First-in-Human Clinical Trial of a Mosaic Quadrivalent Influenza Vaccine Compared With a Licensed Inactivated Seasonal QIV, in Healthy Adults

Study Overview
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Brief Summary
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Background: Influenza (flu) is a contagious respiratory illness. It is caused by influenza viruses that infect the nose, throat, and sometimes the lungs. Vaccines are given to teach the body to prevent or fight infection. Researchers want to study a new vaccine to prevent the seasonal flu. Objective: To see if the FluMos-v1 vaccine is safe and how the body responds to it. Eligibility: Healthy adults ages 18-50 who received at least one licensed flu vaccine from 2016 through the 2019-2020 influenza season. Design: Participants will be screened through a separate protocol. Participants will be tested for COVID-19. They may have a pregnancy test. Participants will receive the FluMos-v1 vaccine or the Flucelvax vaccine. It will be injected in the upper arm. Participants will complete a diary card for 7 days. They will record any symptoms they have. They will be given a thermometer to check their temperature. They will also be given a ruler to measure any skin changes at the injection site. Participants will have about 10 study visits. They will be asked how they are feeling and if they have taken any medications. They will have blood drawn. Participants will have oral mucosal samples collected using a thin swab. They may have nose and throat secretions collected using a thin swab. Some participants will have optional apheresis. Blood will be removed through a needle in a vein in one arm. A machine will separate the white blood cells. The rest of the blood will be returned through a needle in a vein in the other arm. Participation will last for 40 weeks.

Detailed Description
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Design: This is a Phase I, open-label, dose escalation study to evaluate the dose, safety, tolerability, and immunogenicity of the mosaic quadrivalent influenza vaccine VRC-FLUMOS0111-00-VP (FluMos-v1). The hypotheses are that the FluMos-v1 vaccine is safe and tolerable and will elicit an immune response. The primary objective is to evaluate the safety and tolerability of the investigational vaccine alone or with adjuvant in healthy adults. Secondary objectives relate to immunogenicity of the investigational vaccine and dosing regimen compared with the licensed inactivated seasonal Flucelvax (Registered Trademark) quadrivalent influenza vaccine (QIV) in healthy adults. Study Products: The investigational vaccine FluMos-v1 was developed by the Vaccine Research Center (VRC), National Institute of Allergy and Infectious Diseases (NIAID) and is composed of the following 4 influenza strains: Influenza A (H1: A/Idaho/07/2018 and H3: A/Perth/1008/2019) and Influenza B (Victoria lineage: B/Colorado/06/2017 and Yamagata lineage: B/Phuket/3073/2013. FluMos-v1 is supplied in a single-use vial at a concentration of 180 mcg/mL. In Part A, FluMos-v1 was compared to licensed 2020-2021 QIV Flucelvax (Registered Trademark) developed by Seqirus, Inc. and composed of the following 4 influenza strains: Influenza A (H1: A/Hawaii/70/2019 (H1N1) pdm09- like virus and H3: A/Hong Kong/45/2019 (H3N2)-like virus) and Influenza B: Victoria lineage: B/Washington/02/2019-like virus and Yamagata lineage: B/Phuket/3073/2013-like virus). In Part B, a higher dose of FluMos-v1 was tested that more closely matches the amount of each HA antigen in Flucelvax. The adjuvant Adjuplex (Registered Trademark) was added to FluMos-v1 to evaluate the potential for increased immunogenicity. All study enrollments and injections have been completed, and no further enrollments are planned in this study. Adjuplex is provided as a sterile, pyrogen-free, homogeneous solution filled to 0.7 mL in 3-mL glass vials. Adjuplex is mixed with study products in the pharmacy during preparation prior to vaccination at a 20% dose by volume. FluMos-v1, FluMos-V1 plus Adjuplex, and Flucelvax (Registered Trademark) are administered intramuscularly (IM) in the deltoid muscle via needle and syringe. Subjects: Healthy adults between the ages of 18-50 years inclusive will be enrolled. Study Plan: In Part A, the study evaluated the safety, tolerability, and immunogenicity of a single dose of FluMos-v1 vaccine alone in a dose-escalation design. In Part B, the study evaluated the safety, tolerability, and immunogenicity of a single dose of FluMos-v1 vaccine with or without Adjuplex. Group 6 and Part C are optional, and a decision was made not to enroll the optional groups 6-8 in the study. All study enrollments and injections have been completed for groups 1-5, and no further enrollments are planned in this study. The protocol requires 1 vaccination visit, about 8 follow-up visits, and a telephone contact on the day after vaccination. Solicited reactogenicity will be evaluated using a 7-day diary card. Assessment of vaccine safety will include clinical observation and monitoring of hematological and chemical parameters at clinical visits throughout the study. Study Duration: Subjects will be evaluated for 40 weeks following vaccine administration and through an influenza season.

Official Title
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VRC 325 (000410): A Phase I Open-Label Clinical Trial to Evaluate the Dose, Safety, Tolerability and Immunogenicity of Mosaic Quadrivalent Influenza Vaccine With and Without Adjuplex Compared With a Licensed Inactivated Seasonal QIV, In Healthy Adults

Conditions
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Influenza, Seasonal Influenza

Intervention / Treatment
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* Other: VRC-GENADJ0110-AP-NV
* Biological: Flucelvax
* Drug: VRC-FLUMOS0111-00-VP (FluMos-v1)


Participation Criteria
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Eligibility Criteria
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INCLUSION CRITERIA: A subject must meet all of the following criteria: Healthy adults between the ages of 18-50 years inclusive Based on history and physical examination, in good general health and without history of any of the conditions listed in the exclusion criteria Part A: Received at least one licensed influenza vaccine from 2016 through the 2019-2020 influenza season Part B and C: Received at least one licensed influenza vaccine from 2017 through the 2022-2023 influenza season Able and willing to complete the informed consent process Available for clinic visits for 40 weeks after enrollment and through an influenza season Able to provide proof of identity to the satisfaction of the study clinician completing the enrollment process Physical examination and laboratory results without clinically significant findings and a Body Mass Index (BMI) <=35 within the 56 days before enrollment Laboratory Criteria within 56 days before enrollment 8. White blood cells (WBC) and differential within institutional normal range or accompanied by the site Principal Investigator (PI) or designee approval 9. Total lymphocyte count >=800 cells/microliter 10. Platelets = 125,000 - 500,000 cells/microliter 11. Hemoglobin within institutional normal range or accompanied by the PI or designee approval 12. Alanine aminotransferase (ALT) <=1.25 x institutional upper limit of normal (ULN) 13. Aspartate aminotransferase (AST) <=1.25 x institutional ULN 14. Alkaline phosphatase (ALP) <1.1 x institutional ULN 15. Total bilirubin within institutional normal range or accompanied by the PI or designee approval. 16. Serum creatinine <=1.1 x institutional ULN 17. Negative for HIV infection by an FDA-approved method of detection 18. Negative for SARS-CoV-2 prior to enrollment Criteria applicable to women of childbearing potential: 19. Negative beta-human chorionic gonadotropin (beta-HCG) pregnancy test (urine or serum) on the day of enrollment 20. Agrees to use an effective means of birth control from at least 21 days prior to enrollment through the end of the study EXCLUSION CRITERIA: A subject will be excluded if one or more of the following conditions apply: Breast-feeding or planning to become pregnant during the study Subject has received any of the following substances: More than 10 days of systemic immunosuppressive medications or cytotoxic medications within the 4 weeks prior to enrollment or any within the 14 days prior to enrollment Blood products within 16 weeks prior to enrollment Live attenuated vaccines within 4 weeks prior to enrollment Inactivated vaccines within 2 weeks prior to enrollment Investigational research agents within 4 weeks prior to enrollment or planning to receive investigational products while on the study Current allergy treatment with allergen immunotherapy with antigen injections, unless on maintenance schedule Current anti-TB prophylaxis or therapy Previous investigational H1, H2, or H10 influenza vaccines, including Part A participants Part A: Groups 1A, 2A, and 3A only: Receipt of the 2020-2021 season s licensed influenza vaccine at any time prior to enrollment Groups 1B, 2B, and 3B only: Receipt of the 2020-2021 season s licensed influenza vaccine within 4 months prior to enrollment. Part B and C: Groups 4A, 5A, 6A, 7A, and 8A only: Receipt of the 2021-2022 or 2022-2023 season s licensed influenza vaccine at any time prior to enrollment Groups 4B, 5B, 6B, 7B, and 8B only: Receipt of the 2021-2022 or 2022-2023 season s licensed influenza vaccine within 4 months prior to enrollment. Subject has a history of any of the following clinically significant conditions: Serious reactions to vaccines that preclude receipt of the study vaccination as determined by the investigator Hereditary angioedema, acquired angioedema, or idiopathic forms of angioedema Asthma that is not well controlled Diabetes mellitus (type I or II), with the exception of gestational diabetes Thyroid disease that is not well controlled Idiopathic urticaria within the past year Autoimmune disease or immunodeficiency Hypertension that is not well controlled Bleeding disorder diagnosed by a doctor (e.g. factor deficiency, coagulopathy, or platelet disorder requiring special precautions) or significant bruising or bleeding difficulties with IM injections or blood draws Malignancy that is active or history of malignancy that is likely to recur during the period of the study Seizure disorder other than 1) febrile seizures, 2) seizures secondary to alcohol withdrawal more than 3 years ago, or 3) seizures that have not required treatment within the last 3 years Asplenia, functional asplenia or any condition resulting in the absence or removal of the spleen Guillain-Barre Syndrome Any medical, psychiatric, social condition, occupational reason or other responsibility that, in the judgment of the investigator, is a contraindication to protocol participation or impairs a subject s ability to give informed consent.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 50 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

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: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Group 1A-1B<br>20 mcg of FluMos-v1 | Drug: VRC-FLUMOS0111-00-VP (FluMos-v1)<br>* The VRC-FLUMOS0111-00-VP (FluMos-v1) vaccine is composed of engineered pentamer yeast C. albicans lumazine synthase assembled with 20 HA ectodomain trimers from the following influenza strains: Influenza A (H1: A/Idaho/07/2018, H3: A/Perth/1008/2019) and Influenza B (B/Victoria lineage: B/Colorado/06/2017, B/Yamagata lineage: B/Phuket/3073/2013)<br>|
| Experimental: Group 2A-2B<br>60 mcg of FluMos-v1 | Drug: VRC-FLUMOS0111-00-VP (FluMos-v1)<br>* The VRC-FLUMOS0111-00-VP (FluMos-v1) vaccine is composed of engineered pentamer yeast C. albicans lumazine synthase assembled with 20 HA ectodomain trimers from the following influenza strains: Influenza A (H1: A/Idaho/07/2018, H3: A/Perth/1008/2019) and Influenza B (B/Victoria lineage: B/Colorado/06/2017, B/Yamagata lineage: B/Phuket/3073/2013)<br>|
| Active Comparator: Group 3A-3B<br>standard dose of 60 mcg of the licensed QIV Flucelvax | Biological: Flucelvax<br>* Flucelvax is a cell-based vaccine which contains the same four influenza strains selected by the WHO, and has shown better safety and immunogenicity profiles than the traditional licensed seasonal egg based vaccine.<br>|
| Experimental: Group 4A-4B<br>100 mcg of FluMos-v1 | Drug: VRC-FLUMOS0111-00-VP (FluMos-v1)<br>* The VRC-FLUMOS0111-00-VP (FluMos-v1) vaccine is composed of engineered pentamer yeast C. albicans lumazine synthase assembled with 20 HA ectodomain trimers from the following influenza strains: Influenza A (H1: A/Idaho/07/2018, H3: A/Perth/1008/2019) and Influenza B (B/Victoria lineage: B/Colorado/06/2017, B/Yamagata lineage: B/Phuket/3073/2013)<br>|
| Experimental: Group 5A-5B<br>100 mcg of FluMos-v1 plus Adjuplex | Other: VRC-GENADJ0110-AP-NV<br>* Adjuplex is an adjuvant, a sterile, pyrogen-free adjuvant solution produced by VRC Pilot Plant. Adjuplex comprises highly purified de-oiled soy lecithin and benzene-free carbomer homopolymer formulated in phosphate buffered saline at a pH of 6.5 plus or minus 0.3. Adjuplex adjuvant will be mixed with FluMos-v1 at 20% by volume in the pharmacy during product preparation for the vaccinations of Groups 5A-5B, 6A-6B, and 8A-8B.<br>Drug: VRC-FLUMOS0111-00-VP (FluMos-v1)<br>* The VRC-FLUMOS0111-00-VP (FluMos-v1) vaccine is composed of engineered pentamer yeast C. albicans lumazine synthase assembled with 20 HA ectodomain trimers from the following influenza strains: Influenza A (H1: A/Idaho/07/2018, H3: A/Perth/1008/2019) and Influenza B (B/Victoria lineage: B/Colorado/06/2017, B/Yamagata lineage: B/Phuket/3073/2013)<br>|
| Experimental: Group 6A-6B<br>Optional: 60 mcg of FluMos-v1 plus Adjuplex | Other: VRC-GENADJ0110-AP-NV<br>* Adjuplex is an adjuvant, a sterile, pyrogen-free adjuvant solution produced by VRC Pilot Plant. Adjuplex comprises highly purified de-oiled soy lecithin and benzene-free carbomer homopolymer formulated in phosphate buffered saline at a pH of 6.5 plus or minus 0.3. Adjuplex adjuvant will be mixed with FluMos-v1 at 20% by volume in the pharmacy during product preparation for the vaccinations of Groups 5A-5B, 6A-6B, and 8A-8B.<br>Drug: VRC-FLUMOS0111-00-VP (FluMos-v1)<br>* The VRC-FLUMOS0111-00-VP (FluMos-v1) vaccine is composed of engineered pentamer yeast C. albicans lumazine synthase assembled with 20 HA ectodomain trimers from the following influenza strains: Influenza A (H1: A/Idaho/07/2018, H3: A/Perth/1008/2019) and Influenza B (B/Victoria lineage: B/Colorado/06/2017, B/Yamagata lineage: B/Phuket/3073/2013)<br>|
| Experimental: Group 7A-7B<br>Optional: TBD mcg of FluMos-v1 | Drug: VRC-FLUMOS0111-00-VP (FluMos-v1)<br>* The VRC-FLUMOS0111-00-VP (FluMos-v1) vaccine is composed of engineered pentamer yeast C. albicans lumazine synthase assembled with 20 HA ectodomain trimers from the following influenza strains: Influenza A (H1: A/Idaho/07/2018, H3: A/Perth/1008/2019) and Influenza B (B/Victoria lineage: B/Colorado/06/2017, B/Yamagata lineage: B/Phuket/3073/2013)<br>|
| Experimental: Group 8A-8B<br>Optional: TBD of FluMos-v1 plus Adjuplex | Other: VRC-GENADJ0110-AP-NV<br>* Adjuplex is an adjuvant, a sterile, pyrogen-free adjuvant solution produced by VRC Pilot Plant. Adjuplex comprises highly purified de-oiled soy lecithin and benzene-free carbomer homopolymer formulated in phosphate buffered saline at a pH of 6.5 plus or minus 0.3. Adjuplex adjuvant will be mixed with FluMos-v1 at 20% by volume in the pharmacy during product preparation for the vaccinations of Groups 5A-5B, 6A-6B, and 8A-8B.<br>Drug: VRC-FLUMOS0111-00-VP (FluMos-v1)<br>* The VRC-FLUMOS0111-00-VP (FluMos-v1) vaccine is composed of engineered pentamer yeast C. albicans lumazine synthase assembled with 20 HA ectodomain trimers from the following influenza strains: Influenza A (H1: A/Idaho/07/2018, H3: A/Perth/1008/2019) and Influenza B (B/Victoria lineage: B/Colorado/06/2017, B/Yamagata lineage: B/Phuket/3073/2013)<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Serious adverse events | Occurrence of serious adverse events | Day 0 through Day 280 | 
| New chronic medical conditions | Occurrence of new-onset of chronic medical conditions | Day 0 through Day 280 | 
| Local Reactogenicity | Occurrence of local reactogenicity signs and symptoms | 7 days after product administration | 
| Unsolicited adverse events | Occurrence of unsolicited non-serious adverse events | Day 0 through 28 days post product administration | 
| Laboratory measures | Occurrence of laboratory safety measures | Day 0 through 28 days post product administration | 
| Systemic Reactogenicity | Occurrence of systemic reactogenicity signs and symptoms | 7 days after product administration | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Part B: Group 4A-4B: vaccine-induced antibodies | antibody responses to 100 mcg of FluMos-v1 as a single dose | 2 weeks after product administration | 
| Part B: Groups 4A-4B and 5A-5B | Evaluate antibody responses between 100 mcg of FluMos-v1 and FluMos-v1 plus Adjuplex | 2 weeks after product administration | 
| Part B: Group 6A-6B: If Enrolled: vaccine-induced antibodies | antibody responses to 60 mcg of FluMos-v1 plus Adjuplex as a single dose | 2 weeks after product administration | 
| Part A: Group 1A-1B: vaccine-induced antibodies | antibody responses to 20 and 60 mcg of FluMos-v1 as a single dose | 2 weeks after product administration | 
| Part A: Group 2A-2B: vaccine-induced antibodies | antibody responses to 60 mcg of FluMos-v1 as a single dose | 2 weeks after product administration | 
| Part B: Group 5A-5B: vaccine-induced antibodies | antibody responses to 100 mcg of FluMos-v1 plus Adjuplex as a single dose | 2 weeks after product administration | 
| Part A: Group 3A-3B: vaccine-induced antibodies | antibody responses to 60 of FluMos-v1 and Flucelvax as a single dose | 2 weeks after product administration | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Seasonal Influenza, Flu Virus, Respiratory Illness, Viral Infection, Experimental Vaccine