Evaluation of the Safety and Immunogenicity of Influenza and COVID-19 Combination Vaccine

Study Overview
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Brief Summary
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This is a randomized, observer-blinded, Phase 1/2 study evaluating the safety and immunogenicity of a quadrivalent HA nanoparticle influenza and SARS-CoV-2 rS nanoparticle combination vaccine with Matrix-M1 adjuvant; this combination is referred to as ICC vaccine.

Detailed Description
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This is a randomized, observer-blinded, Phase 1/2 study evaluating the safety and immunogenicity of a quadrivalent hemagglutinin (HA) nanoparticle influenza vaccine (qNIV) and severe acute respiratory syndrome coronavirus 2 (SARSCoV2) recombinant spike (rS) nanoparticle combination vaccine with Matrix-M1™ adjuvant; this combination vaccine is referred to as Influenza COVID-19 Combination (ICC) vaccine. The study will enroll approximately 640 healthy (based on history and physical examination) adult male and female participants 50 to 70 years of age, inclusive, targeting participants who are baseline seropositive (either previously infected with SARS-CoV-2 ≥ 8 weeks prior to enrollment, or have been previously immunized against SARS-CoV-2 with a completed regimen of an authorized vaccine at ≥ 8 weeks prior to enrollment). Randomization will be stratified on age ≥ 50 to ≤60 or ≥ 60 to ≤ 70 years to distribute the proportions of each age stratum evenly across vaccine groups.

Official Title
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A Phase 1/2, Randomized, Observer-Blinded Study to Evaluate the Safety and Immunogenicity of a Quadrivalent Hemagglutinin Nanoparticle Influenza and SARS-CoV-2 rS Nanoparticle Combination Vaccine With Matrix M1™ Adjuvant in Healthy Participants ≥ 50 to ≤ 70 Years of Age

Conditions
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SARS-CoV Infection, Covid19

Intervention / Treatment
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* Biological: ICC Vaccine
* Biological: qNIV Nanoparticle Vaccine2 in-clinic mixed with Matrix-M1 Adjuvant
* Biological: SARS-CoV-2 rS Nanoparticle Vaccine in-clinic mixed with Matrix-M1 Adjuvant


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Healthy, medically stable adult males or females ≥ 50 to ≤ 70 years of age at screening. Willing and able to give informed consent prior to study enrollment. Able to attend study visits, comply with study requirements, and provide reliable and complete reports of AEs. Participants must have been baseline seropositive to SARS-CoV-2 defined as either: • Having completed a primary vaccination series against SARS-CoV-2 with an authorized COVID-19 vaccine with receipt of second/final dose of authorized vaccine ≥ 8 weeks prior to enrollment (first study vaccination). OR • Previously infected with SARS CoV-2 ≥ 8 weeks prior to enrollment (first study vaccination). Note: Baseline SARS-CoV-2 serostatus determination at screening will be based on vaccination documentation (eg, vaccination card or vaccination registry) or participants' report of a previous SARS-CoV-2 infection. Women of childbearing potential (defined as any female participant who is NOT surgically sterile [ie, hysterectomy, bilateral tubal ligation, or bilateral oophorectomy] or postmenopausal [defined as amenorrhea at least 12 consecutive months]) must agree to be heterosexually inactive from at least 28 days prior to enrollment and through the end of the study OR agree to consistently use a medically acceptable method of contraception listed below from at least 28 days prior to enrollment and through the end of the study. Condoms (male or female) with spermicide (if acceptable in-country) Diaphragm with spermicide Cervical cap with spermicide Intrauterine device Oral or patch contraceptives Norplant®, Depo-Provera®, or other in-country regulatory approved contraceptive method that is designed to protect against pregnancy Abstinence, as a form of contraception, is acceptable if in line with the participant's lifestyle Participants must be healthy and medically stable, as determined by the investigator (based on a review of health status, vital signs [to include body temperature], medical history, and targeted physical examination [to include body weight]). Participants must have a body mass index (BMI) of 17 to 34 kg/m2, inclusive, at screening. Vital signs must be within medically acceptable ranges prior to the first vaccination. Participants must agree to not participate in any other SARS-CoV-2 or influenza prevention or treatment studies for the duration of the study. Note: For participants who become hospitalized with COVID-19, participation in investigational treatment studies is permitted. Exclusion Criteria: Any ongoing, symptomatic acute, or chronic illness requiring medical or surgical care. Asymptomatic chronic conditions or findings (eg, mild hypertension, dyslipidemia) that are not associated with evidence of end-organ damage are not exclusionary provided that they are being appropriately managed and are clinically stable (ie, unlikely to result in symptomatic illness within the time-course of this study), in the opinion of the investigator. Acute or chronic illnesses or conditions which may be reasonably predicted to become symptomatic if treatment were withdrawn or interrupted are exclusionary, even if stable. Acute or chronic illnesses reasonably expected to be associated with increased risks in the event of influenza or SARS-CoV-2 infection (eg, cardio-pulmonary diseases, diabetes mellitus, renal or hepatic dysfunction, hemoglobinopathies) are exclusionary, even if stable. Participation in research involving an investigational product (drug/biologic/device) within 90 days before the planned date of the first injection. Use of COVID-19 prophylactic or treatment monoclonal antibodies or antibody cocktails within 90 days prior to the planned date of the first injection. History of a serious reaction to prior influenza vaccination or known allergy to constituents of influenza vaccines - including egg proteins - or polysorbate 80; or any known allergies to products contained in the investigational product. Any history of anaphylaxis to any prior vaccine. History of Guillain-Barré Syndrome within 6 weeks following a previous influenza vaccine. Receipt of any vaccine in the 4 weeks preceding the study vaccination and any influenza vaccine within 2 months preceding the study vaccination. Note: Routine vaccinations will not be allowed until after study Day 70. Any known or suspected autoimmune or immunosuppressive illness, congenital or acquired, based on medical history and/or physical examination. Chronic administration (defined as more than 14 continuous days) of immunosuppressants or other immune-modifying drugs within 6 months prior to the administration of the study vaccines. An immunosuppressant dose of glucocorticoid will be defined as a systemic dose ≥ 10 mg of prednisone per day or equivalent. The use of topical, inhaled, and nasal glucocorticoids will be permitted. Administration of immunoglobulins and/or any blood products within the 3 months preceding the administration of the study vaccine or during the study. Active cancer (malignancy) therapy within 3 years prior to first study vaccination (with the exception of adequately treated non-melanomatous skin carcinoma or lentigo maligna and uterine cervical carcinoma in situ without evidence of disease, at the discretion of the investigator). Participants who are breastfeeding, pregnant, or who plan to become pregnant prior to the EoS. Known disturbance of coagulation. Suspected or known history of alcohol abuse or drug addiction within 2 years prior to the first trial vaccine dose that, in the opinion of the investigator, might interfere with protocol compliance. Acute disease at the time of enrollment (defined as the presence of a moderate or severe illness with or without fever, or an oral temperature > 38.0°C, on the planned day of vaccine administration). Any condition that in the opinion of the investigator would pose a health risk to the participant if enrolled or could interfere with evaluation of the vaccine or interpretation of study results (including neurologic or psychiatric conditions deemed likely to impair the quality of safety reporting). Study team member or immediate family member of any study team member (inclusive of Sponsor, Contract Research Organization, and study site personnel involved in the conduct or planning of the study).

Ages Eligible for Study
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Minimum Age: 50 Years
Maximum Age: 70 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: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Group A - ICC Vaccine Formulation<br>2 doses of Formulation 1. 1 dose each on Days 0 and Day 56. | Biological: ICC Vaccine<br>* Intramuscular (deltoid) injections of in-clinic mix of various doses of qNIV2, SARS-CoV-2 rS, and 50 μg Matrix-M1 Adjuvant (ICC Vaccine) on Day 0 and Day 56.<br>|
| Experimental: Group B -ICC Vaccine Formulation<br>2 doses of Formulation 2. 1 dose each on Days 0 and Day 56. | Biological: ICC Vaccine<br>* Intramuscular (deltoid) injections of in-clinic mix of various doses of qNIV2, SARS-CoV-2 rS, and 50 μg Matrix-M1 Adjuvant (ICC Vaccine) on Day 0 and Day 56.<br>|
| Experimental: Group C - ICC Vaccine Formulation<br>2 doses of Formulation 1. 1 dose each on Days 0 and Day 56. | Biological: ICC Vaccine<br>* Intramuscular (deltoid) injections of in-clinic mix of various doses of qNIV2, SARS-CoV-2 rS, and 50 μg Matrix-M1 Adjuvant (ICC Vaccine) on Day 0 and Day 56.<br>|
| Experimental: Group D - ICC Vaccine Formulation<br>2 doses of Formulation 3. 1 dose each on Days 0 and Day 56. | Biological: ICC Vaccine<br>* Intramuscular (deltoid) injections of in-clinic mix of various doses of qNIV2, SARS-CoV-2 rS, and 50 μg Matrix-M1 Adjuvant (ICC Vaccine) on Day 0 and Day 56.<br>|
| Experimental: Group E - ICC Vaccine Formulation<br>2 doses of Formulation 4. 1 dose each on Days 0 and Day 56. | Biological: ICC Vaccine<br>* Intramuscular (deltoid) injections of in-clinic mix of various doses of qNIV2, SARS-CoV-2 rS, and 50 μg Matrix-M1 Adjuvant (ICC Vaccine) on Day 0 and Day 56.<br>|
| Experimental: Group F- ICC Vaccine Formulation<br>2 doses of Formulation 5. 1 dose each on Days 0 and Day 56. | Biological: ICC Vaccine<br>* Intramuscular (deltoid) injections of in-clinic mix of various doses of qNIV2, SARS-CoV-2 rS, and 50 μg Matrix-M1 Adjuvant (ICC Vaccine) on Day 0 and Day 56.<br>|
| Experimental: Group G- ICC Vaccine Formulation<br>2 doses of Formulation 6. 1 dose each on Days 0 and Day 56. | Biological: ICC Vaccine<br>* Intramuscular (deltoid) injections of in-clinic mix of various doses of qNIV2, SARS-CoV-2 rS, and 50 μg Matrix-M1 Adjuvant (ICC Vaccine) on Day 0 and Day 56.<br>|
| Experimental: Group H- ICC Vaccine Formulation<br>2 doses of Formulation 7. 1 dose each on Days 0 and Day 56. | Biological: ICC Vaccine<br>* Intramuscular (deltoid) injections of in-clinic mix of various doses of qNIV2, SARS-CoV-2 rS, and 50 μg Matrix-M1 Adjuvant (ICC Vaccine) on Day 0 and Day 56.<br>|
| Experimental: Group I- ICC Vaccine Formulation<br>2 doses of Formulation 8. 1 dose each on Days 0 and Day 56. | Biological: ICC Vaccine<br>* Intramuscular (deltoid) injections of in-clinic mix of various doses of qNIV2, SARS-CoV-2 rS, and 50 μg Matrix-M1 Adjuvant (ICC Vaccine) on Day 0 and Day 56.<br>|
| Experimental: Group J -ICC Vaccine Formulation<br>2 doses of Formulation 9. 1 dose each on Days 0 and Day 56. | Biological: ICC Vaccine<br>* Intramuscular (deltoid) injections of in-clinic mix of various doses of qNIV2, SARS-CoV-2 rS, and 50 μg Matrix-M1 Adjuvant (ICC Vaccine) on Day 0 and Day 56.<br>|
| Experimental: Group K - ICC Vaccine Formulation<br>2 doses of Formulation 10. 1 dose each on Days 0 and Day 56. | Biological: ICC Vaccine<br>* Intramuscular (deltoid) injections of in-clinic mix of various doses of qNIV2, SARS-CoV-2 rS, and 50 μg Matrix-M1 Adjuvant (ICC Vaccine) on Day 0 and Day 56.<br>|
| Experimental: Group L - ICC Vaccine Formulation<br>2 doses of Formulation 11. 1 dose each on Days 0 and Day 56. | Biological: ICC Vaccine<br>* Intramuscular (deltoid) injections of in-clinic mix of various doses of qNIV2, SARS-CoV-2 rS, and 50 μg Matrix-M1 Adjuvant (ICC Vaccine) on Day 0 and Day 56.<br>|
| Experimental: Group M -ICC Vaccine Formulation<br>2 doses of Formulation 12. 1 dose each on Days 0 and Day 56. | Biological: ICC Vaccine<br>* Intramuscular (deltoid) injections of in-clinic mix of various doses of qNIV2, SARS-CoV-2 rS, and 50 μg Matrix-M1 Adjuvant (ICC Vaccine) on Day 0 and Day 56.<br>|
| Experimental: Group N- ICC Vaccine Formulation<br>2 doses of Formulation 7. 1 dose each on Days 0 and Day 56. | Biological: ICC Vaccine<br>* Intramuscular (deltoid) injections of in-clinic mix of various doses of qNIV2, SARS-CoV-2 rS, and 50 μg Matrix-M1 Adjuvant (ICC Vaccine) on Day 0 and Day 56.<br>|
| Experimental: Group O - qNIV with Matrix-M1 adjuvant<br>2 doses of Formulation 13. 1 dose each on Days 0 and Day 56 and an additional dose of 5 µg SARS-CoV-2 rS+50 µg Matrix-M1 at Day 70. | Biological: qNIV Nanoparticle Vaccine2 in-clinic mixed with Matrix-M1 Adjuvant<br>* Intramuscular (deltoid) injections of 60 μg qNIV Nanoparticle Vaccine2 in-clinic mixed with 75 μg Matrix-M1 Adjuvant on Days 0, Day 56, and an additional dose on Day 70.<br>|
| Experimental: Group P- SARS-CoV-2 rS with Matrix-M1 adjuvant<br>2 doses of Formulation 14. 1 dose each on Days 0 and Day 56. | Biological: SARS-CoV-2 rS Nanoparticle Vaccine in-clinic mixed with Matrix-M1 Adjuvant<br>* Intramuscular (deltoid) injections of 5 μg SARS-CoV-2 rS Nanoparticle Vaccine in-clinic mixed with 50 μg Matrix-M1 Adjuvant on Days 0 and Day 56.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of participants with solicited local and systemic AE's | Numbers of participants with solicited local and systemic AEs over the 7 days post-injection after first and second doses. | Day 0 to Day 63 | 
| Percentage of participants reporting all AE's | Percentage of participants reporting all AEs, solicited and unsolicited, over 70 days after the first dose. | Day 0 to Day 70 | 
| Percentage of participants with MAAE's, AESI's (including PIMMCs), SAEs | Percentage of participants with MAAEs, AESIs (including PIMMCs), SAEs, will be collected for 6 months (approximately 180 days) after the first dose. | Day 0 to Day 180 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| HAI antibody titers specific for the HA receptor binding domains of vaccine homologous A and B strain(s) expressed as GMT | HAI antibody titers specific for the HA receptor binding domains of vaccine homologous A and B strain(s) calculated as GMT , defined as the antilog of the mean of the log-transformed HAI titers on Days 56, 70, and other follow-up time points. | Day 56 to Day 180 | 
| HAI antibody titers specific for the HA receptor binding domains of vaccine homologous A and B strain(s) expressed as (GMFRPost/Pre) | HAI antibody titers specific for the HA receptor binding domains of vaccine homologous A and B strain(s) calculated as (GMFRPost/Pre), defined as the within-group ratio of post-vaccination to pre-vaccination (Day 0) HAI GMTs within the same vaccine group on Days 56, 70, and other follow-up time points. | Day 56 to Day 180 | 
| HAI antibody titers specific for the HA receptor binding domains of vaccine homologous A and B strain(s) expressed as SCR | HAI antibody titers specific for the HA receptor binding domains of vaccine homologous A and B strain(s) calculated as SCR defined as proportion of participants in a given treatment group with either a baseline reciprocal (Day 0) titer of < 10 and a post-vaccination reciprocal titer ≥ 40, or a baseline reciprocal (Day 0) titer of ≥ 10 and a post-vaccination titer ≥ 4-fold higher than the baseline titer as measured on Days 56, 70, and other follow-up time points. | Day 56 to Day 180 | 
| Percentage of participants with a reciprocal HAI titer ≥ 40 expressed as SPR | Percentage of participants with a reciprocal HAI titer ≥ 40 on Days 56, 70, and other follow-up time points. | Day 56 to Day 180 | 
| HAI antibody titers specific for the HA receptor binding domains of vaccine homologous A and B strain(s) expressed as GMTR | GMT ratio (GMTR) between select treatment arms at Days 56, 70, and other follow-up time points post-vaccination (adjusted for intergroup variation in baseline [pre-vaccination] titers) | Day 56 to Day 180 | 
| Microneutralization (MN50) antibody responses expressed as GMT | Microneutralization (MN50) antibody responses: neutralizing antibody titers specific to vaccine homologous wild-type A and B strain(s) and/or antigenically-drifted influenza strains, as measured by a MN assay , expressed as GMT. | Day 56 to Day 180 | 
| Microneutralization (MN50) antibody responses expressed as GMFR | Microneutralization (MN50) antibody responses: neutralizing antibody titers specific to vaccine homologous wild-type A and B strain(s) and/or antigenically-drifted influenza strains, as measured by a MN assay , expressed as GMFR. | Day 56 to Day 180 | 
| Microneutralization (MN50) antibody responses expressed as SCR | Microneutralization (MN50) antibody responses: neutralizing antibody titers specific to vaccine homologous wild-type A and B strain(s) and/or antigenically-drifted influenza strains, as measured by a MN assay, expressed as SCR. | Day 56 to Day 180 | 
| Microneutralization (MN50) antibody responses expressed as GMTR | Microneutralization (MN50) antibody responses: neutralizing antibody titers specific to vaccine homologous wild-type A and B strain(s) and/or antigenically-drifted influenza strains, as measured by a MN assay , expressed as GMTR. | Day 56 to Day 180 | 
| Serum IgG antibody concentrations as ELISA units to the SARS-CoV-2 spike protein expressed as GMEU | IgG geometric mean ELISA unit concentrations (EU/mL) to the SARS-CoV-2 spike protein from the matched vaccine construct (and mismatched variant if available), at Days 0, 56, 70, and other follow-up time points. | Day 0 to Day 180 | 
| Serum IgG antibody concentrations as ELISA units to the SARS-CoV-2 spike protein expressed as GMFR | IgG geometric mean ELISA unit concentrations (EU/mL) to the SARS-CoV-2 spike protein from the matched vaccine construct (and mismatched variant if available), at Days 0, 56, 70, and other follow-up time points. | Day 0 to Day 180 | 
| Serum IgG antibody concentrations as ELISA units to the SARS-CoV-2 spike protein expressed as SCR | IgG geometric mean ELISA unit concentrations (EU/mL) to the SARS-CoV-2 spike protein from the matched vaccine construct (and mismatched variant if available), at Days 0, 56, 70, and other follow-up time points. | Day 0 to Day 180 | 
| Serum IgG antibody concentrations as ELISA units to the SARS-CoV-2 spike protein expressed as GMEUR | IgG geometric mean ELISA unit concentrations (EU/mL) to the SARS-CoV-2 spike protein from the matched vaccine construct (and mismatched variant if available), at Days 0, 56, 70, and other follow-up time points. | Day 0 to Day 180 | 
| MN50 GMTs to the SARS-CoV-2 expressed as GMT | MN50 GMTs to the SARS-CoV-2 from the matched vaccine construct (and mismatched variant if available), at Days 0, 56, 70, and other follow-up time points. | Day 0 to Day 180 | 
| MN50 GMTs to the SARS-CoV-2 expressed as GMFR | MN50 GMTs to the SARS-CoV-2 from the matched vaccine construct (and mismatched variant if available), at Days 0, 56, 70, and other follow-up time points. | Day 0 to Day 180 | 
| MN50 GMTs to the SARS-CoV-2 expressed as SCR | MN50 GMTs to the SARS-CoV-2 from the matched vaccine construct (and mismatched variant if available), at Days 0, 56, 70, and other follow-up time points. | Day 0 to Day 180 | 
| MN50 GMTs to the SARS-CoV-2 expressed as GMTR | MN50 GMTs to the SARS-CoV-2 from the matched vaccine construct (and mismatched variant if available), at Days 0, 56, 70, and other follow-up time points. | Day 0 to Day 180 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Coronavirus