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Safety and Immunogenicity of a Live-attenuated Universal Flu Vaccine Followed by an Inactivated Universal Flu Vaccine

Primary Purpose

Influenza, Vaccine

Status

Completed

Phase

Phase 1

Locations

United States

Study Type

Interventional

Intervention

cH8/1N1 LAIV

AS03-adjuvanted cH5/1N1 IIV

cH5/1N1 IIV

AS03-adjuvanted cH8/1N1 IIV

Normal saline

Phosphate buffered saline (PBS)

About this trial

This is an interventional prevention trial for Influenza focused on measuring live attenuated influenza vaccine, inactivated influenza vaccine

Eligibility Criteria

18 Years - 39 Years (Adult)All SexesAccepts Healthy Volunteers

Inclusion Criteria:

Able to understand planned study procedures and demonstrate comprehension of the protocol procedures and knowledge of study by passing a written examination prior to vaccination.
In the opinion of the investigator, can and will comply with the requirements of the protocol (e.g., completion of the diary cards, return for follow-up visits).
Written informed consent obtained from the subject prior to performance of any study specific procedure.
Male or non-pregnant female between, and including, 18 and 39 years of age at the time of the first vaccination.
Healthy subjects without acute or chronic, clinically significant pulmonary, cardiovascular, hepatic or renal functional abnormality*.
Female subjects of non-childbearing potential may be enrolled in the study.
Female subjects of childbearing potential must have a negative pregnancy test within 24 hours of vaccination.
Female subjects of childbearing potential must have practiced adequate contraception for 30 days prior to first vaccination and agree to continue adequate contraception until 2 months after completion of the vaccination series (Month 5).
Male subjects must be surgically sterile (e.g., vasectomy) or agree to practice adequate contraception from the first vaccination until 2 months after completion of the vaccination series (Month 5). Please refer to the glossary of terms for the definition of adequate contraception.

Exclusion Criteria:

Use of any investigational or non-registered product (drug or vaccine) other than the study vaccines.
Any medical condition that in the judgment of the investigator would make intramuscular injection unsafe.
Medically diagnosed deviated nasal septum or nasal obstruction.
Chronic administration (defined as more than 14 days in total) of immunosuppressants or other immune-modifying drugs within 6 months before the first dose.
Administration of long-acting immune-modifying drugs (e.g., infliximab, rituximab) within 6 months before the first dose (Visit 03), or planned administration any time during the study period.
Planned administration/administration of a vaccine not foreseen by the study protocol in the period starting 30 days before the first dose (Visit 03) up to Month 15 (Visit 15)
Persons who should be annually vaccinated against influenza who live with or care for persons at high risk for influenza-related complications.
History of influenza vaccination within 6 months prior to study enrollment or unwillingness to forego seasonal influenza vaccination during the entire study period.
History of vaccination with an investigational pandemic influenza vaccine other than an 2009 H1N1 Pandemic (H1N1pdm09) vaccine.
Any confirmed or suspected immunosuppressive or immunodeficient condition, based on medical history and physical examination.
Infection with human immunodeficiency virus regardless of clinical stage of immunodeficiency.
History of current infection with hepatitis B virus or hepatitis C virus regardless of clinical presentation.
History of or current autoimmune disease.
Subjects diagnosed with excessive daytime sleepiness or narcolepsy; or history of narcolepsy in a subject's parent or sibling.
History of Guillain-Barré syndrome.
History of any reaction or hypersensitivity likely to be exacerbated by any component of the vaccines (including egg proteins); a history of anaphylactic-type reaction to consumption of eggs; or a history of severe adverse reaction to a previous influenza vaccine.
Hypersensitivity to latex.
Administration of immunoglobulins and/or any blood products during the period starting 3 months before the first dose of study vaccines or planned administration during the study period.
Pregnant or lactating female.
Female planning to become pregnant or male planning to father a child or either planning to discontinue contraceptive precautions.
Current smoker.
During screening, have a positive test for opiates without a prescription.
History of chronic alcohol consumption and/or drug abuse as deemed by the investigator to render the potential subject unable/unlikely to provide accurate safety reports.
Have a history of convulsions or encephalomyelitis within 90 days prior to study vaccination.
Have any diagnosis, current or past, of schizophrenia, bipolar disease, or other psychiatric diagnosis that may interfere with subject compliance or safety evaluations.
Have been hospitalized for psychiatric illness, history of suicide attempt, or confinement for danger to self or others within 10 years prior to study vaccination.
Blood donation or planned blood donation within 30 days prior to the study vaccination through 30 days after the last blood drawn for this study.
Have signs or symptoms that could confound or confuse assessment of study vaccine reactogenicity.
Any hematological or biochemical parameter that is out of range of normal, and is considered clinically significant by the investigator.

Sites / Locations

Duke University
Cincinnati Children's Hospital Medical Center

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm 4

Arm 5

Arm Type

Experimental

Placebo Comparator

Experimental

Placebo Comparator

Arm Label

Group 1: cH8/1N1 LAIV and cH5/1N1 IIV + adjuvant

Group 2: cH8/1N1 LAIV and cH5/1N1 IIV

Group 3: Placebo

Group 4: cH8/1N1 IIV + adjuvant and cH5/1N1 IIV + adjuvant

Group 5: Placebo

Arm Description

Participants received 0.5 mL cH8/1N1 LAIV administered as 0.25 mL drops per nostril on Day 1 followed by 0.5 mL AS03-adjuvanted cH5/1N1 IIV administered as an intramuscular injection on Day 85.

Participants received 0.5 mL cH8/1N1 LAIV administered as 0.25 mL drops per nostril on Day 1 followed by 0.5 mL cH5/1N1 IIV administered as an intramuscular injection on Day 85.

Participants received 0.5 mL of normal saline administered as 0.25 mL drops per nostril on Day 1 followed by 0.5 mL phosphate buffered saline (PBS) administered as an intramuscular injection on Day 85.

Participants received 0.5 mL AS03-adjuvanted cH8/1N1 IIV administered as an intramuscular injection on Day 1 followed by 0.5 mL AS03-adjuvanted cH5/1N1 IIV administered as an intramuscular injection on Day 85.

Participants received 0.5 mL PBS administered as an intramuscular injection on Day 1 followed by 0.5 mL PBS administered as an intramuscular injection on Day 85.

Outcomes

Primary Outcome Measures

Number of Participants With Solicited Local Reactions Within 7 Days Following Each Vaccination

Solicited adverse events were assessed by study staff for 60 minutes after each vaccination and and then by study participants daily for 7 days on a a diary card. Solicited local reactions included: Post LAIV dose: nasal congestion, rhinorrhea; Post IIV dose: pain, redness, swelling.

Number of Participants With Solicited General Reactions Within 7 Days Following Each Vaccination

Solicited adverse events were assessed by study staff for 60 minutes after each vaccination and and then by study participants daily for 7 days on a a diary card. Solicited general reactions included: abdominal pain arthralgia cough diarrhea fatigue fever headache myalgia nausea shivering sore throat vomiting wheezing

Number of Participants With Unsolicited Adverse Events Within 28 Days Following Any Vaccination

Unsolicited adverse events (AEs) are any AEs reported spontaneously by the participant, observed by the study personnel during study visits or those identified during review of medical records or source documents, such as diary cards. Participants were asked to record any unsolicited symptoms or other illness description in their diary card during the 28 days after each vaccination. All AEs, including clinical laboratory test results, were assessed by a study clinician and the study subject (as applicable) to quantify severity using a protocol-defined grading system as mild (mild symptoms, easily tolerated, not interfering with daily activities), moderate (causing some interference with daily activity), or severe (severe symptoms that prevent normal every day activities). The investigator assessed the relationship between study vaccines and the occurrence of each AE using clinical judgment.

Number of Participants With Grade 2 or Higher Hematological and Biochemical Laboratory Abnormalities From Day 8 to Day 113

Hematological and biochemical parameters assessed included hemoglobin, platelets, red blood cells, white blood cells (WBC), absolute neutrophil count (ANC), lymphocytes, monocytes, eosinophils, basophils, alanine aminotransferase (ALT), aspartate aminotransferase (AST), creatinine, blood urea nitrogen (BUN) and BUN-to-creatinine ratio. Grading of laboratory parameters was based on the FDA Guidance for Industry: Toxicity Grading Scale for Healthy Adult and Adolescent Volunteers Enrolled in Preventive Vaccine Clinical Trials as Grade 1 (Mild), Grade 2 (Moderate), Grade 3 (severe), or Grade 4 (Potentially life-threatening). Grade 2 or higher: BUN: > 26 mg/dL Creatinine: > 1.7 mg/dL ALT, AST: > 2.5 × upper limit of normal (ULN) Hemoglobin: < 11.0 g/dL (females) or < 12.5 g/dL (males) or change from baseline > 1.5 g/dL WBC: > 15,000 cell/mm³ or < 2,500 cell/mm³ Lymphocytes: < 750 cell/mm³ ANC: < 1,500 cell/mm³ Eosinophils: > 1,500 cell/mm³ Platelets: < 125,000 cell/mm³

Number of Participants With a Medically Attended Event (MAE), Laboratory-Confirmed Influenza-like Illness (LC-ILI), Potential Immune-mediated Disease (pIMD), or Serious Adverse Event (SAE) up to Day 113

An MAE is an event for which the participant received medical attention such as hospitalization, an emergency room visit, or a visit to or from medical personnel. pIMDs are a subset of AEs that include autoimmune diseases and other inflammatory and/or neurologic disorders of interest which may or may not have an autoimmune etiology. LC-ILI is defined as at least 1 systemic symptom (fever or myalgia) AND at least 1 respiratory symptom (cough or sore throat), confirmed by polymerase chain reaction (PCR) assay. An SAE is an AE that met any of the following: Death Life threatening Required inpatient hospitalization or prolongation of existing hospitalization Results in persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions Results in congenital anomaly/birth defect An important medical event that may jeopardize the well-being of the subject or require medical or surgical intervention to prevent an above outcome.

Secondary Outcome Measures

Number of Participants With Any Grade 2 or Higher Hematological and Biochemical Laboratory Abnormalities From Month 9 to Month 15

An MAE is an event for which the participant received medical attention such as hospitalization, an emergency room visit, or a visit to or from medical personnel. pIMDs are a subset of AEs that include autoimmune diseases and other inflammatory and/or neurologic disorders of interest which may or may not have an autoimmune etiology. LC-ILI is defined as at least 1 systemic symptom (fever or myalgia) AND at least 1 respiratory symptom (cough or sore throat), confirmed by PCR assay. An SAE is an AE that met any of the following: Death Life threatening Required inpatient hospitalization or prolongation of existing hospitalization Resulted in persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions Resulted in congenital anomaly/birth defect An important medical event that may jeopardize the well-being of the subject or require medical or surgical intervention to prevent an above outcome.

Number of Participants in Groups 1, 2, and 3 With Detectable Influenza A Virus in Nasal and Oropharyngeal Swabs on Days 1 to 5

To detect viral shedding participants who received LAIV vaccine or intranasal sterile saline as the prime dose had nasal and oropharyngeal swabs collected on Days 1 to 5. Influenza type A virus ribonucleic acid (RNA) was detected using reverse transcription polymerase chain reaction (RT-PCR).

Number of Participants in Groups 1, 2, and 3 With Viable Vaccine Virus in Cell Culture Through 5 Days Post-vaccination

To study virus infectivity, nasal and oropharyngeal swab specimens that tested influenza A positive by RT-PCR were further tested for viability of virus in Madin Darby canine kidney (MDCK) cell culture and stained with monoclonal antibody specific to the cH8/1N1 LAIV virus to confirm detected virus is of vaccine origin.

Percentage of Participants With Serum Anti-H1 Hemagglutinin Stalk Immunoglobulin G Antibody Seropositivity

Anti-H1 hemagglutinin (HA) stalk immunoglobulin G (IgG) was quantified using an enzyme-linked immunosorbent assay (ELISA). The ELISA measured IgG antibodies against the H1 stalk domain by using a chimeric protein containing an exotic H6 hemagglutinin head domain that the vaccinees have not previously been exposed to (strain A/mallard/Sweden/81/02 [H6N1]) and the same H1 stalk domain as expressed by the vaccine (strain A/California/04/09 [H1N1]) . Titers are expressed as ELISA units (EU) per mL and were calculated on the basis of an internal standard to which units were arbitrarily assigned. Seropositivity rate was defined as the percentage of participants with an antibody titer of at least the cut-off for the assay; ≥ 65.3 EU/mL.

Geometric Mean Titer of Serum Anti-H1 Hemagglutinin Stalk IgG Antibodies

Anti-H1 hemagglutinin stalk immunoglobulin G (IgG) was quantified using an enzyme-linked immunosorbent assay (ELISA). The ELISA measured IgG antibodies against the H1 stalk domain by using a chimeric protein containing an exotic H6 hemagglutinin head domain that the vaccinees have not previously been exposed to (strain A/mallard/Sweden/81/02 [H6N1]) and the same H1 stalk domain as expressed by the vaccine (strain A/California/04/09 [H1N1]) . Titers are expressed as ELISA units (EU) per mL and were calculated on the basis of an internal standard to which units were arbitrarily assigned. The lower limit of quantitation (LLOQ) for the assay was 65.3 EU/mL.

Percentage of Participants With a ≥ 4-fold Increase From Baseline in Serum Anti-H1 Hemagglutinin Stalk IgG Antibodies

Percentage of Participants With a ≥ 10-fold Increase From Baseline in Serum Anti-H1 Hemagglutinin Stalk IgG Antibodies

Mean Geometric Increase From Baseline in Serum Anti-H1 Hemagglutinin Stalk IgG Antibodies

Anti-H1 hemagglutinin stalk immunoglobulin G (IgG) was quantified using an enzyme-linked immunosorbent assay (ELISA). The ELISA measured IgG antibodies against the H1 stalk domain by using a chimeric protein containing an exotic H6 hemagglutinin head domain that the vaccinees have not previously been exposed to (strain A/mallard/Sweden/81/02 [H6N1]) and the same H1 stalk domain as expressed by the vaccine (strain A/California/04/09 [H1N1]). Mean geometric increase represents the fold-rise in antibody titer from baseline to each post-baseline time point (ratio of post-baseline titer to Baseline titer).

Percentage of Participants With Serum Anti-H1 Hemagglutinin Stalk Immunoglobulin A Antibody Seropositivity

Anti-H1 hemagglutinin stalk immunoglobulin A (IgA) was quantified using an enzyme-linked immunosorbent assay (ELISA). The ELISA measured IgA antibodies against the H1 stalk domain by using a chimeric protein containing an exotic H6 hemagglutinin head domain that the vaccinees have not previously been exposed to (strain A/mallard/Sweden/81/02 [H6N1]) and the same H1 stalk domain as expressed by the vaccine (strain A/California/04/09 [H1N1]) . Seropositivity rate was defined as the percentage of participants with an antibody titer of at least the cut-off for the assay; ≥ 1:100.

Geometric Mean Titer of Serum Anti-H1 Hemagglutinin Stalk IgA Antibodies

Percentage of Participants With a ≥ 4-fold Increase From Baseline in Serum Anti-H1 Hemagglutinin Stalk IgA Antibodies

Percentage of Participants With a ≥ 10-fold Increase From Baseline in Serum Anti-H1 Hemagglutinin Stalk IgA Antibodies

Mean Geometric Increase From Baseline in Serum Anti-H1 Hemagglutinin Stalk IgA Antibodies

Anti-H1 hemagglutinin stalk immunoglobulin A (IgA) was quantified using an enzyme-linked immunosorbent assay (ELISA). The ELISA measured IgA antibodies against the H1 stalk domain by using a chimeric protein containing an exotic H6 hemagglutinin head domain that the vaccinees have not previously been exposed to (strain A/mallard/Sweden/81/02 [H6N1]) and the same H1 stalk domain as expressed by the vaccine (strain A/California/04/09 [H1N1]) . Mean geometric increase represents the fold-rise in antibody titer from baseline to each post-baseline time point (ratio of post-baseline titer to Baseline titer).

Percentage of Participants With Serum Anti-H1 Hemagglutinin Stalk Neutralizing Antibody Seropositivity

Anti H1 hemagglutinin stalk neutralizing antibodies were quantified using a microneutralization (MN) assay using a virus that expresses a chimeric hemagglutinin that contains an exotic HA head domain (strain A/mallard/Sweden/81/2002 [H6N1]) and the H1 stalk domain (strain A/California/04/2009 [H1N1pandemic]) and an exotic neuraminidase, N5, for which humans are generally naïve (strain: A/mallard/Sweden/86/2003 [H12N5]). Seropositivity rate was defined as the percentage of participants with an antibody titer of ≥ 1:10.

Geometric Mean Titer of Serum Anti-H1 Hemagglutinin Stalk Neutralizing Antibodies

Anti H1 hemagglutinin stalk neutralizing antibodies were quantified using a microneutralization (MN) assay using a virus that expresses a chimeric hemagglutinin that contains an exotic HA head domain (strain A/mallard/Sweden/81/2002 ([H6N1]) and the H1 stalk domain (strain A/California/04/2009 ([H1N1pandemic]) and an exotic neuraminidase, N5, for which humans are generally naïve (strain: A/mallard/Sweden/86/2003 [H12N5]). The LLOQ for the assay was 1:10.

Percentage of Participants With a ≥ 4-fold Increase From Baseline in Serum Anti-H1 Hemagglutinin Stalk Neutralizing Antibodies

Anti H1 hemagglutinin stalk neutralizing antibodies were quantified using a microneutralization (MN) assay using a virus that expresses a chimeric hemagglutinin that contains an exotic HA head domain (strain A/mallard/Sweden/81/2002 ([H6N1]) and the H1 stalk domain (strain A/California/04/2009 ([H1N1pandemic]) and an exotic neuraminidase, N5, for which humans are generally naïve (strain: A/mallard/Sweden/86/2003 [H12N5]).

Percentage of Participants With a ≥ 10-fold Increase From Baseline in Serum Anti-H1 Hemagglutinin Stalk Neutralizing Antibodies

Anti H1 hemagglutinin stalk neutralizing antibodies were quantified using a microneutralization (MN) assay using a virus that expresses a chimeric hemagglutinin that contains an exotic HA head domain (strain A/mallard/Sweden/81/2002 ([H6N1]) and the H1 stalk domain (strain A/California/04/2009 ([H1N1pandemic]) and an exotic neuraminidase, N5, for which humans are generally naïve (strain: A/mallard/Sweden/86/2003 [H12N5]).

Mean Geometric Increase From Baseline in Serum Anti-H1 Hemagglutinin Stalk Neutralizing Antibodies

Anti H1 hemagglutinin stalk neutralizing antibodies were quantified using a microneutralization (MN) assay using a virus that expresses a chimeric hemagglutinin that contains an exotic HA head domain (strain A/mallard/Sweden/81/2002 [H6N1]) and the H1 stalk domain (strain A/California/04/2009 [H1N1pandemic]) and an exotic neuraminidase, N5, for which humans are generally naïve (strain: A/mallard/Sweden/86/2003 [H12N5]). Mean geometric increase represents the fold-rise in antibody titer from baseline to each post-baseline time point (ratio of post-baseline titer to Baseline titer).

Serum Antibody-dependent Cell-mediated Cytotoxicity (ADCC) to the H1 Hemagglutinin Stalk

Antibody-dependent cell-mediated cytotoxicity (ADCC) is an immune response leading to lysis of antibody-coated target cells by immune effector cells and is triggered by the interaction between the Fc portion of an antibody and Fc-gamma receptors expressed on immune effector cells. This bioluminescent assay measured antibodies to a chimeric hemagglutinin (H6 head domain and H1 stalk domain) virus that mediate ADCC activity via the Fc-receptor. ADCC activity was measured in relative luciferase units (RLU) for serial dilutions of serum samples using a plate reader. ADCC activity was expressed by the area under the curve (AUC) of luminescence (RLU) per serial dilution (X-fold serial dilutions).

Fold-Increase From Baseline in Serum ADCC to the H1 Hemagglutinin Stalk

Antibody-dependent cell-mediated cytotoxicity (ADCC) is an immune response leading to lysis of antibody-coated target cells by immune effector cells and is triggered by the interaction between the Fc portion of an antibody and Fc-gamma receptors expressed on immune effector cells. This bioluminescent assay measured antibodies to a chimeric hemagglutinin (H6 head domain and H1 stalk domain) virus that mediate ADCC activity via the Fc-receptor. ADCC activity was measured by the area under the curve (AUC) of luminescence per serial dilution.

Percentage of Participants With a ≥ 4-fold Increase From Baseline in Serum ADCC to the H1 Hemagglutinin Stalk

Antibody-dependent cell-mediated cytotoxicity (ADCC) is an immune response leading to lysis of antibody-coated target cells by immune effector cells and is triggered by the interaction between the Fc portion of an antibody and Fc-gamma receptors expressed on immune effector cells. This bioluminescent assay measured antibodies to a chimeric hemagglutinin (H6 head domain and H1 stalk domain) virus that mediate ADCC activity via the Fc-receptor. ADCC activity was measured by the area under the curve (AUC) of luminescence per serial dilution.

Percentage of Participants With a ≥ 10-fold Increase From Baseline in Serum ADCC to the H1 Hemagglutinin Stalk

Antibody-dependent cell-mediated cytotoxicity (ADCC) is an immune response leading to lysis of antibody-coated target cells by immune effector cells and is triggered by the interaction between the Fc portion of an antibody and Fc-gamma receptors expressed on immune effector cells. This bioluminescent assay measured antibodies to a chimeric hemagglutinin (H6 head domain and H1 stalk domain) virus that mediate ADCC activity via the Fc-receptor. ADCC activity was measured by the area under the curve (AUC) of luminescence per serial dilution.

Percentage of Participants With Anti-H1 Hemagglutinin Stalk Salivary IgG Antibody Seropositivity

Anti-H1 hemagglutinin stalk immunoglobulin G (IgG) in saliva was quantified using an enzyme-linked immunosorbent assay (ELISA). The ELISA measured IgG antibodies in saliva against the H1 stalk domain by using a chimeric protein containing an exotic H6 hemagglutinin head domain that the vaccinees have not previously been exposed to (strain A/mallard/Sweden/81/02 [H6N1]) and the same H1 stalk domain as expressed by the vaccine (strain A/California/04/09 [H1N1]). Seropositivity rate was defined as the percentage of participants with an antibody titer of at least the cut-off for the assay; ≥ 1:10.

Geometric Mean Titer of Anti-H1 Hemagglutinin Stalk Salivary IgG Antibodies

Anti-H1 hemagglutinin stalk immunoglobulin G (IgG) in saliva was quantified using an enzyme-linked immunosorbent assay (ELISA). The ELISA measured IgG antibodies against the H1 stalk domain by using a chimeric protein containing an exotic H6 hemagglutinin head domain that the vaccinees have not previously been exposed to (strain A/mallard/Sweden/81/02 [H6N1]) and the same H1 stalk domain as expressed by the vaccine (strain A/California/04/09 [H1N1]). The LLOQ for the assay was 1:10.

Percentage of Participants With a ≥ 4-fold Increase From Baseline in Anti-H1 Hemagglutinin Stalk Salivary IgG

Percentage of Participants With a ≥ 10-fold Increase From Baseline in Anti-H1 Hemagglutinin Stalk Salivary IgG

Mean Geometric Increase of Anti-H1 Hemagglutinin Stalk Salivary IgG Antibodies

Anti-H1 hemagglutinin stalk immunoglobulin G (IgG) in saliva was quantified using an enzyme-linked immunosorbent assay (ELISA). The ELISA measured IgG antibodies in saliva against the H1 stalk domain by using a chimeric protein containing an exotic H6 hemagglutinin head domain that the vaccinees have not previously been exposed to (strain A/mallard/Sweden/81/02 [H6N1]) and the same H1 stalk domain as expressed by the vaccine (strain A/California/04/09 [H1N1]). Mean geometric increase represents the fold-rise in antibody titer from baseline to each post-baseline time point (ratio of post-baseline titer to Baseline titer).

Percentage of Participants With Anti-H1 Hemagglutinin Stalk Secretory IgA Antibody Seropositivity in Saliva

Anti-H1 hemagglutinin stalk secretory immunoglobulin A (IgA) in saliva was quantified using an enzyme-linked immunosorbent assay (ELISA). The ELISA measured secretory IgA antibodies antibodies (actively secreted in the mucosa) against the H1 stalk domain in saliva using a chimeric protein containing an exotic H6 hemagglutinin head domain that the vaccinees have not previously been exposed to (strain A/mallard/Sweden/81/02 [H6N1]) and the same H1 stalk domain as expressed by the vaccine (strain A/California/04/09 [H1N1]). Seropositivity rate was defined as the percentage of participants with an antibody titer of at least the cut-off for the assay; ≥ 1:4.

Geometric Mean Titer of Anti-H1 Hemagglutinin Stalk Secretory IgA Antibodies in Saliva

Percentage of Participants With a ≥ 4-fold Increase From Baseline in Anti-H1 Hemagglutinin Stalk Secretory IgA Antibodies in Saliva

Anti-H1 hemagglutinin stalk secretory immunoglobulin A (IgA) in saliva was quantified using an enzyme-linked immunosorbent assay (ELISA). The ELISA measured secretory IgA antibodies (actively secreted in the mucosa) against the H1 stalk domain in saliva by using a chimeric protein containing an exotic H6 hemagglutinin head domain that the vaccinees have not previously been exposed to (strain A/mallard/Sweden/81/02 [H6N1]) and the same H1 stalk domain as expressed by the vaccine (strain A/California/04/09 [H1N1]).

Percentage of Participants With a ≥ 10-fold Increase From Baseline in Anti-H1 Hemagglutinin Stalk Secretory IgA Antibodies in Saliva

Anti-H1 hemagglutinin stalk secretory immunoglobulin A (IgA) in saliva was quantified using an enzyme-linked immunosorbent assay (ELISA). The ELISA measured secretory IgA antibodies (actively secreted in the mucosa) against the H1 stalk domain in saliva by using a chimeric protein containing an exotic H6 hemagglutinin head domain that the vaccinees have not previously been exposed to (strain A/mallard/Sweden/81/02 [H6N1]) and the same H1 stalk domain as expressed by the vaccine (strain A/California/04/09 [H1N1]).

Mean Geometric Increase From Baseline in Anti-H1 Hemagglutinin Stalk Secretory IgA in Saliva

Anti-H1 hemagglutinin stalk secretory immunoglobulin A (IgA) in saliva was quantified using an enzyme-linked immunosorbent assay (ELISA). The ELISA measured secretory IgA antibodies antibodies (actively secreted in the mucosa) against the H1 stalk domain in saliva using a chimeric protein containing an exotic H6 hemagglutinin head domain that the vaccinees have not previously been exposed to (strain A/mallard/Sweden/81/02 [H6N1]) and the same H1 stalk domain as expressed by the vaccine (strain A/California/04/09 [H1N1]). Mean geometric increase represents the fold-rise in antibody titer from Baseline to each post-baseline time point (ratio of post-baseline titer to Baseline titer).

Percentage of Participants With Anti-H1 Hemagglutinin Stalk Total IgA Antibody Seropositivity in Saliva

Anti-H1 hemagglutinin stalk total immunoglobulin A (IgA) in saliva was quantified using an enzyme-linked immunosorbent assay (ELISA). The ELISA measured total IgA antibodies antibodies (secreted through active and passive transfer processes in the mucosa) against the H1 stalk domain in saliva using a chimeric protein containing an exotic H6 hemagglutinin head domain that the vaccinees have not previously been exposed to (strain A/mallard/Sweden/81/02 [H6N1]) and the same H1 stalk domain as expressed by the vaccine (strain A/California/04/09 [H1N1]). Seropositivity rate was defined as the percentage of participants with an antibody titer of at least the cut-off for the assay; ≥ 1:10.

Geometric Mean Titer of Anti-H1 Hemagglutinin Stalk Total IgA Antibodies in Saliva

Percentage of Participants With a ≥ 4-fold Increase From Baseline in Anti-H1 Hemagglutinin Stalk Total IgA Antibodies in Saliva

Percentage of Participants With a ≥ 10-fold Increase From Baseline in Anti-H1 Hemagglutinin Stalk Total IgA Antibodies in Saliva

Mean Geometric Increase From Baseline in Anti-H1 Hemagglutinin Stalk Total IgA Antibodies in Saliva

Anti-H1 hemagglutinin stalk total immunoglobulin A (IgA) in saliva was quantified using an enzyme-linked immunosorbent assay (ELISA). The ELISA measured total IgA antibodies (secreted through active and passive transfer processes in the mucosa) against the H1 stalk domain in saliva using a chimeric protein containing an exotic H6 hemagglutinin head domain that the vaccinees have not previously been exposed to (strain A/mallard/Sweden/81/02 [H6N1]) and the same H1 stalk domain as expressed by the vaccine (strain A/California/04/09 [H1N1]). Mean geometric increase represents the fold-rise in antibody titer from baseline to each post-baseline time point (ratio of post-baseline titer to Baseline titer).

Percentage of Participants With Serum Anti-H2 Full-length Hemagglutinin IgG Antibody Seropositivity

To determine antibody breadth, assays were performed to measure the induction of cross-reactive IgG antibodies to a Group 1 influenza A virus with a heterosubtypic hemagglutinin, subtype H2, of which the stalk domain shares about 78% amino acid identity with the H1 vaccine stalk domain. Anti-H2 full-length (ecto-domain) hemagglutinin IgG was quantified by ELISA using a recombinant antigen based on A/mallard/Netherlands/5/1999 (H2N9) HA. Titers are expressed as ELISA units (EU) per mL and were calculated on the basis of an internal standard to which units were arbitrarily assigned. Seropositivity rate was defined as the percentage of participants with an antibody titer of at least the cut-off for the assay; ≥ 22.

Geometric Mean Titer of Serum Anti-H2 Full-length Hemagglutinin IgG Antibodies

Percentage of Participants With a ≥ 4-fold Increase From Baseline in Serum Anti-H2 Full-length Hemagglutinin IgG Antibodies

To determine antibody breadth, assays were performed to measure the induction of cross-reactive IgG antibodies to a Group 1 influenza A virus with a heterosubtypic hemagglutinin, subtype H2, of which the stalk domain shares about 78% amino acid identity with the H1 vaccine stalk domain. Anti-H2 full-length (ecto-domain) hemagglutinin IgG was quantified by ELISA using a recombinant antigen based on A/mallard/Netherlands/5/1999 (H2N9) HA.

Percentage of Participants With a ≥ 10-fold Increase From Baseline in Serum Anti-H2 Full-length Hemagglutinin IgG Antibodies

To determine antibody breadth, assays were performed to measure the induction of cross-reactive IgG antibodies to a Group 1 influenza A virus with a heterosubtypic hemagglutinin, subtype H2, of which the stalk domain shares about 78% amino acid identity with the H1 vaccine stalk domain. Anti-H2 full-length (ecto-domain) hemagglutinin IgG was quantified by ELISA using a recombinant antigen based on A/mallard/Netherlands/5/1999 (H2N9) HA.

Mean Geometric Increase of Serum Anti-H2 Full-length Hemagglutinin IgG Antibodies

To determine antibody breadth, assays were performed to measure the induction of cross-reactive IgG antibodies to a Group 1 influenza A virus with a heterosubtypic hemagglutinin, subtype H2, of which the stalk domain shares about 78% amino acid identity with the H1 vaccine stalk domain. Anti-H2 full-length (ecto-domain) hemagglutinin IgG was quantified by ELISA using a recombinant antigen based on A/mallard/Netherlands/5/1999 (H2N9) HA. Mean geometric increase represents the fold-rise in antibody titer from Baseline to each post-baseline time point (ratio of post-baseline titer to Baseline titer).

Percentage of Participants With Serum Anti-H9 Full-length Hemagglutinin IgG Antibody Seropositivity

To determine antibody breadth, assays were performed to measure the induction of cross-reactive IgG antibodies to a Group 1 influenza A virus with a heterosubtypic hemagglutinin, subtype H9, the stalk domain of which shares about 59% amino acid identity with the H1 vaccine stalk domain. Anti-H9 full-length (ecto-domain) hemagglutinin IgG was quantified by ELISA using a recombinant antigen based on Strain A/chicken/Hong Kong/G9/1997 (H9N2) HA. Titers are expressed as ELISA units (EU) per mL and were calculated on the basis of an internal standard to which units were arbitrarily assigned. Seropositivity rate was defined as the percentage of participants with an antibody titer of at least the cut-off for the assay; ≥ 31.

Geometric Mean Titer of Serum Anti-H9 Full-length Hemagglutinin IgG Antibodies

To determine antibody breadth, assays were performed to measure the induction of cross-reactive IgG antibodies to a Group 1 influenza A virus with a heterosubtypic hemagglutinin, subtype H9, the stalk domain of which shares about 59% amino acid identity with the H1 vaccine stalk domain. Anti-H9 full-length (ecto-domain) hemagglutinin IgG was quantified by ELISA using a recombinant antigen based on Strain A/chicken/Hong Kong/G9/1997 (H9N2) HA. Titers are expressed as ELISA units (EU) per mL and were calculated on the basis of an internal standard to which units were arbitrarily assigned. The LLOQ for the assay was 31 EU/mL.

Percentage of Participants With a ≥ 4-fold Increase From Baseline in Serum Anti-H9 Full-length Hemagglutinin IgG Antibodies

To determine antibody breadth, assays were performed to measure the induction of cross-reactive IgG antibodies to a Group 1 influenza A virus with a heterosubtypic hemagglutinin, subtype H9, the stalk domain of which shares about 59% amino acid identity with the H1 vaccine stalk domain. Anti-H9 full-length (ecto-domain) hemagglutinin IgG was quantified by ELISA using a recombinant antigen based on Strain A/chicken/Hong Kong/G9/1997 (H9N2) HA.

Percentage of Participants With a ≥ 10-fold Increase From Baseline in Serum Anti-H9 Full-length Hemagglutinin IgG Antibodies

To determine antibody breadth, assays were performed to measure the induction of cross-reactive IgG antibodies to a Group 1 influenza A virus with a heterosubtypic hemagglutinin, subtype H9, the stalk domain of which shares about 59% amino acid identity with the H1 vaccine stalk domain. Anti-H9 full-length(ecto-domain) hemagglutinin IgG was quantified by ELISA using a recombinant antigen based on Strain A/chicken/Hong Kong/G9/1997 (H9N2) HA.

Mean Geometric Increase of Serum Anti-H9 Full-length Hemagglutinin IgG Antibodies

To determine antibody breadth, assays were performed to measure the induction of cross-reactive IgG antibodies to a Group 1 influenza A virus with a heterosubtypic hemagglutinin, subtype H9, the stalk domain of which shares about 59% amino acid identity with the H1 vaccine stalk domain. Anti-H9 full-length (ecto-domain) hemagglutinin IgG was quantified by ELISA using a recombinant antigen based on Strain A/chicken/Hong Kong/G9/1997 (H9N2) HA. Mean geometric increase represents the fold-rise in antibody titer from Baseline to each post-baseline time point (ratio of post-baseline titer to Baseline titer).

Percentage of Participants With Serum Anti-H18 Full-length Hemagglutinin IgG Antibody Seropositivity

To determine antibody breadth, assays were performed to measure the induction of cross-reactive IgG antibodies to a Group 1 influenza A virus with a heterosubtypic hemagglutinin distantly related to the currently circulating influenza A/H1 viruses, subtype H18, the stalk domain of which shares about 65% amino acid identity with the H1 vaccine stalk domain. Anti-H18 full-length (ecto-domain) hemagglutinin IgG was quantified by ELISA using a recombinant antigen based on Strain A/flat-faced bat/Peru/033/10 (H18N11) HA. Titers are expressed as ELISA units (EU) per mL and were calculated on the basis of an internal standard to which units were arbitrarily assigned. Seropositivity rate was defined as the percentage of participants with an antibody titer of at least the cut-off for the assay; ≥ 42.3.

Geometric Mean Titer of Serum Anti-H18 Full-length Hemagglutinin IgG Antibodies

To determine antibody breadth, assays were performed to measure the induction of cross-reactive IgG antibodies to a Group 1 influenza A virus with a heterosubtypic hemagglutinin distantly related to the currently circulating influenza A/H1 viruses, H18, the stalk domain of which shares about 65% amino acid identity with the H1 vaccine stalk domain. Anti-H18 full-length (ecto-domain) hemagglutinin IgG was quantified by ELISA using a recombinant antigen based on Strain A/flat-faced bat/Peru/033/10 (H18N11) HA. Titers are expressed as ELISA units (EU) per mL and were calculated on the basis of an internal standard to which units were arbitrarily assigned.

Percentage of Participants With a ≥ 4-fold Increase From Baseline in Serum Anti-H18 Full-length Hemagglutinin IgG Antibodies

Percentage of Participants With a ≥ 10-fold Increase From Baseline in Serum Anti-H18 Full-length Hemagglutinin IgG Antibodies

Mean Geometric Increase of Serum Anti-H18 Full-length Hemagglutinin IgG Antibodies

To determine antibody breadth, assays were performed to measure the induction of cross-reactive IgG antibodies to a Group 1 influenza A virus with a heterosubtypic hemagglutinin distantly related to the currently circulating influenza A/H1 viruses, subtype H18, the stalk domain of which shares about 65% amino acid identity with the H1 vaccine stalk domain. Anti-H18 full-length (ecto-domain) hemagglutinin IgG was quantified by ELISA using a recombinant antigen based on Strain A/flat-faced bat/Peru/033/10 (H18N11) HA. Mean geometric increase represents the fold-rise in antibody titer from Baseline to each post-baseline time point (ratio of post-baseline titer to Baseline titer).

Percentage of Participants With Serum Anti-Human H1N1 Virus Neutralizing Antibody Seropositivity

This assay was performed to measure the neutralizing potential of antibodies against the currently circulating human H1N1 isolate which is similar to the stalk used in study vaccines. Anti-human H1N1 virus neutralizing antibodies were quantified using a microneutralization (MN) assay using Strain A/Singapore/GP1908/2015 (IVR-180). Seropositivity rate was defined as the percentage of participants with an antibody titer of ≥ 1:10.

Geometric Mean Titer of Serum Anti-Human H1N1 Virus Neutralizing Antibodies

Percentage of Participants With a ≥ 4-fold Increase in Serum Anti-Human H1N1 Virus Neutralizing Antibodies

Percentage of Participants With a ≥ 10-fold Increase From Baseline in Serum Anti-Human H1N1 Virus Neutralizing Antibodies

Mean Geometric Increase of Serum Anti-Human H1N1 Virus Neutralizing Antibodies

This assay was performed to measure the neutralizing potential of antibodies against the currently circulating human H1N1 isolate which is similar to the stalk used in study vaccines. Anti-human H1N1 virus neutralizing antibodies were quantified using a microneutralization (MN) assay using Strain A/Singapore/GP1908/2015 (IVR-180). Mean geometric increase represents the fold-rise in antibody titer from Baseline to each post-baseline time point (ratio of post-baseline titer to Baseline titer).

Percentage of Participants With Serum Anti-Avian-Swine H1N1 Virus Neutralizing Antibody Seropositivity

This assay was performed to measure the neutralizing potential of cross-reactive antibodies to a Group 1 influenza against an H1N1 virus isolate that currently circulates in animals and is antigenically different from current human isolates. Anti-avian-swine H1N1 virus neutralizing antibodies were quantified using a microneutralization (MN) assay using Strain A/Swine/Jiangsu/40/2011 (asH1N1). Seropositivity rate was defined as the percentage of participants with an antibody titer of ≥ 1:10.

Geometric Mean Titer of Serum Anti-Avian-Swine H1N1 Virus Neutralizing Antibodies

Percentage of Participants With a ≥ 4-fold Increase in Serum Anti-Avian-Swine H1N1 Virus Neutralizing Antibodies

Percentage of Participants With a ≥ 10-fold Increase in Serum Anti-Avian-Swine H1N1 Virus Neutralizing Antibodies

Mean Geometric Increase From Baseline in Serum Anti-Avian-Swine H1N1 Virus Neutralizing Antibodies

This assay was performed to measure the neutralizing potential of cross-reactive antibodies to a Group 1 influenza against an H1N1 virus isolate that currently circulates in animals and is antigenically different from current human isolates. Anti-avian-swine H1N1 virus neutralizing antibodies were quantified using a microneutralization (MN) assay using Strain A/Swine/Jiangsu/40/2011 (asH1N1). Mean geometric increase represents the fold-rise in antibody titer from Baseline to each post-baseline time point (ratio of post-baseline titer to Baseline titer).

Percentage of Participants With Serum Anti-H5N8 Virus Neutralizing Antibody Seropositivity

This assay was performed to measure the induction of antibodies reactive against the head domain of a group 1 influenza virus with a heterosubtypic hemagglutinin from a recent avian influenza virus. Anti-H5N8 virus neutralizing antibodies were quantified using a microneutralization (MN) assay using a reverse genetics (RG) reassortant virus based on Puerto Rico (PR)/8 for 6 genes with 2 surface proteins: HA and neuraminidase (NA) from A/Gyrfalcon/Washington/41088-6/2014 (H5N8). Seropositivity rate was defined as the percentage of participants with an antibody titer of ≥ 1:10.

Geometric Mean Titer of Serum Anti-H5N8 Virus Neutralizing Antibodies

This assay was performed to measure the induction of antibodies reactive against the head domain of a group 1 influenza virus with a heterosubtypic hemagglutinin from a recent avian influenza virus. Anti-H5N8 virus neutralizing antibodies were quantified using a microneutralization (MN) assay using a reverse genetics (RG) reassortant virus based on PR8 for 6 genes with 2 surface proteins: HA and NA from A/Gyrfalcon/Washington/41088-6/2014 (H5N8). The LLOQ for the assay was 1:10.

Percentage of Participants With a ≥ 4-fold Increase in Serum Anti-H5N8 Virus Neutralizing Antibodies

This assay was performed to measure the induction of antibodies reactive against the head domain of a group 1 influenza virus with a heterosubtypic hemagglutinin from a recent avian influenza virus. Anti-H5N8 virus neutralizing antibodies were quantified using a microneutralization (MN) assay using a reverse genetics (RG) reassortant virus based on PR8 for 6 genes with 2 surface proteins: HA and NA from A/Gyrfalcon/Washington/41088-6/2014 (H5N8).

Percentage of Participants With a ≥ 10-fold Increase in Serum Anti-H5N8 Virus Neutralizing Antibodies

This assay was performed to measure the induction of antibodies reactive against the head domain of a group 1 influenza virus with a heterosubtypic hemagglutinin from a recent avian influenza virus. Anti-H5N8 virus neutralizing antibodies were quantified using a microneutralization (MN) assay using a reverse genetics (RG) reassortant virus based on PR8 for 6 genes with 2 surface proteins: HA and NA from A/Gyrfalcon/Washington/41088-6/2014 (H5N8).

Mean Geometric Increase From Baseline in Serum Anti-H5N8 Virus Neutralizing Antibodies

This assay was performed to measure the induction of antibodies reactive against the head domain of a group 1 influenza virus with a heterosubtypic hemagglutinin from a recent avian influenza virus. Anti-H5N8 virus neutralizing antibodies were quantified using a microneutralization (MN) assay using a reverse genetics (RG) reassortant virus based on PR8 for 6 genes with 2 surface proteins: HA and NA from A/Gyrfalcon/Washington/41088-6/2014 (H5N8). Mean geometric increase represents the fold-rise in antibody titer from Baseline to each post-baseline time point (ratio of post-baseline titer to Baseline titer).

Full Information

NCT ID

NCT03300050

First Posted

September 28, 2017

Last Updated

February 1, 2021

Sponsor

PATH

Collaborators

Icahn School of Medicine at Mount Sinai, Children's Hospital Medical Center, Cincinnati, Duke University, The Emmes Company, LLC, GlaxoSmithKline

1. Study Identification

Unique Protocol Identification Number

NCT03300050

Brief Title

Safety and Immunogenicity of a Live-attenuated Universal Flu Vaccine Followed by an Inactivated Universal Flu Vaccine

Official Title

A Phase 1, Randomized, Controlled, Observer-blind Study to Assess the Reactogenicity, Safety, and Immunogenicity of a Live Attenuated Universal Influenza Vaccine (cH8/1N1 LAIV) Administered as a Single Priming Dose Followed Three Months Later by a Single Booster Dose of an Inactivated Universal Influenza Vaccine (cH5/1N1 IIV) (Adjuvanted With AS03A or Unadjuvanted) in 18 Through 39 Year-old Healthy Subjects, Contrasted With a Two Dose Schedule of an Inactivated Universal Influenza Vaccine (cH8/1N1 IIV + AS03A Followed Three Months Later by cH5/1N1 IIV + AS03A)

Study Type

Interventional

2. Study Status

Record Verification Date

July 2020

Overall Recruitment Status

Completed

Study Start Date

October 10, 2017 (Actual)

Primary Completion Date

April 24, 2018 (Actual)

Study Completion Date

August 9, 2019 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

PATH

Collaborators

Icahn School of Medicine at Mount Sinai, Children's Hospital Medical Center, Cincinnati, Duke University, The Emmes Company, LLC, GlaxoSmithKline

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Yes

Studies a U.S. FDA-regulated Device Product

Data Monitoring Committee

Yes

5. Study Description

Brief Summary

The clinical study will evaluate safety and the immune response of a prime- boost regimen with a live attenuated influenza vaccine (LAIV) prime and an inactivated split influenza vaccine (IIV) boost with or without adjuvant.

Detailed Description

This is a prospective, multi-center, randomized, controlled, observer-blind, Phase 1 trial in healthy male and female adults 18 through 39 years of age to evaluate safety and the immune response of a prime boost regimen with LAIV prime and IIV boost with or without adjuvant. Participants will be randomized 4:3:1:3:2 to one of five groups to receive a first dose of study cH8/1N1 LAIV (or placebo) or study cH8/1N1 IIV + AS03A adjuvant (or placebo) followed three months later by study cH5/1N1 IIV +/- AS03A adjuvant (or placebo).

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Influenza, Vaccine

Keywords

live attenuated influenza vaccine, inactivated influenza vaccine

7. Study Design

Primary Purpose

Prevention

Study Phase

Phase 1

Interventional Study Model

Parallel Assignment

Model Description

Eligible enrolled subjects will be randomized to any of the treatment arms (LAIV-IIV, Groups 1, 2, and 3; or IIV-IIV, Groups 4 and 5) under one allocation sequence, stratified by site, to allow comparability between study groups, such as LAIV-IIV vs IIV-IIV regimens (Groups 1 vs 4). Groups 1-3 will be inpatient and receive either LAIV or placebo as nasal drops at Dose 1. Groups 4-5 ill be outpatient and receive either IIV or placebo as an injection at Dose 1.

Masking

ParticipantCare ProviderInvestigator

Masking Description

An unblinded pharmacist will prepare Dose 1 and Dose 2. Participants and study staff will remain blinded to their exact treatment group but will be unblinded to their overall group allocation (inpatient or outpatient).

Allocation

Randomized

Enrollment

65 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Group 1: cH8/1N1 LAIV and cH5/1N1 IIV + adjuvant

Arm Type

Experimental

Arm Description

Participants received 0.5 mL cH8/1N1 LAIV administered as 0.25 mL drops per nostril on Day 1 followed by 0.5 mL AS03-adjuvanted cH5/1N1 IIV administered as an intramuscular injection on Day 85.

Arm Title

Group 2: cH8/1N1 LAIV and cH5/1N1 IIV

Arm Type

Experimental

Arm Description

Participants received 0.5 mL cH8/1N1 LAIV administered as 0.25 mL drops per nostril on Day 1 followed by 0.5 mL cH5/1N1 IIV administered as an intramuscular injection on Day 85.

Arm Title

Group 3: Placebo

Arm Type

Placebo Comparator

Arm Description

Arm Title

Group 4: cH8/1N1 IIV + adjuvant and cH5/1N1 IIV + adjuvant

Arm Type

Experimental

Arm Description

Arm Title

Group 5: Placebo

Arm Type

Placebo Comparator

Arm Description

Participants received 0.5 mL PBS administered as an intramuscular injection on Day 1 followed by 0.5 mL PBS administered as an intramuscular injection on Day 85.

Intervention Type

Biological

Intervention Name(s)

cH8/1N1 LAIV

Intervention Description

Live-attenuated influenza virus vaccine (LAIV) expressing chimeric hemagglutinin (HA) with the H8 head and H1 stalk and neuraminidase (NA) subtype 1 (N1) (cH8/1N1): HA head, A/mallard/Sweden/24/2002 (H8N4); HA stalk, A/California/04/2009 (H1N1); NA, A/California/04/2009 (H1N1) containing the backbone of the cold-adapted/temperature sensitive of the Russian LAIV A/Leningrad/134/17/1957 (Len17 IDCDCRG46D). Administered intranasally as drops at a dose of 10⁷·⁵ (plus or minus ⁰·⁵) 50% egg infectious dose (EID50), formulated in a total volume of 0.5 mL sterile saline (0.25 mL per nostril).

Intervention Type

Biological

Intervention Name(s)

AS03-adjuvanted cH5/1N1 IIV

Other Intervention Name(s)

cH5/1N1 IIV + AS03 adjuvant

Intervention Description

Chimeric H5 head with H1 stalk plus N1 (cH5/1N1) split virion inactivated influenza virus vaccine (IIV) plus AS03 adjuvant: HA head, A/Vietnam/1203/2004 (H5N1); HA stalk, A/California/04/2009 (H1N1); NA, A/California/04/2009 (H1N1). Administered intramuscularly at a dose of 15 μg of hemagglutinin in a volume of 0.5 mL of phosphate buffered saline (PBS).

Intervention Type

Biological

Intervention Name(s)

cH5/1N1 IIV

Intervention Description

Chimeric H5 head with H1 stalk plus N1 (cH5/1N1) split virion inactivated influenza virus vaccine (IIV): HA head, A/Vietnam/1203/2004 (H5N1); HA stalk, A/California/04/2009 (H1N1); NA, A/California/04/2009 (H1N1). Administered intramuscularly at a dose of 15 μg of hemagglutinin in a volume of 0.5 mL of phosphate buffered saline (PBS).

Intervention Type

Biological

Intervention Name(s)

AS03-adjuvanted cH8/1N1 IIV

Other Intervention Name(s)

cH8/1N1 IIV + AS03 adjuvant

Intervention Description

Chimeric H8 head with H1 stalk plus N1 (cH8/1N1) inactivated influenza vaccine plus AS03 adjuvant: HA head, A/mallard/Sweden/24/2002 (H8N4); HA stalk, A/California/04/2009 (H1N1); NA, A/California/04/2009 (H1N1). Administered intramuscularly at a dose of 15 μg of hemagglutinin in a volume of 0.5 mL of phosphate buffered saline (PBS).

Intervention Type

Biological

Intervention Name(s)

Normal saline

Intervention Description

Administered intranasally as 0.25 mL nasal drops per nostril

Intervention Type

Biological

Intervention Name(s)

Phosphate buffered saline (PBS)

Intervention Description

Administered intramuscularly as 0.5 mL injection

Primary Outcome Measure Information:

Title

Number of Participants With Solicited Local Reactions Within 7 Days Following Each Vaccination

Description

Time Frame

7 days after each vaccination (Days 1-8 and Days 85-92)

Title

Number of Participants With Solicited General Reactions Within 7 Days Following Each Vaccination

Description

Time Frame

7 days after each vaccination (Days 1-8 and Days 85-92)

Title

Number of Participants With Unsolicited Adverse Events Within 28 Days Following Any Vaccination

Description

Time Frame

28 days after each vaccination (Days 1 to 28 and Days 85 to 113)

Title

Number of Participants With Grade 2 or Higher Hematological and Biochemical Laboratory Abnormalities From Day 8 to Day 113

Description

Time Frame

Days 8, 29, 85, 92, and 113

Title

Description

Time Frame

Through Day 113 (28 days post-dose 2)

Secondary Outcome Measure Information:

Title

Number of Participants With Any Grade 2 or Higher Hematological and Biochemical Laboratory Abnormalities From Month 9 to Month 15

Description

Time Frame

Month 9 (6 months post-dose 2) and Month 15 (12 months post-dose 2)

Title

Description

An MAE is an event for which the participant received medical attention such as hospitalization, an emergency room visit, or a visit to or from medical personnel. pIMDs are a subset of AEs that include autoimmune diseases and other inflammatory and/or neurologic disorders of interest which may or may not have an autoimmune etiology. LC-ILI is defined as at least 1 systemic symptom (fever or myalgia) AND at least 1 respiratory symptom (cough or sore throat), confirmed by PCR assay. An SAE is an AE that met any of the following: Death Life threatening Required inpatient hospitalization or prolongation of existing hospitalization Resulted in persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions Resulted in congenital anomaly/birth defect An important medical event that may jeopardize the well-being of the subject or require medical or surgical intervention to prevent an above outcome.

Time Frame

From first dose to end of study, 588 days (21 months; 18 months post-dose 2)

Title

Number of Participants in Groups 1, 2, and 3 With Detectable Influenza A Virus in Nasal and Oropharyngeal Swabs on Days 1 to 5

Description

Time Frame

Days 1 to 5

Title

Number of Participants in Groups 1, 2, and 3 With Viable Vaccine Virus in Cell Culture Through 5 Days Post-vaccination

Description

Time Frame

Days 1 to 5

Title

Percentage of Participants With Serum Anti-H1 Hemagglutinin Stalk Immunoglobulin G Antibody Seropositivity

Description

Time Frame

Baseline (pre-dose 1), Month 1 (28 days post-dose 1), Month 4 (28 days post-dose 2), Month 9 (6 months post-dose 2), and Month 15 (12 months post-dose 2)

Title

Geometric Mean Titer of Serum Anti-H1 Hemagglutinin Stalk IgG Antibodies

Description

Time Frame

Baseline (pre-dose 1), Month 1 (28 days post-dose 1), Month 4 (28 days post-dose 2), Month 9 (6 months post-dose 2), and Month 15 (12 months post-dose 2)

Title

Percentage of Participants With a ≥ 4-fold Increase From Baseline in Serum Anti-H1 Hemagglutinin Stalk IgG Antibodies

Description

Time Frame

Baseline (pre-dose 1), Month 1 (28 days post-dose 1), Month 4 (28 days post-dose 2), Month 9 (6 months post-dose 2), and Month 15 (12 months post-dose 2)

Title

Percentage of Participants With a ≥ 10-fold Increase From Baseline in Serum Anti-H1 Hemagglutinin Stalk IgG Antibodies

Description

Time Frame

Baseline (pre-dose 1), Month 1 (28 days post-dose 1), Month 4 (28 days post-dose 2), Month 9 (6 months post-dose 2), and Month 15 (12 months post-dose 2)

Title

Mean Geometric Increase From Baseline in Serum Anti-H1 Hemagglutinin Stalk IgG Antibodies

Description

Anti-H1 hemagglutinin stalk immunoglobulin G (IgG) was quantified using an enzyme-linked immunosorbent assay (ELISA). The ELISA measured IgG antibodies against the H1 stalk domain by using a chimeric protein containing an exotic H6 hemagglutinin head domain that the vaccinees have not previously been exposed to (strain A/mallard/Sweden/81/02 [H6N1]) and the same H1 stalk domain as expressed by the vaccine (strain A/California/04/09 [H1N1]). Mean geometric increase represents the fold-rise in antibody titer from baseline to each post-baseline time point (ratio of post-baseline titer to Baseline titer).

Time Frame

Baseline (pre-dose 1), Month 1 (28 days post-dose 1), Month 4 (28 days post-dose 2), Month 9 (6 months post-dose 2), and Month 15 (12 months post-dose 2)

Title

Percentage of Participants With Serum Anti-H1 Hemagglutinin Stalk Immunoglobulin A Antibody Seropositivity

Description

Time Frame