Safety and Immunogenicity of Omicron Variant-Matched Vaccine Booster in Adults

Study Overview
=================
Brief Summary
-----------------
The five recently emerged SARS-CoV2 variants that were designated as VOCs are the Alpha variant, Beta variant, Gamma variant, Delta variant and the Omicron variant. The current dominant Omicron variant was designated a VOC by WHO on Nov 26, 2021, and was found to comprise 85% of reported variants in late January 2022. Studies have shown that the prevalent Omicron mutations in the S1 subunit RBD region and NTD region could dramatically change the antigenic features of the viral spike, leading to significantly reduced neutralization Omicron harbors 30 signature mutations (>50% prevalence) of which 15 are in the S1 subunit RBD region and 8 are in the S1 subunit NTD region. Omicron is a highly contagious variant with threatening immune evasion capabilities even despite robust immune response. Initial modeling showed the Omicron variant being 2.8 times more infectious than the Delta variant. While current vaccines are losing protection against Omicron with respect to infection and mild disease, there is still considerable protection from hospitalisation and severe COVID-19, especially after a booster dose. The International Coalition of Medicines Regulatory Authorities (ICMRA) COVID-19 Omicron Variant Workshop encouraged the international scientific community and vaccine developers to look at alternative approaches to monovalent vaccines. In ICMRA's view, companies should also explore the feasibility of developing bivalent or multivalent variant vaccines to determine if they offer advantages to monovalent vaccines. As advised by ICMRA, the investigated vaccine, mRNA-1273.214 is a bivalent vaccine containing the ancestral SARS-CoV-2 and the Omicron variant spike sequences that will be evaluated as a heterologous boost.

Detailed Description
-----------------
The trial aims to evaluate the safety and immunogenicity of the investigated covalent vaccine, mRNA-1273.214, administered as a heterologous vaccine after the primary series vaccination and boost with the BNT162b2 or mRNA-1273, in healthy adults aged ≥21 years. Three different treatment arms will be compared with participants being administered either: mRNA-1273.214 (Day 1) and mRNA-1273.214 (Day 56) mRNA-1273.214 (Day 1) and placebo (Day 56) mRNA-1273 (Day 1) and placebo (Day 56) Study procedures include two administrations of vaccine and/or placebo, nasopharyngeal swab for SARS-CoV-2 PCR, blood draws for antibody response: IgG, IgA, pseudo-neutralization antibody (ab) titers, B-Cell response, T-Cell response, and solicited and non-solicited adverse events. Subjects will be asked to complete an electronic diary for 7 consecutive days after each vaccination dose, regarding vaccine-related symptoms + temperature measured at home. One week after the day of vaccination or placebo, subjects will be asked to complete a COVID-19 questionnaire once a week, in which they will have to answer the question of whether they have experienced COVID-19 symptoms. Adverse reactions will be measured by the occurrence of solicited injection site reaction and systemic reaction from the time of each vaccination through 7 days post each vaccination/placebo administration. Unsolicited non-serious Adverse Events (AEs), Serious adverse events (SAEs), new-onset chronic medical conditions (NOCMCs), and medically-attended adverse events (MAAEs) will be collected from baseline through 6 months after the first booster dose vaccination. Nasopharyngeal Swab for SARS-CoV-2 PCR, Blood Samples For Immunogenicity Assessment, Serology and PBMC will be collected at each study visit (6 times during the subject's participation in the study).

Official Title
-----------------
Phase 2, Randomized, Observer-Blind, Investigator-Initiated, Collaborative Study to Evaluate the Safety and Immunogenicity of Omicron Variant-Matched Vaccine Booster in Adults

Conditions
-----------------
COVID-19 Pandemic, Immunogenicity, SARS CoV 2 Infection, COVID-19

Intervention / Treatment
-----------------
* Biological: mRNA-1273.214 Vaccine
* Biological: MRNA-1273 Vaccine
* Biological: Placebo


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Male or female participants 21 years of age, inclusively. Individuals who previously received mRNA primary series vaccination AND a booster dose at least 4 months prior to Day 1. Documented confirmation of prior mRNA series vaccination receipt must be obtained prior to randomization. Females and males of childbearing potential must be willing to use effective methods of contraception such as hormones (OCP, oral contraceptive pill), condom or occlusive cap with spermicidal agents, intrauterine device (IUD), or intrauterine system (IUS) as well as to refrain from donating sperm through 28 days following the last vaccination. Participant who is willing and able to comply with all scheduled visits, vaccination plan, laboratory tests, lifestyle considerations, and other study procedures. For Women of Child Bearing Potential (WOCBP): a negative pregnancy test on the day of vaccination (Visit 1 and Visit 4). Participant who is willing and able to operate an electronic diary. Healthy participants who are determined by medical history, physical examination (if required), and clinical judgment of the investigator to be eligible for inclusion in the study. Note: Healthy participants with preexisting stable disease, defined as disease not requiring significant change in therapy or hospitalization for worsening disease during the six (6) weeks before enrollment, can be included. Capable of giving signed informed consent as described which includes understanding and compliance with the study procedures, requirements and restrictions listed in the informed consent form (ICF) and in this protocol. Must agree not to enroll in another study of an investigational agent prior to completion of the study. Exclusion Criteria: History of severe adverse reaction associated with a vaccine and/or severe allergic reaction (e.g., anaphylaxis) to any component of the study intervention(s). Previous clinical (based on COVID-19 symptoms/signs alone, if a SARS-CoV-2 NAAT result was not available) or microbiological (based on COVID-19 symptoms/signs and a positive SARS-CoV-2 NAAT result) diagnosis of COVID-19 or positive antigen test for SARS-CoV-2 at baseline. Immunocompromised individuals with known or suspected immunodeficiency, as determined by history and/or laboratory/physical examination. Has known or suspected allergy or history of anaphylaxis, urticaria, or other significant AR to the vaccine or its excipients. Bleeding diathesis or condition associated with prolonged bleeding that would, in the opinion of the investigator, contraindicate intramuscular injection. Inability to observe possible local reactions at the injection sites due to a physical condition or permanent body art. Any medical or psychiatric condition including recent (within the past year) or active suicidal ideation/behavior or laboratory abnormality that may increase the risk of study participation or, in the investigator's judgment, make the participant inappropriate for the study. Pregnant or breastfeeding women. Individuals who receive treatment with radiotherapy or immunosuppressive therapy, including cytotoxic agents or systemic corticosteroids (if systemic corticosteroids are administered for ≥14 days at a dose of ≥20 mg/day of prednisone or equivalent), e.g., for cancer or an autoimmune disease, or planned receipt throughout the study. Inhaled/nebulized, intra-articular, intrabursal, or topical (skin or eyes) corticosteroids are permitted. Receipt of blood/plasma products, immunoglobulin, or monoclonal antibodies, from 60 days before study intervention administration, or receipt of any passive antibody therapy specific to COVID-19, from 90 days before study intervention administration, or planned receipt throughout the study. Participation in other studies involving study intervention within 28 days prior to study entry through and including 28 days after the last dose of study intervention.

Ages Eligible for Study
-----------------
Minimum Age: 21 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: Randomized, Observer-Blinded (2:2:1 ratio)
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: mRNA-1273.214 + mRNA-1273.214<br>Fourth & Fifth doses of an investigational mRNA vaccine, 56 days apart N ≈ 60 | Biological: mRNA-1273.214 Vaccine<br>* Omicron Variant-Matched Vaccine<br>|
| Experimental: mRNA-1273.214 + Placebo<br>Fourth dose of an investigational mRNA vaccine followed by a fifth dose of placebo, 56 days apart N ≈ 60 | Biological: mRNA-1273.214 Vaccine<br>* Omicron Variant-Matched Vaccine<br>Biological: Placebo<br>* Normal Saline for injection<br>|
| Active Comparator: mRNA-1273 + Placebo<br>Fourth dose of the commercial mRNA vaccine, followed by a fifth dose of placebo, 56 days apart N ≈ 30 | Biological: MRNA-1273 Vaccine<br>* Moderna's commercial COVID-19 Vaccine<br>* Other names: Spikevax;Biological: Placebo<br>* Normal Saline for injection<br>|

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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety of the study vaccines after each dose | Safety of the study vaccines will be measured by solicited and unsolicited adverse injection site reactions and systemic reactions from the time of each vaccination through 7 days post each vaccination/placebo administrations. AEs will be collected up to 29 days after injection. Unsolicited non-serious AEs, SAEs, NOCMCs, and MAAEs will be collected through 6 months after the first vaccine dose. | 6 Months | 
| Reactogenicity of the study vaccines after each dose | Reactogenicity of the study vaccines will be measured by solicited and unsolicited adverse injection site reactions and systemic reactions from the time of each vaccination through 7 days post each vaccination/placebo administrations. AEs will be collected up to 29 days after injection. Unsolicited non-serious AEs, SAEs, NOCMCs, and MAAEs will be collected through 6 months after the first vaccine dose. The study will also assess reactogenicity using Toxicity Grading Scale for Healthy Adult and Adolescent Volunteers Enrolled in Preventive Vaccine Clinical Trials Guide, via an electronic diary the participants would be required to complete every day for 7 consecutive days starting the day of each vaccine. | 6 Months | 
| Immune response to mRNA-1273.214, given as a fourth and fifth dose to participants who previously received mRNA primary series vaccination and one booster dose (third dose). | Primary immunogenicity outcome will be measured by changes in geometric titers (GMTs) and geometric fold raise (GMFRs) of IgG and neutralizing antibodies (nAb), using a pseudovirus assay during all visits. Blood for immunogenicity will be collected at all visits (total of 6 visits). | 6 Months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Immunogenicity | Describe direct virus neutralization of Omicron VOC, Delta VOC and ancestral SARS-COV-2 VOC. Direct virus neutralization (in Biosafety Level 3 - BL3 - facility) of Omicron variant of concern (VOC) and two (2) additional strains [ancestral SARS-COV-2 and Delta VOC] Measured by GMT. | 6 Months | 
| Investigational Product's Efficacy | COVID-19 infections and severity [based on CDC definition] in participants without evidence of past SARS-CoV-2 infection, occurring after day 7 from the booster dose throughout the blinded follow-up period. Laboratory defined SARS-CoV-2 infection and symptomatic COVID-19 and severe COVID-19. | 6 Months | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
mRNA1273.214, Omicron, Immunogenicity, COVID-19, Safety