Immunogenicity Trial of Recombinant Influenza Vaccine Among HCP in Israel

Randomized Comparison of the Immunogenicity of Recombinant and Egg-based Influenza Vaccines Among Healthcare Personnel in Israel

Status

Completed

Phases

Phase 4

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT04523324

Enrollment

577

Registered

2020-08-21

Start date

2019-10-31

Completion date

2022-08-30

Last updated

2023-11-15

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Influenza

Keywords

Influenza, Healthcare personnel, Immunogenicity, Repeat vaccination

Brief summary

This randomized, open-label, active-controlled trial will assess humoral immune responses to a single dose of 2019-20 recombinant hemagglutinin quadrivalent influenza vaccines (RIV4) compared with standard egg-based unadjuvanted quadrivalent influenza vaccines (IIV4) among healthcare personnel (HCP) vaccinated during the previous 2018-19 season with IIV4. The trial will be conducted at two hospital sites in Israel during the 2019-20 influenza season among HCP who were enrolled in the Study of Healthcare Personnel with Influenza and other Respiratory Viruses in Israel (SHIRI).

Detailed description

This is a randomized, open-label study design. Starting in July 2019, approximately 550 to 700 HCP from two hospitals (275-350 per hospital site) in Israel will be enrolled. Following completion of a written consent form, participants will complete an enrollment survey and grant permission for review of information collected during the SHIRI study, including vaccination status and immune response during the SHIRI study years. Participants will complete an enrollment survey and grant permission to include and integrate information collected during the SHIRI study into the current study's data, including health history, influenza vaccination history, and immune response to vaccination during the SHIRI study years. HCP will be randomly assigned 1:1 to receive a single dose of IIV4 licensed in Israel (expected to be Vaxigrip® Quadrivalent, 15µg of HA per strain) or RIV4 (Flublok® Quadrivalent by Sanofi Pasteur, 45µg of HA per strain) during August-October of 2019. Adverse events following vaccination will be monitored and documented. Blood specimens will be collected prior to vaccination and approximately 28 days after to evaluate immune responses to vaccination. Eligible HCP who were already vaccinated with Vaxigrip, the vaccine that is routinely available in Israel, at the time they are approached to join the study, will be invited to join the study as part of the Vaxigrip arm. Like randomized participants, participants who were vaccinated with Vaxigrip outside the study will complete a written consent form, an enrollment survey and grant permission for review of information collected during the SHIRI study, including vaccination status and immune response during the SHIRI study years. As part of the consent form, participants will record the estimated date that they received the vaccine, and the location, and will authorize study staff to verify the date of current-year Vaxigrip vaccination in the Clalit EMR and with the hospital vaccination staff. Participants will complete an enrollment survey and grant permission to include and integrate information collected during the SHIRI study into the current study's data, including health history, influenza vaccination history, and immune response to vaccination during the SHIRI study years. Blood specimens will be collected approximately 28 days after to evaluate immune responses to vaccination.

Interventions

BIOLOGICALFlublok™ Quadrivalent by Sanofi, Inc.

0.5 mL intramuscular dose of Flublok

BIOLOGICALVaxigripTetra™ by Sanofi, Inc.

0.5 mL intramuscular dose of Vaxigrip

Study design

Allocation

RANDOMIZED

Intervention model

PARALLEL

Primary purpose

BASIC_SCIENCE

Masking

SINGLE (Subject)

Masking description

Open-label trial. Eligible HCP who report already having been vaccinated with Vaxigrip at the time they are approached to join the study will be eligible to participate.

Eligibility

Sex/Gender

ALL

Age

18 Years to No maximum

Healthy volunteers

Yes

Inclusion criteria

* Aged ≥18 * Current member of Clalit Health Services * Consent to randomized receipt of influenza vaccination with either RIV4 or IIV4, or, if already vaccinated in the current year outside of the study, consent to receive a post-vaccination blood draw * Participated in the SHIRI study and received influenza vaccination during the 2018-19 influenza season (Group 1) * Participated in any year of the SHIRI study, not vaccinated in 2018-2019, but vaccinated in at least one study year (Group 1 supplemental) * Participated in the SHIRI study during all three years, regardless of vaccination status (Group 1 supplemental) * Participated in any year of the SHIRI study and had PCR-confirmed influenza virus infection during any of the three study years (Group 2)

Exclusion criteria

* Already received an influenza vaccine during the current influenza season * Not willing or able to get the flu vaccines being used in this study; * Previous hypersensitivity reaction to the study vaccines, or any vaccine, as reported by the subject * Received any non-influenza vaccine (e.g., Hepatitis B or other vaccine recommended for HCP) in the 4 weeks prior to the first study visit or plans to receive a vaccine 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 or employment status that the potential participant or local study site principle investigator (PI) believes may interfere with successful completion of the study prior to December 2019, including being currently pregnant.

Design outcomes

Primary

Measure	Time frame	Description
Post-vaccination Geometric Mean Titer Against Influenza Virus A/H1N1	Day 28 days after vaccination	The geometric mean of antibody titers following a single dose of RIV4 or IIV4 as measured by hemagglutination inhibition (HI) for influenza virus A/H1N1
Geometric Mean Titer Ratio (GMR) Against Influenza Virus A/H1N1	0 to 28 days after vaccination	The ratio of the pre- vs. post-vaccination titer against influenza virus A/H1N1 following a single dose of RIV4 versus IIV4.
Post-vaccination Geometric Mean Titer Against Egg-grown Influenza Virus A/H3N2	Day 28 days after vaccination	The geometric mean of antibody titers following a single dose of RIV4 or IIV4 as measured by hemagglutination inhibition (HI) for egg-grown influenza virus A/H3N2
Geometric Mean Titer Ratio (GMR) Against Egg-grown Influenza Virus A/H3N2	0 to 28 days after vaccination	The ratio of the pre- vs. post-vaccination titer against egg-grown influenza virus A/H3N2 following a single dose of RIV4 versus IIV4.
Post-vaccination GMT Against Cell-grown Influenza Virus A/H3N2	Day 28 days after vaccination	The geometric mean of antibody titers following a single dose of RIV4 or IIV4 as measured by hemagglutination inhibition (HI) for cell-grown influenza virus A/H3N2
Geometric Mean Titer Ratio (GMR) Against Cell-grown Influenza Virus A/H3N2	0 to 28 days after vaccination	The ratio of the pre- vs. post-vaccination titer against cell-grown influenza virus A/H3N2 following a single dose of RIV4 versus IIV4.
Post-vaccination Geometric Mean Titer Against Influenza B(Victoria)	Day 28 days after vaccination	The geometric mean of antibody titers following a single dose of RIV4 or IIV4 as measured by hemagglutination inhibition (HI) for Influenza B(Victoria)
Geometric Mean Titer Ratio (GMR) Against Influenza B(Victoria)	0 to 28 days after vaccination	The ratio of the pre- vs. post-vaccination titer against Influenza B(Victoria) following a single dose of RIV4 versus IIV4.
Post-vaccination Geometric Mean Titer Against Influenza B(Yamagata)	Day 28 days after vaccination	The geometric mean of antibody titers following a single dose of RIV4 or IIV4 as measured by hemagglutination inhibition (HI) for Influenza B(Yamagata)
Geometric Mean Titer Ratio (GMR) Against Influenza B(Yamagata)	0 to 28 days after vaccination	The ratio of the pre- vs. post-vaccination titer against Influenza B(Yamagata) following a single dose of RIV4 versus IIV4.

Countries

Israel

Participant flow

Pre-assignment details

577 HCP were randomly allocated to receive either IIV4 or RIV4. Due to a delay in the delivery of RIV4 vaccines, 67 participants randomized to receive RIV4 had already been vaccinated in the community with IIV4 before the study started. Because they received the same IIV4 brand (Vaxigrip) as the study control vaccine, we allowed them to continue in the study as controls.

Participants by arm

Arm	Count
RIV4 (Flublok Quadrivalent) Flublok® Quadrivalent by Sanofi Pasteur, 45µg of HA per strain Flublok™ Quadrivalent by Sanofi, Inc.: 0.5 mL intramuscular dose of Flublok	203
IIV4 (Vaxigrip Quadrivalent) VaxigripTetra™ by Sanofi, Inc., 15µg of HA per strain, egg-based VaxigripTetra™ by Sanofi, Inc.: 0.5 mL intramuscular dose of Vaxigrip	334
Total	537

Baseline characteristics

Characteristic	RIV4 (Flublok Quadrivalent)	IIV4 (Vaxigrip Quadrivalent)	Total
Age, Continuous	47 years	44 years	45 years
Race/Ethnicity, Customized Ethnicity Arab	16 Participants	22 Participants	38 Participants
Race/Ethnicity, Customized Ethnicity Jewish, not Ultra-Orthodox	181 Participants	305 Participants	486 Participants
Race/Ethnicity, Customized Ethnicity Jewish, Ultra-Orthodox	6 Participants	7 Participants	13 Participants
Region of Enrollment Israel	203 participants	334 participants	537 participants
Sex: Female, Male Female	133 Participants	229 Participants	362 Participants
Sex: Female, Male Male	70 Participants	105 Participants	175 Participants

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk
deaths Total, all-cause mortality	0 / 203	0 / 334
other Total, other adverse events	0 / 203	0 / 334
serious Total, serious adverse events	0 / 203	0 / 334

Outcome results

Primary

Geometric Mean Titer Ratio (GMR) Against Cell-grown Influenza Virus A/H3N2

The ratio of the pre- vs. post-vaccination titer against cell-grown influenza virus A/H3N2 following a single dose of RIV4 versus IIV4.

Time frame: 0 to 28 days after vaccination

Population: Cell-grown influenza virus A/H3N2 Hemagglutination Inhibition Assay Outcome

Arm	Measure	Value (GEOMETRIC_MEAN)
RIV4 (Flublok Quadrivalent)	Geometric Mean Titer Ratio (GMR) Against Cell-grown Influenza Virus A/H3N2	6.1 Mean-Fold Change
IIV4 (Vaxigrip Quadrivalent)	Geometric Mean Titer Ratio (GMR) Against Cell-grown Influenza Virus A/H3N2	2.6 Mean-Fold Change

Primary

Geometric Mean Titer Ratio (GMR) Against Egg-grown Influenza Virus A/H3N2

The ratio of the pre- vs. post-vaccination titer against egg-grown influenza virus A/H3N2 following a single dose of RIV4 versus IIV4.

Time frame: 0 to 28 days after vaccination

Population: egg-grown influenza virus A/H3N2 Hemagglutination Inhibition Assay Outcome

Arm	Measure	Value (GEOMETRIC_MEAN)
RIV4 (Flublok Quadrivalent)	Geometric Mean Titer Ratio (GMR) Against Egg-grown Influenza Virus A/H3N2	4.1 Mean-Fold Change
IIV4 (Vaxigrip Quadrivalent)	Geometric Mean Titer Ratio (GMR) Against Egg-grown Influenza Virus A/H3N2	2.4 Mean-Fold Change

Primary

Geometric Mean Titer Ratio (GMR) Against Influenza B(Victoria)

The ratio of the pre- vs. post-vaccination titer against Influenza B(Victoria) following a single dose of RIV4 versus IIV4.

Time frame: 0 to 28 days after vaccination

Population: Influenza B(Victoria) Hemagglutination Inhibition Assay Outcome

Arm	Measure	Value (GEOMETRIC_MEAN)
RIV4 (Flublok Quadrivalent)	Geometric Mean Titer Ratio (GMR) Against Influenza B(Victoria)	1.9 Mean-Fold Change
IIV4 (Vaxigrip Quadrivalent)	Geometric Mean Titer Ratio (GMR) Against Influenza B(Victoria)	1.5 Mean-Fold Change

Primary

Geometric Mean Titer Ratio (GMR) Against Influenza B(Yamagata)

The ratio of the pre- vs. post-vaccination titer against Influenza B(Yamagata) following a single dose of RIV4 versus IIV4.

Time frame: 0 to 28 days after vaccination

Population: Influenza virus B(Yamagata) Hemagglutination Inhibition Assay Outcome

Arm	Measure	Value (GEOMETRIC_MEAN)
RIV4 (Flublok Quadrivalent)	Geometric Mean Titer Ratio (GMR) Against Influenza B(Yamagata)	2.7 Mean-Fold Change
IIV4 (Vaxigrip Quadrivalent)	Geometric Mean Titer Ratio (GMR) Against Influenza B(Yamagata)	1.5 Mean-Fold Change

Primary

Geometric Mean Titer Ratio (GMR) Against Influenza Virus A/H1N1

The ratio of the pre- vs. post-vaccination titer against influenza virus A/H1N1 following a single dose of RIV4 versus IIV4.

Time frame: 0 to 28 days after vaccination

Population: Influenza A(H1N1)pdm09 Hemagglutination Inhibition Assay Outcome

Arm	Measure	Value (GEOMETRIC_MEAN)
RIV4 (Flublok Quadrivalent)	Geometric Mean Titer Ratio (GMR) Against Influenza Virus A/H1N1	4.0 Mean-Fold Change
IIV4 (Vaxigrip Quadrivalent)	Geometric Mean Titer Ratio (GMR) Against Influenza Virus A/H1N1	1.9 Mean-Fold Change

Primary

Post-vaccination Geometric Mean Titer Against Egg-grown Influenza Virus A/H3N2

The geometric mean of antibody titers following a single dose of RIV4 or IIV4 as measured by hemagglutination inhibition (HI) for egg-grown influenza virus A/H3N2