Safety and Immunogenicity of H1N1 Vaccine With Trivalent Inactivated Seasonal Influenza Vaccine in Adults

GlaxoSmithKline611 enrolled

Overview

The purpose of this study is to characterize the safety and immunogenicity of the H1N1 (swine) flu vaccines GSK2340274A and GSK2340273A when co-administered with the seasonal flu vaccine in adults 19 to 40 years of age.

Collaborators: United States Department of Health and Human Services, Office of Biomedical Advanced Research and Development Authority

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

PREVENTION

Masking

TRIPLE

Enrollment

611

Conditions

Influenza

Interventions

GSK2340274ABIOLOGICAL

Two intramuscular injections

GSK2340273ABIOLOGICAL

Two intramuscular injections

Seasonal trivalent influenza vaccine (TIV)BIOLOGICAL

Single intramuscular injection

Eligibility

Sex: ALLMin age: 19 YearsMax age: 40 YearsHealthy volunteers:

Medical Language ↔ Plain English

Inclusion Criteria: * Subjects who the investigator believes can and will comply with the requirements of the protocol. * Written informed consent obtained from the subject. * Male or female adults, 19-40 years of age at the time of the first vaccination. * Safety laboratory tests results within the parameters specified in the protocol. * Satisfactory baseline medical assessment by physical examination. * Comprehension of the study requirements, ability to comprehend and comply with procedures for collection of safety data, expressed availability for the required study period, and ability and willingness to attend scheduled visits as documented by signature on the informed consent document. * Access to a consistent means of telephone contact, which may be either in the home or at the workplace, land line, or mobile, but NOT a pay phone or other multiple-user device. * Female subjects of non-childbearing potential may be enrolled in the study. * Female subjects of childbearing potential may be enrolled in the study, if the subject: * has practiced adequate contraception for 30 days prior to vaccination, and * has a negative pregnancy test on the day of first vaccination, and * has agreed to continue adequate contraception during the entire treatment period and for 2 months after completion of the vaccination series. Exclusion Criteria: * Previous vaccination with an H1N1v-like virus vaccine or a medical history of physician-confirmed infection with an H1N1v-like virus. * Prior receipt at any time of any seasonal influenza vaccine. * Planned administration of any vaccine not foreseen by the study protocol between Day 0 and the Day 63 phlebotomy. * Administration of any licensed vaccine within 4 weeks before the first study vaccine dose. * Use of any investigational or non-registered product other than the study vaccines within 30 days preceding the first dose of study vaccine, or planned use during the study period. * Receipt of systemic glucocorticoids within one month prior to study enrolment, or any other cytotoxic or immunosuppressive drug within six months of study enrolment. Topical, intra-articularly injected, or inhaled glucocorticoids, topical calcineurin inhibitors or imiquimod are allowed. * Receipt of any immunoglobulins and/or any blood products within three months of study enrolment or planned administration of any of these products during the study period. * Presence of evidence of substance abuse or of neurological or psychiatric diagnoses which, even if stable, are deemed by the investigator to render the potential subject unable/unlikely to provide accurate safety reports. * Presence of a temperature \>= 38.0ºC (\>=100.4ºF), or acute symptoms greater than "mild" severity on the scheduled date of first vaccination. * Diagnosed with cancer, or treatment for cancer, within 3 years. * Any confirmed or suspected immunosuppressive or immunodeficient condition, based on medical history and physical examination. * Any significant disorder of coagulation or treatment with warfarin derivatives or heparin. Persons receiving individual doses of low molecular weight heparin outside of 24 hours prior to vaccination are eligible. Persons receiving prophylactic antiplatelet medications, e.g., low-dose acetylsalicylic acid, and without a clinically-apparent bleeding tendency, are eligible. * An acute evolving neurological disorder or history of Guillain-Barré syndrome within six weeks of receipt of seasonal influenza vaccine. * Any known or suspected allergy to any constituent of influenza vaccines; a history of anaphylactic-type reaction to any constituent of influenza vaccines; or a history of severe adverse reaction to a previous influenza vaccine. * Known pregnancy or a positive urine beta-human chorionic gonadotropin test result prior to first vaccination. * Lactating or nursing women.

Locations (7)

GSK Investigational Site

Stockbridge, Georgia, United States

GSK Investigational Site

Raleigh, North Carolina, United States

GSK Investigational Site

Austin, Texas, United States

GSK Investigational Site

Fort Worth, Texas, United States

Outcomes

Primary Outcomes

Hemagglutination Inhibition (HI) Antibody Titers Against A/California/7/2009 H1N1 Vaccine Strain.

The A/California vaccine virus-homologous antibody response was measured in subjects having received Flulaval vaccine co-administered with the first dose of Arepanrix vaccine, and in subjects having received two doses of Arepanrix vaccine alone. Titers were expressed as geometric mean antibody titers (GMTs).

Time frame: 21 days after the second dose of Arepanrix vaccine (at Day 42).

Hemagglutination Inhibition (HI) Antibody Titers Against A/California/7/2009 H1N1 Vaccine Strain.

The A/California vaccine virus-homologous antibody response was measured in subjects having received Flulaval vaccine co-administered with the first dose of the unadjuvanted formulation of Arepanrix vaccine, and in subjects having received two doses of the unadjuvanted formulation of Arepanrix vaccine alone. Titers were expressed as geometric mean antibody titers (GMTs).

Time frame: 21 days after the second dose of the unadjuvanted formulation of Arepanrix vaccine (at Day 42)

Secondary Outcomes

Number of Influenza-specific Cluster of Differentiation 4 (CD4) T-cells Per Million Producing Two or More Markers Within Cluster Differentiation 40 Ligand (CD40L), Interleukin-2 (IL-2), Interferon-γ (IFN-γ) and Tumor Necrosis Factor-α (TNF-α).

Influenza-specific CD4 T-Cells were stimulated in vitro with A/California virus and seasonal Influenza viruses, related antigens or derived peptides. Stimulating antigens were A/Brisbane, A/California, pool peptides H1N1 and pool FLU.

Time frame: On Days 0, 7, 21, 28, 42, 63 and 182

Number of Influenza-specific Cluster of Differentiation 8 (CD8) T-cells Per Million Producing Two or More Markers Within Cluster Differentiation 40 Ligand (CD40L), Interleukin-2 (IL-2), Interferon-γ (IFN-γ) and Tumor Necrosis Factor-α (TNF-α).

Influenza-specific CD8 T-Cells were stimulated in vitro with A/California virus and seasonal Influenza viruses, related antigens or derived peptides. Stimulating antigens were A/Brisbane, A/California, pool peptides H1N1 and pool FLU.

Data from ClinicalTrials.gov

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Single intramuscular injection

GSK Investigational Site

Halifax, Nova Scotia, Canada

GSK Investigational Site

Montreal, Quebec, Canada

GSK Investigational Site

Sherbrooke, Quebec, Canada

Time frame: On Days 0, 7, 21, 28, 42, 63 and 182

Number of Subjects Reporting Clinical Laboratory Abnormalities in Biochemical and Haematological Parameters Assessed

Laboratory parameters assessed were alanine aminotransferase (ALAT), aspartate aminotransferase (ASAT), alkaline phosphatase (AP), bilirubin (BIL) (total (T)), basophils (BAS). For each parameter and for each range it was assessed whether the values of the subjects were in unkown, above, below or within the range.

Time frame: On Days 0, 7, 21, 28, 42, 63 and 182

Number of Subjects Reporting Clinical Laboratory Abnormalities in Biochemical and Haematological Parameters Assessed

Laboratory parameters assessed were creatinine (CREA), bilirubin (BIL) (direct (D)), eosinophils (EOS), hemoglobin (Hgb), hematocrit (Hct). For each parameter and for each range it was assessed whether the values of the subjects were unknown, in above, below or within the range.

Time frame: On Days 0, 7, 21, 28, 42, 63 and 182

Number of Subjects Reporting Solicited Local Symptoms.

Solicited local symptoms assessed were pain, redness and swelling

Time frame: During a 7-day follow-up period (Days 0-6) post-vaccination period

Number of Subjects Reporting Solicited General Symptoms.

Solicited general symptoms assessed were fatigue, headache, joint pain at other location, muscle aches, shivering, sweating and temperature. Temperature is defined as an axillary temperature equal to or above 38.0 degrees Celsius (°C).

Time frame: During a 7-day follow-up period (Days 0-6) post-vaccination period

Number of Subjects Reporting Clinical Laboratory Abnormalities in Biochemical and Haematological Parameters Assessed

Laboratory parameters assessed were serum urea nitrogen (SUN), white blood cells (WBC), red blood cells (RBC). For each parameter and for each range it was assessed whether the values of the subjects were unknown, above, below or within the range.

Time frame: On Days 0, 7, 21, 28, 42, 63 and 182

Number of Subjects Reporting Unsolicited Adverse Events (AEs).

An unsolicited adverse event is any adverse event (i.e. any untoward medical occurrence in a patient or clinical investigation subject, temporally associated with use of a medicinal product, whether or not considered related to the medicinal product) reported in addition to those solicited during the clinical study and any solicited symptom with onset outside the specified period of follow-up for solicited symptoms.

Time frame: Within the 84-day (Days 0-83) post-vaccination period.

Number of Subjects Reporting Medically Attended Visits (MAEs).

The day 368 was the last contact day for the last subject reporting the event. For each solicited and unsolicited symptom the subject experienced, the subject was asked if they received medical attention defined as hospitalization, an emergency room visit or a visit to or from medical personnel for any reason.

Time frame: During the entire study period (Days 0-368).

Number of Subjects Reporting Potential Immune Diseases (pIMDs).

The day 406 was the last contact day with the subjects reporting the event. Potential immune-mediated diseases (pIMDs) are a subset of AEs that include both clearly autoimmune diseases and also other inflammatory and/or neurologic disorders which may or may not have an autoimmune etiology.

Time frame: During the entire study period (Days 0-406).

Number of Subjects Reporting Serious Adverse Events (SAEs).

The day 329 was the last contact day with the subjects reporting serious adverse events. SAEs assessed include medical occurrences that results in death, are life threatening, require hospitalization or prolongation of hospitalization, results in disability/incapacity or are a congenital anomaly/birth defect in the offspring of a study subjects.

Time frame: During the entire study period (Days 0-329).

Number of Subjects Reporting Clinical Laboratory Abnormalities in Biochemical and Haematological Parameters Assessed

Laboratory parameters assessed were neutrophils (NEU), lymphocytes (LYM), monocytes (MON) and platelets (PLA). For each parameter and for each range it was assessed whether the values of the subjects were unknown, in above, below or within the range.

Time frame: On Days 0, 7, 21, 28, 42, 63 and 182

Microneutralization Antibody Titers Against A/California/7/2009 (H1N1) Strain.

Titers were expressed as geometric mean titers (GMTs) and measured by microneutralization. Arepanrix vaccine strain and the unadjuvanted formulation of Arepanrix vaccine strain was A/California/7/2009 (H1N1). Microneutralization testing was cancelled.

Time frame: On Days 0, 21, 42, 63 and 182

Number of Subjects With a Microneutralization Titer Greater Than or Equal to 1:28 for Antibodies Against A/California/7/2009 (H1N1) Strain.

Arepanrix vaccine strain and the unadjuvanted formulation of Arepanrix vaccine strain was A/California/7/2009 (H1N1). The antibody cut-off value assessed was a titer of 1:10 and this value was considered as seropositivity. Seronegative subject is a subject whose antibody titer is below the cut-off value, a seropositive subject is a subject whose antibody titer is greater than or equal to the cut-off value. Microneutralization titers \< 1:28 were considered below the cut-off. Microneutralization testing was cancelled.

Time frame: On Days 0, 21, 42, 63 and 182

Vaccine Response Rates (VRR) for Microneutralization Antibody Titers Against A/California/7/2009 (H1N1) Strain.

Arepanrix vaccine strain and the unadjuvanted formulation of Arepanrix vaccine strain was A/California/7/2009 (H1N1). Vaccine Response Rate for microneutralization titers was defined as the incidence rate of vaccinees with at least a 4-fold increase in post vaccination reciprocal titer relative to Day 0. Microneutralization testing was cancelled.

Time frame: On Days 0, 21, 42, 63 and 182

Hemagglutination Inhibition (HI) Antibody Titers Against A/California/7/2009 H1N1 Vaccine Strain.

The A/California vaccine virus-homologous antibody response was measured in subjects having received two doses of Arepanrix vaccine, with prior treatment with Flulaval vaccine 21 days before the first dose and in subjects having received two doses of Arepanrix vaccine alone. Titers were expressed as geometric mean antibody titers (GMTs).

Time frame: 21 days after the second dose of Arepanrix vaccine (Day 63 for Flulaval/placebo/Arepanrix Group and Day 42 for Arepanrix/placebo/Flulaval Group)

Hemagglutination Inhibition (HI) Antibody Titers Against A/California/7/2009 H1N1 Vaccine Strain.

The A/California vaccine virus-homologous antibody response was measured in subjects having received two doses of the unadjuvanted formulation of Arepanrix vaccine, with prior treatment with Flulaval vaccine 21 days before the first dose and in subjects having received two doses of the unadjuvanted formulation of Arepanrix vaccine alone. Titers were expressed as geometric mean antibody titers (GMTs).

Time frame: 21 days after the second dose of the unadjuvanted formulation of Arepanrix vaccine (Day 63 for Flulaval/placebo/unadjuvanted Arepanrix Group and Day 42 for Unadjuvanted Arepanrix/placebo/Flulaval Group)

Hemagglutination Inhibition (HI) Antibody Titers Against A/California/7/2009 H1N1 Vaccine Strain.

The A/California vaccine virus-homologous antibody response was measured in subjects pre-treated with Flulaval who subsequently received two doses of the unadjuvanted formulation of Arepanrix vaccine compared to subjects pre-treated with Flulaval vaccine who subsequently received two doses of Arepanrix vaccine. Titers were expressed as geometric mean antibody titers (GMTs).

Time frame: 21 days after the second dose of the pandemic vaccine (at Day 63)

Hemagglutination Inhibition (HI) Antibody Titers Against Each of the Three Flulaval Strains.

The antibody response against each of the three Flulaval vaccine components in subjects exposed to co-administration of Flulaval vaccine with the first of two doses of Arepanrix vaccine and in subjects exposed to a single dose of Flulaval vaccine. Flulaval vaccine strains were Flu A/Brisbane/59/2007 H1N1, Flu A/Uruguay/716/2007 H3N2 and Flu B/Brisbane/60/2008. Titers were expressed as geometric mean antibody titers (GMTs).

Time frame: 21 days after the Flulaval vaccination (at Day 21).

Hemagglutination Inhibition (HI) Antibody Titers Against Each of the Three Flulaval Strains.

The antibody response against each of the three Flulaval vaccine components in subjects exposed to co-administration of Flulaval vaccine with the first of two doses of the unadjuvanted formulation of Arepanrix vaccine and in subjects exposed to a single dose of Flulaval vaccine. Flulaval vaccine strains were Flu A/Brisbane/59/2007 H1N1, Flu A/Uruguay/716/2007 H3N2 and Flu B/Brisbane/60/2008. Titers were expressed as geometric mean antibody titers (GMTs).

Time frame: 21 days after the Flulaval vaccination (at Day 21).

Hemagglutination Inhibition (HI) Antibody Titers Against Each of the Three Flulaval Strains.

The antibody response against each of the three Flulaval vaccine components in subjects exposed to pre-treatment with two doses of Arepanrix vaccine and in subjects exposed to a single dose of Flulaval vaccine. Flulaval vaccine strains were Flu A/Brisbane/59/2007 H1N1, Flu A/Uruguay/716/2007 H3N2 and Flu B/Brisbane/60/2008. Titers were expressed as geometric mean antibody titers (GMTs).

Time frame: 21 days after the Flulaval vaccination (Day 63 for Arepanrix/placebo/Flulaval Group and Day 21 for Flulaval/placebo/unadjuvanted Arepanrix and Flulaval/placebo/Arepanrix Groups)

Hemagglutination Inhibition (HI) Antibody Titers Against Each of the Three Flulaval Strains.

The antibody response against each of the three Flulaval vaccine components in subjects exposed to pre-treatment with two doses of the unadjuvanted formulation of Arepanrix vaccine and in subjects exposed to a single dose of Flulaval vaccine. Flulaval vaccine strains were Flu A/Brisbane/59/2007 H1N1, Flu A/Uruguay/716/2007 H3N2 and Flu B/Brisbane/60/2008. Titers were expressed as geometric mean antibody titers (GMTs).

Time frame: 21 days after the Flulaval vaccination (Day 63 for Unadjuvanted Arepanrix/placebo/Flulaval Group and Day 21 for Flulaval/placebo/unadjuvanted Arepanrix and Flulaval/placebo/Arepanrix Groups)

Geometric Mean Antibody Titers (GMTs) for Hemagglutination Inhibition (HI) Antibodies Against Flu A/California H1N1 Strain.

Titers were expressed as geometric mean antibody titers (GMTs).

Time frame: On Days 0, 21, 42 and 63

Geometric Mean Antibody Titers (GMTs) for Hemagglutination Inhibition (HI) Antibodies Against Flu A/California H1N1 Strain.

Titers were expressed as geometric mean antibody titers (GMTs).

Time frame: At Day 182

Number of Seroconverted Subjects for Antibodies Against A/ California Strain.

Seroconversion rate was defined as the incidence rate of vaccinees who had either a pre-vaccination titer recorded as \< 1:10 and a post-vaccination reciprocal titer ≥ 40 or a pre-vaccination reciprocal titer ≥ 10 and at least a 4-fold increase in post vaccination reciprocal titer. Seroconversion defined as: For initially seronegative subjects, antibody titer ≥ 1:40 after vaccination For initially seropositive subjects, antibody titer after vaccination ≥ 4 fold the pre-vaccination antibody titer

Time frame: At Day 63 from Day 21 for Flulaval/placebo/unadjuvanted Arepanrix and Flulaval/placebo/Arepanrix Groups; At Day 42 from Day 0 for the 4 other groups

Number of Seroprotected Subjects for Antibodies Against A/California Strain.

Seroprotection rate was defined as the proportion of subjects with H1N1 reciprocal HI titers ≥ 40 against the tested vaccine virus.

Time frame: At Day 63 for Flulaval/placebo/unadjuvanted Arepanrix and Flulaval/placebo/Arepanrix Groups; At Day 42 for the 4 other groups.

Seroconversion Factor for Antibodies Against A/California Strain.

Seroconversion factor was defined as the geometric mean of the within-subject ratios of the post-vaccination reciprocal HI titer to the prevaccination reciprocal HI titer.

Time frame: At Day 63 from Day 21 for Flulaval/placebo/unadjuvanted Arepanrix and Flulaval/placebo/Arepanrix Groups; At Day 42 from Day 0 for the 4 other groups

Number of Seroconverted Subjects for Antibodies Against Flulaval Vaccine Strains.

Seroconversion defined as: For initially seronegative subjects, antibody titer ≥ 1:40 after vaccination For initially seropositive subjects, antibody titer after vaccination ≥ 4 fold the pre-vaccination antibody titer Flulaval vaccines strains were A/Brisbane/59/2007 H1N1, A/Uruguay/716/2007 H3N2 and B/Brisbane/60/2008. For the analysis the Flulaval/placebo/unadjuvanted Arepanrix Group and the Flulaval/placebo/Arepanrix Group were pooled.

Time frame: At Day 21 from Day 0 for the pooled group, Flulaval/unadjuvanted Arepanrix/placebo and Flulaval/Arepanrix/placebo Groups; at Day 63 from Day 42 for Unadjuvanted Arepanrix/placebo/Flulaval Group and Arepanrix/placebo/Flulaval Group

Number of Seroprotected Subjects for Antibodies Against Flulaval Vaccine Strains

Seroprotection was defined as the proportion of subjects with H1N1 reciprocal Hemagglutination Inhibition (HI) titers ≥ 1:40 against the tested vaccine virus. Flulaval vaccines strains were A/Brisbane/59/2007 H1N1, A/Uruguay/716/2007 H3N2 and B/Brisbane/60/2008. For the analysis the Flulaval/placebo/unadjuvanted Arepanrix Group and the Flulaval/placebo/Arepanrix Group were pooled.

Time frame: At Day 21 for the pooled group, Flulaval/unadjuvanted Arepanrix/placebo and Flulaval/Arepanrix/placebo Groups; at Day 63 for Unadjuvanted Arepanrix/placebo/Flulaval Group and Arepanrix/placebo/Flulaval Group

Seroconversion Factor for Antibodies Against Flulaval Vaccine Strains.

Seroconversion factor was defined as the geometric mean of the within-subject ratios of the post-vaccination reciprocal Hemagglutination Inhibition (HI) titer to the prevaccination reciprocal HI titer. Flulaval vaccines strains were A/Brisbane/59/2007 H1N1, A/Uruguay/716/2007 H3N2 and B/Brisbane/60/2008. For the analysis the Flulaval/placebo/unadjuvanted Arepanrix Group and the Flulaval/placebo/Arepanrix Group were pooled.

Number of Seroconverted Subjects for Antibodies Against Flulaval Vaccine Strains

Time frame: on Days 21 and 63 from Day 0 for the first 4 groups; on Days 42 and 63 from Day 0 for the Unadjuvanted Arepanrix/placebo/Flulaval and Arepanrix/placebo/Flulaval Groups

Number of Seroconverted Subjects for Antibodies Against Flulaval Vaccine Strains

Time frame: At Day 182 from Day 0

Number of Seroprotected Subjects for Antibodies Against Flulaval Vaccine Strains.

Seroprotection rate was defined as the proportion of subjects with H1N1 reciprocal HI titers ≥ 40 against the tested vaccine virus. Flulaval vaccines strains were A/Brisbane/59/2007 H1N1, A/Uruguay/716/2007 H3N2 and B/Brisbane/60/2008.

Time frame: before vaccination and on days 21 and 63 for the first 4 groups and before vaccination and on days 42 and 63 for the Unadjuvanted Arepanrix/placebo/Flulaval and Arepanrix/placebo/Flulaval Groups

Number of Seroprotected Subjects for Antibodies Against Flulaval Vaccine Strains.

Time frame: At Day 182 after the first dose

Seroconversion Factor for Antibodies Against Flulaval Vaccine Strains.

Seroconversion factor of the within-subject ratios of the post-vaccination reciprocal HI titer to the Day 0 reciprocal HI titer. Flulaval vaccines strains were A/Brisbane/59/2007 H1N1, A/Uruguay/716/2007 H3N2 and B/Brisbane/60/2008.

Time frame: On Days 21 and 63 from Day 0 for the first 4 groups and on Days 42 and 63 from Day 0 for the Unadjuvanted Arepanrix/placebo/Flulaval and Arepanrix/placebo/Flulaval Groups

Seroconversion Factor for Antibodies Against Flulaval Vaccine Strains.

Time frame: At Day 182 from Day 0

Geometric Mean Antibody Titers (GMTs) for Hemagglutination Inhibition (HI) Antibodies Against Flulaval Vaccine Strains.

Titers were expressed as geometric mean titers (GMTs). Flulaval vaccines strains were A/Brisbane/59/2007 H1N1, A/Uruguay/716/2007 H3N2 and B/Brisbane/60/2008.

Time frame: On Days 0, 21 and 63 for the first 4 groups and on Days 0, 42 and 63 for the Unadjuvanted Arepanrix/placebo/Flulaval and Arepanrix/placebo/Flulaval Groups

Geometric Mean Antibody Titers (GMTs) for Hemagglutination Inhibition (HI) Antibodies Against Flulaval Vaccine Strains.

Titers were expressed as geometric mean titers (GMTs). Flulaval vaccines strains were A/Brisbane/59/2007 H1N1, A/Uruguay/716/2007 H3N2 and B/Brisbane/60/2008.

Time frame: At Day 182 after dose 1 vaccination