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

Study Results

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Outcome measurements, participant flow, baseline characteristics, and adverse events have been published for this study.

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Basic Information

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Recruitment Status

COMPLETED

Clinical Phase

PHASE1

Total Enrollment

65 participants

Study Classification

INTERVENTIONAL

Study Start Date

2017-10-10

Study Completion Date

2019-08-09

Brief Summary

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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.

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Detailed Description

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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).

Conditions

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Influenza Vaccine

Study Design

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Allocation Method

RANDOMIZED

Intervention Model

PARALLEL

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.

Primary Study Purpose

PREVENTION

Blinding Strategy

TRIPLE

Participants Caregivers Investigators

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).

Study Groups

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

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.

Group Type EXPERIMENTAL

cH8/1N1 LAIV

Intervention Type BIOLOGICAL

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).

AS03-adjuvanted cH5/1N1 IIV

Intervention Type BIOLOGICAL

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).

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

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.

Group Type EXPERIMENTAL

cH8/1N1 LAIV

Intervention Type BIOLOGICAL

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).

cH5/1N1 IIV

Intervention Type BIOLOGICAL

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).

Group 3: Placebo

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.

Group Type PLACEBO_COMPARATOR

Normal saline

Intervention Type BIOLOGICAL

Administered intranasally as 0.25 mL nasal drops per nostril

Phosphate buffered saline (PBS)

Intervention Type BIOLOGICAL

Administered intramuscularly as 0.5 mL injection

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

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.

Group Type EXPERIMENTAL

AS03-adjuvanted cH5/1N1 IIV

Intervention Type BIOLOGICAL

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).

AS03-adjuvanted cH8/1N1 IIV

Intervention Type BIOLOGICAL

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).

Group 5: Placebo

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.

Group Type PLACEBO_COMPARATOR

Phosphate buffered saline (PBS)

Intervention Type BIOLOGICAL

Administered intramuscularly as 0.5 mL injection

Interventions

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cH8/1N1 LAIV

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

AS03-adjuvanted cH5/1N1 IIV

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

cH5/1N1 IIV

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

AS03-adjuvanted cH8/1N1 IIV

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

Normal saline

Administered intranasally as 0.25 mL nasal drops per nostril

Intervention Type BIOLOGICAL

Phosphate buffered saline (PBS)

Administered intramuscularly as 0.5 mL injection

Intervention Type BIOLOGICAL

Other Intervention Names

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cH5/1N1 IIV + AS03 adjuvant cH8/1N1 IIV + AS03 adjuvant

Eligibility Criteria

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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.

Minimum Eligible Age

18 Years

Maximum Eligible Age

39 Years

Eligible Sex

ALL

Accepts Healthy Volunteers

Yes