A Study to Evaluate the Safety, Tolerability, and Immunogenicity of a Modified RNA Vaccine Against Influenza

Study Overview
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Brief Summary
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This study will be divided into two substudies - Substudy A (SSA) and Substudy B (SSB) Substudy A This is a Phase 1 randomized substudy to evaluate the safety and immunogenicity of monovalent influenza modRNA vaccine (mIRV) and bivalent influenza modRNA vaccine (bIRV) at various dose levels, and quadrivalent influenza modRNA vaccine (qIRV), in participants 65 to 85 years of age. Participants will receive at Vaccination 1 either: 1 of 4 dose levels of mIRV (either A or B Strain), 1 of 4 dose levels of bIRV (containing both A and B strains), qIRV (at 1 dose level), or A licensed quadrivalent influenza vaccine (QIV). At approximately 8 weeks following Vaccination 1, participants will be unblinded and QIV (Vaccination 2) administered to participants not having previously received this at Vaccination 1. Additionally, participants who previously received QIV at Vaccination 1 will receive one of the following for Vaccination 2: mIRV encoding A strain at dose level 4, or mIRV encoding B strain at dose level 4. Substudy B This is a randomized substudy to evaluate the safety and immunogenicity of the following vaccination schedules in participants 65 to 85 years of age: 2-Visit Schedules 2 doses of qIRV (at a dose level 1), administered 21 days apart. 2 doses of licensed QIV, administered 21 days apart (as a control group) A dose of licensed QIV following by a dose of bIRV encoding 2 A strains at dose level combination 1 or 2, administered 21 days apart. 1-Visit Schedules A dose of licensed QIV administered concurrently in the opposite arm with bIRV encoding 2 A strains at dose level combination 1 or 2. A dose of bIRV encoding 2 A strains administered concurrently in the opposite arm with a dose of bIRV encoding 2 B strains.at dose level 1. A dose of qIRV encoding 2 A strains and 2 B strains at dose level 2 (at one of two possible dose level combinations). A dose of qIRV encoding 2 A strains and 2 B strains at dose level 3. 1 dose of licensed QIV (as a control group). Substudy B In participants 18 to 64 years of age: -A dose of qIRV encoding 2 A strains and 2 B strains at a dose level combination 1 or 2.

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

Conditions
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Influenza, Human

Intervention / Treatment
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* Biological: mIRV
* Biological: bIRV AB
* Biological: qIRV
* Biological: QIV
* Biological: bIRV AA
* Biological: bIRV BB


Participation Criteria
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Eligibility Criteria
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Substudy A Inclusion Criteria: Male or female participants 65 to 85 years of age. Participants who are willing and able to comply with all scheduled visits, treatment 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. Male participant who is able to father children and willing to use an acceptable method of contraception; or female participant not of childbearing potential; or male participant not able to father children. Capable of giving signed informed consent. Exclusion Criteria: 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. History of severe adverse reaction associated with a vaccine and/or severe allergic reaction (eg, anaphylaxis) to any component of the study intervention. 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. Women who are pregnant or breastfeeding. Allergy to egg proteins (egg or egg products) or chicken proteins. Participant who has had significant exposure to laboratory-confirmed SARS-CoV-2 infection, COVID-19, or influenza in the past 14 days known prior to Visit 1 Any participant who has a SARS-CoV-2 RT-PCR or antigen test in the past 10 days prior to Visit 1 that has not been confirmed as negative. Individuals who receive treatment with radiotherapy or immunosuppressive therapy, including cytotoxic agents or systemic corticosteroids, eg, for cancer or an autoimmune disease, or planned receipt throughout 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 influenza vaccine within 6 months (175 days) before study intervention administration. Any participant who has received or plans to receive a modRNA-platform SARS-CoV-2 vaccine within 60 days of Visit 1 Participation in other studies involving study intervention within 28 days prior to study entry and/or during study participation. Screening hematology/blood chemistry lab >=Grade 1 abnormality. Except Bilirubin, other stable Grade1 abnormalities may be considered eligible by Investigator. Screening ECG that is consistent with probable or possible myocarditis or pericarditis, or demonstrates clinically relevant abnormalities that may affect participant safety or study results. Investigator site staff or Pfizer employees directly involved in the conduct of the study, site staff otherwise supervised by the investigator, and their respective family members. Participation in strenuous or endurance exercise through Visit 3. Prior history of heart disease. Substudy B Inclusion Criteria: Male or female participants 65 to 85 years of age or .Male or female participants 18 to 64 years of age Participants who are willing and able to comply with all scheduled visits, treatment 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. For participants 65 to 85 years of age at the time of enrollment, receipt of licensed influenza vaccination for the 2021-2022 northern hemisphere season >4 months (120 days) before study intervention administration. Capable of giving signed informed consent. Exclusion Criteria: 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. History of severe adverse reaction associated with a vaccine and/or severe allergic reaction (eg, anaphylaxis) to any component of the study intervention. 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. Women who are pregnant or breastfeeding. Allergy to egg proteins (egg or egg products) or chicken proteins. Participant who has had significant exposure to laboratory-confirmed SARS-CoV-2 infection, COVID-19, or influenza in the past 14 days known prior to Visit 201 Any participant who has a SARS-CoV-2 RT-PCR or antigen test in the past 10 days prior to Visit 201 that has not been confirmed as negative. Individuals who receive treatment with radiotherapy or immunosuppressive therapy, including cytotoxic agents or systemic corticosteroids, eg, for cancer or an autoimmune disease, or planned receipt throughout the study. Receipt of blood/plasma products, immunoglobulin, or monoclonal antibodies, from 60 days before study intervention administration, or planned receipt throughout the study. Any participant who has received or plans to receive a modRNA-platform SARS-CoV-2 vaccine within 28 days of Visit 201 Any participant who has received licensed influenza vaccination for the 2022-2023 northern hemisphere influenza season. Participation in other studies involving study intervention within 28 days prior to study entry and/or during study participation. Investigator site staff or Pfizer employees directly involved in the conduct of the study, site staff otherwise supervised by the investigator, and their respective family members. Participation in strenuous or endurance exercise through Visit 205. 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.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 85 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: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: SSA: mIRV A (dose level 1) + QIV<br> | Biological: mIRV<br>* Intramuscular injection<br>Biological: QIV<br>* Intramuscular injection<br>|
| Experimental: SSA: mIRV A (dose level 2) + QIV<br> | Biological: mIRV<br>* Intramuscular injection<br>Biological: QIV<br>* Intramuscular injection<br>|
| Experimental: SSA: mIRV A (dose level 3) + QIV<br> | Biological: mIRV<br>* Intramuscular injection<br>Biological: QIV<br>* Intramuscular injection<br>|
| Experimental: SSA: mIRV A (dose level 4) + QIV<br> | Biological: mIRV<br>* Intramuscular injection<br>Biological: QIV<br>* Intramuscular injection<br>|
| Experimental: SSA: mIRV B (dose level 1) + QIV<br> | Biological: mIRV<br>* Intramuscular injection<br>Biological: QIV<br>* Intramuscular injection<br>|
| Experimental: SSA: mIRV B (dose level 2) + QIV<br> | Biological: mIRV<br>* Intramuscular injection<br>Biological: QIV<br>* Intramuscular injection<br>|
| Experimental: SSA: mIRV B (dose level 3) + QIV<br> | Biological: mIRV<br>* Intramuscular injection<br>Biological: QIV<br>* Intramuscular injection<br>|
| Experimental: SSA: mIRV B (dose level 4) + QIV<br> | Biological: mIRV<br>* Intramuscular injection<br>Biological: QIV<br>* Intramuscular injection<br>|
| Experimental: SSA: bIRV AB (dose level combination 1) + QIV<br> | Biological: bIRV AB<br>* Intramuscular injection<br>Biological: QIV<br>* Intramuscular injection<br>|
| Experimental: SSA: bIRV AB (dose level combination 2) + QIV<br> | Biological: bIRV AB<br>* Intramuscular injection<br>Biological: QIV<br>* Intramuscular injection<br>|
| Experimental: SSA: bIRV AB (dose level combination 3) + QIV<br> | Biological: bIRV AB<br>* Intramuscular injection<br>Biological: QIV<br>* Intramuscular injection<br>|
| Experimental: SSA: bIRV AB (dose level combination 4) + QIV<br> | Biological: bIRV AB<br>* Intramuscular injection<br>Biological: QIV<br>* Intramuscular injection<br>|
| Experimental: SSA: QIV + mIRV A strain (dose level 4)<br> | Biological: mIRV<br>* Intramuscular injection<br>Biological: QIV<br>* Intramuscular injection<br>|
| Experimental: SSA: qIRV (dose level 1) + QIV<br> | Biological: qIRV<br>* Intramuscular injection<br>Biological: QIV<br>* Intramuscular injection<br>|
| Experimental: SSA: QIV + mIRV B strain (dose level 4)<br> | Biological: mIRV<br>* Intramuscular injection<br>Biological: QIV<br>* Intramuscular injection<br>|
| Experimental: SSB: 2 doses of qIRV (dose level 1), 2-visit schedule<br> | Biological: qIRV<br>* Intramuscular injection<br>|
| Experimental: SSB: 2 doses of QIV, 2-visit schedule<br> | Biological: QIV<br>* Intramuscular injection<br>|
| Experimental: SSB: QIV + bIRV AA (dose level combination 1), 2-visit schedule<br> | Biological: QIV<br>* Intramuscular injection<br>Biological: bIRV AA<br>* Intramuscular injection<br>|
| Experimental: SSB: QIV + bIRV AA (dose level combination 2), 2-visit schedule<br> | Biological: QIV<br>* Intramuscular injection<br>Biological: bIRV AA<br>* Intramuscular injection<br>|
| Experimental: SSB: QIV + bIRV AA (dose level combination 1), 1-visit schedule<br> | Biological: QIV<br>* Intramuscular injection<br>Biological: bIRV AA<br>* Intramuscular injection<br>|
| Experimental: SSB: QIV + bIRV AA (dose level combination 2), 1-visit schedule<br> | Biological: QIV<br>* Intramuscular injection<br>Biological: bIRV AA<br>* Intramuscular injection<br>|
| Experimental: SSB: qIRV (dose level 2, dose combination 1), 1-visit schedule<br>NOTE: Arm Description has not been entered. | Biological: qIRV<br>* Intramuscular injection<br>|
| Experimental: SSB: qIRV (dose level 2, dose combination 2), 1-visit schedule<br>NOTE: Arm Description has not been entered | Biological: qIRV<br>* Intramuscular injection<br>|
| Experimental: SSB: qIRV (dose level 3), 1-visit schedule<br>NOTE: Arm Description has not been entered | Biological: qIRV<br>* Intramuscular injection<br>|
| Experimental: SSB: bIRV AA + bIRV BB (both dose level combination 1), 1-visit schedule<br>NOTE: Arm Description has not been entered | Biological: bIRV AA<br>* Intramuscular injection<br>Biological: bIRV BB<br>* Intramuscular injection<br>|
| Experimental: SSB: 1 dose of QIV, 1-visit schedule<br>NOTE: Arm Description has not been entered | Biological: QIV<br>* Intramuscular injection<br>|
| Experimental: SSB: qIRV (dose level 1), 1-visit schedule<br>NOTE: Arm Description has not been entered. | Biological: qIRV<br>* Intramuscular injection<br>|
| Experimental: SSB: qIRV (dose level 2), 1-visit schedule<br>NOTE: Arm Description has not been entered. | Biological: qIRV<br>* Intramuscular injection<br>|

What is the study measuring?
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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 Vaccinations 1 and 2 | 
| 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 Vaccinations 1 and 2 | 
| SSA: Percentage of participants reporting adverse events | As elicited by investigational site staff. | From vaccination to 4 weeks after Vaccinations 1 and 2 | 
| SSA: Percentage of participants reporting serious adverse events | As elicited by investigational site staff. | From vaccination to 6 months after the last study vaccination | 
| SSA: Percentage of participants with abnormal hematology and chemistry laboratory values | As measured at the central laboratory | 2 days after Vaccination 1 | 
| SSA: Percentage of participants with abnormal hematology and chemistry laboratory values | As measured at the central laboratory | 1 week after Vaccination 1 | 
| SSA: Percentage of participants with grading shifts in hematology and chemistry laboratory assessments | As measured at the central laboratory | Between baseline and 2 days after Vaccination 1 | 
| SSA: Percentage of participants with grading shifts in hematology and chemistry laboratory assessments | As measured at the central laboratory | Between baseline and 1 week after Vaccination 1 | 
| 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 1 | 
| 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 1 | 
| SSB: Percentage of participants reporting local reactions (18 to 64 and 65 to 85 years of age) | Pain at the injection site, redness, and swelling, as self-reported in electronic diaries. | For 7 days after each vaccination | 
| SSB: Percentage of participants reporting systemic events (18 to 64 and 65 to 85 years of age) | 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 each vaccination | 
| SSB: Percentage of participants reporting adverse events (18 to 64 and 65 to 85 years of age) | As elicited by investigational site staff. | From Vaccination 1 to 4 weeks after the last vaccination | 
| SSB: Percentage of participants reporting serious adverse events (18 to 64 and 65 to 85 years of age) | As elicited by investigational site staff. | From Vaccination 1 to 6 months after the last vaccination | 
| SSB: Percentage of participants with abnormal troponin I laboratory values (18 to 64 and 65 to 85 years of age) | As measured at the central laboratory | 2 days after the last vaccination | 
| SSB: Percentage of participants with new ECG abnormalities (18 to 64 and 65 to 85 years of age) | ECG abnormalities consistent with probable or possible myocarditis or pericarditis, as judged by a cardiologist | 2 days after the last 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 1 | 
| SSA: Geometric mean fold rise (GMFR) in HAI titers from before vaccination to each subsequent timepoint | As measured at the central laboratory | At 1-, 4-, and 8-weeks after Vaccination 1 | 
| SSA: Proportion of participants achieving HAI seroconversion for each strain | As measured at the central laboratory | At 1-, 4-, and 8-weeks after Vaccination 1 | 
| SSA: Proportion of participants with HAI titer >=1:40 for each strain | As measured at the central laboratory. | At Baseline, and 1-, 4-, and 8-weeks after Vaccination 1 | 
| SSA: In participants who receive either qIRV or QIV at Vaccination 1, the proportion of participants achieving HAI seroconversion for all strains | As measured at the central laboratory | At 1-, 4-, and 8-weeks after Vaccination 1 | 
| SSA: In participants who receive either qIRV or QIV at Vaccination 1, the proportion of participants with HAI titer >=1:40 for all strains | As measured at the central laboratory. | At Baseline, and 1-, 4-, and 8-weeks after Vaccination 1 | 
| SSA: The geometric mean ratio (GMR) of the geometric mean of HAI titers from participants receiving qIRV to the geometric mean of HAI titers from participants receiving QIV | As measured at the central laboratory | At 4 weeks after Vaccination 1 | 
| SSA: The difference in percentage of participants achieving HAI seroconversion for each strain in qIRV recipients compared to licensed QIV recipients | As measured at the central laboratory | At 4 week after Vaccination 1 | 
| SSB: GMTs of HAI titers (65-85 years of age) | As measured at the central laboratory | At Baseline, prior to Vaccination 2 (if applicable), and 1-, 4- and 8-weeks after the last vaccination | 
| SSB: GMFR in HAI titers from before vaccination to each subsequent timepoint (65-85 years of age) | As measured at the central laboratory | Prior to Vaccination 2 (if applicable), and at 1-, 4-, and 8-weeks after the last vaccination | 
| SSB: Proportion of participants achieving HAI seroconversion for each strain (65-85 years of age) | As measured at the central laboratory | Prior to Vaccination 2 (if applicable), and at 1-, 4-, and 8-weeks after the last vaccination | 
| SSB: Proportion of participants with HAI titer >=1:40 for each strain (65-85 years of age) | As measured at the central laboratory. | At Baseline, prior to Vaccination 2 (if applicable), and 1-, 4-, and 8-weeks after the last vaccination | 
| SSB: In participants who receive either qIRV or QIV, the proportion of participants achieving HAI seroconversion for all strains (65-85 years of age) | As measured at the central laboratory | Prior to Vaccination 2 (if applicable), and at 1-, 4-, and 8-weeks after the last vaccination | 
| SSB: In participants who receive either qIRV or QIV at Vaccination 1, the proportion of participants with HAI titer >=1:40 for all strains (65-85 years of age) | As measured at the central laboratory. | At Baseline, prior to Vaccination 2 (if applicable), and 1-, 4-, and 8-weeks after the last vaccination | 
| SSB: GMTs of HAI titers (18-64 years of age) | As measured at the central laboratory | At Baseline, prior to Vaccination and 1-, 4- and 8-weeks after vaccination | 
| SSB: GMFR in HAI titers from before vaccination to each subsequent timepoint (18-64years of age) | As measured at the central laboratory | Prior to Vaccination, and at 1-, 4-, and 8-weeks after vaccination | 
| SSB: Proportion of participants achieving HAI seroconversion for each strain (18-64 years of age) | As measured at the central laboratory | Prior to Vaccination, and at 1-, 4-, and 8-weeks after vaccination | 
| SSB: Proportion of participants with HAI titer >=1:40 for each strain (18-64 years of age) | As measured at the central laboratory. | At Baseline, prior to Vaccination, and 1-, 4-, and 8-weeks after vaccination | 
| SSB: In participants who receive either qIRV or QIV, the proportion of participants achieving HAI seroconversion for all strains (18-64 years of age) | As measured at the central laboratory | Prior to Vaccination, and at 1-, 4-, and 8-weeks after vaccination | 
| SSB: In participants who receive either qIRV or QIV at Vaccination 1, the proportion of participants with HAI titer >=1:40 for all strains (18-64 years of age) | As measured at the central laboratory. | At Baseline, prior to Vaccination, and 1-, 4-, and 8-weeks after vaccination | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Grippe, Flu, Influenza, Vaccine, RNA vaccine