Assess the Safety and Immunogenicity of One or Two Doses of Sing2016 M2SR H3N2 Influenza Vaccine

Study Overview
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Brief Summary
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This is a Phase 1b, randomized, double-blind, dose-escalating, age de-escalating, placebo-controlled study of 200 children, ages 6 months to 17 years. This clinical trial is designed to assess the safety, tolerability/reactogenicity, and immunogenicity of one and two doses of Sing2016 M2SR H3N2 influenza vaccine (manufactured by FluGen) administered intranasally in seven cohorts of children. The study design includes pre-planned Safety Review Committee( SRC) reviews. The first two groups to be vaccinated will be Cohorts 1 and 2. Cohort 1 consists of 45 children 9-17 years old. Thirty of them will receive one dose of the vaccine at a dose of 10^9 TCID50, and 15 will receive one dose of placebo. Cohort 2 comprises 45 children 2-8 years old. Thirty of them will receive one dose of the vaccine at a dose of 10^8 TCID50 and 15 will receive one dose of placebo. Cohort 3 consists of 25 children 2-8 years old. 15 of them will receive one dose of vaccine at 10^9 TCID50 and 10 will receive one dose of placebo. Once 25 participants in Cohort 3 have completed Day 8 of follow-up, similar to Cohorts 1 and 2, the SRC will review to ensure no halting rules are met and if no rules are met, and the SRC determines it is safe to proceed, simultaneous enrollment into Cohorts 4 and 5 can begin. If any halting rules are met or any concerns are raised by the SRC, an external SMC may meet to discuss the data for recommendations on either progression or clinical trial modification before progression to the next cohort. Cohort 4 consists of 25 children 2-8 years old; 15 of them will receive two doses of vaccine at 10^9 TCID50 and 10 will receive two doses of placebo, with a 28-day interval between the first and second doses. Cohort 5 will enroll 8 influenza naïve children (defined as children without receipt of influenza vaccine and without previous documented influenza infection) who are 6-23 months old who will be randomly assigned to receive two doses of 10^7 TCID50 Sing2016 M2SR (n=6) or two doses of placebo (n=2) with a 28-day interval between the first and second dose. Once all 8 participants in Cohort 5 have completed Day 8 of follow-up after the first dose, the SRC will conduct a safety assessment before beginning enrollment in Cohort 6. Cohorts 6 and 7 will also enroll 6- to 23-month-olds who are influenza-naïve. Cohort 6 will consist of 26 children. A lead-in group of 8 children will be randomly assigned to receive either two doses of 10^8 TCID50 of the Sing2016 M2SR (n=6) or two doses of placebo (n=2). Once the first 8 children have completed Day 8 of follow-up after the first dose, the SRC will review the safety and determine if Cohort 7 may open to enrollment. Cohort 7 enrollment will not begin until Cohort 6 is fully enrolled. Similar to other cohorts, the additional 18 children in Cohort 6 may continue to enroll during the SRC review. Cohort 7 will be the final cohort. Twenty-six children will be randomly allocated to receive two doses of either 10^9 TCID50 Sing2016 M2SR (n=18) or placebo (n=8). This cohort does not have a lead-in group since data from such a group are not needed to allow the enrollment in a subsequent cohort. However, the study-wide and individual halting rules still apply. The primary study objective is to assess the safety and tolerability of one and two administrations of the Sing2016 M2SR H3N2 influenza vaccine at 10^7, 10^8, or 10^9 TCID50 delivered intranasally to healthy participants, 6 months to 17 years of age

Detailed Description
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This is a Phase 1b, randomized, double-blind, dose-escalating, age de-escalating, placebo-controlled study of 200 children, ages 6 months to 17 years. This clinical trial is designed to assess the safety, tolerability/reactogenicity, and immunogenicity of one and two doses of Sing2016 M2SR H3N2 influenza vaccine (manufactured by FluGen) administered intranasally in seven cohorts of children. The study design includes pre-planned Safety Review Committee( SRC) reviews. The first two groups to be vaccinated will be Cohorts 1 and 2. Cohort 1 consists of 45 children 9-17 years old. Thirty of them will receive one dose of the vaccine at a dose of 10^9 TCID50, and 15 will receive one dose of placebo. Cohort 2 comprises 45 children 2-8 years old. Thirty of them will receive one dose of the vaccine at a dose of 10^8 TCID50 and 15 will receive one dose of placebo. Sites will enroll participants into Cohorts 1 and 2 simultaneously. Once 25 or more participants in each of the first 2 cohorts (Cohorts 1 and 2) have completed Day 8, SRC will evaluate if any halting rules are met and if it is deemed safe enrollment in Cohort 3 may open. Cohort 2 must fully enroll before enrollment in Cohort 3 may begin. Cohort 3 consists of 25 children 2-8 years old. 15 of them will receive one dose of vaccine at 10^9 TCID50 and 10 will receive one dose of placebo. Once all 25 participants in Cohort 3 have completed Day 8 of follow-up, similar to Cohorts 1 and 2, the SRC will review to ensure no halting rules are met and if no rules are met, and the SRC determines it is safe to proceed, simultaneous enrollment into Cohorts 4 and 5 can begin. If any halting rules are met or any concerns are raised by the SRC, an external SMC may meet to discuss the data for recommendations on either progression or clinical trial modification before progression to the next cohort. Cohort 4 consists of 25 children 2-8 years old; 15 of them will receive two doses of vaccine at 10^9 TCID50 and 10 will receive two doses of placebo, with a 28-day interval between the first and second doses. Cohort 5 will enroll 8 influenza naïve children (defined as children without receipt of influenza vaccine and without previous documented influenza infection) who are 6-23 months old who will be randomly assigned to receive two doses of 10^7 TCID50 Sing2016 M2SR (n=6) or two doses of placebo (n=2) with a 28-day interval between the first and second dose. Once all 8 participants in Cohort 5 have completed Day 8 of follow-up after the first-dose, the SRC will conduct a safety assessment before beginning enrollment in Cohort 6. Cohorts 6 and 7 will also enroll 6- to 23-month-olds who are influenza-naïve. Cohort 6 will consist of 26 children. A lead-in group of 8 children will be randomly assigned to receive either two doses of 10^8 TCID50 of the Sing2016 M2SR (n=6) or two doses of placebo (n=2). Once the first 8 children have completed Day 8 of follow up after the first dose, the SRC will review the safety and determine if Cohort 7 may open to enrollment. Cohort 7 enrollment will not begin until Cohort 6 is fully enrolled. Similar to other cohorts, the additional 18 children in Cohort 6 may continue to enroll during the SRC review. Cohort 7 will be the final cohort. Twenty-six children will be randomly allocated to receive two doses of either 10^9 TCID50 Sing2016 M2SR (n=18) or placebo (n=8). This cohort does not have a lead-in group since data from such a group are not needed to allow the enrollment in a subsequent cohort. However, the study-wide and individual halting rules still apply. The primary study objective is to assess the safety and tolerability of one and two administrations of the Sing2016 M2SR H3N2 influenza vaccine at 10^7, 10^8, or 10^9 TCID50 delivered intranasally to healthy participants, 6 months to 17 years of age. The secondary study objective is to assess the humoral immunogenicity (serum antibody and mucosal antibody responses) directed against homologous viral strains after one and two administrations of Sing2016 M2SR H3N2 influenza vaccine at 10^7, 10^8, or 10^9 TCID50 delivered intranasally to healthy participants, 6 months to 17 years of age

Official Title
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A Phase 1b, Double-Blind, Randomized, Dose-Escalating, Age De-Escalating, Placebo-Controlled Study to Assess the Safety and Immunogenicity of One or Two Doses of Sing2016 M2SR H3N2 Influenza Vaccine Delivered Intranasally In a Healthy Pediatric Population 6 Months Through 17 Years of Age.

Conditions
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H3N2 Influenza

Intervention / Treatment
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* Other: Placebo
* Biological: Sing2016 M2SR H3N2


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 1. Participant is a male or female child aged 6 months to 17 years inclusive at time of enrollment (each cohort has its own age upper and lower limits*) Cohort 1: 9-17 years (on or after the ninth birthday and before the eighteenth birthday at the time of the first dose); Cohorts 2, 3, and 4: 2-8 years (on or after the second birthday and before the ninth birthday at the time of the first dose); Cohorts 5, 6, and 7: 6 months to 23 months (on or after the sixth month of life based on calendar day and before the second birthday at the time of the first dose) 2. For Cohorts 1 to 4, receipt of at least 2 doses of seasonal influenza vaccine in the past. 3. For Cohorts 5 to 7, receipt of no seasonal influenza vaccines in the past and no documented history of laboratory-confirmed influenza illness 4. Parent/guardian of the participating child provides written informed permission and participating child provides assent* prior to initiation of any study procedures As appropriate by age or development and approved by the Institutional Review Board (IRB) 5. Parent/guardian and participant, as appropriate, are able to understand and comply with planned study procedures and are available for all study visits 6. Participant is in good health as assessed by the principal investigator or other designated study investigator* Based on medical history and physical examination (physical examination may be done as part of routine medical care or specifically for eligibility screening) 7. Parent/guardian of the participating child agrees not to allow the participant to join another clinical trial that includes an investigational agent or device during the study period 8. A female participant of child-bearing potential* agrees to abstain from sexual intercourse or to correctly use an acceptable method of contraception** A female of child-bearing potential is defined as a female who is post-menarchal and not sterilized via tubal ligation, bilateral oophorectomy, salpingectomy, hysterectomy, or successful Essure (R) placement (permanent, non-surgical, non-hormonal sterilization) with documented radiological confirmation test at least 90 days after the procedure. This applies only to participants in Cohort 1. **Acceptable methods of contraception must be used from 30 days prior to vaccination until 60 days after the last study vaccination (not Inactivated Influenza Vaccine (IIV4)) and include full abstinence from sexual intercourse with a male partner, monogamous relationship with vasectomized partner who has been vasectomized for 180 days or more or shown to be azoospermic prior to the participant receiving the study vaccination, barrier methods such as condoms or diaphragms/cervical cap, intrauterine devices, NuvaRing (R), and licensed hormonal methods such as implants, injectables, or oral contraceptives (the pill). 9. A female participant of child-bearing potential must have a negative urine pregnancy test within 24 hours prior to each study product 10. A male who is sexually active with a female of childbearing potential must agree to use an acceptable method of contraception* From the time of the first dose of study vaccine until 60 days after receipt of the last dose study vaccine, only in cohort 1. The only acceptable method of contraception for males who are sexually active with females of childbearing potential is condoms. Exclusion Criteria: Has a body temperature of 38 degrees Celsius or 100.4 degrees Fahrenheit (oral or axillary) or greater or another acute illness* within the 72 hours prior to study vaccination *Potential participants who are recovering from an acute illness and have residual minimal symptoms, which, in the opinion of the site principal investigator or appropriate sub-investigator, will not likely affect the evaluation of outcome measures are not ineligible. Temperature evaluation will not be performed as a study procedure on participants prior to administration of seasonal influenza vaccine Has any medical or mental health disease or condition* that would render study participation unsafe, or would interfere with the evaluation of the responses *In the opinion of the site principal investigator or appropriate sub-investigator Has a history of provider-diagnosed asthma requiring the use of medications at any age or has had a wheezing episode or use of medications to treat asthma in the 12 months prior to screening. Has immunosuppression as a result of an underlying illness or treatment, a recent history or current use of immunosuppressive or immunomodulating disease therapy Has a diagnosis of or history of malignant neoplastic disease Has taken oral, parenteral (intramuscular or intravenous), inhaled, or nasal corticosteroids of any dose within 30 days prior to study vaccination Has known HIV, hepatitis B, or hepatitis C infection Has known hypersensitivity or allergy to any components of the study vaccine or material in the nasal delivery device* *Vaccine components: sucrose, sodium chloride, phosphate, glutamate; delivery device material: polycarbonate, polypropylene, synthetic rubber Has a history of severe reactions following previous immunization with licensed or unlicensed influenza vaccines Has a history of an anatomic disorder of the nares or nasopharynx Has a history of chronic sinus infections Has a history of or currently smokes or vapes Has a history of Guillain-Barré syndrome Use of aspirin- or salicylate-containing products in the 30 days prior to or intends to use these products in the 30 days following administration of the investigational vaccine Has a history of documented influenza or receipt of influenza antiviral treatment in the 4 months prior to the first vaccination Receipt of any antiviral drug within the week prior to or following the investigational vaccine. Receipt of a licensed live vaccine within 30 days prior to the first study vaccination or plans to receive a licensed live vaccine within the 30 days after the last study vaccination. Receipt of licensed inactivated non-influenza vaccine within 14 days prior to the first study vaccination, or plans to receive licensed, inactivated vaccine within the 30 days after the last study vaccination. ** Participants will be asked to avoid receipt of any routine licensed vaccines or vaccines under emergency use authorization during the periods described. Receipt of an influenza vaccine within the 4 months prior to the first study vaccination or plans to receive an influenza vaccine following the last study vaccination. Seasonal IIV4 will be received by participants as part of this trial. Receipt of immunoglobulin or other blood products within the 6 months prior to the first study vaccination or plans to receive during the period of study participation. Receipt of an experimental* agent or device within the 6 months prior to the first study vaccination or expects to receive an experimental agent or device during the study period. *Products for treatment or prevention of coronavirus disease 2019 (COVID-19), when received under Emergency Use Authorization (EUA) or full FDA approval and not as part of a clinical trial, will not be deemed experimental for the purposes of this criterion and will not make an otherwise eligible prospective participant ineligible. Is a family member of study personnel or personnel directly involved in the conduct or monitoring of the study. Receipt of an approved or experimental product for treatment or prevention of COVID-19 within the 10 days prior to study enrollment. Participants may enroll if greater than 10 days after receipt of the COVID-19 treatment or prevention. Participants who are receiving COVID-19 vaccines around the time of dosing of the investigational product will be asked to avoid COVID-19 vaccination within the 10 days before any vaccination in the study and within any reactogenicity period (the day of and 7 days following each intranasal vaccination). Inability of the study team to collect 5 mL of blood from the participant before the first vaccination (pre-vaccination blood).

Ages Eligible for Study
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Minimum Age: 6 Months
Maximum Age: 17 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: Cohort 1<br>A cohort of influenza non-naïve 45 healthy children, 9-17 years old, will receive a single dose of 10^9 TCID50 of intranasal Sing2016 M2SR H3N2 vaccine (N=30) or placebo (N=15) at Day 1. N=45. | Other: Placebo<br>* Physiological saline, i.e., 0.9% sodium chloride.<br>Biological: Sing2016 M2SR H3N2<br>* Novel intranasal live attenuated influenza vaccine with a defective M2 gene which renders the virus unable to replicate and generate progeny in animals and in humans, making its infectivity self-limiting. It induces both a mucosal and cell-mediated immune response and is administered intranasally. Supplied by Flugen Inc.<br>|
| Experimental: Cohort 2<br>A cohort of influenza non-naïve 45 healthy children, 2-8 years old, will receive a single dose of 10^8 TCID50 of intranasal Sing2016 M2SR H3N2 vaccine (N=30) or placebo (N=15) at Day 1 intranasally. N= 45 | Other: Placebo<br>* Physiological saline, i.e., 0.9% sodium chloride.<br>Biological: Sing2016 M2SR H3N2<br>* Novel intranasal live attenuated influenza vaccine with a defective M2 gene which renders the virus unable to replicate and generate progeny in animals and in humans, making its infectivity self-limiting. It induces both a mucosal and cell-mediated immune response and is administered intranasally. Supplied by Flugen Inc.<br>|
| Experimental: Cohort 3<br>Once, there is sufficient evidence of safety and tolerability in Cohorts 1 and 2,and enrollment has completed of all 45 in each of these cohorts. Cohort 3 will begin enrollment. A cohort of influenza non-naïve 25 healthy children, 2-8 years old, will receive a single dose of 10^9 TCID50 of intranasal Sing2016 M2SR H3N2 vaccine (N=15) or placebo (N=10) at Day 1. N=25. | Other: Placebo<br>* Physiological saline, i.e., 0.9% sodium chloride.<br>Biological: Sing2016 M2SR H3N2<br>* Novel intranasal live attenuated influenza vaccine with a defective M2 gene which renders the virus unable to replicate and generate progeny in animals and in humans, making its infectivity self-limiting. It induces both a mucosal and cell-mediated immune response and is administered intranasally. Supplied by Flugen Inc.<br>|
| Experimental: Cohort 4<br>Once, there is sufficient evidence of safety and tolerability in Cohort 3 and enrollment has been completed for this cohort, and fifth cohorts (Cohorts 4 and 5) will begin enrollment. A cohort of influenza non-naïve 25 healthy children, 2-8 years old, will receive two doses of the 10^9 TCID50 of intranasal Sing2016 M2SR H3N2 vaccine (N=15) or two doses of placebo (N=10) at Day 1 and Day 29. N=25 | Other: Placebo<br>* Physiological saline, i.e., 0.9% sodium chloride.<br>Biological: Sing2016 M2SR H3N2<br>* Novel intranasal live attenuated influenza vaccine with a defective M2 gene which renders the virus unable to replicate and generate progeny in animals and in humans, making its infectivity self-limiting. It induces both a mucosal and cell-mediated immune response and is administered intranasally. Supplied by Flugen Inc.<br>|
| Experimental: Cohort 5<br>Participants in Cohort 4, will enroll concurrently. A cohort of influenza-naïve healthy children, 6-23 months old, will be randomized to receive two doses of 10^7 TCID50 of intranasal Sing2016 M2SR vaccine (N=6) or two doses of placebo (N=2) at Day 1 and Day 29. N=8. | Other: Placebo<br>* Physiological saline, i.e., 0.9% sodium chloride.<br>Biological: Sing2016 M2SR H3N2<br>* Novel intranasal live attenuated influenza vaccine with a defective M2 gene which renders the virus unable to replicate and generate progeny in animals and in humans, making its infectivity self-limiting. It induces both a mucosal and cell-mediated immune response and is administered intranasally. Supplied by Flugen Inc.<br>|
| Experimental: Cohort 6<br>Once, there is sufficient evidence of safety in Cohort 5, Cohort 6 will begin enrollment. A cohort of influenza-naïve healthy children, 6-23 months old, where a lead-in group (N=20) will be randomly assigned to receive either two doses of 10^8 TCID50 of intranasal Sing2016 M2SR vaccine (N=6) or two doses of placebo (N=2) at Day 1 and Day 29. N=20. Once lead-in group completes Day 8, the SRC will review the safety and determine if Cohort 7 may begin enrollment. Additional group of children may continue to enroll during the SRC review, which will be assigned randomly to receive two doses of 10^8 TCID50 of intranasal Sing2016 M2SR (N=12) or two doses of placebo (N=6) at Day 1 and Day 29. N= 26 | Other: Placebo<br>* Physiological saline, i.e., 0.9% sodium chloride.<br>Biological: Sing2016 M2SR H3N2<br>* Novel intranasal live attenuated influenza vaccine with a defective M2 gene which renders the virus unable to replicate and generate progeny in animals and in humans, making its infectivity self-limiting. It induces both a mucosal and cell-mediated immune response and is administered intranasally. Supplied by Flugen Inc.<br>|
| Experimental: Cohort 7<br>Once, there is sufficient evidence of safety in Cohort 6, Cohort 7 will begin enrollment. A cohort of influenza-naïve healthy children, 6-23 months old, will be randomly assigned to receive two doses of 10^9 TCID50 dose of intranasal Sing2016 M2SR vaccine (N=18) or two doses of placebo (N=8) at Day 1 and Day 29. N=26 | Other: Placebo<br>* Physiological saline, i.e., 0.9% sodium chloride.<br>Biological: Sing2016 M2SR H3N2<br>* Novel intranasal live attenuated influenza vaccine with a defective M2 gene which renders the virus unable to replicate and generate progeny in animals and in humans, making its infectivity self-limiting. It induces both a mucosal and cell-mediated immune response and is administered intranasally. Supplied by Flugen Inc.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Occurrence of Adverse Events of Special Interest (AESIs) |  | Day 1 through Day 395 | 
| Occurrence of New-onset Chronic Medical Conditions (NOCMCs) |  | Day 1 through Day 395 | 
| Occurrence of Serious Adverse Event (SAEs) |  | Day 1 through Day 395 | 
| Occurrence of solicited reactogenicity Adverse Events (AEs) | Both local and systemic solicited reactogenicity adverse events (AEs) will be assessed. | Through 7 days post vaccination | 
| Occurrence of unsolicited non serious Adverse Events (AE) |  | Through 28 days post vaccination | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change from baseline in Geometric Mean Fold Rise (GMFR) in Hemagglutination inhibition (HAI) antibody titers | Hemagglutination inhibition (HAI) antibody titers against an H3N2 M2SR-like virus | Day 1 through Day 57 | 
| Change from baseline in Geometric Mean Fold Rise (GMFR) in neutralization titers | Neutralization titers against an H3N2 M2SR-like virus | Day 1 through Day 57 | 
| Change from baseline in Geometric mean titer (GMT) of secretory Immunoglobulin A (sIgA) | Secretory ImmunoglobulinA (sIgA) against an H3N2 M2SR-like virus | Day 1 through Day 57 | 
| Geometric mean fold rise (GMFR) of secretory Immunoglobulin A (sIgA) | Secretory ImmunoglobulinA (sIgA) against an H3N2 M2SR-like virus | Day 1 through Day 57 | 
| Geometric Mean Titers (GMTs) of serum Hemagglutination inhibition (HAI) antibody | Hemagglutination inhibition (HAI) antibody against an H3N2 M2SR-like virus | Up to Day 57 | 
| Geometric Mean Titers (GMTs) of serum neutralizing antibodies | Serum neutralizing antibodies against an H3N2 M2SR-like virus | Up to Day 57 | 
| Occurrence of greater than or equal to 2- and 4-fold mean rises in Hemagglutination inhibition (HAI) antibody titers | Hemagglutination inhibition (HAI) antibody titers against an H3N2 M2SR-like virus | Day 1 through Day 57 | 
| Occurrence of greater than or equal to 2- and 4-fold mean rises in neutralization titers | Neutralization titers against an H3N2 M2SR-like virus | Day 1 through Day 57 | 
| Occurrence of neutralization titer > / =1:40 | Neutralization titer > / =1:40 against an H3N2 M2SR-like virus | Up to Day 57 | 
| Occurrence of putative seroprotection | Seroprotection defined as Hemagglutination inhibition (HAI) antibody titer > / = 1:40 against an H3N2 M2SR-like virus | Up to Day 57 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Healthy Pediatric Population, Immunogenicity, Influenza, M2SR H3N2 Influenza Vaccine, Phase 1b, Sing2016 M2SR H3N2 Influenza Vaccine