A Study to Evaluate the Safety, Tolerability, and Immunogenicity of Combined Modified RNA Vaccine Candidates Against COVID-19 and Influenza

Study Overview
=================
Brief Summary
-----------------
Substudy A: This is a Phase 1 randomized, open-label study to describe the safety and immunogenicity of up to 3 dose- level combinations of modRNA quadrivalent influenza vaccine (qIRV (22/23)) and bivalent BNT162b2 (original/Omi BA.4/BA.5). Participants will receive either: qIRV (22/23)/bivalent BNT162b2 (original/Omi BA.4/BA.5), at 1 of the 3 dose-level combinations qIRV (22/23) at dose level 1, qIRV (22/23) at dose level 2, or bivalent BNT162b2 (original/Omi BA.4/BA.5) at dose level 1 administered concurrently in the opposite arm to commercially licensed quadrivalent influenza vaccine (QIV). Substudy B: This Phase 1/2 study will describe the safety, tolerability, and immunogenicity of quadrivalent influenza vaccine (qIRV)/bivalent BNT162b2 (original/Omi BA.4/BA.5), trivalent influenza vaccine (tIRV)/bivalent BNT162b2 (original/Omi BA.4/BA.5), and bivalent influenza vaccine (bIRV)/bivalent BNT162b2 (original/Omi BA.4/BA.5) when given concurrently with licensed quadrivalent influenza vaccine (QIV).

Official Title
-----------------
A PHASE 1/2 STUDY TO EVALUATE THE SAFETY, TOLERABILITY, AND IMMUNOGENICITY OF COMBINED MODIFIED RNA VACCINE CANDIDATES AGAINST COVID-19 AND INFLUENZA IN HEALTHY INDIVIDUALS

Conditions
-----------------
Influenza, Human, COVID-19

Intervention / Treatment
-----------------
* Biological: bivalent BNT162b2 (original/Omi BA.4/BA.5)
* Biological: qIRV (22/23)
* Biological: QIV
* Biological: bIRV
* Biological: tIRV


Participation Criteria
=================
Eligibility Criteria
-----------------
SSA: Inclusion Criteria: Male or female participants 18 years of age and older Participants who are willing and able to comply with all scheduled visits, investigational plan, laboratory tests, lifestyle considerations, and other study procedures. 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. Capable of giving signed informed consent as described in the protocol. For participants 18 through 64 years of age: participants who have received 3 prior doses of 30 µg BNT162b2, with the last dose being 150 to 365 days before Visit 1 (Day 1). For participants 65 years of age and older: participants who have received 4 or 5 prior doses of a modRNA SARS-CoV-2 vaccine, with the last dose being a bivalent vaccine, 120 days to 365 days before Visit 1 (Day 1). For Participants 65 years of age and older: receipt of licensed influenza vaccination for the 2022-2023 northern hemisphere season 120 days or more before study intervention administration. SSA: Exclusion Criteria: History of severe adverse reaction associated with any vaccine and/or severe allergic reaction (eg, anaphylaxis) to any component of the study intervention(s). Immunocompromised individuals with known or suspected immunodeficiency. Bleeding diathesis or condition associated with prolonged bleeding. Women who are pregnant or breastfeeding. Allergy to egg proteins (egg or egg products) or chicken proteins. Other 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. Receipt of chronic systemic treatment with known immunosuppressant medications (including cytotoxic agents or systemic corticosteroids), or radiotherapy, within 60 days before enrollment through conclusion of the study. Receipt of blood/plasma products, immunoglobulin, or monoclonal antibodies, from 60 days before study intervention administration, or planned receipt throughout the study. For participants 18 through 64 years of age: vaccination with any investigational or licensed influenza vaccine within 6 months (175 days) before study intervention administration. Participation in other studies involving a study intervention within 28 days before randomization. Anticipated participation in other studies within 28 days after receipt of study intervention in this study. Investigator site staff directly involved in the conduct of the study and their family members, site staff otherwise supervised by the investigator, and sponsor and sponsor delegate employees directly involved in the conduct of the study and their family members. Participation in strenuous or endurance exercise through Visit 3 of the study. Prior history of heart disease. Any abnormal screening troponin I laboratory value. Screening 12-lead ECG that, as judged by the investigator, is consistent with probable or possible myocarditis or pericarditis, or demonstrates clinically relevant abnormalities that may affect participant safety or interpretation of study results. SSB: Inclusion Criteria Male or female participants 18 years of age and older Participants who are willing and able to comply with all scheduled visits, investigational plan, laboratory tests, lifestyle considerations, and other study procedures. 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. Capable of giving signed informed consent as described in the protocol. Participants who have received at least 3 prior US-authorized mRNA COVID-19 vaccines, with the last dose being an updated (bivalent) vaccine given at least 150 days before Day 1. SSB: Exclusion Criteria 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. History of severe adverse reaction associated with any vaccine and/or severe allergic reaction (eg, anaphylaxis) to any component of the study intervention(s). Immunocompromised individuals with known or suspected immunodeficiency, as determined by history and/or laboratory/physical examination. Bleeding diathesis or condition associated with prolonged bleeding that would, in the opinion of the investigator, contraindicate intramuscular injection Receipt of chronic systemic treatment with known immunosuppressant medications (including cytotoxic agents or systemic corticosteroids), or radiotherapy, within 60 days before enrollment through conclusion of the study. Receipt of blood/plasma products, immunoglobulin, or monoclonal antibodies, from 60 days before study intervention administration, or planned receipt throughout the study. Vaccination with any investigational or licensed influenza vaccine within 6 months (175 days) before study intervention administration, or ongoing receipt of chronic antiviral therapy with activity against influenza Participation in other studies involving administration of a study intervention within 28 days prior to, and/or during, participation in this study. Investigator site staff directly involved in the conduct of the study and their family members, site staff otherwise supervised by the investigator, and sponsor and sponsor delegate employees directly involved in the conduct of the study and their family members. Initial enrollment only: Participation in strenuous or endurance exercise through Visit 3 (initial enrollment phase). Initial enrollment only: Prior history of heart disease of concern Initial enrollment only: Screening 12-lead ECG that, as judged by the investigator, is consistent with probable or possible myocarditis or pericarditis, or demonstrates clinically relevant abnormalities that may affect participant safety or interpretation of study results.

Ages Eligible for Study
-----------------
Minimum Age: 18 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
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: SSA: qIRV + bivalent BNT162b2 (dose level combination 1)<br>Administered intramuscularly into the deltoid muscle of the right arm | Biological: bivalent BNT162b2 (original/Omi BA.4/BA.5)<br>* Intramuscular injection<br>Biological: qIRV (22/23)<br>* Intramuscular injection<br>|
| Experimental: SSA: qIRV + bivalent BNT162b2 (dose level combination 2)<br>Administered intramuscularly into the deltoid muscle of the right arm | Biological: bivalent BNT162b2 (original/Omi BA.4/BA.5)<br>* Intramuscular injection<br>Biological: qIRV (22/23)<br>* Intramuscular injection<br>|
| Experimental: SSA: qIRV + bivalent BNT162b2 (dose level combination 3)<br>Administered intramuscularly into the deltoid muscle of the right arm | Biological: bivalent BNT162b2 (original/Omi BA.4/BA.5)<br>* Intramuscular injection<br>Biological: qIRV (22/23)<br>* Intramuscular injection<br>|
| Experimental: SSA: qIRV (dose level 1)<br>Administered intramuscularly into the deltoid muscle of the right arm | Biological: qIRV (22/23)<br>* Intramuscular injection<br>|
| Experimental: SSA: qIRV (dose level 2)<br>Administered intramuscularly into the deltoid muscle of the right arm | Biological: qIRV (22/23)<br>* Intramuscular injection<br>|
| Experimental: SSA: bivalent BNT162b2 (dose level 1) + QIV<br>BNT162b2 administered intramuscularly into the deltoid muscle of the right arm, QIV administered intramuscularly into the deltoid muscle of the left arm | Biological: bivalent BNT162b2 (original/Omi BA.4/BA.5)<br>* Intramuscular injection<br>Biological: QIV<br>* Intramuscular injection<br>|
| Experimental: SSB: QIV + bivalent BNT162b2 (original/Omi BA.4/BA.5)<br>BNT162b2 administered intramuscularly into the deltoid muscle of the right arm, QIV administered intramuscularly into the deltoid muscle of the left arm | Biological: bivalent BNT162b2 (original/Omi BA.4/BA.5)<br>* Intramuscular injection<br>Biological: QIV<br>* Intramuscular injection<br>|
| Experimental: SSB: QIV + bIRV/bivalent BNT162b2 (original/Omi BA.4/BA.5)<br>BNT162b2 administered intramuscularly into the deltoid muscle of the right arm, QIV administered intramuscularly into the deltoid muscle of the left arm | Biological: bivalent BNT162b2 (original/Omi BA.4/BA.5)<br>* Intramuscular injection<br>Biological: QIV<br>* Intramuscular injection<br>Biological: bIRV<br>* Intramuscular injection<br>|
| Experimental: SSB: qIRV/bivalent BNT162b2 (original/ Omi BA.4/BA.5) at dose-level combination 1<br>Administered intramuscularly into the deltoid muscle of the right arm | Biological: bivalent BNT162b2 (original/Omi BA.4/BA.5)<br>* Intramuscular injection<br>Biological: qIRV (22/23)<br>* Intramuscular injection<br>|
| Experimental: SSB: qIRV/bivalent BNT162b2 (original/ Omi BA.4/BA.5) at dose-level combination 2<br>Administered intramuscularly into the deltoid muscle of the right arm | Biological: bivalent BNT162b2 (original/Omi BA.4/BA.5)<br>* Intramuscular injection<br>Biological: qIRV (22/23)<br>* Intramuscular injection<br>|
| Experimental: SSB: qIRV/bivalent BNT162b2 (original/ Omi BA.4/BA.5) at dose-level combination 3<br>Administered intramuscularly into the deltoid muscle of the right arm | Biological: bivalent BNT162b2 (original/Omi BA.4/BA.5)<br>* Intramuscular injection<br>Biological: qIRV (22/23)<br>* Intramuscular injection<br>|
| Experimental: SSB: qIRV/bivalent BNT162b2 (original/ Omi BA.4/BA.5) at dose-level combination 4<br>Administered intramuscularly into the deltoid muscle of the right arm | Biological: bivalent BNT162b2 (original/Omi BA.4/BA.5)<br>* Intramuscular injection<br>Biological: qIRV (22/23)<br>* Intramuscular injection<br>|
| Experimental: SSB: qIRV/bivalent BNT162b2 (original/ Omi BA.4/BA.5) at dose-level combination 5<br>Administered intramuscularly into the deltoid muscle of the right arm | Biological: bivalent BNT162b2 (original/Omi BA.4/BA.5)<br>* Intramuscular injection<br>Biological: qIRV (22/23)<br>* Intramuscular injection<br>|
| Experimental: SSB: qIRV/bivalent BNT162b2 (original/ Omi BA.4/BA.5) at dose-level combination 6<br>Administered intramuscularly into the deltoid muscle of the right arm | Biological: bivalent BNT162b2 (original/Omi BA.4/BA.5)<br>* Intramuscular injection<br>Biological: qIRV (22/23)<br>* Intramuscular injection<br>|
| Experimental: SSB: qIRV/bivalent BNT162b2 (original/ Omi BA.4/BA.5) at dose-level combination 7<br>Administered intramuscularly into the deltoid muscle of the right arm | Biological: bivalent BNT162b2 (original/Omi BA.4/BA.5)<br>* Intramuscular injection<br>Biological: qIRV (22/23)<br>* Intramuscular injection<br>|
| Experimental: SSB: qIRV/bivalent BNT162b2 (original/ Omi BA.4/BA.5) at dose-level combination 8<br>Administered intramuscularly into the deltoid muscle of the right arm | Biological: bivalent BNT162b2 (original/Omi BA.4/BA.5)<br>* Intramuscular injection<br>Biological: qIRV (22/23)<br>* Intramuscular injection<br>|
| Experimental: SSB: tIRV/bivalent BNT162b2(original/Omi\BA.4/BA.5)<br>Administered intramuscularly into the deltoid muscle of the right arm | Biological: bivalent BNT162b2 (original/Omi BA.4/BA.5)<br>* Intramuscular injection<br>Biological: tIRV<br>* Intramuscular injection<br>|
| Experimental: SSB: qIRV<br>Administered intramuscularly into the deltoid muscle of the right arm | Biological: qIRV (22/23)<br>* Intramuscular injection<br>|

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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| SSA: Percentage of participants reporting local reactions | Pain at the injection site, redness, and swelling, as self-reported in electronic diaries. | For 7 days after vaccination | 
| SSA: Percentage of participants reporting systemic events | Fever, fatigue, headache, chills, vomiting, diarrhea, new or worsened muscle pain, and new or worsened joint pain, as self-reported in electronic diaries. | For 7 days after vaccination | 
| SSA: Percentage of participants reporting adverse events | As elicited by investigational site staff. | For 4 weeks after vaccination | 
| SSA: Percentage of participants reporting serious adverse events | As elicited by investigational site staff. | For 6 months after vaccination | 
| SSA: Percentage of participants with abnormal troponin I laboratory values | As measured at the central laboratory | 2 days after vaccination | 
| SSA: Percentage of participants with abnormal troponin I laboratory values | As measured at the central laboratory | 1 week after vaccination | 
| SSA: Percentage of participants with new electrocardiogram (ECG) abnormalities | ECG abnormalities consistent with probable or possible myocarditis or pericarditis, as judged by a cardiologist | 2 days after vaccination | 
| SSA: Percentage of participants with new ECG abnormalities | ECG abnormalities consistent with probable or possible myocarditis or pericarditis, as judged by a cardiologist | 1 week after vaccination | 
| SSB Initial Enrollment: Percentage of participants with abnormal troponin I laboratory values | Measured at the central laboratory | 2 days after vaccination | 
| SSB Initial Enrollment: Percentage of participants with abnormal troponin I laboratory values | As measured at the central laboratory | 1 week after vaccination | 
| SSB Initial Enrollment: Percentage of participants with new electrocardiogram (ECG) abnormalities | ECG abnormalities consistent with probably or possible myocarditis or pericarditis as judged by a cardiologist | 2 days after vaccination | 
| SSB Initial Enrollment: Percentage of participants with new electrocardiogram (ECG) abnormalities | ECG abnormalities consistent with probably or possible myocarditis or pericarditis as judged by a cardiologist | 1 week after vaccination | 
| SSB: Percentage of participants reporting local reactions | Pain at the injection site, redness, and swelling, as self-reported in electronic diaries. | For 7 days after vaccination | 
| SSB: Percentage of participants reporting systemic events | Fever, fatigue, headache, chills, vomiting, diarrhea, new or worsened muscle pain, and new or worsened joint pain, as self-reported in electronic diaries. | For 7 days after vaccination | 
| SSB: Percentage of participants reporting adverse events | As elicited by investigational site staff. | For 4 weeks after vaccination | 
| SSB: Percentage of participants reporting serious adverse events | As elicited by investigational site staff. | For 6 months after vaccination | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| SSA: Geometric Mean Titers (GMTs) of hemagglutination inhibition (HAI) titers | As measured at the central laboratory | At baseline, and 1-, 4-, and 8-weeks after vaccination | 
| SSA: Geometric Mean Fold Rise (GMFRs) of HAI titers | As measured at the central laboratory | At baseline, and 1-, 4-, and 8-weeks after vaccination | 
| SSA: Proportion of participants achieving HAI seroconversion for each strain | As measured at the central laboratory | At 1-, 4-, and 8-weeks after vaccination | 
| SSA: Percentage of participants with HAI titers ≥ 1:40 for each strain | As measured at the central laboratory | Before vaccination and at 1-, 4-, 8-weeks after vaccination | 
| SSA: Percentage of participants achieving HAI seroconversion for all strains | As measured at the central laboratory | At 1-, 4-, 8-weeks after vaccination | 
| SSA: Percentage of participants with HAI ≥1:40 for all strains | As measured at the central laboratory | At 1-, 4-, 8-weeks after vaccination | 
| SSA: GMTs of SARS-CoV-2 Omicron (BA.4/BA.5)-neutralizing titers and SARS-CoV-2 reference-strain-neutralizing titers | As measured at the central laboratory | At 1-, 4-, and 8 weeks after vaccination | 
| SSA: GMFRs of SARS-CoV-2 Omicron (BA.4/BA.5)-neutralizing titers and SARS-CoV-2 reference-strain-neutralizing titers | As measured at the central laboratory | At 1-, 4-, and 8 weeks after vaccination | 
| SSA: Percentage of participants with seroresponse based on SARS-CoV-2 Omicron (BA.4/BA.5)-neutralizing titers and SARS-CoV-2 reference-strain-neutralizing titers | As measured at the central laboratory | At 1-, 4-, and 8 weeks after vaccination. | 
| SSB: Geometric Mean Titers (GMTs) of hemagglutination inhibition (HAI) titers | As measured at the central laboratory | Initial: At baseline and 4 weeks after vaccination. Expanded: At baseline, 4 weeks and 6 months after vaccination | 
| SSB: Geometric Mean Fold Rise (GMFRs) of HAI titers | As measured at the central laboratory | Initial: At baseline and 4 weeks after vaccination. Expanded: At baseline, 4 weeks and 6 months after vaccination | 
| SSB: Proportion of participants achieving HAI seroconversion for each strain | As measured at the central laboratory | Initial: At baseline and 4 weeks after vaccination. Expanded: At baseline, 4 weeks and 6 months after vaccination | 
| SSB: Percentage of participants with HAI titers ≥ 1:40 for each strain | As measured at the central laboratory | Initial: At baseline and 4 weeks after vaccination. Expanded: At baseline, 4 weeks and 6 months after vaccination | 
| SSB: Percentage of participants achieving HAI seroconversion for all strains | As measured at the central laboratory | Initial: At baseline and 4 weeks after vaccination. Expanded: At baseline, 4 weeks and 6 months after vaccination | 
| SSB: Percentage of participants with HAI ≥1:40 for all strains | As measured at the central laboratory | Initial: At baseline and 4 weeks after vaccination. Expanded: At baseline, 4 weeks and 6 months after vaccination | 
| SSB: GMTs of SARS-CoV-2 Omicron (BA.4/BA.5)-neutralizing titers and SARS-CoV-2 reference-strain-neutralizing titers | As measured at the central laboratory | Initial: At baseline and 4 weeks after vaccination. Expanded: At baseline, 4 weeks and 6 months after vaccination | 
| SSB: GMFRs of SARS-CoV-2 Omicron (BA.4/BA.5)-neutralizing titers and SARS-CoV-2 reference-strain-neutralizing titers | As measured at the central laboratory | Initial: At baseline and 4 weeks after vaccination. Expanded: At baseline, 4 weeks and 6 months after vaccination | 
| SSB: Percentage of participants with seroresponse based on SARS-CoV-2 Omicron (BA.4/BA.5)-neutralizing titers and SARS-CoV-2 reference-strain-neutralizing titers | As measured at the central laboratory | Initial: At baseline and 4 weeks after vaccination. Expanded: At baseline, 4 weeks and 6 months after vaccination | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
SARS-Cov-2, COVID-19, Influenza, Grippe, Flu, Vaccine, RNA vaccine