Safety and Immune Response of Candidate H1N1 Influenza Vaccine GSK2340274A Following Seasonal Influenza Vaccination in Adults

Phase 1

Completed

Conditions: Influenza

Interventions: Biological: Placebo (saline)
Biological: GSK Biologicals' FluLaval®
Biological: GSK Biologicals' investigational H1N1 Influenza Vaccine - GSK2340273A
Biological: GSK Biologicals' investigational H1N1 Influenza Vaccine - GSK2340274A

Registration Number: NCT01059617

Lead Sponsor: GlaxoSmithKline

Brief Summary: This study is designed to characterize the safety and immunogenicity of a' pandemic influenza (H1N1) candidate vaccine GSK2340274A in adults 19 to 40 years who have never received influenza vaccination.

Detailed Description: Not available

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 133

Inclusion Criteria

Subjects who the investigator believes 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.
Male or female adults, 19-40 years of age at the time of the first vaccination.
Body weight of at least 110 pounds (49.9 kg).
Safety laboratory tests results within the parameters specified by protocol.
Satisfactory baseline medical assessment by physical examination (stable health status with no exclusionary conditions). Stable health status is defined as the absence of a health event satisfying the definition of a serious adverse event, or a change in an ongoing drug therapy due to therapeutic failure or symptoms of drug toxicity, within one month prior to enrollment.
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 (i.e., a common-use phone serving multiple rooms or apartments).
Female subjects of non-childbearing potential may be enrolled in the study.
Non-childbearing potential is defined as current tubal ligation, hysterectomy, ovariectomy, or post-menopause.
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 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 A/California/7/2009 (H1N1)v-like virus vaccine
A medical history of physician-confirmed infection with an A/California/7/2009 (H1N1)v-like virus.
Prior receipt at any time of any seasonal influenza vaccine.
Planned administration of any vaccine not foreseen by the study protocol (including any influenza vaccine other than the study vaccine) between Days 0 and the Day 164 phlebotomy.
Administration of any licensed vaccine within 30 days before the first study vaccine dose.
Use of any investigational or non-registered product (drug or vaccine) 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 (e.g., prednisone ≥ 0.5 mg/kg/day, or ≥ 10 mg/day [whichever is less] for more than 14 consecutive days) 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 9 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.
History of anemia.
Presence of a temperature ≥ 38.0ºC (≥100.4ºF), (oral temperature assessment preferred), 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. (No laboratory testing is required.)
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 any vaccine.
Any known or suspected allergy to any constituent of influenza vaccines (including egg proteins or mercurial preservatives); a history of anaphylactic-type reaction to consumption of eggs; or a history of severe adverse reaction to any vaccine.
Known pregnancy or a positive urine beta-human chorionic gonadotropin (β-HCG) test result prior to first vaccination.
Lactating or nursing women.

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Placebo/Arepanrix Group	Placebo (saline)	subjects received a saline placebo on Day 0 and Arepanrix vaccine on Day 122 and Day 143. All vaccines were given intramuscularly, in the deltoid region of the non-dominant arm at Days 0 and 122 and of the dominant arm at Day 143.
Flulaval/Unadjuvanted Arepanrix Group	GSK Biologicals' investigational H1N1 Influenza Vaccine - GSK2340273A	subjects received Flulaval vaccine on Day 0 and the unadjuvanted formulation of Arepanrix vaccine on Day 122 and Day 143. All vaccines were given intramuscularly, in the deltoid region of the non-dominant arm at Days 0 and 122 and of the dominant arm at Day 143.
Placebo/Arepanrix Group	GSK Biologicals' investigational H1N1 Influenza Vaccine - GSK2340274A	subjects received a saline placebo on Day 0 and Arepanrix vaccine on Day 122 and Day 143. All vaccines were given intramuscularly, in the deltoid region of the non-dominant arm at Days 0 and 122 and of the dominant arm at Day 143.
Placebo/Unadjuvanted Arepanrix Group	GSK Biologicals' investigational H1N1 Influenza Vaccine - GSK2340273A	subjects received a saline placebo on Day 0 and the unadjuvanted formulation of Arepanrix vaccine on Day 122 and Day 143. All vaccines were given intramuscularly, in the deltoid region of the non-dominant arm at Days 0 and 122 and of the dominant arm at Day 143.
Placebo/Unadjuvanted Arepanrix Group	Placebo (saline)	subjects received a saline placebo on Day 0 and the unadjuvanted formulation of Arepanrix vaccine on Day 122 and Day 143. All vaccines were given intramuscularly, in the deltoid region of the non-dominant arm at Days 0 and 122 and of the dominant arm at Day 143.
Flulaval/Arepanrix Group	GSK Biologicals' FluLaval®	subjects received Flulaval vaccine on Day 0 and Arepanrix vaccine on Day 122 and Day 143. All vaccines were given intramuscularly, in the deltoid region of the non-dominant arm at Days 0 and 122 and of the dominant arm at Day 143.
Flulaval/Unadjuvanted Arepanrix Group	GSK Biologicals' FluLaval®	subjects received Flulaval vaccine on Day 0 and the unadjuvanted formulation of Arepanrix vaccine on Day 122 and Day 143. All vaccines were given intramuscularly, in the deltoid region of the non-dominant arm at Days 0 and 122 and of the dominant arm at Day 143.
Flulaval/Arepanrix Group	GSK Biologicals' investigational H1N1 Influenza Vaccine - GSK2340274A	subjects received Flulaval vaccine on Day 0 and Arepanrix vaccine on Day 122 and Day 143. All vaccines were given intramuscularly, in the deltoid region of the non-dominant arm at Days 0 and 122 and of the dominant arm at Day 143.

Primary Outcome Measures

Name	Time	Method
Number of Seroconverted Subjects for Hemagglutination Inhibition (HI) Antibodies Against A/California/7/2009 (H1N1)V-like Virus-homologous Vaccine Strain.	21 days following the second dose of Arepanrix or the unadjuvanted formulation of Arepanrix vaccines (At Day 164).	Seroconversion rate (SCR) was defined as the number of subjects who have either a pre-vaccination reciprocal HI titer \< 10 and a post-vaccination reciprocal titer ≥ 40, or a pre-vaccination reciprocal HI titer ≥ 10 and at least a 4-fold increase in post vaccination reciprocal titer against the vaccine virus.
Seroconversion Factor for Hemagglutination Inhibition (HI) Antibodies Against A/California/7/2009 (H1N1)V-like Virus-homologous Vaccine Strain.	21 days following the second dose of Arepanrix or the unadjuvanted formulation of Arepanrix vaccines (At Day 122 to Day 164).	Geometric mean fold-rise (GMFR), or seronversion factor (SCF), was defined as the geometric mean of the within-subject ratios of the post-vaccination reciprocal HI titer to the pre-vaccination reciprocal HI titer for the vaccine virus.
Number of Seropositive Subjects for Hemagglutination Inhibition (HI) Antibodies Against A/California/7/2009 (H1N1)V-like Virus-homologous Vaccine Strain.	21 days following the second dose of Arepanrix or the unadjuvanted formulation of Arepanrix vaccines (At Day 164).	A seropositive subject was a subject whose HI antibody titer was greater than or equal to the assay cut-off value of 1:10.
Number of Seroprotected Subjects for Hemagglutination Inhibition (HI) Antibodies Against A/California/7/2009 (H1N1)V-like Virus-homologous Vaccine Strain.	21 days following the second dose of Arepanrix or the unadjuvanted formulation of Arepanrix vaccines (At Day 164).	Seroprotection rate (SPR) was defined as the number of subjects with H1N1 reciprocal HI titers ≥ 40 against the tested vaccine virus.
Seroconversion Factor for Hemagglutination Inhibition (HI) Antibodies Against A/Brisbane/59/2007 (H1N1) Virus-heterologous Vaccine Strain.	21 days following the second dose of Arepanrix or the unadjuvanted formulation of Arepanrix vaccines (At Day 122 to Day 164).	Geometric mean fold-rise (GMFR), or seronversion factor (SCF), was defined as the geometric mean of the within-subject ratios of the post-vaccination reciprocal HI titer to the pre-vaccination reciprocal HI titer for the vaccine virus.
Vaccine Response Rate (VRR) for Microneutralization (MN) Antibodies Titers Against A/California/7/2009 (H1N1)V-like Virus-homologous Vaccine Strain.	21 days following the second dose of Arepanrix or the unadjuvanted formulation of Arepanrix vaccines (At Day 164).	VRR 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. The cut-off value for microneutralization titers is 1:28.
Number of Seropositive Subjects for Hemagglutination Inhibition (HI) Antibodies Against A/Brisbane/59/2007 (H1N1) Virus-heterologous Vaccine Strain.	21 days following the second dose of Arepanrix or the unadjuvanted formulation of Arepanrix vaccines (At Day 164).	A seropositive subject was a subject whose HI antibody titer was greater than or equal to the assay cut-off value of 1:10.
Titers for Hemagglutination Inhibition (HI) Antibodies Against A/California/7/2009 (H1N1)V-like Virus-homologous Vaccine Strain.	21 days following the second dose of Arepanrix or the unadjuvanted formulation of Arepanrix vaccines (At Day 164).	Titers were expressed as geometric mean antibody titers (GMTs).
Number of Seroconverted Subjects for Hemagglutination Inhibition (HI) Antibodies Against A/Brisbane/59/2007 (H1N1) Virus-heterologous Vaccine Strain.	21 days following the second dose of Arepanrix or the unadjuvanted formulation of Arepanrix vaccines (At Day 164).	Seroconversion rate (SCR) was defined as the number of subjects who have either a pre-vaccination reciprocal HI titer \< 1:10 and a post-vaccination reciprocal titer ≥ 1:40, or a pre-vaccination reciprocal HI titer ≥ 10 and at least a 4-fold increase in post vaccination reciprocal titer against the vaccine virus.
Number of Seroprotected Subjects for Hemagglutination Inhibition (HI) Antibodies Against A/Brisbane/59/2007 (H1N1) Virus-heterologous Vaccine Strain.	21 days following the second dose of Arepanrix or the unadjuvanted formulation of Arepanrix vaccines (At Day 164).	Seroprotection rate (SPR) was defined as the number of subjects with H1N1 reciprocal HI titers ≥ 1:40 against the tested vaccine virus.
Titers for Hemagglutination Inhibition (HI) Antibodies Against A/Brisbane/59/2007 (H1N1) Virus-heterologous Vaccine Strain.	21 days following the second dose of Arepanrix or the unadjuvanted formulation of Arepanrix vaccines (At Day 164).	Titers were expressed as geometric mean antibody titers (GMTs).
Vaccine Response Rate (VRR) for Microneutralization (MN) Antibodies Titers Against A/Brisbane/59/2007 (H1N1) Virus-heterologous Vaccine Strain.	21 days following the second dose of Arepanrix or the unadjuvanted formulation of Arepanrix vaccines (At Day 164).	VRR 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. The cut-off value for microneutralization titers is 1:28.

Secondary Outcome Measures

Name	Time	Method
Number of Seropositive Subjects for Hemagglutination Inhibition (HI) Antibodies Against A/California/7/2009 (H1N1)V-like Virus-homologous Vaccine Strain.	At Days 122, 129, 136, 143, 150, 157 and 164.	A seropositive subject was a subject whose HI antibody titer was greater than or equal to the assay cut-off value of 1:10.
Cell-mediated Immunogenicity (CMI) in Terms of T-cell Markers Related to A/California/7/2009, A/Brisbane/59/2007, B/Brisbane/59/2007 and A/Uruguay/716/2007 Antigens	Before administration of Arepanrix vaccine (Day 0 to Day 122)	CD4 T cell-mediated immune responses against the antigens A/California/7/2009, A/Brisbane/59/2007 and A/Uruguay/716/2007 were analyzed for cells expressing at least 2 of the following immune markers: CD40 Ligand, Interleukin-2, Tumor Necrosis Factor alpha or Interferon-gamma. The frequency was presented as number of cytokine-producing CD4+ cells per million CD4+ cells. All doubles= T cell expressing at least 2 cytokines. Subjects with missing results were not included.
Titers for Hemagglutination Inhibition (HI) Antibodies Against A/Brisbane/59/2007 (H1N1) Virus-heterologous Vaccine Strain.	At Days 122, 129, 136, 143, 150, 157 and 164.	Titers were expressed as geometric mean antibody titers (GMTs).
Number of Subjects Reporting Unsolicited AEs.	Within 84 days following first dose or 63 days following second dose of vaccine.	Unsolicited AEs were collected after the administration of the Arepanrix or the unadjuvanted formulation of Arepanrix vaccine. 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.
Number of Subjects Reporting Solicited Local Symptoms From Flulaval Group and Placebo Group.	During the 7-day (Days 0-6) follow-up period after vaccination.	Solicited local symptoms assessed were pain, redness and swelling and data collected was pooled by administration of vaccination received at Day 0 (i.e. Flulaval or Saline placebo). Any was defined as any solicited local symptom reported irrespective of intensity. Grade 3 pain was defined as pain that prevented normal activity. Grade 3 redness and swelling were defined as redness/swelling above 100 millimeter (mm).
Titers for Hemagglutination Inhibition (HI) Antibodies Against A/California/7/2009 (H1N1)V-like Virus-homologous Vaccine Strain.	At Days 122, 129, 136, 143, 150, 157 and 164.	Titers were expressed as geometric mean antibody titers (GMTs).
Vaccine Response Rate (VRR) for Microneutralization (MN) Antibodies Titers Against A/California/7/2009 (H1N1)V-like Virus-homologous Vaccine Strain.	Entire study period up to Day 507	VRR 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. The cut-off value for microneutralization titers is 1:28.
Number of Seropositive Subjects for Hemagglutination Inhibition (HI) Antibodies Against A/Brisbane/59/2007 (H1N1) Virus-heterologous Vaccine Strain.	At Days 122, 129, 136, 143, 150, 157 and 164.	A seropositive subject was a subject whose HI antibody titer was greater than or equal to the assay cut-off value of 1:10.
Number of Subjects Reporting Solicited General Symptoms From Flulaval Group and Placebo Group.	During the 7-day (Days 0-6) follow-up period after vaccination.	Solicited general symptoms assessed were fatigue, headache, joint pain at other location, muscle aches, shivering, sweating and temperature (= axillary temperature equal to or above 38.0 degrees Celsius (°C)) and data collected was pooled by administration of vaccination received at Day 0 (i.e. Flulaval or Saline placebo). Any = any solicited general symptom reported irrespective of intensity and relationship to vaccination. Related = symptoms considered by the investigator to have a causal relationship to vaccination. Grade 3 symptoms = symptoms that prevented normal activity. Grade 3 fever = axillary temperature above 39.0°C.
Vaccine Response Rate (VRR) for Microneutralization (MN) Antibodies Titers Against A/Brisbane/59/2007 (H1N1) Virus-heterologous Vaccine Strain.	For the entire study period up to Day 507	VRR 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. The cut-off value for microneutralization titers is 1:28.
Cell-mediated Immunogenicity (CMI) in Terms of Tcell Markers Related to A/California/7/2009, A/Brisbane/59/2007, B/Brisbane/59/2007 and A/Uruguay/716/2007 Antigens	After the administration of Arepanrix vaccine (Day 125 to 304)	CD4 T cell-mediated immune responses against the antigens A/California/7/2009, A/Brisbane/59/2007 and A/Uruguay/716/2007 were analyzed for cells expressing at least 2 of the following immune markers: CD40 Ligand, Interleukin2, Tumor Necrosis Factor alpha or Interferongamma. The frequency was presented as number of cytokineproducing CD4+ cells per million CD4+ cells. All doubles= T cell expressing at least 2 cytokines.
Number of Subjects Reporting Any and Related Potential Immune-mediated Disease (pIMDs).	Within Days 0-233	pIMDs are a subset of adverse events (AEs) that include both clearly autoimmune diseases and also other inflammatory and/or neurologic disorders which may or may not have an autoimmune etiology. Related = symptom assed by the investigator as causally related to the study vaccination.
Number of Subjects Reporting Any and Related Serious Adverse Events (SAEs).	Up to Day 234	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. Related = symptom assed by the investigator as causally related to the study vaccination. Missing values will be added once they become available.
Number of Subjects Reporting Any and Related Medically Attended Adverse Events (MAEs).	Within Days 0-233	MAEs refer to events that required medical attention defined as hospitalization, an emergency room visit or a visit to or from medical personnel (medical doctor) for any reason. Related = symptom assed by the investigator as causally related to the study vaccination.
Number of Subjects Reporting Solicited General Symptoms From Flulaval/Arepanrix Group,Flulaval/Unadjuvanted Arepanrix Group, Placebo/Arepanrix Group and Placebo/Unadjuvanted Arepanrix Group.	During the 7-day (Days 0-6) follow-up period after vaccination.	Solicited general symptoms assessed were fatigue, headache, joint pain at other location, muscle aches, shivering, sweating and temperature (= axillary temperature equal to or above 38.0 degrees Celsius (°C)) and were collected after the administration of the Arepanrix or the unadjuvanted formulation of Arepanrix vaccine. Any = any solicited general symptom reported irrespective of intensity and relationship to vaccination. Related = symptoms considered by the investigator to have a causal relationship to vaccination. Grade 3 symptoms = symptoms that prevented normal activity. Grade 3 fever = axillary temperature above 39.0°C.
Number of Subjects Reporting Solicited Local Symptoms From Flulaval/Arepanrix Group,Flulaval/Unadjuvanted Arepanrix Group,Placebo/Arepanrix Group and Placebo/Unadjuvanted Arepanrix Group	During the 7-day (Days 0-6) follow-up period after vaccination.	Solicited local symptoms assessed were pain, redness and swelling and were collected after the administration of the Arepanrix or the unadjuvanted formulation of Arepanrix vaccine. Any was defined as any solicited local symptom reported irrespective of intensity. Grade 3 pain was defined as pain that prevented normal activity. Grade 3 redness and swelling were defined as redness/swelling above 100 millimeter (mm).
Number of Subjects Reporting Clinical Laboratory Abnormalities in Biochemistry Parameters Assessed With Respect to Normal Laboratory Ranges.	At Day 304	Laboratory parameters assessed were alanine aminotransferase (ALAT), aspartate aminotransferase (ASAT), alkaline phosphatase (AP), creatinine (CREA), blood urea nitrogen (BUN), and bilirubin (BIL) (total (T) and direct (D)). For each parameter and for each status at baseline it was assessed whether the post-vaccination values of the parameter were above, below or within the range (unkown values are also indicated).
Number of Subjects Reporting Clinical Laboratory Abnormalities in Haematological Parameters Assessed With Respect to Normal Laboratory Ranges.	At Day 304	Laboratory parameters assessed were white blood cells (WBC), neutrophils (NEU), lymphocytes (LYM), monocytes (MON), eosinophils (EOS), basophils (BAS), red blood cells (RBC), hemoglobin (Hgb), hematocrit (Hct) and platelets (PLA). For each parameter and for each status at baseline it was assessed whether the post-vaccination values of the parameter were above, below or within the range (unkown values are also indicated).