Safety and Immunogenicity of the Bris10 M2SR and Sing2016 M2SR H3N2 Monovalent Influenza Vaccines

Study Overview
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Brief Summary
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This is a Phase I double-blind, randomized, placebo-controlled study in 250 healthy adults, 18-49 years of age, inclusive, who are in good health and meet all eligibility criteria. The purpose of this dose escalation clinical study is to assess the safety, tolerability/reactogenicity, and immunogenicity of H3N2 M2SR investigational vaccines for prevention of influenza, when delivered at higher dosages or in two doses . Eligible subjects will be screened and randomized to receive two administrations 28 days apart of Sing2016 M2SR at three dose levels (low, medium, high), Bris10 M2SR at one dose level (low), or placebo in a 1:1:1:1:1 ratio. Study duration will be approximately 8 months with subject participation duration approximately 7 months. The primary study objective is to assess the safety and reactogenicity of a monovalent live single replication influenza H3N2 M2SR vaccine.

Detailed Description
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This is a Phase I double-blind, randomized, placebo-controlled study in 250 healthy adults, 18-49 years of age, inclusive, who are in good health and meet all eligibility criteria. This dose escalation clinical study is designed to assess the safety, tolerability/reactogenicity, and immunogenicity of H3N2 M2SR investigational vaccines for prevention of influenza, when delivered at increasing dosages or in two doses. Subjects will be enrolled in five groups in a 1:1:1:1:1 ratio. Arm 1 will receive a low dose of Sing2016 M2SR intranasally on days 1 and 29. Arm 2 will receive a medium dose of Sing2016 M2SR intranasally on days 1 and 29. Arm 3 will receive a high dose of Sing2016 M2SR intranasally on days 1 and 29. Arm 4 will receive a low dose of Bris16 M2SR intranasally on days 1 and 29. Arm 5 will receive a placebo intranasally on days 1 and 29. Study duration will be approximately 8 months with subject participation duration approximately 7 months. The primary study objective is to assess the safety and reactogenicity of a monovalent live single replication influenza H3N2 M2SR vaccine. The secondary study objectives are to evaluate systemic and mucosal immune responses induced by H3N2 M2SR vaccination.

Official Title
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Phase 1b Clinical Study to Investigate the Safety and Immunogenicity of the Bris10 (A/Brisbane/10/2007) M2SR and Sing2016 (A/Singapore/INFIMH-16-0019/2016) M2SR H3N2 Monovalent Influenza Vaccines

Conditions
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Influenza A

Intervention / Treatment
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* Biological: LD Sing2016 M2SR H3N2 influenza vaccine
* Biological: MD Sing2016 M2SR H3N2 influenza vaccine
* Biological: HD Sing2016 M2SR H3N2 influenza vaccine
* Biological: LD Bris10 M2SR H3N2 influenza vaccine
* Other: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Give written informed consent to participate. Age 18 - 49 years old. Judged suitable by the PI, as determined by medical history, physical examination, vital signs, and clinical safety laboratory examinations. Willing to use oral, implantable, transdermal or injectable contraceptives, or sexual abstinence, from screening and until 28 days after second vaccine dose. Willing to adhere to the requirements of the study and willing and able to communicate with the Investigator and understand the requirements of the study. Exclusion Criteria: Abnormal screening hematology or chemistry value per the FDA Toxicity Guidance. Pulse rate or blood pressure outside the reference range for this study population and considered as clinically significant by the Investigator. Has an acute or chronic medical condition or history of a medical condition that, in the opinion of the Investigator, would render the study procedures unsafe or would interfere with the evaluation of the responses. Presence or clinically significant history of lung disease, asthma, chronic obstructive pulmonary disease (COPD), or otherwise poor lung function. Any confirmed or suspected immunosuppressive or immunodeficient state. Presence of household member or close personal or professional (i.e., healthcare worker) who is a child under one year of age; is pregnant; has known immunodeficiency or is receiving immunosuppressant medication; is undergoing or soon to undergo cancer chemotherapy; has been diagnosed with emphysema, COPD, or other severe lung disease and resides in a nursing home; and/or has received a bone marrow or solid organ transplant. Females who are pregnant or lactating. Acute febrile illness within 72 hours prior to vaccination. Any condition, in the opinion of the Investigator, (such as subjects who have medically high-risk conditions) that might interfere with the primary study objectives for safety of the study subject.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 49 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: Basic Science
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: This is a randomized, double-blind, placebo-controlled Phase 1 study evaluating the safety and immunogenicity of the Bris10 M2SR and Sing2016 M2SR H3N2 influenza vaccines delivered intranasally to healthy adults. Eligible subjects will be screened and randomized to receive two administrations 28 days apart of Sing2016 M2SR at three dose levels, Bris10 M2SR at one dose level, or placebo in a 1:1:1:1:1 ratio.
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Low dose Sing2016 M2SR<br>Low dose Sing2016 M2SR will be administered intranasally on days 1 and 29 | Biological: LD Sing2016 M2SR H3N2 influenza vaccine<br>* This group will receive a low dose of the Sing2016 M2SR H3N2 monovalent influenza vaccine administered intranasally.<br>|
| Experimental: Medium dose Sing2016 M2SR<br>Medium dose Sing2016 M2SR will be administered intranasally on days 1 and 29 | Biological: MD Sing2016 M2SR H3N2 influenza vaccine<br>* This group will receive a medium dose of the Sing2016 M2SR H3N2 monovalent influenza vaccine administered intranasally.<br>|
| Experimental: High dose Sing2016 M2SR<br>High dose Sing2016 M2SR will be administered intranasally on days 1 and 29 | Biological: HD Sing2016 M2SR H3N2 influenza vaccine<br>* This group will receive a high dose of the Sing2016 M2SR H3N2 monovalent influenza vaccine administered intranasally.<br>|
| Active Comparator: Low dose Bris10 M2SR<br>Low dose Bris10 M2SR will be administered intranasally on days 1 and 29 | Biological: LD Bris10 M2SR H3N2 influenza vaccine<br>* This group will receive a low dose of the Bris10 M2SR H3N2 monovalent influenza vaccine administered intranasally.<br>|
| Placebo Comparator: Placebo<br>Saline will be administered intranasally on days 1 and 29 | Other: Placebo<br>* This group will receive saline placebo administered intranasally.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Local and Systemic Adverse Events (AEs) Through 29 Days Post-vaccination With Bris10 M2SR and Cumulatively Through Day 209 | Record adverse events following one and two administrations of the Bris10 M2SR influenza vaccine to determine the number and percentage of study participants who experience any vaccine associated adverse events (AEs) or serious adverse events (SAEs) after Bris10 M2SR or placebo administration. | From baseline through study completion (Day 209) | 
| Number of Participants With Local and Systemic Adverse Events (AEs) Through 29 Days Post-vaccination With Sing2016 M2SR and Cumulatively Through Day 209 | Record adverse events following one and two administrations of the Sing2016 M2SR influenza vaccine to determine the number and percentage of study participants who experience any vaccine associated adverse events (AEs) or serious adverse events (SAEs) after Sing2016 M2SR or placebo administration. | From baseline through study completion (Day 209) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Bris10 M2SR Subjects Demonstrating Seroconversion to Vaccine HA | Assess the humoral immunogenicity of one administration of Bris10 M2SR vaccine to Bris 10 by HAI at day 29. | From baseline through 28 days post-dose 1 (Day 29) | 
| Percentage of Sing2016 M2SR Subjects Demonstrating Seroconversion to Vaccine HA | Assess the humoral immunogenicity of one administration of Sing2016 M2SR vaccine to Sing2016 by HAI at day 29 | From baseline through 28 days post-dose 1 (Day 29) | 
| Percentage of Bris10 M2SR Subjects Demonstrating Seroconversion to Vaccine HA | Assess the humoral immunogenicity of two administrations of Bris10 M2SR vaccine to Bris 10 by HAI at d57. | From baseline through 28 days post-dose 2 (Day 57) | 
| Percentage of Sing2016 M2SR Subjects Demonstrating Seroconversion to Vaccine HA | Assess the humoral immunogenicity of two administrations of Sing2016 M2SR vaccine to Sing2016 by HAI at day 57 | From baseline through 28 days post-dose 2 (Day 57) | 
| Percentage of Bris10 M2SR Subjects Demonstrating Mucosal Responses to Vaccine HA | Assess the mucosal immunogenicity of one administration of Bris10 M2SR vaccine to Bris 10 by ELISA at day 29. | From baseline through 28 days post-dose 1 (Day 29) | 
| Percentage of Bris10 M2SR Subjects Demonstrating Mucosal Responses to Vaccine HA | Assess the mucosal immunogenicity of two administrations of Bris10 M2SR vaccine to Bris 10 by ELISA at day 57. | From baseline through 28 days post-dose 2 (Day 57) | 
| Percentage of Sing2016 M2SR Subjects Demonstrating Mucosal Responses to Vaccine HA | Assess the mucosal immunogenicity of two administrations of Sing2016 M2SR vaccine to Sing2016 by ELISA at day 57 | From baseline through 28 days post-dose 2 (Day 57) | 
| Percentage of Sing2016 M2SR Subjects Demonstrating Mucosal Responses to Vaccine HA | Assess the mucosal immunogenicity of one administration of Sing2016 M2SR vaccine to Sing2016 by ELISA at day 29 | From baseline through 28 days post-dose 1 (Day 29) |