COVID-19 Variant Immunologic Landscape Trial (COVAIL Trial)

Study Overview
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Brief Summary
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This phase 2 clinical trial will evaluate the safety and immunogenicity of additional doses of prototype and variant (alone or in combination) vaccine candidates in previously vaccinated participants with or without prior severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and will evaluate innate, cellular, and humoral immune responses to inform on how to shift the immune response to cover new variants as they emerge. A randomized open-label, non-placebo controlled, multi-site, multi-stage clinical trial in individuals, 18 years of age and older, who are in a stable state of health, has received a complete authorized/approved vaccine series (primary series + booster either with homologous or heterologous vaccine products) >/ = 16 weeks prior to enrollment. Subjects will be stratified by i) age (18-64 years and = 65 years of age) (however arms 16 and 17 or stage 4 will only enroll participants between the ages of 18-49 years) and ii) history of confirmed prior SARS-CoV-2 infection, and randomly assigned to receive one of several variant vaccines. Enrollment will target a goal of approximately 45% of each of the variant vaccine arms to be in older adults (= 65 years of age) for stages 1, 2 and 3 and approximately 20% to have had confirmed COVID-19 for all 4 stages. The primary objective is to evaluate humoral immune responses of candidate SARS-CoV-2 variant vaccines, alone or in combination.

Detailed Description
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This phase 2 clinical trial will evaluate the safety and immunogenicity of additional doses of prototype and variant (alone or in combination) vaccine candidates in previously vaccinated participants with or without prior severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and will evaluate innate, cellular, and humoral immune responses to inform on how to shift the immune response to cover new variants as they emerge. A randomized open-label, non-placebo controlled, multi-site, multi-stage clinical trial in individuals, 18 years of age and older, who are in a stable state of health, has received a complete authorized/approved vaccine series (primary series + booster either with homologous or heterologous vaccine products) >/= 16 weeks prior to enrollment. Subjects will be stratified by i) age (18-64 years and = 65 years of age) (however arms 16 and 17 or stage 4 will only enroll participants between the ages of 18-49 years) and ii) history of confirmed prior SARS-CoV-2 infection, and randomly assigned to receive one of several variant vaccines. Enrollment will target a goal of approximately 45% of each of the variant vaccine arms to be in older adults (= 65 years of age) for stages 1, 2 and 3 and approximately 20% to have had confirmed COVID-19 for all 4 stages. This is an adaptive design and may add arms of new vaccine platforms and/or variant lineage spike vaccines as needed. The study arms will be conducted in different stages (that could overlap) depending on public health needs and the availability of study products (starting with the available mRNA vaccines). The primary objective is to evaluate humoral immune responses of candidate SARS-CoV-2 variant vaccines, alone or in combination. The secondary objective is to evaluate the safety of candidate SARS-CoV-2 variant vaccines, as assessed by: a) Local and systemic solicited Adverse Events for 7 days following each vaccine dose; b) Unsolicited Adverse Events from Dose 1 to 28 days following each vaccine dose; c) Serious Adverse Events (SAEs), Medically Attended Adverse Events (MAAEs), Adverse Events of Special Interests (AESIs), New Onset of Chronic Medical (NOCMCs) and Adverse Events (AEs) leading to withdrawal from the study from Dose 1 to 12 months after last vaccine dose.

Official Title
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Phase 2 Clinical Trial to Optimize Immune Coverage of SARS-CoV-2 Existing and Emerging Variants

Conditions
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COVID-19

Intervention / Treatment
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* Drug: AS03
* Biological: BNT162b2
* Biological: BNT162b2 (B.1.1.529)
* Biological: BNT162b2 (B.1.351)
* Biological: BNT162b2 bivalent (wildtype and Omicron BA.1)
* Biological: BNT162b2 bivalent (wildtype and Omicron BA.4/BA.5)
* Biological: CoV2 preS dTM [B.1.351]
* Biological: CoV2 preS dTM/D614
* Biological: CoV2 preS dTM/D614+B.1.351
* Biological: mRNA-1273
* Biological: mRNA-1273.351
* Biological: mRNA-1273.529
* Biological: mRNA-1273.617.2
* Other: Sodium Chloride, 0.9%


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Participants must meet all of the following criteria to be eligible to participate in this study: Individuals > / = 18 years of age at the time of consent. (18-49 years for stage 4). Confirmed receipt of a complete primary and booster COVID-19 vaccine series, either homologous or heterologous, with an FDA authorized/approved vaccine at least 16 weeks prior to study vaccine dose 1. Willing and able to comply with all scheduled visits, vaccination plan, laboratory tests and other study procedures. Determined by medical history, targeted physical examination and clinical judgement of the investigator to be in stable state of health. Note: Participants with pre-existing stable chronic medical conditions defined as condition not requiring significant change in therapy or hospitalization for worsening disease within 4 weeks from enrollment, can be included at the discretion of the investigator. Exclusion Criteria: Participants meeting any of the following criteria will be excluded from the study: Confirmed SARS-CoV-2 infection < 16 weeks prior to any study vaccine dose. Pregnant and breastfeeding participants. Prior administration of an investigational coronavirus vaccine at any time or SARS-CoV-2 immunoglobulin, monoclonal antibody or plasma antibody therapy in the preceding 3 months. Note: subjects that participated in clinical trials of products that are now FDA approved/authorized are allowed to participate. Current/planned simultaneous participation in another interventional study or receipt of any investigational study product within 28 days prior to vaccine study dose(s). A history of anaphylaxis, urticaria, or other significant adverse reaction requiring medical intervention after receipt of a vaccine, polyethylene glycol (PEG), polysorbate or nanolipid particles. A history of myocarditis or pericarditis at any time prior to enrollment (for subjects in stages 1, 2 and 4). Received or plans to receive a vaccine within 28 days prior to or after any dose of study vaccine. Note: Receipt of seasonal influenza vaccine is allowed at any time. Bleeding disorder diagnosed by a healthcare provider (e.g., factor deficiency, coagulopathy, or platelet disorder requiring special precautions) or bleeding difficulties with intramuscular injections or blood draws. Current or previous diagnosis of an immunocompromising condition or other immunosuppressive condition. Advanced liver or kidney diseases. Advanced (CD4 count < 200) and/or untreated HIV, untreated Hepatitis B or untreated Hepatitis C. Received oral, intramuscular or intravenous systemic immunosuppressants, or immune-modifying drugs for >14 days in total within 6 months prior to any study vaccine dose (for corticosteroids = 20 mg > / = day of prednisone equivalent). Note: Topical medications are allowed. Received immunoglobulin or blood-derived products, within 3 months prior any study vaccine dose. Received chemotherapy, immunotherapy or radiation therapy within 6 months prior to any study vaccine dose. Study personnel or an immediate family member or household member of study personnel. Is acutely ill or febrile 72 hours prior to or at vaccine dosing (fever defined as > / = 38.0 degrees Celsius/100.4 degrees Fahrenheit). Participants meeting this criterion may be rescheduled within the relevant window periods. Note: Afebrile participants with minor illnesses can be enrolled at the discretion of the Investigator, as long as the illness is not suggestive of COVID-19. Plan to receive a COVID-19 booster vaccine outside of the study within the next 180 days. (for subjects in Stage 4 only)

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: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm 01<br>mRNA-1273 administered through 0.2 mg/ml intramuscular injection in the deltoid muscle on Day 1 in participants from 18 to 64; > / = 65 years ( 45% in > / = 65 years) N=100 | Biological: mRNA-1273<br>* Lipid nanoparticle (LNP) dispersion containing an mRNA that encodes for the prefusion stabilized spike (S) protein of the 2019 novel coronavirus (2019-nCoV).<br>Other: Sodium Chloride, 0.9%<br>* 0.9% Sodium Chloride Injection<br>|
| Experimental: Arm 02<br>0.1 mg/ml of mRNA-1273.351 and 0.2 mg/ml of mRNA-1273.529 mg/ml administered through intramuscular injection in the deltoid muscle on Day 1 in participants from 18 to 64; > / = 65 years ( 45% in > / = 65 years) N=100 | Biological: mRNA-1273.351<br>* Lipid nanoparticle (LNP) dispersion containing an mRNA that encodes for the pre fusion stabilized spike (S) protein of the B.1.351 variant SARS-CoV-2 strain.<br>Biological: mRNA-1273.529<br>* Lipid nanoparticle (LNP) dispersion containing an mRNA that encodes for the prefusion stabilized S protein of the B.1.1.529 (Omicron) variant SARS-CoV-2 strain.<br>Other: Sodium Chloride, 0.9%<br>* 0.9% Sodium Chloride Injection<br>|
| Experimental: Arm 03<br>0.1 mg/ml of mRNA-1273.351 and 0.2 mg/ml of mRNA-1273.529 mg/ml administered through intramuscular injection in the deltoid muscle on Day 1 and Day 57 in participants from 18 to 64; > / = 65 years ( 45% in > / = 65 years) N=100 | Biological: mRNA-1273.351<br>* Lipid nanoparticle (LNP) dispersion containing an mRNA that encodes for the pre fusion stabilized spike (S) protein of the B.1.351 variant SARS-CoV-2 strain.<br>Biological: mRNA-1273.529<br>* Lipid nanoparticle (LNP) dispersion containing an mRNA that encodes for the prefusion stabilized S protein of the B.1.1.529 (Omicron) variant SARS-CoV-2 strain.<br>Other: Sodium Chloride, 0.9%<br>* 0.9% Sodium Chloride Injection<br>|
| Experimental: Arm 04<br>0.2 mg/ml of mRNA-1273.617.2 and 0.2 mg/ml of mRNA-1273.529 administered through intramuscular injection in the deltoid muscle on Day 1 in participants from 18 to 64; > / = 65 years ( 45% in > / = 65 years) N=100 | Biological: mRNA-1273.529<br>* Lipid nanoparticle (LNP) dispersion containing an mRNA that encodes for the prefusion stabilized S protein of the B.1.1.529 (Omicron) variant SARS-CoV-2 strain.<br>Biological: mRNA-1273.617.2<br>* Lipid nanoparticle (LNP) dispersion containing an mRNA that encodes for the prefusion stabilized S protein of the B.1.617.2 (Delta) variant SARS-CoV-2 strain.<br>Other: Sodium Chloride, 0.9%<br>* 0.9% Sodium Chloride Injection<br>|
| Experimental: Arm 05<br>0.2 mg/ml of mRNA-1273.529 administered through intramuscular injection in the deltoid muscle on Day 1 in participants from 18 to 64; > / = 65 years ( 45% in > / = 65 years) N=100 | Biological: mRNA-1273.529<br>* Lipid nanoparticle (LNP) dispersion containing an mRNA that encodes for the prefusion stabilized S protein of the B.1.1.529 (Omicron) variant SARS-CoV-2 strain.<br>Other: Sodium Chloride, 0.9%<br>* 0.9% Sodium Chloride Injection<br>|
| Experimental: Arm 06<br>0.2 mg/ml of mRNA-1273.529 and mRNA-1273 0.2 mg/ml administered through intramuscular injection in the deltoid muscle on Day 1 in participants from 18 to 64; > / = 65 years ( 45% in > / = 65 years) N=100 | Biological: mRNA-1273<br>* Lipid nanoparticle (LNP) dispersion containing an mRNA that encodes for the prefusion stabilized spike (S) protein of the 2019 novel coronavirus (2019-nCoV).<br>Biological: mRNA-1273.529<br>* Lipid nanoparticle (LNP) dispersion containing an mRNA that encodes for the prefusion stabilized S protein of the B.1.1.529 (Omicron) variant SARS-CoV-2 strain.<br>Other: Sodium Chloride, 0.9%<br>* 0.9% Sodium Chloride Injection<br>|
| Experimental: Arm 07<br>500 mcg/mL of BNT162b2 (Wildtype) administered through intramuscular injection in the deltoid muscle on Day 1 in participants from 18 to 64; > / = 65 years ( 45% in > / = 65 years) N=50 | Biological: BNT162b2<br>* A nucleoside-modified messenger RNA (modRNA) encoding the viral spike glycoprotein (S) of SARS-CoV-2.<br>|
| Experimental: Arm 08<br>500 mcg/mL of BNT162b2 (Beta) and 500 mcg/mL of BNT162b2 (Omicron) administered through intramuscular injection in the deltoid muscle on Day 1 in participants from 18 to 64; > / = 65 years ( 45% in > / = 65 years) N=50 | Biological: BNT162b2 (B.1.1.529)<br>* A preservative-free, sterile dispersion of RNA formulated in LNP in aqueous cryoprotectant buffer contains mRNA that encodes for the prefusion stabilized S protein of the B.1.1.529 (Omicron) variant SARS-CoV-2 strain.<br>Biological: BNT162b2 (B.1.351)<br>* A preservative-free, sterile dispersion of RNA formulated in LNP in aqueous cryoprotectant buffer contains mRNA that encodes for the prefusion stabilized S protein of the B.1.351 (Beta) variant SARS-CoV-2 strain.<br>|
| Experimental: Arm 09<br>500 mcg/mL of BNT162b2 (Omicron) administered through intramuscular injection in the deltoid muscle on Day 1 and Day 57 in participants from 18 to 64; > / = 65 years ( 45% in > / = 65 years) N=50 | Biological: BNT162b2 (B.1.1.529)<br>* A preservative-free, sterile dispersion of RNA formulated in LNP in aqueous cryoprotectant buffer contains mRNA that encodes for the prefusion stabilized S protein of the B.1.1.529 (Omicron) variant SARS-CoV-2 strain.<br>|
| Experimental: Arm 10<br>500 mcg/mL of BNT162b2 (Beta) administered through intramuscular injection in the deltoid muscle on Day 1 in participants from 18 to 64; > / = 65 years ( 45% in > / = 65 years) N=50 | Biological: BNT162b2 (B.1.351)<br>* A preservative-free, sterile dispersion of RNA formulated in LNP in aqueous cryoprotectant buffer contains mRNA that encodes for the prefusion stabilized S protein of the B.1.351 (Beta) variant SARS-CoV-2 strain.<br>|
| Experimental: Arm 11<br>500 mcg/mL of BNT162b2 (Beta) and 500 mcg/mL of BNT162b2 (Wildtype) administered through intramuscular injection in the deltoid muscle on Day 1 in participants from 18 to 64; > / = 65 years ( 45% in > / = 65 years) N=50 | Biological: BNT162b2<br>* A nucleoside-modified messenger RNA (modRNA) encoding the viral spike glycoprotein (S) of SARS-CoV-2.<br>Biological: BNT162b2 (B.1.351)<br>* A preservative-free, sterile dispersion of RNA formulated in LNP in aqueous cryoprotectant buffer contains mRNA that encodes for the prefusion stabilized S protein of the B.1.351 (Beta) variant SARS-CoV-2 strain.<br>|
| Experimental: Arm 12<br>500 mcg/mL of BNT162b2 (Omicron) and 500 mcg/mL of BNT162b2 (Wildtype) administered through intramuscular injection in the deltoid muscle on Day 1 in participants from 18 to 64; > / = 65 years ( 45% in > / = 65 years) N=50 | Biological: BNT162b2<br>* A nucleoside-modified messenger RNA (modRNA) encoding the viral spike glycoprotein (S) of SARS-CoV-2.<br>Biological: BNT162b2 (B.1.1.529)<br>* A preservative-free, sterile dispersion of RNA formulated in LNP in aqueous cryoprotectant buffer contains mRNA that encodes for the prefusion stabilized S protein of the B.1.1.529 (Omicron) variant SARS-CoV-2 strain.<br>|
| Experimental: Arm 13<br>500 mcg/mL CoV2 preS dTM-AS03 [D614] (prototype) administered through intramuscular injection in the deltoid muscle on Day 1 in participants from 18 to 64; > / = 65 years ( 45% in > / = 65 years) N=50 | Drug: AS03<br>* AS03 oil-in-water emulsion adjuvant.<br>Biological: CoV2 preS dTM/D614<br>* Is a liquid formulation made of recombinant protein placed in a formulation buffer. The antigen solution contains the spike protein sequence of the ancestral strain of SARS-CoV-2.<br>|
| Experimental: Arm 14<br>500 mcg/mL CoV2 preS dTM-AS03 [B.1.351] (Beta) administered through intramuscular injection in the deltoid muscle on Day 1 in participants from 18 to 64; > / = 65 years ( 45% in > / = 65 years) N=50 | Drug: AS03<br>* AS03 oil-in-water emulsion adjuvant.<br>Biological: CoV2 preS dTM [B.1.351]<br>* Is a liquid formulation made of recombinant protein placed in a formulation buffer that contains the spike protein sequence of the B.1.351 (Beta) variant SARS-CoV-2 strain.<br>|
| Experimental: Arm 15<br>500 mcg/mL CoV2 preS dTM-AS03 [D614 + B.1.351] (prototype + Beta) administered through intramuscular injection in the deltoid muscle on Day 1 in participants from 18 to 64; > / = 65 years ( 45% in > / = 65 years) N=50 | Drug: AS03<br>* AS03 oil-in-water emulsion adjuvant.<br>Biological: CoV2 preS dTM/D614+B.1.351<br>* Is a liquid formulation made of recombinant protein placed in a formulation buffer contains the spike protein sequences of the ancestral and B.1.351 (Beta) variant SARS-CoV-2 strains<br>|
| Experimental: Arm 16<br>100 mcg/mL BNT162b2 bivalent (wildtype and Omicron BA.1) + Wildtype (Prototype) administered through intramuscular injection in the deltoid muscle on Day 1 in participants from 18 to 49 years; ( 45% in > / = 49 years) N=100 | Biological: BNT162b2 bivalent (wildtype and Omicron BA.1)<br>* A preservative-free, sterile dispersion of RNA formulated in LNP in aqueous cryoprotectant buffer. Contains mRNA that encodes for the prefusion stabilized S protein of the Omicron BA.1 variant SARS-CoV-2 strain and the ancestral strain of SARS-CoV-2.<br>|
| Experimental: Arm 17<br>100 mcg/mL BNT162b2 bivalent (wildtype and Omicron BA.4/BA.5) + Wildtype (Prototype) administered through intramuscular injection in the deltoid muscle on Day 1 in participants from 18 to 49 years; ( 45% in > / = 49 years) N=100 | Biological: BNT162b2 bivalent (wildtype and Omicron BA.4/BA.5)<br>* A preservative-free, sterile dispersion of RNA formulated in LNP in aqueous cryoprotectant buffer. Contains mRNA that encodes for the prefusion stabilized S protein of the Omicron BA.4/BA.5 variant SARS-CoV-2 strain and the ancestral strain of SARS-CoV-2.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change from baseline in Geometric Mean Fold Rise (GMFR) | As measured by Immunoglobin G (IgG) Enzyme-Linked Immunosorbent Assay (ELISA) or Multiplex Meso Scale Discovery (MSD) antibody binding assays to Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) proteins. Neutralization titers will be calculated by neutralization assays using SARS-CoV-2 variant-specific S-pseudotyped viruses and different strains of live SARS-CoV-2. | Day 1 through Day 366 | 
| Change from baseline in Geometric Mean Titers (GMT) | As measured by Immunoglobin G (IgG) Enzyme-Linked Immunosorbent Assay (ELISA) or Multiplex Meso Scale Discovery (MSD) antibody binding assays to Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) proteins. Neutralization titers will be calculated by neutralization assays using SARS-CoV-2 variant-specific S-pseudotyped viruses and different strains of live SARS-CoV-2. | Day 1 through Day 366 | 
| Change in Geometric Mean Ratio | As measured by Immunoglobin G (IgG) Enzyme-Linked Immunosorbent Assay (ELISA) or Multiplex Meso Scale Discovery (MSD) antibody binding assays to Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) proteins. Neutralization titers will be calculated by neutralization assays using SARS-CoV-2 variant-specific S-pseudotyped viruses and different strains of live SARS-CoV-2. | Day 1 through Day 366 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Adverse Events (AEs) leading to withdrawal from the study |  | Day 1 through Day 366 | 
| Incidence of Adverse Events of Special Interest (AESI) |  | Day 1 through Day 366 | 
| Incidence of Medically Attended Adverse Events (MAAEs) |  | Day 1 through Day 366 | 
| Incidence of New Onset Chronic Medical Conditions (NOCMCs) |  | Day 1 through Day 366 | 
| Incidence of Serious Adverse Events (SAE) |  | Day 1 through Day 366 | 
| Incidence of Solicited Adverse Events | Local and systemic events | Day 1 through Day 8 | 
| Incidence of Unsolicited Adverse Events |  | Day 1 through Day 29 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Adaptive, COVAIL, Covid-19, Multivalent, Omicron, SARS-CoV-2, Vaccine, Variants