, sterile, preservative-free, frozen suspension for intramuscular injection, supplied with 0.9% sodium chloride diluent for injection plastic ampoules.<br>* Other names: Comirnaty;Other: 0, 112 day schedule<br>* Second injection administered 112 days post first injection<br>|
| Active Comparator: Group 9: Astra Zeneca, Moderna - 28 days apart<br>Participants will be blinded and receive one dose (0.5 ml) of ChAdOx1-S [recombinant] vaccine via intramuscular injection in the deltoid muscle followed by one dose (0.20 mg/mL) of mRNA-1273 SARS-CoV-2 vaccine after 28 days. Vaccine-exposed participants will only be blinded to, and receive, the second injection. | Biological: mRNA-1273 SARS-CoV-2 vaccine<br>* Contains 1.26 mg of CX-024414 mRNA and 24.38 mg of SM-102 LNP as a white to off-white dispersion in preservative-free diluent buffer at pH 7.5.<br>* Other names: Spikevax;Biological: ChAdOx1-S [recombinant]<br>* A colourless to slightly brown, clear to slightly opaque solution containing 5 x 1010 viral particles (not less than 2.5 x 108 infectious units).<br>* Other names: Vaxzevria;Other: 0, 28 day schedule<br>* Second injection administered 28 days post first injection<br>|
| Active Comparator: Group 10: Astra Zeneca, Moderna - 112 days apart<br>Participants will be blinded and receive one dose (0.5 ml) of ChAdOx1-S [recombinant] vaccine via intramuscular injection in the deltoid muscle followed by one dose (0.20 mg/mL) of mRNA-1273 SARS-CoV-2 vaccine after 112 days. Vaccine-exposed participants will only be blinded to, and receive, the second injection. | Biological: mRNA-1273 SARS-CoV-2 vaccine<br>* Contains 1.26 mg of CX-024414 mRNA and 24.38 mg of SM-102 LNP as a white to off-white dispersion in preservative-free diluent buffer at pH 7.5.<br>* Other names: Spikevax;Biological: ChAdOx1-S [recombinant]<br>* A colourless to slightly brown, clear to slightly opaque solution containing 5 x 1010 viral particles (not less than 2.5 x 108 infectious units).<br>* Other names: Vaxzevria;Other: 0, 112 day schedule<br>* Second injection administered 112 days post first injection<br>|
| Active Comparator: Group 11: Astra Zeneca, Pfizer/BioNTech - 28 days apart<br>Participants will be blinded and receive one dose (0.5 ml) of ChAdOx1-S [recombinant] vaccine via intramuscular injection in the deltoid muscle followed by one dose (0.3 mL) of BNT162b2 vaccine after 28 days. Vaccine-exposed participants will only be blinded to, and receive, the second injection. | Biological: BNT162b2<br>* A white to off-white, sterile, preservative-free, frozen suspension for intramuscular injection, supplied with 0.9% sodium chloride diluent for injection plastic ampoules.<br>* Other names: Comirnaty;Biological: ChAdOx1-S [recombinant]<br>* A colourless to slightly brown, clear to slightly opaque solution containing 5 x 1010 viral particles (not less than 2.5 x 108 infectious units).<br>* Other names: Vaxzevria;Other: 0, 28 day schedule<br>* Second injection administered 28 days post first injection<br>|
| Active Comparator: Group 12: Astra Zeneca, Pfizer/BioNTech - 112 days apart<br>Participants will be blinded and receive one dose (0.5 ml) of ChAdOx1-S [recombinant] vaccine via intramuscular injection in the deltoid muscle followed by one dose (0.3 mL) of BNT162b2 vaccine after 112 days. Vaccine-exposed participants will only be blinded to, and receive, the second injection. | Biological: BNT162b2<br>* A white to off-white, sterile, preservative-free, frozen suspension for intramuscular injection, supplied with 0.9% sodium chloride diluent for injection plastic ampoules.<br>* Other names: Comirnaty;Biological: ChAdOx1-S [recombinant]<br>* A colourless to slightly brown, clear to slightly opaque solution containing 5 x 1010 viral particles (not less than 2.5 x 108 infectious units).<br>* Other names: Vaxzevria;Other: 0, 112 day schedule<br>* Second injection administered 112 days post first injection<br>|
| Active Comparator: Group 1b<br>Participants will be blinded and receive one dose (0.3mL) of BNT162b2 vaccine via intramuscular injection in the deltoid muscle. | Biological: BNT162b2<br>* A white to off-white, sterile, preservative-free, frozen suspension for intramuscular injection, supplied with 0.9% sodium chloride diluent for injection plastic ampoules.<br>* Other names: Comirnaty;|
| Active Comparator: Group 2b<br>Participants will be blinded and receive one half dose (0.25mL) of mRNA-1273 vaccine via intramuscular injection in the deltoid muscle. | Biological: mRNA-1273 SARS-CoV-2 vaccine<br>* Contains 1.26 mg of CX-024414 mRNA and 24.38 mg of SM-102 LNP as a white to off-white dispersion in preservative-free diluent buffer at pH 7.5.<br>* Other names: Spikevax;|
| Active Comparator: Group 3b<br>Participants will be blinded and receive one half dose (0.25mL) of mRNA-1273 vaccine via intramuscular injection in the deltoid muscle. | Biological: mRNA-1273 SARS-CoV-2 vaccine<br>* Contains 1.26 mg of CX-024414 mRNA and 24.38 mg of SM-102 LNP as a white to off-white dispersion in preservative-free diluent buffer at pH 7.5.<br>* Other names: Spikevax;|
| Active Comparator: Group 4b<br>Participants will be blinded and receive one dose (0.3mL) of BNT162b2 vaccine via intramuscular injection in the deltoid muscle. | Biological: BNT162b2<br>* A white to off-white, sterile, preservative-free, frozen suspension for intramuscular injection, supplied with 0.9% sodium chloride diluent for injection plastic ampoules.<br>* Other names: Comirnaty;|
| Active Comparator: Group 5b<br>Participants will be blinded and receive one half dose (0.25mL) of mRNA-1273 vaccine via intramuscular injection in the deltoid muscle. | Biological: mRNA-1273 SARS-CoV-2 vaccine<br>* Contains 1.26 mg of CX-024414 mRNA and 24.38 mg of SM-102 LNP as a white to off-white dispersion in preservative-free diluent buffer at pH 7.5.<br>* Other names: Spikevax;|
| Active Comparator: Group 6b<br>Participants will be blinded and receive one dose (0.3mL) of BNT162b2 vaccine via intramuscular injection in the deltoid muscle. | Biological: BNT162b2<br>* A white to off-white, sterile, preservative-free, frozen suspension for intramuscular injection, supplied with 0.9% sodium chloride diluent for injection plastic ampoules.<br>* Other names: Comirnaty;|
| Active Comparator: Group 7b<br>Participants will be blinded and receive one dose (0.3mL) of BNT162b2 vaccine via intramuscular injection in the deltoid muscle. | Biological: BNT162b2<br>* A white to off-white, sterile, preservative-free, frozen suspension for intramuscular injection, supplied with 0.9% sodium chloride diluent for injection plastic ampoules.<br>* Other names: Comirnaty;|
| Active Comparator: Group 8b<br>Participants will be blinded and receive one half dose (0.25mL) of mRNA-1273 vaccine via intramuscular injection in the deltoid muscle. | Biological: mRNA-1273 SARS-CoV-2 vaccine<br>* Contains 1.26 mg of CX-024414 mRNA and 24.38 mg of SM-102 LNP as a white to off-white dispersion in preservative-free diluent buffer at pH 7.5.<br>* Other names: Spikevax;|
| Experimental: Group 9b<br>Participants will receive one dose (0.5mL) of Covifenz vaccine via intramuscular injection in the deltoid muscle. | Biological: Covifenz<br>* COVIFENZ is an emulsion for intramuscular injection. The 3.75 mcg antigen component of COVIFENZ is a suspension, which must be mixed 1:1 with the 0.25 mL AS03 adjuvant emulsion component prior to administration<br>* Other names: Medicago COVID-19 vaccine;|
| Active Comparator: Group 1c<br>Participants will be blinded and receive one dose (0.3mL) of BNT162b2 vaccine via intramuscular injection in the deltoid muscle. | Biological: BNT162b2<br>* A white to off-white, sterile, preservative-free, frozen suspension for intramuscular injection, supplied with 0.9% sodium chloride diluent for injection plastic ampoules.<br>* Other names: Comirnaty;|
| Active Comparator: Group 2c<br>Participants will be blinded and receive one dose (0.5mL) of Covifenz vaccine via intramuscular injection in the deltoid muscle. | Biological: Covifenz<br>* COVIFENZ is an emulsion for intramuscular injection. The 3.75 mcg antigen component of COVIFENZ is a suspension, which must be mixed 1:1 with the 0.25 mL AS03 adjuvant emulsion component prior to administration<br>* Other names: Medicago COVID-19 vaccine;|
| Active Comparator: Group 3c<br>Participants will be blinded and receive one half dose (0.25mL) of mRNA-1273 vaccine via intramuscular injection in the deltoid muscle. | Biological: mRNA-1273 SARS-CoV-2 vaccine<br>* Contains 1.26 mg of CX-024414 mRNA and 24.38 mg of SM-102 LNP as a white to off-white dispersion in preservative-free diluent buffer at pH 7.5.<br>* Other names: Spikevax;|
| Active Comparator: Group 4c<br>Participants will be blinded and receive one dose (0.5mL) of Covifenz vaccine via intramuscular injection in the deltoid muscle. | Biological: Covifenz<br>* COVIFENZ is an emulsion for intramuscular injection. The 3.75 mcg antigen component of COVIFENZ is a suspension, which must be mixed 1:1 with the 0.25 mL AS03 adjuvant emulsion component prior to administration<br>* Other names: Medicago COVID-19 vaccine;|
| Active Comparator: Group 5c<br>Participants will be blinded and receive either one dose (0.3mL) of BNT162b2 or one half dose (0.25mL) of mRNA-1273 via intramuscular injection in the deltoid muscle. | Biological: mRNA-1273 SARS-CoV-2 vaccine<br>* Contains 1.26 mg of CX-024414 mRNA and 24.38 mg of SM-102 LNP as a white to off-white dispersion in preservative-free diluent buffer at pH 7.5.<br>* Other names: Spikevax;Biological: BNT162b2<br>* A white to off-white, sterile, preservative-free, frozen suspension for intramuscular injection, supplied with 0.9% sodium chloride diluent for injection plastic ampoules.<br>* Other names: Comirnaty;|
| Active Comparator: Group 6c<br>Participants will be blinded and receive one dose (0.5mL) of Covifenz vaccine via intramuscular injection in the deltoid muscle. | Biological: Covifenz<br>* COVIFENZ is an emulsion for intramuscular injection. The 3.75 mcg antigen component of COVIFENZ is a suspension, which must be mixed 1:1 with the 0.25 mL AS03 adjuvant emulsion component prior to administration<br>* Other names: Medicago COVID-19 vaccine;|
| Experimental: Group 7c<br>Participants will receive one dose (0.5mL) of Covifenz vaccine via intramuscular injection in the deltoid muscle. | Biological: Covifenz<br>* COVIFENZ is an emulsion for intramuscular injection. The 3.75 mcg antigen component of COVIFENZ is a suspension, which must be mixed 1:1 with the 0.25 mL AS03 adjuvant emulsion component prior to administration<br>* Other names: Medicago COVID-19 vaccine;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Antibody response to SARS-CoV-2 S protein after 2 doses | The co-primary outcome for the non-inferiority comparison of 0, 28-day schedules with heterologous second dose is the immune response to SARS-CoV-2 at day 56 (28 days after the second dose of vaccine) based on anti-spike antibody titers. | Day 56 | 
| Antibody response to SARS-CoV-2 S protein after 2 doses | The co-primary outcome for the non-inferiority comparison of schedules in which the timing of the second dose of vaccine is different (0, 28 days v 0, 112 days) is the immune response to SARS-CoV-2 at day 140 (28 days after the last dose in the 0, 112 day schedule) based on anti-spike antibody titers. | Day 140 | 
| Antibody response to SARS-CoV-2 S protein after 3 doses | To determine if a vaccination schedule with a heterologous third dose of a COVID-19 vaccine induces a non-inferior serum immune response to SARS-CoV-2, compared to a third dose/booster with a homologous vaccine. | Day 28 | 
| Antibody response to SARS-CoV-2 S protein after 4 doses | To determine if a vaccination schedule with a heterologous fourth dose of a COVID-19 vaccine induces a non-inferior serum immune response to SARS-CoV-2, compared to a third dose/booster with a homologous vaccine. | Day 28 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Durability of antibody response to SARS-CoV-2 S over 12 months after 2 doses | Assess durability of immune responses in each study group over 12 months based on anti-spike antibody titers and pseudoneutralization assay. | Baseline and Days 28, 56, 112, 140, 365 | 
| Pseudoneutralization assay, T cell testing, Antibody dependent cellular cytotoxicity (ADCC), Antibody avidity, RNA seq after 2 doses | Characterization of the immune response to COVID-19 vaccines in schedules with 0, 28 days versus 0, 112 days dosing and heterologous schedules to day 365. | Days 28, 56, 112, 140, 365 | 
| Incidence of grade 3 solicited local and systemic adverse events, SAEs, AEFIs, MAAEs, AESIs in the 7 days following vaccine receipt after 2 doses | Description of safety outcomes over 12 months post-vaccination including SAEs (serious adverse events), provincially reportable AEFIs (adverse events following immunization), MAAEs (medically attended adverse events), AESIs (adverse events of special interest). | From time of first study injection through Day 365. | 
| Incidence of grade 3 solicited local and systemic adverse events, SAEs, AEFIs, MAAEs, AESIs in the 7 days following vaccine receipt after 3 doses | Description of safety outcomes over 12 months post-vaccination including SAEs (serious adverse events), provincially reportable AEFIs (adverse events following immunization), MAAEs (medically attended adverse events), AESIs (adverse events of special interest). | From time of first study injection through Day 365. | 
| Acceptability of vaccines as determined by participant-completed questionnaire after 2 doses | Four 5 point likert scale type questions asking whether they would want to receive the vaccine again, recommend it to a friend, whether they were anxious about receiving it, and whether they would prefer a more painful injection if it conferred better protection. | Days 56, 140, and 365 | 
| Acceptability of vaccines as determined by participant-completed questionnaire after 3 doses | Four 5 point likert scale type questions asking whether they would want to receive the vaccine again, recommend it to a friend, whether they were anxious about receiving it, and whether they would prefer a more painful injection if it conferred better protection. | Days 28, 180 | 
| Antibody to SARS-CoV-2 S and N, RBD after 3 doses | Assess durability of the immune responses in each study group over 12 months after the study vaccine. | Days 180 and 365 | 
| Pseudoneutralization assay, T cell testing, Antibody dependent cellular cytotoxicity after 3 doses | Further characterize the immune response to COVID-19 vaccine in schedules with homologous and heterologous third doses to day 365 | Day 365 | 
| Incidence of grade 3 solicited local and systemic adverse events, SAEs, AEFIs, MAAEs, AESIs in the 7 days following vaccine receipt after 4 doses | Description of safety outcomes over 12 months post-vaccination including SAEs (serious adverse events), provincially reportable AEFIs (adverse events following immunization), MAAEs (medically attended adverse events), AESIs (adverse events of special interest). | From time of first study injection through Day 365. | 
| Acceptability of vaccines as determined by participant-completed questionnaire after 4 doses | Four 5 point likert scale type questions asking whether they would want to receive the vaccine again(Yes, definitely; Yes, probably; I don't know; No, probably not; No, definitely not), recommend it to a friend(Yes, definitely; Yes, probably; I don't know; No, probably not; No, definitely not), whether they were anxious about receiving it(Not at all; A little; Moderately; Very; Extremely), and whether they would prefer a more painful injection if it conferred better protection(Vaccine A; Vaccine B; No preference; Unsure/don't know). | Days 28, 180 | 
| Antibody to SARS-CoV-2 S and N, RBD after 4 doses | Assess durability of the immune responses in each study group over 12 months after the study vaccine. | Days 180 and 365 | 
| Antibody dependent cellular cytotoxicity after 4 doses | Further characterize the immune response to COVID-19 vaccine in schedules with homologous and heterologous third doses to day 365 | Day 365 | 
| Pseudoneutralization assay after 4 doses | Measuring the 50% Neutralization Titer to further characterize the immune response to COVID-19 vaccine in schedules with homologous and heterologous third doses to day 365 | Day 365 | 
| T cell testing after 4 doses | Measuring the number of T cells to further characterize the immune response to COVID-19 vaccine in schedules with homologous and heterologous third doses to day 365 | Day 365 | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
SARS-CoV-2, vaccine, clinical trial