Efficacy of Candidate Influenza Vaccine MVA-NP+M1 in Adults

Study Overview
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Brief Summary
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A Phase 2b Study to Determine the Efficacy of Candidate Influenza Vaccine MVA-NP+M1 in Adults aged 18 years and over. To assess the effect of MVA-NP+M1 on the reduction of laboratory confirmed influenza when given as an adjunct to licensed quadrivalent influenza vaccine (QIV) in adults

Detailed Description
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This is a Phase 2b, multicentre, randomised, single-blind study in up to 6000 adults to compare the efficacy, safety and immunogenicity of MVA-NP+M1 when given as an adjunct to a standard, licensed adult dose of QIV. The study will be conducted on an outpatient basis and will run over two consecutive influenza seasons. It is aimed to recruit 2200 participants in Season 1 and 2800-3800 participants in Season 2.

Official Title
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A Phase 2b Study to Determine the Efficacy of Candidate Influenza Vaccine MVA-NP+M1 in Adults Aged 18 Years and Over

Conditions
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Influenza

Intervention / Treatment
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* Biological: MVA-NP+M1
* Drug: Saline


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Healthy male or female adults aged 18 years and over Receipt of a standard-dose licensed influenza QIV vaccine on the day of, or within 28 days prior to, randomisation A female participant is eligible for this study if she is not pregnant or breast feeding and one of the following: Of non-childbearing potential (i.e. women who have had a hysterectomy or tubal ligation or are postmenopausal, as defined by no menses in greater than or equal to 1 year) Of childbearing potential but agrees to practice effective contraception 8 weeks post-vaccination and has a negative urine pregnancy test pre-vaccination. Acceptable methods of contraception include one or more of the following: i. Male partner who is sterile prior to the female participant's entry into the study and is the sole sexual partner for the female participant ii. Implants of levonorgestrel iii. Injectable progestogen iv. An intrauterine device with a documented failure rate of <1% v. Oral contraceptives vi. Double barrier methods including diaphragm or condom vii. Abstinence as long as it is line with the usual and preferred lifestyle of the participant Participant is willing and has capacity to provide written informed consent for participation in the study (in the Investigator's opinion) Able and willing (in the Investigator's opinion) to comply with all study requirements Willing to allow the Investigators to discuss the participant's medical history with their healthcare provider Present and able to visit the clinic in the event of an ILI episode during the influenza season Exclusion Criteria: Any other significant disease, disorder or finding (including blood test results), which, in the opinion of the Investigator, would either put the participant at risk because of participation in the study, or may influence the result of the study Receipt of any investigational product within 6 months prior to study, or prior participation in a clinical study of any Influenza vaccine and agreement not to participate in another clinical study for the duration of study follow-up Prior receipt of an investigational vaccine likely to impact on interpretation of the study data Active infection with HIV, Hepatitis B or Hepatitis C (from patient history or medical records) History of severe allergic reactions (e.g. anaphylaxis) History of auto-immune disease e.g. Guillain-Barré syndrome Not willing to comply with study procedures Immunosuppressed or taking immunosuppressive medications Use of warfarin or other blood thinning medications (aspirin is acceptable) Tattoos or birthmarks at the vaccination site Participant bruises easily, has haematoma or keloid scarring Receipt of a licenced inactivated vaccine (e.g. pneumococcal vaccine) within 2 weeks prior to vaccination Receipt of an off licensed live vaccine (e.g. herpes zoster vaccine) within 4 weeks prior to vaccination

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: MVA-NP+M1<br>Vaccination administered: MVA-NP+M1 (IM injection, 0.5 ml, 1.5 x10^8 pfu.) | Biological: MVA-NP+M1<br>* Trial Vaccine<br>|
| Placebo Comparator: Saline Placebo<br>Vaccination administered: Sodium Chloride (IM injection, 0.5 ml, 0.9%) | Drug: Saline<br>* Sodium Chloride Placebo<br>* Other names: Placebo;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number and Percentage of Participants With Laboratory Confirmed Influenza Using Reverse Transcription Polymerase Chain Reaction (RT-PCR). | The measure used reverse transcription polymerase chain reaction (RT-PCR) on deep nasal/mid-turbinate swab samples to record confirmed cases of influenza. If influenza symptoms are experienced at any time during the Follow Up period, after the vaccination, participants will attend the clinic on two occasions, the first as soon as possible and at least within 72 hours of the onset of symptoms for deep nasal swabs to be taken. Both swabs must be taken within 96 hours of symptom onset. The incidence rate of laboratory confirmed influenza using RT-PCR will be estimated for each vaccine group. The 95% CI for the incidence rate will be estimated by mid-p exact method. The difference in incidence rate between vaccine groups will be compared by Fisher's exact method. | 210 days (during the influenza season, starting on 01 May 2019 and ending on or before 15 October 2019) in line with official Australian influenza season. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number and Percentage of Participants With Influenza-like Illness (ILI) as Derived From Daily ILI eDiary | ILI is defined as feeling feverish or having a fever (feeling feverish or having a fever (≥37.8Celsius)) and at least one of the following symptoms: cough, sore throat. The incidence rate of ILI by the participant completing of eDiaries will be estimated for each vaccine group. The 95% CI for the incidence will be estimated by mid-p exact method. The difference in incidence between groups will be compared by Fisher's exact method. | 210 days (during the influenza season, starting on 01 May 2019 and ending on or before 15 October 2019) | 
| Number and Percentage of Participants With Solicited Local and Systemic Reactogenicity Signs and Symptoms for 7 Days Following Vaccination (and Occurrence of Serious Adverse Events SAEs) | The solicited adverse events are commonly observed soon after receipt of vaccines and relate to local and systemic signs and symptoms. The solicited local injection site reactions (ISR) include pain, induration, warmth, and erythema (redness). The solicited systemic reactions include feverishness, chills, myalgia, fatigue, headache, nausea, arthralgia, and malaise. Participants completed eDiaries post vaccination to record ISR and systemic reactogenicity over the first 7 days post-vaccination (and the ongoing (S)AEs throughout the study). The participant reporting of all ISR categories and solicited systemic reactions was compared between the MVA-NP+M1 treated group and the Placebo treated group. Diary reported ISRs and solicited systemic reactions were summarized, by vaccination group, using descriptive statistics. | 7 days to a total of 210 days for SAEs (over the duration of the influenza season, between 01 May and 15 October) | 
| Number of Participants With Immunogenic Response (Immunogenicity of MVA-NP+M1 in Adjunction With Licensed QIV as Assessed Via Titres of Influenza-specific Neutralizing Antibodies) | The numbers of Immunogenic Participants (participants with positive immune response as assessed at Day 28 and week 26 in relation to the baseline day 0 Immunogenicity) were summarized and listed. The immunogenicity here was assessed as the geometric mean titers of influenza-specific neutralizing antibodies at different timepoints in relation to the baseline, against the antigens included in the licensed QIV(Influenza A/H3N2 (HI), Influenza A/H3N2 (MN), Influenza A/H3N2 (H1N1pdm), Influenza B/Victoria, and Influenza B/Yamagata). The neutralizing antibody assays included microneutralisation and hemagglutination inhibition titers using standard methodologies for the four strains that were in the licensed vaccine. The immunogenicity analyses were conducted only on the Immunology Analysis Set of Participants. | Day 28 and Week 26 | 
| Duration of Influenza-like Illness (ILI) as Derived From Daily ILI eDiary | The duration of ILI is defined as the duration (days) from the first day ILI criteria met (as defined at the Secondary Outcome Measure 2) until the first day afterwards ILI criteria not met (event, ILI recovery). ILI positive participants with ILI criteria met throughout the entire influenza season were censored at the last day recorded with the ILI dairy. Survival analysis was used for the analysis of duration of ILI. The survival function for the duration of ILI was estimated by the Kaplan-Meier method. | 210 days (during the influenza season, starting on 01 May 2019 and ending on or before 15 October 2019) | 
| Severity of Influenza-like Illness (ILI) Derived From Daily ILI eDiary as Time Weighted AUC | The severity of ILI was assessed by each participant completing of electronic Diaries for symptom severity daily for the following symptoms: Feeling hot, Temperature, Cough, Sore throat, Blocked nose, Chest pain, Muscle aches, Shortness of breath with their severities (scores) recorded as: Not Present (0), Mild (1), Moderate (2), Severe (3). For each symptom, the severity score was used to calculate the area under the curve (AUC), along with the calendar day, for the entire influenza season using trapezoidal rule. Participants could be followed for varying days in the influenza season, therefore the AUC will be time weighted to 168 days: Time weighted AUC=((raw AUC [time in days])/(number of days used for analysis)) * 168 | 210 days (during the influenza season, starting on 01 May 2019 and ending on or before 15 October 2019) | 
| Number of Participants With Immunogenic Response to MVA-NP+M1 (as Assessed Via the Frequency of Influenza-specific T-cells) | The numbers of immunogenic Participants (with positive immune response as assessed at Day 28 and week 26 in relation to the baseline day 0 Immunogenicity) were listed. The immunogenicity here was determined via the frequency of influenza-specific T-cells measured by IFN-γ/granzyme B ELISpot assay (enzyme linked immunospot) where the adjusted Spot Forming Units (SFU) per million PBMCs (peripheral blood mononuclear cells) after background subtraction (dimethyl sulfoxide, DMSO) were counted. The immunogenicity analyses were conducted only in the Immunology Analysis Set of Participants. | Day 28 and Week 26 |