COVID-19 Variant Immunologic Landscape Trial (COVAIL Trial)

Phase 2

Completed

• Conditions: COVID-19
• Interventions: Biological: mRNA-1273.351; Biological: mRNA-1273; Biological: BNT162b2 (B.1.1.529); Biological: BNT162b2; Drug: AS03; Biological: BNT162b2 bivalent (wildtype and Omicron BA.1); Biological: BNT162b2 bivalent (wildtype and Omicron BA.4/BA.5); Other: Sodium Chloride, 0.9%; Biological: mRNA-1273.529; Biological: mRNA-1273.617.2; Biological: BNT162b2 (B.1.351); Biological: CoV2 preS dTM/D614; Biological: CoV2 preS dTM [B.1.351]; Biological: CoV2 preS dTM/D614+B.1.351

• Registration Number: NCT05289037
• Lead Sponsor: National Institute of Allergy and Infectious Diseases (NIAID)

Brief Summary

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

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.

Study Timeline

• Study First Submitted: 2022-03-17
• Study First Submitted QC: 2022-03-18
• Study First Posted: 2022-03-21
• Study Start: 2022-03-30
• Status Verified: 2022-10-03
• Primary Completion: 2023-11-22
• Study Completion: 2023-11-27
• Last Update Submitted: 2024-08-09
• Last Update Posted: 2024-08-13

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 1270

Inclusion Criteria

Participants must meet all of the following criteria to be eligible to participate in this study:

1. Individuals > / = 18 years of age at the time of consent. (18-49 years for stage 4).
2. 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.
3. Willing and able to comply with all scheduled visits, vaccination plan, laboratory tests and other study procedures.
4. 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.

Read More

Exclusion Criteria

Participants meeting any of the following criteria will be excluded from the study:

1. Confirmed SARS-CoV-2 infection < 16 weeks prior to any study vaccine dose.

2. Pregnant and breastfeeding participants.

3. 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.

4. Current/planned simultaneous participation in another interventional study or receipt of any investigational study product within 28 days prior to vaccine study dose(s).

5. 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.

6. A history of myocarditis or pericarditis at any time prior to enrollment (for subjects in stages 1, 2 and 4).

7. 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.

8. 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.

9. Current or previous diagnosis of an immunocompromising condition or other immunosuppressive condition.

10. Advanced liver or kidney diseases.

11. Advanced (CD4 count < 200) and/or untreated HIV, untreated Hepatitis B or untreated Hepatitis C.

12. 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.

13. Received immunoglobulin or blood-derived products, within 3 months prior any study vaccine dose.

14. Received chemotherapy, immunotherapy or radiation therapy within 6 months prior to any study vaccine dose.

15. Study personnel or an immediate family member or household member of study personnel.

16. 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.

17. Plan to receive a COVID-19 booster vaccine outside of the study within the next 180 days. (for subjects in Stage 4 only)

Read More

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Arm 01	Sodium Chloride, 0.9%	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
Arm 02	mRNA-1273.351	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
Arm 02	mRNA-1273.529	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
Arm 02	Sodium Chloride, 0.9%	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
Arm 03	mRNA-1273.351	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
Arm 01	mRNA-1273	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
Arm 03	mRNA-1273.529	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
Arm 03	Sodium Chloride, 0.9%	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
Arm 04	mRNA-1273.529	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
Arm 04	mRNA-1273.617.2	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
Arm 08	BNT162b2 (B.1.351)	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
Arm 09	BNT162b2 (B.1.1.529)	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
Arm 04	Sodium Chloride, 0.9%	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
Arm 05	mRNA-1273.529	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
Arm 05	Sodium Chloride, 0.9%	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
Arm 06	mRNA-1273	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
Arm 06	mRNA-1273.529	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
Arm 06	Sodium Chloride, 0.9%	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
Arm 07	BNT162b2	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
Arm 08	BNT162b2 (B.1.1.529)	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
Arm 10	BNT162b2 (B.1.351)	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
Arm 11	BNT162b2	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
Arm 11	BNT162b2 (B.1.351)	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
Arm 12	BNT162b2	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
Arm 12	BNT162b2 (B.1.1.529)	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
Arm 13	AS03	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
Arm 13	CoV2 preS dTM/D614	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
Arm 14	AS03	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
Arm 14	CoV2 preS dTM [B.1.351]	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
Arm 15	AS03	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
Arm 15	CoV2 preS dTM/D614+B.1.351	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
Arm 16	BNT162b2 bivalent (wildtype and Omicron BA.1)	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
Arm 17	BNT162b2 bivalent (wildtype and Omicron BA.4/BA.5)	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

Primary Outcome Measures

Name	Time	Method
Change in Geometric Mean Ratio	Day 1 through Day 366	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.
Change from baseline in Geometric Mean Fold Rise (GMFR)	Day 1 through Day 366	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.
Change from baseline in Geometric Mean Titers (GMT)	Day 1 through Day 366	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.

Secondary Outcome Measures

Name	Time	Method
Incidence of Adverse Events of Special Interest (AESI)	Day 1 through Day 366
Incidence of Serious Adverse Events (SAE)	Day 1 through Day 366
Adverse Events (AEs) leading to withdrawal from the study	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 Solicited Adverse Events	Day 1 through Day 8	Local and systemic events
Incidence of Unsolicited Adverse Events	Day 1 through Day 29

Trial Locations

Locations (20)

University of Texas Medical Branch; 🇺🇸 League City, Texas, United States

Tulane University Clinical Translational Unit; 🇺🇸 New Orleans, Louisiana, United States

Washington University School of Medicine in St. Louis - Infectious Disease Clinical Research Unit; 🇺🇸 Saint Louis, Missouri, United States

NYU Grossman School, NYU Langone Vaccine Center, Long Island; 🇺🇸 Mineola, New York, United States

University of Iowa Hospitals & Clinics - Department of Internal Medicine; 🇺🇸 Iowa City, Iowa, United States

University of Alabama at Birmingham School of Medicine - Alabama Vaccine Research Clinic; 🇺🇸 Birmingham, Alabama, United States

Zuckerberg San Francisco General Hospital, UCSF Positive Health Program; 🇺🇸 San Francisco, California, United States

Duke Vaccine and Trials Unit; 🇺🇸 Durham, North Carolina, United States

Kaiser Permanente Washington Health Research Institute; 🇺🇸 Seattle, Washington, United States

The University of Washington - Virology Research Clinic; 🇺🇸 Seattle, Washington, United States

George Washington University Medical Faculty Associates; 🇺🇸 Washington, District of Columbia, United States

Morehouse School of Medicine - Clinical Research Center; 🇺🇸 Atlanta, Georgia, United States

Howard University - Department of Medicine - Division of Infectious Disease; 🇺🇸 Washington, District of Columbia, United States

Emory University School of Medicine; 🇺🇸 Atlanta, Georgia, United States

University of Illinois at Chicago College of Medicine - Division of Infectious Diseases; 🇺🇸 Chicago, Illinois, United States

Brigham and Women's Hospital; 🇺🇸 Boston, Massachusetts, United States

Saint Louis University Center for Vaccine Development; 🇺🇸 Saint Louis, Missouri, United States

NYU Langone Vaccine Center Research Clinic, Manhattan; 🇺🇸 New York, New York, United States

The Hope Clinic of Emory University; 🇺🇸 Decatur, Georgia, United States

University of Rochester Medical Center - Vaccine Research Unit; 🇺🇸 Rochester, New York, United States