Influenza
Conditions
Keywords
broad, universal, vaccine, influenza, peptide, T cell, H1N1, human challenge
Brief summary
FLU-v is a broad spectrum influenza vaccine that targets regions conserved among multiple influenza strains. FLU-v adjuvanted with Montanide ISA-51 was shown to be safe in previous trials. This study aims to assess efficacy of adjuvanted FLU-v vaccine in protecting healthy volunteers against an influenza challenge delivered intranasally under quarantine. Efficacy of FLU-v will be assessed by measuring the incidence and severity of the disease in the treatment groups compared to the placebo group. In addition, the immune responses of the volunteers to FLU-v will also be explored.
Detailed description
Influenza is a highly variable virus. Most of the variability comes from the proteins on the viral capsid surface; NA and HA. Current vaccines use these highly variable, immunogenic proteins to induce production of neutralising antibodies, however because these proteins are different for each strain, and can also change over time within strains due to antigenic drift, a new vaccine is required each year designed specifically to the strain predicted to circulate that year. In the event of a mismatch between predicted and actual circulating strains, or the emergence of a new strain due to antigenic shift, the effectiveness of the annual vaccine is drastically reduced. These limitations are further compounded by the short manufacturing window between strain prediction and the start of the influenza season, as well as the limited supply of suitable eggs used for vaccine production. As a result of these issues, only a limited supply of annual vaccine is available. FLU-v, a novel peptide vaccine, aims to provide a broad-spectrum response using peptide antigens matching immunogenic regions of conserved viral proteins found inside the viral capsid. These antigens have been shown to induce cytotoxic T-cell responses and non-neutralising antibodies in both pre-clinical and clinical studies. The FLU-v vaccine administered with and without adjuvant has been demonstrated to be safe in previous trials, and addition of adjuvant Montanide ISA-51 was shown to produce superior immunological responses compared to non-adjuvanted FLU-v. Data from a previous phase IIb study conducted as part of the UNISEC consortium suggest that the cellular and/or humoral responses resulting from vaccination with adjuvanted FLU-v may reduce influenza symptom severity and duration, although the study was not powered to assess these efficacy measures. Presently, efficacy will be evaluated as a primary endpoint alongside safety as part of a single centre, placebo controlled, phase IIb viral challenge study, using influenza A 2009 H1N1 human virus, in suitable healthy subjects aged 18-60 years. Two dosing regimens will be explored. In addition, immunological endpoints will be addressed as exploratory endpoints.
Interventions
BIOLOGICALadjuvanted FLU-v
Subcutaneous injection in the upper arm with 500mcg of FLU-v as 0.5ml emulsion in 0.25ml of WFI and 0.25ml of adjuvant Montanide ISA-51
BIOLOGICALadjuvanted placebo
Subcutaneous injection in the upper arm with 0.5ml emulsion made of 0.25ml of WFI and 0.25ml of adjuvant Montanide ISA-51
OTHERInfluenza challenge
On day 0, administration with an intranasal sprayer of 1ml of PBS containing 10(7) TCID50 of Influenza A 2009 H1N1 human virus manufactured under GMP in certified Vero cells.
Sponsors
National Institute of Allergy and Infectious Diseases (NIAID)
PepTcell Limited
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 55 Years
Healthy volunteers
Yes
Inclusion criteria
1. Healthy males and females aged ≥18 and ≤55 years of age at the point of enrolment. 2. Willingness to remain in isolation for the duration of viral shedding and to comply with all study requirements. 3. The following criteria are applicable to subjects in a heterosexual relationship and female subjects in a same sex relationship (i.e., the criteria do not apply to male subjects in a same sex relationship): 1. True abstinence- when this is in line with the preferred and usual lifestyle of the subject. (Periodic abstinence \[e.g. calendar, ovulation, symptothermal, post-ovulation methods\] and withdrawal are not acceptable methods of contraception). Or 2. Two forms of effective contraceptive methods among (between) the couple, which are defined as: * For males: condom with spermicidal foam/gel/film/cream, sterilisation (with the appropriate post-vasectomy documentation of the absence of sperm in the ejaculate. This applies only to males participating in the study). * For females: Women no longer of child bearing potential (post-menopausal females are defined as having a history of amenorrhea for at least 2 years, otherwise they should have documented status as being surgically sterile or post hysterectomy. The latter applies only to females participating in the study). If of childbearing potential, then acceptable forms of contraception include: * Established (a minimum of 2 weeks prior to admission) use of oral, injected or implanted hormonal methods of contraception. * Placement of an intrauterine device (IUD) or intrauterine system (IUS). * Barrier methods of contraception or occlusive cap (diaphragm or cervical/vault caps), both with one of the following - spermicidal foam/gel/film/cream/suppository. * The longevity of contraception is as follows: Males: * Comply with agreed contraception at entry to quarantine, and continuing until 90 days after the date of viral challenge/last dosing with IMP (whichever occurs last). * Must not donate sperm following discharge from quarantine until 90 days after the date of viral challenge/last dosing with IMP (whichever occurs last). Females: If of childbearing potential must have a negative pregnancy test at screening and just prior to the date of Viral Challenge, and must be using contraception consisting of two forms of birth control (one of which must be a barrier method) starting from at least 2 weeks prior to the first vaccination and continuing until 90 days after the date of Viral Challenge/last dosing with IMP (whichever occurs last). 4. Willing to have samples stored for future research. 5. Sero-suitable to the study challenge virus within 90 days of Day 0. 6. Agrees to abstain from alcohol intake 24 hours before admission on Day -2 or Day -1 and all other outpatient visits. 7. Agrees to not use prescription or over-the-counter medications (including aspirin, decongestants, antihistamines, and other NSAIDs), and herbal medication (including, but not limited to, Vitamin C, Vitamin D, immune booster products, herbal tea, St. John's Wort), within 14 days prior to study vaccine administration through the final follow-up visit, unless approved by the investigator and sponsor medical monitor. 8. An informed consent document signed and dated by the subject and the Investigator or delegate. 9. A history of childhood asthma before the age of 12 years is acceptable provided the subject is asymptomatic without treatment. Subjects with a single episode of wheezing (lasting less than 2 weeks) after the age of 12 years can be included at the Investigator's discretion provided the episode was more than 1 year ago and did not require a hospital admission and/or oral/intravenous steroids. 10. In good health with no history of major medical conditions that will interfere with subject safety, as defined by medical history, physical examination, and routine laboratory tests and determined by the Investigator at a screening evaluation. * A subject with a history of Herpes type 1 or 2 infection may be included if there are no active lesions present and the subject is not taking active medication. * A subject with or without any evidence of atopy including any history of allergic rhinitis, dermatitis, and conjunctivitis will be included as long as they do not conflict with
Exclusion criteria
. Mild to moderate arthritis of non-inflammatory origin may be allowed if the subject is not at risk from relative immobility in the Quarantine Unit and does not require regular medication. 11. A documented medical history for a minimum of the last 2 years prior to inoculation.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Subjects With Treatment Emergent Adverse Event Classified by Relatedness and Severity. | From the day of the first vaccination up to the end of the study on day +63. | Number of subjects with one or more AE are reported by severity (mild, moderate and severe) and relatedness to vaccine or challenge virus inoculation (definitely, probably, possibly, unlikely, not related). |
| Number of Participants With Mild to Moderate Influenza Disease (MMID) | From 24h post-viral inoculation (Day 1) until the end of the quarantine phase on Day 7 | To determine the effect of FLU-v on reducing the incidence of Mild to Moderate Influenza Disease (MMID) defined as detectable viral shedding by Luminex Respiratory Pathogen Panel Test (RPP) in the presence of at least one influenza symptom. |
| Number of Treatment Emergent Adverse Events (TEAEs) Per Subject. | From the first vaccination on day -43 to the last follow up visit on day 63. | To determine the number of TEAEs that were reported after the first administration of the vaccine until the end of the study (overall) and then separated into pre-inoculation (events reported from the time of first vaccination up to Day 0 prior to time of inoculation) and post-inoculation (Day 0 inoculation time through study completion). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Total Viral Shedding (Area Under the Curve) | from the evening of Day 1 post-inoculation to the morning of Day 7 (last timepoint before expected quarantine discharge) | Shedding is quantified by RT-PCR from nasal swabs taken twice daily (am/pm) during the quarantine period. Plotting the log copy number/ml for each time point against time is done to calculate the area under the curve (AUC) using the trapezoidal rule. |
| Peak Viral Load | from the evening of Day 1 post-inoculation to the morning of Day 7 (last timepoint before expected quarantine discharge) | Shedding is quantified by RT-PCR from nasal swabs taken twice daily (am/pm) during the quarantine period. Peak viral load is the highest recorded log10copy number/ml. |
| Duration of Influenza Symptoms | from the evening of Day 1 post-inoculation to the morning of Day 7 (last timepoint before expected quarantine discharge) | Subjects were assessed by the physician whilst under quarantine post-inoculation. The number of days subjects experienced influenza symptoms was recorded. |
| Peak Number of Symptoms Experienced Per Subject in a Single Day. | from the evening of Day 1 post-inoculation until the day of last symptom noted during the expected quarantine period (up to Day 7). | The highest level of the total sum of all upper and lower respiratory tract and systemic symptoms recorded on any day starting from the evening of Day 1 post-inoculation until the day of last symptom noted during the expected quarantine period (up to Day 7). |
| Assessment of Self-reported Influenza Symptoms by FLU-PRO Questionnaire. | from Day 1 post-inoculation until the day 7. | FLU-PRO assesses 32 influenza symptoms. Subjects rate each symptom on a 5-point ordinal scale, with higher scores indicating a more frequent sign or symptom. For 27 of the items, the scale is as follows: 0 (Not at all), 1 (A little bit), 2 (Somewhat), 3 (Quite a bit), and 4 (Very much). For 5 items, severity is assessed in terms of numerical frequency, i.e., vomiting or diarrhea (0 times, 1 time, 2 times, 3 times, or 4 or more times); with frequency of sneezing, coughing, and coughed up mucus or phlegm evaluated on a scale from 0 (Never) to 4 (Always).The FLU-PRO total score is computed as a mean score across all 32 items comprising the instrument. Total scores can range from 0 (symptom free) to 4 (very severe symptoms). |
| Number of Symptoms Experienced Per Subject Per Day. | from the evening of Day 1 post-inoculation to the morning until the day of last symptom noted during the expected quarantine period (up tp Day 7) | Mean of total number of symptoms (upper and lower respiratory and systemic symptoms) experienced calculated as the total sum of symptoms experienced divided by the number of days in which symptoms were collected. |
| Number of Subjects With Detectable Viral Shedding and Number of Subjects With Recorded Influenza Symptoms During the Quarantine Period. | Quarantine period from day 1 to day 7 post-inoculation. | Number of subjects experiencing at least one influenza symptom and at least two influenza symptoms. Number of subjects with detectable shedding by RPP (Luminex) test from nasal swabs. Number asymptomatic subjects with detectable virus by RPP (Luminex) test from nasal swabs. |
| Viral Shedding Duration | starting from evening of Day 1 post-inoculation up to Day 7. | Number of days with detectable viral shedding measured using the Luminex Respiratory Pathogen Panel test. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Immunogenicity of FLU-v | At pre-inoculation post-vaccination (Day -2), and post-influenza challenge (Day 35/Day 63) | To determine the antibody responses specific to FLU-v. |
Countries
United Kingdom
Participant flow
Pre-assignment details
An excess number of subjects were vaccinated to ensure 123 subjects were able to complete the quarantine period . Any subject that dropped out after vaccination but before inoculation with the challenge virus was replaced with another vaccinated subject.
Participants by arm
| Arm | Count |
|---|---|
| Group 1 Adjuvanted Placebo adjuvanted placebo on Day -43 and on Day -22 followed | 42 |
| Group 2 Adjuvanted FLU-v One Dose 500mcg adjuvanted FLU-v vaccine on Day -43 and adjuvanted placebo on Day -22 | 40 |
| Group 3 Adjuvanted FLU-v Two Doses 500mcg adjuvanted FLU-v vaccine on Day -43 and on Day -22 | 41 |
| Total | 123 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Adverse Event | 1 | 0 | 2 |
| Overall Study | Inoculation Target Reached | 1 | 1 | 3 |
| Overall Study | Lost to Follow-up | 0 | 2 | 3 |
| Overall Study | Non-compliance | 1 | 4 | 0 |
| Overall Study | Physician Decision | 3 | 3 | 1 |
| Overall Study | Withdrawal by Subject | 2 | 2 | 1 |
Baseline characteristics
| Characteristic | Group 1 Adjuvanted Placebo | Group 2 Adjuvanted FLU-v One Dose | Group 3 Adjuvanted FLU-v Two Doses | Total |
|---|---|---|---|---|
| Age, Continuous | 28.8 years STANDARD_DEVIATION 7.5 | 29.9 years STANDARD_DEVIATION 8.9 | 27.4 years STANDARD_DEVIATION 9.2 | 28.7 years STANDARD_DEVIATION 8.6 |
| Number of subjects with challenge strain HAI titers > or = 40 at screening | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Ethnicity Asian/Asian British | 1 Participants | 0 Participants | 1 Participants | 2 Participants |
| Race/Ethnicity, Customized Ethnicity Black/Black British | 3 Participants | 0 Participants | 2 Participants | 5 Participants |
| Race/Ethnicity, Customized Ethnicity Chinese | 0 Participants | 1 Participants | 0 Participants | 1 Participants |
| Race/Ethnicity, Customized Ethnicity Hispanic | 0 Participants | 1 Participants | 0 Participants | 1 Participants |
| Race/Ethnicity, Customized Ethnicity Japanese | 1 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race/Ethnicity, Customized Ethnicity Mixed | 4 Participants | 0 Participants | 3 Participants | 7 Participants |
| Race/Ethnicity, Customized Ethnicity Other | 0 Participants | 1 Participants | 1 Participants | 2 Participants |
| Race/Ethnicity, Customized Ethnicity White | 33 Participants | 37 Participants | 34 Participants | 104 Participants |
| Region of Enrollment United Kingdom | 42 participants | 40 participants | 41 participants | 123 participants |
| Sex: Female, Male Female | 13 Participants | 12 Participants | 11 Participants | 36 Participants |
| Sex: Female, Male Male | 29 Participants | 28 Participants | 30 Participants | 87 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 50 | 0 / 52 | 0 / 51 |
| other Total, other adverse events | 27 / 50 | 33 / 52 | 45 / 51 |
| serious Total, serious adverse events | 0 / 50 | 0 / 52 | 0 / 51 |
Outcome results
Primary
Number of Participants With Mild to Moderate Influenza Disease (MMID)
To determine the effect of FLU-v on reducing the incidence of Mild to Moderate Influenza Disease (MMID) defined as detectable viral shedding by Luminex Respiratory Pathogen Panel Test (RPP) in the presence of at least one influenza symptom.
Time frame: From 24h post-viral inoculation (Day 1) until the end of the quarantine phase on Day 7
Population: ITT includes those participants who received both vaccination and were challenged with the H1N1 influenza virus
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Group 1 Adjuvanted Placebo | Number of Participants With Mild to Moderate Influenza Disease (MMID) | positive MMID | 23 Participants |
| Group 1 Adjuvanted Placebo | Number of Participants With Mild to Moderate Influenza Disease (MMID) | Negative MMID | 19 Participants |
| Group 2 Adjuvanted FLU-v One Dose | Number of Participants With Mild to Moderate Influenza Disease (MMID) | positive MMID | 13 Participants |
| Group 2 Adjuvanted FLU-v One Dose | Number of Participants With Mild to Moderate Influenza Disease (MMID) | Negative MMID | 27 Participants |
| Group 3 Adjuvanted FLU-v Two Doses | Number of Participants With Mild to Moderate Influenza Disease (MMID) | positive MMID | 15 Participants |
| Group 3 Adjuvanted FLU-v Two Doses | Number of Participants With Mild to Moderate Influenza Disease (MMID) | Negative MMID | 26 Participants |
Comparison: One-sided Fisher exact test is used to test if vaccine group has lower MMID rate than placebo.p-value: 0.03Fisher Exact
Comparison: One-sided Fisher exact test is used to test if vaccine group has lower MMID rate than placebo.p-value: 0.07Fisher Exact
Primary
Number of Subjects With Treatment Emergent Adverse Event Classified by Relatedness and Severity.
Number of subjects with one or more AE are reported by severity (mild, moderate and severe) and relatedness to vaccine or challenge virus inoculation (definitely, probably, possibly, unlikely, not related).
Time frame: From the day of the first vaccination up to the end of the study on day +63.
Population: Safety population
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Group 1 Adjuvanted Placebo | Number of Subjects With Treatment Emergent Adverse Event Classified by Relatedness and Severity. | Subjects with mild TEAEs | 37 Number of participants |
| Group 1 Adjuvanted Placebo | Number of Subjects With Treatment Emergent Adverse Event Classified by Relatedness and Severity. | Subjects with TEAEs definately related to virus | 1 Number of participants |
| Group 1 Adjuvanted Placebo | Number of Subjects With Treatment Emergent Adverse Event Classified by Relatedness and Severity. | Subjects with TEAEs possibly related to vaccine | 3 Number of participants |
| Group 1 Adjuvanted Placebo | Number of Subjects With Treatment Emergent Adverse Event Classified by Relatedness and Severity. | Subjects with TEAEs not related to virus | 37 Number of participants |
| Group 1 Adjuvanted Placebo | Number of Subjects With Treatment Emergent Adverse Event Classified by Relatedness and Severity. | Subjects with TEAEs probably related to virus | 3 Number of participants |
| Group 1 Adjuvanted Placebo | Number of Subjects With Treatment Emergent Adverse Event Classified by Relatedness and Severity. | Subjects withTEAEs probably related to vaccine | 1 Number of participants |
| Group 1 Adjuvanted Placebo | Number of Subjects With Treatment Emergent Adverse Event Classified by Relatedness and Severity. | Subjects with TEAEs unlikely related to virus | 7 Number of participants |
| Group 1 Adjuvanted Placebo | Number of Subjects With Treatment Emergent Adverse Event Classified by Relatedness and Severity. | Subjects with TEAEs possibly related to virus | 4 Number of participants |
| Group 1 Adjuvanted Placebo | Number of Subjects With Treatment Emergent Adverse Event Classified by Relatedness and Severity. | Subjects with moderate TEAEs | 13 Number of participants |
| Group 1 Adjuvanted Placebo | Number of Subjects With Treatment Emergent Adverse Event Classified by Relatedness and Severity. | Subjects with TEAEs unlikely related to vaccine | 11 Number of participants |
| Group 1 Adjuvanted Placebo | Number of Subjects With Treatment Emergent Adverse Event Classified by Relatedness and Severity. | Subjects with Serious Adverse Events (SAEs) | 0 Number of participants |
| Group 1 Adjuvanted Placebo | Number of Subjects With Treatment Emergent Adverse Event Classified by Relatedness and Severity. | Subjects with TEAEs definately related to vaccine | 7 Number of participants |
| Group 1 Adjuvanted Placebo | Number of Subjects With Treatment Emergent Adverse Event Classified by Relatedness and Severity. | Subjects with TEAEs not related to vaccine | 37 Number of participants |
| Group 1 Adjuvanted Placebo | Number of Subjects With Treatment Emergent Adverse Event Classified by Relatedness and Severity. | Subjects with Severe TEAEs | 0 Number of participants |
| Group 2 Adjuvanted FLU-v One Dose | Number of Subjects With Treatment Emergent Adverse Event Classified by Relatedness and Severity. | Subjects with mild TEAEs | 33 Number of participants |
| Group 2 Adjuvanted FLU-v One Dose | Number of Subjects With Treatment Emergent Adverse Event Classified by Relatedness and Severity. | Subjects with TEAEs definately related to vaccine | 24 Number of participants |
| Group 2 Adjuvanted FLU-v One Dose | Number of Subjects With Treatment Emergent Adverse Event Classified by Relatedness and Severity. | Subjects withTEAEs probably related to vaccine | 0 Number of participants |
| Group 2 Adjuvanted FLU-v One Dose | Number of Subjects With Treatment Emergent Adverse Event Classified by Relatedness and Severity. | Subjects with TEAEs possibly related to vaccine | 2 Number of participants |
| Group 2 Adjuvanted FLU-v One Dose | Number of Subjects With Treatment Emergent Adverse Event Classified by Relatedness and Severity. | Subjects with TEAEs unlikely related to vaccine | 4 Number of participants |
| Group 2 Adjuvanted FLU-v One Dose | Number of Subjects With Treatment Emergent Adverse Event Classified by Relatedness and Severity. | Subjects with TEAEs not related to vaccine | 21 Number of participants |
| Group 2 Adjuvanted FLU-v One Dose | Number of Subjects With Treatment Emergent Adverse Event Classified by Relatedness and Severity. | Subjects with TEAEs definately related to virus | 0 Number of participants |
| Group 2 Adjuvanted FLU-v One Dose | Number of Subjects With Treatment Emergent Adverse Event Classified by Relatedness and Severity. | Subjects with TEAEs probably related to virus | 1 Number of participants |
| Group 2 Adjuvanted FLU-v One Dose | Number of Subjects With Treatment Emergent Adverse Event Classified by Relatedness and Severity. | Subjects with TEAEs possibly related to virus | 3 Number of participants |
| Group 2 Adjuvanted FLU-v One Dose | Number of Subjects With Treatment Emergent Adverse Event Classified by Relatedness and Severity. | Subjects with TEAEs unlikely related to virus | 0 Number of participants |
| Group 2 Adjuvanted FLU-v One Dose | Number of Subjects With Treatment Emergent Adverse Event Classified by Relatedness and Severity. | Subjects with TEAEs not related to virus | 32 Number of participants |
| Group 2 Adjuvanted FLU-v One Dose | Number of Subjects With Treatment Emergent Adverse Event Classified by Relatedness and Severity. | Subjects with moderate TEAEs | 4 Number of participants |
| Group 2 Adjuvanted FLU-v One Dose | Number of Subjects With Treatment Emergent Adverse Event Classified by Relatedness and Severity. | Subjects with Severe TEAEs | 1 Number of participants |
| Group 2 Adjuvanted FLU-v One Dose | Number of Subjects With Treatment Emergent Adverse Event Classified by Relatedness and Severity. | Subjects with Serious Adverse Events (SAEs) | 0 Number of participants |
| Group 3 Adjuvanted FLU-v Two Doses | Number of Subjects With Treatment Emergent Adverse Event Classified by Relatedness and Severity. | Subjects with Severe TEAEs | 3 Number of participants |
| Group 3 Adjuvanted FLU-v Two Doses | Number of Subjects With Treatment Emergent Adverse Event Classified by Relatedness and Severity. | Subjects with TEAEs not related to virus | 44 Number of participants |
| Group 3 Adjuvanted FLU-v Two Doses | Number of Subjects With Treatment Emergent Adverse Event Classified by Relatedness and Severity. | Subjects with TEAEs not related to vaccine | 34 Number of participants |
| Group 3 Adjuvanted FLU-v Two Doses | Number of Subjects With Treatment Emergent Adverse Event Classified by Relatedness and Severity. | Subjects with TEAEs unlikely related to vaccine | 9 Number of participants |
| Group 3 Adjuvanted FLU-v Two Doses | Number of Subjects With Treatment Emergent Adverse Event Classified by Relatedness and Severity. | Subjects with mild TEAEs | 42 Number of participants |
| Group 3 Adjuvanted FLU-v Two Doses | Number of Subjects With Treatment Emergent Adverse Event Classified by Relatedness and Severity. | Subjects with TEAEs possibly related to vaccine | 3 Number of participants |
| Group 3 Adjuvanted FLU-v Two Doses | Number of Subjects With Treatment Emergent Adverse Event Classified by Relatedness and Severity. | Subjects with TEAEs definately related to vaccine | 29 Number of participants |
| Group 3 Adjuvanted FLU-v Two Doses | Number of Subjects With Treatment Emergent Adverse Event Classified by Relatedness and Severity. | Subjects with moderate TEAEs | 11 Number of participants |
| Group 3 Adjuvanted FLU-v Two Doses | Number of Subjects With Treatment Emergent Adverse Event Classified by Relatedness and Severity. | Subjects withTEAEs probably related to vaccine | 6 Number of participants |
| Group 3 Adjuvanted FLU-v Two Doses | Number of Subjects With Treatment Emergent Adverse Event Classified by Relatedness and Severity. | Subjects with TEAEs possibly related to virus | 6 Number of participants |
| Group 3 Adjuvanted FLU-v Two Doses | Number of Subjects With Treatment Emergent Adverse Event Classified by Relatedness and Severity. | Subjects with TEAEs probably related to virus | 1 Number of participants |
| Group 3 Adjuvanted FLU-v Two Doses | Number of Subjects With Treatment Emergent Adverse Event Classified by Relatedness and Severity. | Subjects with Serious Adverse Events (SAEs) | 0 Number of participants |
| Group 3 Adjuvanted FLU-v Two Doses | Number of Subjects With Treatment Emergent Adverse Event Classified by Relatedness and Severity. | Subjects with TEAEs unlikely related to virus | 6 Number of participants |
| Group 3 Adjuvanted FLU-v Two Doses | Number of Subjects With Treatment Emergent Adverse Event Classified by Relatedness and Severity. | Subjects with TEAEs definately related to virus | 0 Number of participants |
Primary
Number of Treatment Emergent Adverse Events (TEAEs) Per Subject.
To determine the number of TEAEs that were reported after the first administration of the vaccine until the end of the study (overall) and then separated into pre-inoculation (events reported from the time of first vaccination up to Day 0 prior to time of inoculation) and post-inoculation (Day 0 inoculation time through study completion).
Time frame: From the first vaccination on day -43 to the last follow up visit on day 63.
Population: Safety population
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Group 1 Adjuvanted Placebo | Number of Treatment Emergent Adverse Events (TEAEs) Per Subject. | Pre-inoculation | 1.00 Number of TEAEs per subject | Standard Error 0.21 |
| Group 1 Adjuvanted Placebo | Number of Treatment Emergent Adverse Events (TEAEs) Per Subject. | Overall | 1.86 Number of TEAEs per subject | Standard Error 0.26 |
| Group 1 Adjuvanted Placebo | Number of Treatment Emergent Adverse Events (TEAEs) Per Subject. | Post-Inoculation | 0.86 Number of TEAEs per subject | Standard Error 0.16 |
| Group 2 Adjuvanted FLU-v One Dose | Number of Treatment Emergent Adverse Events (TEAEs) Per Subject. | Pre-inoculation | 0.81 Number of TEAEs per subject | Standard Error 0.13 |
| Group 2 Adjuvanted FLU-v One Dose | Number of Treatment Emergent Adverse Events (TEAEs) Per Subject. | Overall | 1.38 Number of TEAEs per subject | Standard Error 0.24 |
| Group 2 Adjuvanted FLU-v One Dose | Number of Treatment Emergent Adverse Events (TEAEs) Per Subject. | Post-Inoculation | 0.58 Number of TEAEs per subject | Standard Error 0.15 |
| Group 3 Adjuvanted FLU-v Two Doses | Number of Treatment Emergent Adverse Events (TEAEs) Per Subject. | Overall | 2.35 Number of TEAEs per subject | Standard Error 0.27 |
| Group 3 Adjuvanted FLU-v Two Doses | Number of Treatment Emergent Adverse Events (TEAEs) Per Subject. | Post-Inoculation | 0.84 Number of TEAEs per subject | Standard Error 0.16 |
| Group 3 Adjuvanted FLU-v Two Doses | Number of Treatment Emergent Adverse Events (TEAEs) Per Subject. | Pre-inoculation | 1.51 Number of TEAEs per subject | Standard Error 0.19 |
Comparison: One sided Fisher's exact test is used to test if the TEAE rates pre-inoculation recorded for the treatment group are higher than for placebo.p-value: 0.647Fisher Exact
Comparison: One-sided Fisher's exact test is used to test if TEAE rate of vaccine group recorded pre-inoculation is higher than placebo.p-value: 1Fisher Exact
Comparison: One sided Fisher's exact test is used to test if TEAE rate of vaccine group post-inoculation is higher than the placebo group.p-value: 0.024Fisher Exact
Comparison: One sided Fisher's exact test is used to test if TEAE rate of vaccine group post-inoculation is higher than the placebo group.p-value: 0.186Fisher Exact
Secondary
Assessment of Self-reported Influenza Symptoms by FLU-PRO Questionnaire.
FLU-PRO assesses 32 influenza symptoms. Subjects rate each symptom on a 5-point ordinal scale, with higher scores indicating a more frequent sign or symptom. For 27 of the items, the scale is as follows: 0 (Not at all), 1 (A little bit), 2 (Somewhat), 3 (Quite a bit), and 4 (Very much). For 5 items, severity is assessed in terms of numerical frequency, i.e., vomiting or diarrhea (0 times, 1 time, 2 times, 3 times, or 4 or more times); with frequency of sneezing, coughing, and coughed up mucus or phlegm evaluated on a scale from 0 (Never) to 4 (Always).The FLU-PRO total score is computed as a mean score across all 32 items comprising the instrument. Total scores can range from 0 (symptom free) to 4 (very severe symptoms).
Time frame: from Day 1 post-inoculation until the day 7.
Population: ITT
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Group 1 Adjuvanted Placebo | Assessment of Self-reported Influenza Symptoms by FLU-PRO Questionnaire. | 0.05 FLU-PRO total score | Standard Error 0.01 |
| Group 2 Adjuvanted FLU-v One Dose | Assessment of Self-reported Influenza Symptoms by FLU-PRO Questionnaire. | 0.03 FLU-PRO total score | Standard Error 0.01 |
| Group 3 Adjuvanted FLU-v Two Doses | Assessment of Self-reported Influenza Symptoms by FLU-PRO Questionnaire. | 0.04 FLU-PRO total score | Standard Error 0.01 |
Comparison: One-sided Wilcoxon test is used to test if vaccine group has lower FLU-PRO scores than placebo.p-value: 0.064Wilcoxon (Mann-Whitney)
Comparison: One-sided Wilcoxon test is used to test if vaccine group has lower FLU-PRO scores than placebo.p-value: 0.201Wilcoxon (Mann-Whitney)
Secondary
Duration of Influenza Symptoms
Subjects were assessed by the physician whilst under quarantine post-inoculation. The number of days subjects experienced influenza symptoms was recorded.
Time frame: from the evening of Day 1 post-inoculation to the morning of Day 7 (last timepoint before expected quarantine discharge)
Population: ITT
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Group 1 Adjuvanted Placebo | Duration of Influenza Symptoms | 3.26 days | Standard Error 0.37 |
| Group 2 Adjuvanted FLU-v One Dose | Duration of Influenza Symptoms | 2.67 days | Standard Error 0.35 |
| Group 3 Adjuvanted FLU-v Two Doses | Duration of Influenza Symptoms | 2.76 days | Standard Error 0.37 |
Comparison: One-sided Wilcoxon test is used to test if vaccine group has shorter duration of symptoms than placebo.p-value: 0.142Wilcoxon (Mann-Whitney)
Comparison: One-sided Wilcoxon test is used to test if vaccine group has shorter duration of symptoms than placebo.p-value: 0.147Wilcoxon (Mann-Whitney)
Secondary
Number of Subjects With Detectable Viral Shedding and Number of Subjects With Recorded Influenza Symptoms During the Quarantine Period.
Number of subjects experiencing at least one influenza symptom and at least two influenza symptoms. Number of subjects with detectable shedding by RPP (Luminex) test from nasal swabs. Number asymptomatic subjects with detectable virus by RPP (Luminex) test from nasal swabs.
Time frame: Quarantine period from day 1 to day 7 post-inoculation.
Population: ITT
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Group 1 Adjuvanted Placebo | Number of Subjects With Detectable Viral Shedding and Number of Subjects With Recorded Influenza Symptoms During the Quarantine Period. | Subjects with at least one symptom | 37 Participants |
| Group 1 Adjuvanted Placebo | Number of Subjects With Detectable Viral Shedding and Number of Subjects With Recorded Influenza Symptoms During the Quarantine Period. | Subjects with at least two symptoms | 27 Participants |
| Group 1 Adjuvanted Placebo | Number of Subjects With Detectable Viral Shedding and Number of Subjects With Recorded Influenza Symptoms During the Quarantine Period. | Subjects with detectable shedding | 23 Participants |
| Group 1 Adjuvanted Placebo | Number of Subjects With Detectable Viral Shedding and Number of Subjects With Recorded Influenza Symptoms During the Quarantine Period. | Asymptomatic subjects with detectable shedding | 0 Participants |
| Group 2 Adjuvanted FLU-v One Dose | Number of Subjects With Detectable Viral Shedding and Number of Subjects With Recorded Influenza Symptoms During the Quarantine Period. | Asymptomatic subjects with detectable shedding | 2 Participants |
| Group 2 Adjuvanted FLU-v One Dose | Number of Subjects With Detectable Viral Shedding and Number of Subjects With Recorded Influenza Symptoms During the Quarantine Period. | Subjects with at least one symptom | 34 Participants |
| Group 2 Adjuvanted FLU-v One Dose | Number of Subjects With Detectable Viral Shedding and Number of Subjects With Recorded Influenza Symptoms During the Quarantine Period. | Subjects with detectable shedding | 15 Participants |
| Group 2 Adjuvanted FLU-v One Dose | Number of Subjects With Detectable Viral Shedding and Number of Subjects With Recorded Influenza Symptoms During the Quarantine Period. | Subjects with at least two symptoms | 16 Participants |
| Group 3 Adjuvanted FLU-v Two Doses | Number of Subjects With Detectable Viral Shedding and Number of Subjects With Recorded Influenza Symptoms During the Quarantine Period. | Asymptomatic subjects with detectable shedding | 3 Participants |
| Group 3 Adjuvanted FLU-v Two Doses | Number of Subjects With Detectable Viral Shedding and Number of Subjects With Recorded Influenza Symptoms During the Quarantine Period. | Subjects with at least two symptoms | 23 Participants |
| Group 3 Adjuvanted FLU-v Two Doses | Number of Subjects With Detectable Viral Shedding and Number of Subjects With Recorded Influenza Symptoms During the Quarantine Period. | Subjects with detectable shedding | 18 Participants |
| Group 3 Adjuvanted FLU-v Two Doses | Number of Subjects With Detectable Viral Shedding and Number of Subjects With Recorded Influenza Symptoms During the Quarantine Period. | Subjects with at least one symptom | 30 Participants |
Comparison: One-sided Fisher exact test is used to test if vaccine group has lower rate of subjects experiencing at least one symptomp-value: 0.465Fisher Exact
Comparison: One-sided Fisher exact test is used to test if vaccine group has lower rate of subjects experiencing at least one symptomp-value: 0.074Fisher Exact
Comparison: One-sided Fisher exact test is used to test if vaccine group has lower rate of subjects experiencing at least two symptomsp-value: 0.024Fisher Exact
Comparison: One-sided Fisher exact test is used to test if vaccine group has lower rate of subjects experiencing at least two symptoms.p-value: 0.23Fisher Exact
Comparison: One-sided Fisher exact test is used to test if vaccine group has lower rate of subjects with detectable virus sheddingp-value: 0.09Fisher Exact
Comparison: One-sided Fisher exact test is used to test if vaccine group has lower rate of subjects with detectable virus sheddingp-value: 0.22Fisher Exact
Comparison: One-sided Fisher exact test is used to test if vaccine group has lower rate of subjects asymptomatic with detectable virus sheddingp-value: 0.23Fisher Exact
Comparison: One-sided Fisher exact test is used to test if vaccine group has lower rate of subjects asymptomatic with detectable virus sheddingp-value: 0.12Fisher Exact
Secondary
Number of Symptoms Experienced Per Subject Per Day.
Mean of total number of symptoms (upper and lower respiratory and systemic symptoms) experienced calculated as the total sum of symptoms experienced divided by the number of days in which symptoms were collected.
Time frame: from the evening of Day 1 post-inoculation to the morning until the day of last symptom noted during the expected quarantine period (up tp Day 7)
Population: ITT
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Group 1 Adjuvanted Placebo | Number of Symptoms Experienced Per Subject Per Day. | 2.57 number of symptoms per day | Standard Error 0.33 |
| Group 2 Adjuvanted FLU-v One Dose | Number of Symptoms Experienced Per Subject Per Day. | 2.08 number of symptoms per day | Standard Error 0.32 |
| Group 3 Adjuvanted FLU-v Two Doses | Number of Symptoms Experienced Per Subject Per Day. | 2.51 number of symptoms per day | Standard Error 0.41 |
Comparison: One-sided Wilcoxon test is used to test if vaccine group has fewer average number of symptoms than placebo.p-value: 0.08Wilcoxon (Mann-Whitney)
Comparison: One-sided Wilcoxon test is used to test if vaccine group has fewer average number of symptoms than placebo.p-value: 0.271Wilcoxon (Mann-Whitney)
Secondary
Peak Number of Symptoms Experienced Per Subject in a Single Day.
The highest level of the total sum of all upper and lower respiratory tract and systemic symptoms recorded on any day starting from the evening of Day 1 post-inoculation until the day of last symptom noted during the expected quarantine period (up to Day 7).
Time frame: from the evening of Day 1 post-inoculation until the day of last symptom noted during the expected quarantine period (up to Day 7).
Population: ITT
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Group 1 Adjuvanted Placebo | Peak Number of Symptoms Experienced Per Subject in a Single Day. | 2.12 number of symptoms | Standard Error 0.26 |
| Group 2 Adjuvanted FLU-v One Dose | Peak Number of Symptoms Experienced Per Subject in a Single Day. | 1.68 number of symptoms | Standard Error 0.22 |
| Group 3 Adjuvanted FLU-v Two Doses | Peak Number of Symptoms Experienced Per Subject in a Single Day. | 1.88 number of symptoms | Standard Error 0.28 |
Comparison: One-sided Wilcoxon test is used to test if vaccine group has fewer peak symptoms than placebo.p-value: 0.099Wilcoxon (Mann-Whitney)
Comparison: One-sided Wilcoxon test is used to test if vaccine group has fewer peak symptoms than placebo.p-value: 0.178Wilcoxon (Mann-Whitney)
Secondary
Peak Viral Load
Shedding is quantified by RT-PCR from nasal swabs taken twice daily (am/pm) during the quarantine period. Peak viral load is the highest recorded log10copy number/ml.
Time frame: from the evening of Day 1 post-inoculation to the morning of Day 7 (last timepoint before expected quarantine discharge)
Population: ITT
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Group 1 Adjuvanted Placebo | Peak Viral Load | 2.24 log10copy number/ml | Standard Error 0.4 |
| Group 2 Adjuvanted FLU-v One Dose | Peak Viral Load | 1.54 log10copy number/ml | Standard Error 0.39 |
| Group 3 Adjuvanted FLU-v Two Doses | Peak Viral Load | 2.28 log10copy number/ml | Standard Error 0.42 |
Comparison: One-sided Wilcoxon test is used to test if vaccine group has lower peak viral shedding than placebo.p-value: 0.128Wilcoxon (Mann-Whitney)
Comparison: One-sided Wilcoxon test is used to test if vaccine group has lower peak viral shedding than placebo.p-value: 0.601Wilcoxon (Mann-Whitney)
Secondary
Total Viral Shedding (Area Under the Curve)
Shedding is quantified by RT-PCR from nasal swabs taken twice daily (am/pm) during the quarantine period. Plotting the log copy number/ml for each time point against time is done to calculate the area under the curve (AUC) using the trapezoidal rule.
Time frame: from the evening of Day 1 post-inoculation to the morning of Day 7 (last timepoint before expected quarantine discharge)
Population: ITT
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Group 1 Adjuvanted Placebo | Total Viral Shedding (Area Under the Curve) | 153.67 hours*log10copy number/ml | Standard Error 33.39 |
| Group 2 Adjuvanted FLU-v One Dose | Total Viral Shedding (Area Under the Curve) | 98.47 hours*log10copy number/ml | Standard Error 27.39 |
| Group 3 Adjuvanted FLU-v Two Doses | Total Viral Shedding (Area Under the Curve) | 138.79 hours*log10copy number/ml | Standard Error 31.73 |
Comparison: One-sided Wilcoxon test is used to test if vaccine group has smaller shedding AUC than placebo.p-value: 0.102Wilcoxon (Mann-Whitney)
Comparison: One-sided Wilcoxon test is used to test if vaccine group has a smaller shedding AUC than placebo.p-value: 0.481Wilcoxon (Mann-Whitney)
Secondary
Viral Shedding Duration
Number of days with detectable viral shedding measured using the Luminex Respiratory Pathogen Panel test.
Time frame: starting from evening of Day 1 post-inoculation up to Day 7.
Population: ITT
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Group 1 Adjuvanted Placebo | Viral Shedding Duration | 1.95 days | Standard Error 0.36 |
| Group 2 Adjuvanted FLU-v One Dose | Viral Shedding Duration | 1.20 days | Standard Error 0.31 |
| Group 3 Adjuvanted FLU-v Two Doses | Viral Shedding Duration | 1.90 days | Standard Error 0.39 |
Comparison: One-sided Wilcoxon test is used to test if vaccine group has shorter shedding duration than placebo.p-value: 0.0501Wilcoxon (Mann-Whitney)
Comparison: One-sided Wilcoxon test is used to test if vaccine group has shorter shedding duration than placebo.p-value: 0.3139Wilcoxon (Mann-Whitney)
Other Pre-specified
Immunogenicity of FLU-v
To determine the antibody responses specific to FLU-v.
Time frame: At pre-inoculation post-vaccination (Day -2), and post-influenza challenge (Day 35/Day 63)
Population: Subjects that received vaccination, underwent influenza challenge and provided serum samples.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Group 1 Adjuvanted Placebo | Immunogenicity of FLU-v | Day 63 | 6.26 ng/ml | Standard Error 1.06 |
| Group 1 Adjuvanted Placebo | Immunogenicity of FLU-v | Day 35 | 6.09 ng/ml | Standard Error 0.93 |
| Group 1 Adjuvanted Placebo | Immunogenicity of FLU-v | Day -2 | 5.94 ng/ml | Standard Error 0.99 |
| Group 2 Adjuvanted FLU-v One Dose | Immunogenicity of FLU-v | Day 63 | 60.33 ng/ml | Standard Error 5.81 |
| Group 2 Adjuvanted FLU-v One Dose | Immunogenicity of FLU-v | Day -2 | 72.17 ng/ml | Standard Error 6.28 |
| Group 2 Adjuvanted FLU-v One Dose | Immunogenicity of FLU-v | Day 35 | 66.86 ng/ml | Standard Error 6.07 |
| Group 3 Adjuvanted FLU-v Two Doses | Immunogenicity of FLU-v | Day 35 | 73.55 ng/ml | Standard Error 5.69 |
| Group 3 Adjuvanted FLU-v Two Doses | Immunogenicity of FLU-v | Day -2 | 75.74 ng/ml | Standard Error 5.5 |
| Group 3 Adjuvanted FLU-v Two Doses | Immunogenicity of FLU-v | Day 63 | 67.90 ng/ml | Standard Error 5.35 |
Comparison: comparison on day -2p-value: <0.001t-test, 2 sided
Comparison: Comparion on day -2p-value: <0.001t-test, 2 sided
Comparison: Comparison on day 35p-value: <0.001t-test, 2 sided
Comparison: Comparison on day 35p-value: <0.001t-test, 2 sided
Comparison: Comparison on day 63p-value: <0.001t-test, 2 sided
Comparison: Comparison on day 63p-value: <0.001t-test, 2 sided