Immunogenicity Trial of Egg- Versus Non-Egg-Based Influenza Vaccines Among HCP

Study Overview
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Brief Summary
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This randomized, open-label trial will assess humoral and cell-mediated immune responses to cell culture-based and recombinant unadjuvanted quadrivalent influenza vaccines compared to conventional egg-based unadjuvanted quadrivalent standard dose (15µg of HA per strain) influenza vaccines among persons aged 18-64 years. The trial will be conducted at two sites in the United States during two influenza seasons (2018-19 and 2019-20). Stratified enrollment procedures will be used to enroll a mix of participants based on age.

Detailed Description
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In year 1 of the trial (the 2018-19 Northern Hemisphere influenza season), eligible participants at each site will be randomized 2:2:1:1 to receive a single dose of cell culture-based vaccine (Flucelvax™ Quadrivalent by Seqirus, Inc., 15µg of HA per strain) versus recombinant vaccine (Flublok® Quadrivalent by Sanofi Pasteur, 45µg of HA per strain) versus one of two standard dose egg-based vaccines (Fluzone® Quadrivalent by Sanofi Pasteur, 15µg of HA per strain and Fluarix® Quadrivalent by GlaxoSmithKlein, 15µg of HA per strain) during August-September of 2018. All study vaccines are licensed for use in adults aged >18 years in the United States. Participants will have blood collected just prior to vaccination and at approximately 28 days and 6 months post-vaccination (or at the end of influenza virus circulation as determined by available surveillance data) to evaluate humoral immune responses to vaccination. Additional blood will be collected from a subset of participants pre-vaccination and at approximately 7 days, 28 days and 6 months post-vaccination (or at the end of influenza virus circulation) to evaluate cell-mediated immune responses to vaccination. Active surveillance with mid-turbinate nasal swab collection for influenza-like illness (ILI) defined as new onset of cough or worsening of chronic cough within the preceding 7 days will be conducted during the period of influenza circulation at each study site. Additional blood will also be collected at 6 months post-vaccination (or at the end of influenza virus circulation) from participants with reverse-transcription polymerase chain reaction (RT-PCR)-confirmed ILI during the influenza season to evaluate cell-mediated immune responses to natural influenza virus infection. In year 1, sites will aim to enroll 864 participants (432 per site) at the start of the 2018-19 season, including up to 200 participants (up to 100 per site) who will contribute additional blood at all study visits to evaluate cell-mediated immune responses to vaccination. Efforts will be made to retain participants enrolled in the first year of the study for both years of the study. Sites will also enroll additional participants at the start of the 2019-20 season to make up for participants who withdraw or are lost to follow-up prior to the start of the 2019-20 season. Both participants and study investigators will be aware of study arm assignments with the exception of laboratory investigators who will be blinded to study arm assignment until testing is completed, as appropriate. In year 1 , relative efficacy of single doses of study vaccines will be assessed by comparing immunologic responses to vaccination among participants between study arms using Fluzone® Quadrivalent and Fluarix® Quadrivalent as the comparator groups for participants in the Flucelvax™ Quadrivalent or Flublok® Quadrivalent arms. In addition, the effect of frequency of prior vaccination during the preceding five years on immunologic responses to vaccine will be evaluated in subgroup analysis. Both humoral (influenza antibody) and cell-mediated (influenza- specific CD4 and CD8 T cell) immune responses will be evaluated. In year 2 of the trial, (the 2019-20 Northern Hemisphere influenza season), participants from the first year of the trial who received Flucelvax™ Quadrivalent or Flublok® Quadrivalent will be randomized 1:1 to receive Flucelvax™ Quadrivalent or Flublok® Quadrivalent, and participants who received an egg-based standard-dose vaccine in year one (Fluzone® Quadrivalent or Fluarix Quadrivalent) will be randomized 1:1:1 to receive Flucelvax™ Quadrivalent , Flublok® Quadrivalent , or Fluzone® Quadrivalent. In addition, both sites will enroll additional participants in year 2 to achieve a total of 150 participants per site (including participants who continue from year one plus additional newly enrolled participants) who received egg-based standard dose influenza vaccine during the 2018-2019 influenza season and who will be randomized 1:1:1 to receive Flucelvax™ Quadrivalent, Flublok® Quadrivalent, or Fluzone® Quadrivalent in year two. The Kaiser Permanente Northwest site site will also enroll up to 80 new participants for a non-randomized study arm that will receive Fluzone® High-Dose. All study vaccines except Fluzone High-Dose are licensed for use in adults aged >=18 years in the United States. Fluzone High-Dose is licensed for use in adults aged >=64 years in the United States and will be used off-label in this trial. Participants will have blood collected just prior to vaccination and at approximately 28 days post-vaccination (or at the end of influenza virus circulation as determined by available surveillance data) to evaluate humoral immune responses to vaccination. Additional blood will be collected from a subset of participants pre-vaccination and at approximately 7 and 28 days post-vaccination to evaluate cell-mediated immune responses to vaccination. In year 2, sites will aim to retain from year 1 or newly enroll 750 participants.

Official Title
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Randomized Open-Label Trial to Compare the Immunogenicity of Cell Culture-Based and Recombinant Unadjuvanted Quadrivalent Influenza Vaccines to Conventional Egg-Based Unadjuvanted Quadrivalent Influenza Vaccines Among Healthcare Personnel Aged 18-64 Years

Conditions
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Influenza

Intervention / Treatment
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* Biological: Flublok
* Biological: Flucelvax
* Biological: Fluarix
* Biological: Fluzone
* Biological: Fluzone High-Dose


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Healthcare personnel (HCP) who have direct contact with patients, including dentists and other dental health personnel Enrolled in Scott & White Healthcare or Kaiser Permanente health network for at least one month Aged 18-64 years for newly enrolled participants Aged 18-65 years for participants who were originally enrolled in year one of the study and return for year 2 Available and willing to participate in study follow-up through the end of the 2019-2020 influenza season (i.e. at least approximately 18 months if enrolled during season 1 or 6 months if enrolled during season 2) Received an egg-based standard dose influenza vaccine during the 2018-2019 influenza season (for participants enrolled for the first-time during year two) Exclusion Criteria: Already received an influenza vaccine during the current influenza season Previous hypersensitivity reaction to the study vaccines as reported by the subject Received any vaccine in the 4 weeks prior to the first study visit or plans to receive a vaccine (other than influenza vaccine provided through the study protocol) in the 4 weeks following the first study visit Currently participating in a study that involves an experimental agent (vaccine, drug, biologic, device, blood product, or medication), or has received an experimental agent within 1 month prior to enrollment in this study, or expects to receive an experimental agent during participation in this study Any condition that the principle investigator (PI) believes may interfere with successful completion of the study

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 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: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Flublok (Recombinant)<br>Flublok® Quadrivalent by Sanofi Pasteur, 45µg of HA per strain | Biological: Flublok<br>* 0.5 mL intramuscular dose of Flublok<br>|
| Active Comparator: Flucelvax (Cell-based)<br>Flucelvax™ Quadrivalent by Seqirus, Inc., 15µg of HA per strain | Biological: Flucelvax<br>* 0.5 mL intramuscular dose of Flucelvax<br>|
| Active Comparator: Fluarix (Egg-based)<br>Fluarix® Quadrivalent by GlaxoSmithKlein, 15µg of HA per strain | Biological: Fluarix<br>* 0.5 mL intramuscular dose of Fluarix<br>|
| Active Comparator: Fluzone (Egg-based)<br>Fluzone® Quadrivalent by Sanofi Pasteur, 15µg of HA per strain | Biological: Fluzone<br>* 0.5 mL intramuscular dose of Fluzone<br>|
| Active Comparator: Fluzone (Egg-based) High-Dose<br>Fluzone® Trivalent High-Dose by Sanofi Pasteur, 60µg of HA per strain | Biological: Fluzone High-Dose<br>* 0.5 mL intramuscular dose of Fluzone<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Microneutralization (MN) assay response to cell-grown influenza A/H3N2 - seroconversion rate (SCR) | MN responses to the cell-grown influenza A/H3N2 vaccine reference viruses for each study season at approximately 28 days post-vaccination, including by assessing SCR in the various vaccine arms defined as the proportion of participants with paired samples that achieved ≥ 4 fold rises comparing post- versus pre-vaccination titers, and post vaccination titers ≥ 40 | 28 days post-vaccination | 
| MN assay response to cell-grown influenza A/H3N2 - geometric mean titer (GMT) | MN responses to the cell-grown influenza A/H3N2 vaccine reference viruses for each study season at approximately 28 days post-vaccination, including by assessing GMTs in the various vaccine arms | 28 days post-vaccination | 
| MN assay response to cell-grown influenza A/H3N2 - mean fold rise (MFR) | MN responses to the cell-grown influenza A/H3N2 vaccine reference viruses for each study season at approximately 28 days post-vaccination, including MFR defined as the ratio of the post-vaccination titer value to the pre-vaccination value | 28 days post-vaccination | 
| MN assay response to cell-grown influenza A/H3N2 - GMT ratio | MN responses to the cell-grown influenza A/H3N2 vaccine reference viruses for each study season at approximately 28 days post-vaccination, including GMT ratio defined as the ratio of the post-vaccination GMT between comparison groups | 28 days post-vaccination | 
| Hemagglutination inhibition (HI) responses to the cell-grown influenza A/H1N1, influenza B/Yamagata, and influenza B/Victoria viruses - SCR | HI responses to the cell-grown influenza A/H1N1, influenza B/Yamagata, and influenza B/Victoria vaccine reference viruses for each study season at approximately 28 days post-vaccination, including by assessing SCR in the various vaccine arms | 28 days post-vaccination | 
| HI responses to the cell-grown influenza A/H1N1, influenza B/Yamagata, and influenza B/Victoria viruses - GMT | HI responses to the cell-grown influenza A/H1N1, influenza B/Yamagata, and influenza B/Victoria vaccine reference viruses for each study season at approximately 28 days post-vaccination, including by assessing GMTs in the various vaccine arms | 28 days post-vaccination | 
| HI responses to the cell-grown influenza A/H1N1, influenza B/Yamagata, and influenza B/Victoria viruses - MFR | HI responses to the cell-grown influenza A/H1N1, influenza B/Yamagata, and influenza B/Victoria vaccine reference viruses for each study season at approximately 28 days post-vaccination, including by assessing MFR in the various vaccine arms | 28 days post-vaccination | 
| HI responses to the cell-grown influenza A/H1N1, influenza B/Yamagata, and influenza B/Victoria viruses - GMT ratio | HI responses to the cell-grown influenza A/H1N1, influenza B/Yamagata, and influenza B/Victoria vaccine reference viruses for each study season at approximately 28 days post-vaccination, including by assessing GMT ratio for each vaccine arm | 28 days post-vaccination | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| HI responses to cell-grown influenza A/H3N2 vaccine reference viruses for each study season at approximately 28 days - seropositivity | HI responses to cell-grown influenza A/H3N2 vaccine reference viruses for each study season at approximately 28 days, including post-vaccination titers greater than or equal to seropositive thresholds at 1:40, 1:80, and 1:160 | 28 days post-vaccination | 
| HI responses to cell-grown influenza A/H3N2 vaccine reference viruses for each study season at approximately 28 days - SCR | HI responses to cell-grown influenza A/H3N2 vaccine reference viruses for each study season at approximately 28 days, including by assessing SCR in the various vaccine arms defined as the proportion of participants with paired samples that achieved ≥ 4 fold rises comparing post- versus pre-vaccination titers, and post vaccination titers ≥ 40 | 28 days post-vaccination | 
| HI responses to cell-grown influenza A/H3N2 vaccine reference viruses for each study season at approximately 28 days - GMT | HI responses to cell-grown influenza A/H3N2 vaccine reference viruses for each study season at approximately 28 days, including by assessing GMTs in the various vaccine arms | 28 days post-vaccination | 
| HI responses to cell-grown influenza A/H3N2 vaccine reference viruses for each study season at approximately 28 days - GMT ratio | HI responses to cell-grown influenza A/H3N2 vaccine reference viruses for each study season at approximately 28 days, including GMT ratio defined as the ratio of the post-vaccination GMT between comparison groups | 28 days post-vaccination | 
| HI responses to cell-grown influenza A/H3N2 vaccine reference viruses for each study season at approximately 28 days - MFR | HI responses to cell-grown influenza A/H3N2 vaccine reference viruses for each study season at approximately 28 days, including MFR defined as the ratio of the post-vaccination titer value to the pre-vaccination value | 28 days post-vaccination | 
| MN responses to cell-grown influenza A/H1N1, influenza B/Yamagata, and influenza B/Victoria vaccine reference viruses for each study season at approximately 28 days - SCR | MN responses to cell-grown influenza A/H3N2 vaccine reference viruses for each study season at approximately 28 days, including by assessing SCR in the various vaccine arms defined as the proportion of participants with paired samples that achieved ≥ 4 fold rises comparing post- versus pre-vaccination titers, and post vaccination titers ≥ 40 | 28 days post-vaccination | 
| HI responses to cell-grown influenza A/H1N1, influenza B/Yamagata, and influenza B/Victoria vaccine reference viruses for each study season at approximately 28 days - seropositivity | HI responses to cell-grown influenza A/H1N1, influenza B/Yamagata, and influenza B/Victoria vaccine reference viruses for each study season at approximately 28 days, including post-vaccination titers greater than or equal to seropositive thresholds at 1:40, 1:80, and 1:160 | 28 days post-vaccination | 
| HI and/or MN responses to egg-grown vaccine reference viruses for all vaccine viruses - GMT | HI and/or MN responses to egg-grown vaccine reference viruses for all vaccine viruses for each study season at approximately 28 days, including GMT | 28 days post-vaccination | 
| HI and/or MN responses to egg-grown vaccine reference viruses for all vaccine viruses - SCR | HI and/or MN responses to egg-grown vaccine reference viruses for all vaccine viruses for each study season at approximately 28 days, including SCR | 28 days post-vaccination | 
| HI and/or MN responses to egg-grown vaccine reference viruses for all vaccine viruses - MFR | HI and/or MN responses to egg-grown vaccine reference viruses for all vaccine viruses for each study season at approximately 28 days, including MFR | 28 days post-vaccination | 
| HI and/or MN responses to egg-grown vaccine reference viruses for all vaccine viruses - seropositivity | HI and/or MN responses to egg-grown vaccine reference viruses for all vaccine viruses for each study season at approximately 28 days, including post-vaccination titers greater than or equal to seropositive thresholds at 1:40, 1:80 and 1:160 as measured by HI | 28 days post-vaccination | 
| GMT by HI for all vaccine viruses at 6 months - cell-grown | GMT as measured by HI for all vaccine virus subtypes/lineages at 6 months post-vaccination using cell-grown vaccine reference viruses | 6 months post-vaccination | 
| GMT by HI for all vaccine viruses at 6 months - egg-grown | GMT as measured by HI for all vaccine virus subtypes/lineages at 6 months post-vaccination using egg-grown vaccine reference viruses | 6 months post-vaccination |