SARS-CoV-2 Immune Responses After COVID-19 Therapy and Subsequent Vaccine

Study Overview
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Brief Summary
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The purpose of this study is to evaluate the safety and efficacy of mRNA COVID-19 vaccines in: • People with prior COVID-19 (SARS-CoV-2 infection) who were in the ACTIV-2/A5401 study. And • People who have never had COVID-19 (SARS-CoV-2 infection).

Detailed Description
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A5404 is a phase IV, open-label study. The objective of A5404 is to evaluate how prior investigational therapy for COVID-19 versus comparator (placebo or active comparator) affects vaccine response. The safety of mRNA COVID-19 vaccines is also explored. Eligible A5404 participants include: Participants of ACTIV-2/A5401 at selected sites who received an investigational therapy or its comparator; and persons without known history of prior SARS-CoV-2 infection defined as no known history of any SARS-CoV-2 positive test (non-A5401 participants). In line with our protocol, for outcome measures related to neutralizing antibodies and adverse events, we further break down the ACTIV-2/A5401 participants into two exposure groups: those who received an active therapy (AZD7442 IM or IV, BRII-196 + BRII 198 IV, SAB 185 (3,840 or 10,240 units/kg) IV, BMS 096414+BMS 986413 subcutaneous) and those who received Camostat Oral or Placebo. Participants of ACTIV-2/A5401 received study-provided standard dosing of the Moderna mRNA-1273 vaccine, or a community-provided mRNA-based COVID-19 vaccine (e.g., Moderna or Pfizer). Participants in ACTIV-2/A5401 received their mRNA-based COVID-19 vaccine 60-240 days after receiving their last dose of a select ACTIV-2/A5401 investigational therapy, or its comparator. Participants without prior COVID-19 received study-provided standard dosing of the Moderna mRNA-1273 vaccine. The study closed early to accrual on February 25, 2022 due to slow enrollment. Clarification Memo #1 (dated January 11, 2023) reflects decisions to discontinue follow up at study Day 365 instead of following participants to Day 730 after the first dose of vaccine and to reallocate some secondary outcome measures to exploratory outcome measures.

Official Title
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SARS-CoV-2 Immune Responses After COVID-19 Therapy and Subsequent Vaccine

Conditions
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Covid19, SARS-CoV2 Infection

Intervention / Treatment
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* Biological: Study-provided Moderna mRNA-1273 COVID-19 vaccine
* Biological: Community-provided Moderna mRNA-1273 COVID-19 Vaccine
* Biological: Community-Provided Pfizer-BioNTech BNT162b2 COVID-19 Vaccine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: For all participants: Ability and willingness of participant (or legally authorized representative) to provide informed consent prior to initiation of any study procedures. For participants who are in, or who have completed, the ACTIV-2/A5401 trial: Receipt of all selected investigational therapy or active comparator/placebo for that therapy at selected sites. For participants who are in, or who have completed, the ACTIV-2/A5401 trial and receive study-provided Moderna mRNA-1273 COVID-19 vaccine: Receipt of the last dose of investigational therapy or active comparator/placebo for that therapy ≥30 days and ≤240 days prior to study entry. For participants who are in, or who have completed, the ACTIV-2/A5401 trial and have received or will be receiving community-provided mRNA-based COVID-19 vaccine: Receipt of the last dose of investigational therapy or active comparator/placebo for that therapy ≥30 and ≤240 days prior to receipt or planned receipt of the first dose of community-provided vaccine. Exclusion Criteria: For participants who are in, or who have completed, the ACTIV-2/A5401 trial: Self-report of prior receipt of a non-mRNA-based COVID-19 vaccine. For participants who are in, or who have completed, the ACTIV-2/A5401 trial: Self-report of receipt of the first dose of an mRNA-based COVID-19 vaccine 140 days or more before A5404 enrollment. For participants who are in, or who have completed, the ACTIV-2/A5401 trial: Self-report of a second SARS-CoV-2 infection after the infection that qualified the participant for ACTIV-2/A5401. For non-A5401/ACTIV-2 participants: Self-report of receipt of any prior COVID-19 vaccine. For non-A5401/ACTIV-2 participants: Known prior history of any SARS-CoV-2-positive test (e.g., PCR test, Nucleic Acid Amplification Test (NAAT), antigen test, serology test). For participants who receive study-provided Moderna mRNA-1273 COVID-19 vaccine: Known allergy to any component of the Moderna COVID-19 vaccine.

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: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cohort: ACTIV-2/A5401<br>Participants of the ACTIV-2/A5401 randomized trial who received a select investigational (active) therapy (AZD7442 IM or IV, BRII-196 + BRII 198 IV, SAB 185 (3,840 or 10,240 units/kg) IV, BMS 096414+BMS 986413 subcutaneous, Camostat Oral) or its corresponding comparator (Placebo). | Biological: Study-provided Moderna mRNA-1273 COVID-19 vaccine<br>* Participants received a two-dose series (100 µg (0.5 mL) was administered intramuscularly (IM) at Day 0 and Day 28).<br>Biological: Community-provided Moderna mRNA-1273 COVID-19 Vaccine<br>* Participants received a two-dose series.<br>Biological: Community-Provided Pfizer-BioNTech BNT162b2 COVID-19 Vaccine<br>* Participants received a two-dose series.<br>|
| Experimental: Cohort: COVID-19 Naïve<br>Participants without known history of prior SARS-CoV-2 infection defined as no known history of any SARS-CoV-2 positive test (non-ACTIV-2/A5401 participants). | Biological: Study-provided Moderna mRNA-1273 COVID-19 vaccine<br>* Participants received a two-dose series (100 µg (0.5 mL) was administered intramuscularly (IM) at Day 0 and Day 28).<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Neutralizing Antibody (NAb) Level | NAb level was measured by using both 50% neutralizing dilution titers (ND50) and 80% neutralizing titers (ND80). A higher NAb level corresponds to a stronger immune response. For ND50 values less than lower limit of quantification (LLQ), we impute with 10 (which is ½ LLQ of 20). For ND50 values exceeding the upper limit of quantification (ULQ), we impute with 20,000 (a value suggested by the immunology lab, which is 2 times the ULQ of 10,000). For ND80, we impute similarly with 10 and 20,000. We carry forward the Day 56 NAb measurement if the Day 140 measurement is not reported. | Measured 140 days after the first dose of the vaccine | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Geometric Mean of Relative Change in Neutralizing Antibody Levels From Pre-vaccine to Post-vaccine | Relative change is defined as the ratio of post-vaccine NAb level/pre-vaccine NAb level. A ratio greater than one indicates an increase of NAb response. For ND50 values less than lower limit of quantification (LLQ), we impute with 10 (which is ½ LLQ of 20). For ND50 values exceeding the upper limit of quantification (ULQ), we impute with 20,000 (a value suggested by the immunology lab, which is 2 times the ULQ of 10,000). For ND80, we impute similarly with 10 and 20,000. | Measured before the first dose of the vaccine, and 56 days after the first dose of the vaccine | 
| Proportion of Participants With New Grade 3 or Higher AE, or SAE, or AE Leading to Change or Discontinuation in Vaccine Receipt | An adverse event (AE) is any unfavorable and unintended sign, symptom, or diagnosis that occurs in a study participant during the conduct of the study REGARDLESS of the attribution. A serious adverse event (SAE) is defined as any untoward medical occurrence that results in death; is life-threatening; requires inpatient hospitalization or prolongation of existing hospitalization; results in persistent or significant disability/incapacity; is a congenital anomaly/birth defect; is an important medical event that may not be immediately life-threatening or result in death or hospitalization but may jeopardize the patient or may require intervention to prevent one of the other outcomes listed in the definition above. Adverse events are graded on a scale from 1-5: 1=mild, 2=moderate, 3=severe, 4=life-threatening, 5=death. AE grading was per Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events (DAIDS AE Grading Table V2.1). | From first dose of the vaccine through 140 days after the first dose of the vaccine | 
| Number of Participants With Grade 1 or Higher Allergic Reaction | Adverse events are graded on a scale from 1-5: 1=mild, 2=moderate, 3=severe, 4=life-threatening, 5=death. AE grading was per Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events (DAIDS AE Grading Table V2.1). | From first dose of the vaccine through 56 days after the first dose of the vaccine | 
| Proportion of Participants With Grade 2 or Higher Injection Site Reaction | Adverse events are graded on a scale from 1-5: 1=mild, 2=moderate, 3=severe, 4=life-threatening, 5=death. AE grading was per Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events (DAIDS AE Grading Table V2.1). | From first dose of the vaccine through 56 days after the first dose of the vaccine | 
| Geometric Mean of Relative Change in Neutralizing Antibody Levels From Pre-vaccine to Post-vaccine by Received Vaccine | Relative change is defined as the ratio of post-vaccine NAb level/pre-vaccine NAb level by received vaccine, i.e., Moderna mRNA-1273 versus Pfizer-BioNTech BNT162b2. A ratio greater than one indicates an increase of NAb response for those on Moderna mRNA-1273 versus Pfizer-BioNTech BNT162b2. For ND50 values less than lower limit of quantification (LLQ), we impute with 10 (which is ½ LLQ of 20). For ND50 values exceeding the upper limit of quantification (ULQ), we impute with 20,000 (a value suggested by the immunology lab, which is 2 times the ULQ of 10,000). For ND80, we impute similarly with 10 and 20,000. | Measured before the first dose of the vaccine, and 56 days after the first dose of the vaccine |