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

Phase 1

Terminated

Conditions: H3N2 Influenza

Interventions: Other: Placebo
Biological: Sing2016 M2SR H3N2

Registration Number: NCT04960397

Lead Sponsor: National Institute of Allergy and Infectious Diseases (NIAID)

Brief Summary: 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. Due to the limited availability of product, and funding to support additional years of enrollment into Cohorts 5, 6, and 7, the decision was made to stop enrollment after the final participant was enrolled into Cohort 4.

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\^8 or 10\^9 TCID50 delivered intranasally to healthy participants, 2 to 17 years of age.

Detailed Description: 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. Due to the limited availability of product, and funding to support additional years of enrollment into Cohorts 5, 6, and 7, the decision was made to stop enrollment after the final participant was enrolled into Cohort 4.

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\^8 or 10\^9 TCID50 delivered intranasally to healthy participants, 2 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\^8 or 10\^9 TCID50 delivered intranasally to healthy participants, 2 to 17 years of age.

Recruitment & Eligibility

Status: TERMINATED

Sex: All

Target Recruitment: 140

Inclusion Criteria

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.
1. 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").
1. 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).

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Cohort 3	Placebo	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.
Cohort 1	Sing2016 M2SR H3N2	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.
Cohort 2	Sing2016 M2SR H3N2	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
Cohort 1	Placebo	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.
Cohort 4	Placebo	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
Cohort 3	Sing2016 M2SR H3N2	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.
Cohort 4	Sing2016 M2SR H3N2	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
Cohort 2	Placebo	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

Primary Outcome Measures

Name	Time	Method
Number and Percentage of Participants Experiencing a Solicited Reactogenicity Adverse Event	Day of second vaccination through 7 days post-dose 2 (Day 29 to Day 36)	Number and percentage of participants in Cohort 4 who experience systemic (solicited or local) reactogenicity events, of all severity grades and by grade
Number and Percentage of Participants Experiencing an Unsolicited Non-serious Adverse Event (AE)	Day of second vaccination through 7 days post-dose 2 (Day 29 to Day 36)	Number and percentage of participants in Cohort 4 who experience unsolicited non-serious adverse events, of all severity grades and by grade
Number and Percentage of Participants Experiencing an Adverse Event of Special Interest (AESI)	Day 1 through final visit in the month of April of the calendar year following enrollment (up to 14 months post-baseline)	Number and percentage of participants in Cohorts 1-4 each and across Cohorts 1-4 who experience AESIs
Number and Percentage of Participants Experiencing a Serious Adverse Event (SAE)	Day 1 through final visit in the month of April of the calendar year following enrollment (up to 14 months post-baseline)	Number and percentage of participants in Cohorts 1-4 each and across Cohorts 1-4 who experience serious adverse events (SAEs)
Number and Percentage of Participants Experiencing a New-onset Chronic Medical Condition (NOCMC)	Day 1 through final visit in the month of April of the calendar year following enrollment (up to 14 months post-baseline)	Number and percentage of participants in Cohorts 1-4 each and across Cohorts 1-4 who experience new-onset chronic medical conditions (NOCMCs)

Secondary Outcome Measures

Name	Time	Method
Number and Percentage of Participants With Putative Seroprotection Against an H3N2 M2SR-like Virus	Day 1, Day 29 (Cohorts 1, 2, and 3), and Day 57 (Cohort 4)	Titers for each participant are estimated as the geometric mean of technical replicate results. Putative seroprotection is defined as a serum hemagglutination inhibition (HAI) antibody titer greater than or equal to 1:40
Number and Percentage of Participants With Serum Neutralizing Antibody Titer Against an H3N2 M2SR-like Virus Greater Than or Equal to 1:40	Day 1, Day 29 (Cohorts 1, 2, and 3), and Day 57 (Cohort 4)	Titers for each participant are estimated as the geometric mean of technical replicate results.
Geometric Mean Titers (GMTs) of Serum Hemagglutination Inhibition (HAI) Antibodies Against an H3N2 M2SR-like Virus	Day 1, Day 29 (Cohorts 1, 2, and 3), and Day 57 (Cohort 4)	Titers for each participant are estimated as the geometric mean of technical replicate results, and the geometric mean is taken again across participants in each group at each time point.
Geometric Mean Titers (GMTs) of Serum Neutralizing Antibodies Against an H3N2 M2SR-like Virus	Day 1, Day 29 (Cohorts 1, 2, and 3), and Day 57 (Cohort 4)	Titers for each participant are estimated as the geometric mean of technical replicate results, and the geometric mean is taken again across participants in each group at each time point.
Geometric Mean Fold Rise (GMFR) in Serum Hemagglutination Inhibition (HAI) Antibody Titers Against an H3N2 M2SR-like Virus	Day 29 (Cohorts 1, 2, and 3) and Day 57 (Cohort 4)	Titers for each participant are estimated as the geometric mean of technical replicate results. Fold-rise in titers is calculated as the post-vaccination titer divided by the pre-vaccination titer. The geometric mean of fold-rises is taken again across participants in each group at each time point.
Geometric Mean Fold Rise (GMFR) in Serum Neutralizing Antibody Titers Against an H3N2 M2SR-like Virus	Day 29 (Cohorts 1, 2, and 3) and Day 57 (Cohort 4)	Titers for each participant are estimated as the geometric mean of technical replicate results. Fold-rise in titers is calculated as the post-vaccination titer divided by the pre-vaccination titer. The geometric mean of fold-rises is taken again across participants in each group at each time point.
Percentage of Participants With Greater Than or Equal to 2- and 4-fold Mean Rises in Hemagglutination Inhibition (HAI) Antibody Titer Against an H3N2 M2SR-like Virus	Day 29 (Cohorts 1, 2, and 3) and Day 57 (Cohort 4)	Titers for each participant are estimated as the geometric mean of technical replicate results. Fold-rise in titers is calculated as the post-vaccination titer divided by the pre-vaccination titer.
Percent of Participants With Greater Than or Equal to 2- and 4-fold Mean Rises in Serum Neutralizing Antibody Titer Against an H3N2 M2SR-like Virus	Day 29 (Cohorts 1, 2, and 3) and Day 57 (Cohort 4)	Titers for each participant are estimated as the geometric mean of technical replicate results. Fold-rise in titers is calculated as the post-vaccination titer divided by the pre-vaccination titer.
Mean Secretory Immunoglobulin A (sIgA) Response (i.e., Specific Activity) as Measured by a Binding Antibody Multiplex Assay (BAMA) in Nasal Lavage Specimens Against an H3N2 M2SR-like Virus	Day 1, Day 29 (Cohorts 1, 2, and 3), and Day 57 (Cohort 4)	Antigen-specific electrochemiluminescence (ECL) signal is calculated as the antigen specific background-subtracted ECL signal times the dilution factor at the replicate level. secretory Immunoglobulin A (sIgA) specific activity is calculated as the arithmetic mean of the antigen-specific ECL signal replicates divided by the arithmetic mean of the total sIgA concentration replicates. The arithmetic mean is taken again across participants in each group at each time point. Measured in Mean ECL luminosity signal, as arbitrary units (AU) against each antigen over ug/L sIgA. Higher values correspond to stronger response.
Mean Change (Difference) From Baseline of Secretory Immunoglobulin A (sIgA) Response (i.e., Specific Activity) as Measured by a Binding Antibody Multiplex Assay (BAMA) in Nasal Lavage Specimens Against an H3N2 M2SR-like Virus	Day 29 (Cohorts 1, 2, and 3) and Day 57 (Cohort 4)	Antigen-specific electrochemiluminescence (ECL) signal is calculated as the antigen specific background-subtracted ECL signal times the dilution factor at the replicate level. secretory Immunoglobulin A (sIgA) specific activity is calculated as the arithmetic mean of the antigen-specific ECL signal replicates divided by the arithmetic mean of the total sIgA concentration replicates. The change from baseline is calculated as the post-vaccination response minus the pre-vaccination response. The arithmetic mean of change from baseline is taken again across participants in each group at each time point. Measured in Mean Difference from Baseline in ECL Signal (arbitrary luminescence units) against each antigen over ug/L sIgA. Higher signal represents increased response.

Trial Locations

Locations (4): University of Iowa - Infectious Disease Clinic
🇺🇸
Iowa City, Iowa, United States
University of Maryland, School of Medicine, Center for Vaccine Development and Global Health
🇺🇸
Baltimore, Maryland, United States
Duke Vaccine and Trials Unit
🇺🇸
Durham, North Carolina, United States
Vanderbilt University - Pediatric - Vanderbilt Vaccine Research Center
🇺🇸
Nashville, Tennessee, United States
University of Iowa - Infectious Disease Clinic
🇺🇸Iowa City, Iowa, United States