Dynamics of the Immune Responses to Repeat Influenza Vaccination Exposures

NCT ID: NCT04576377

Last Updated: 2023-12-11

Basic Information

• Recruitment Status: ACTIVE_NOT_RECRUITING
• Clinical Phase: PHASE4
• Total Enrollment: 977 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2020-10-05
• Study Completion Date: 2025-12-31

Brief Summary

The aims of this vaccine trial are: (1) to measure humoral and selected cellular immune responses to repeated influenza vaccination with Flublok, including these responses' associations with age, birth year, and prior vaccination history; (2) to identify the characteristics of study participants who are vaccinated but still become infected with influenza virus ("vaccine failures") and participants who have poor immune responses to vaccination; and (3) to predict how influenza vaccinations and infections shape immunity.

Detailed Description

Background: Influenza vaccine is the most frequently used vaccine in the United States and globally. Influenza vaccination provides variable protection against influenza virus infection from year to year, with multiple factors contributing to variation in vaccine effectiveness. First, viral evolution necessitates regular updates to vaccine strains, and the degree of match between vaccine and circulating strains affects vaccine protection. A more serious issue, which motivates this study, is that repeated influenza vaccination may lead to "focusing" of immune responses to older strains, potentially reducing protection against recent strains.

Aims and objectives: The aims of this trial are: (1) to measure humoral and selected cellular immune responses to repeated influenza vaccination, including these responses' associations with age, birth year, and prior vaccination history; (2) to identify the characteristics of study participants who are vaccinated but still become infected with influenza virus ("vaccine failures"); and (3) to predict how influenza vaccinations and infections shape immunity.

Study design: *DRIVE I* A 4-year immunogenicity study with a randomized controlled design including 447 adults who are 18-45 years of age. Participants will be randomized to 5 groups in equal proportions, where the groups receive Flublok (Sanofi Pasteur) vaccine (V) or saline placebo (P) in years 1-4: group 1: V+V+V+V; group 2: P+V+V+V; group 3: P+P+V+V; group 4: P+P+P+V; group 5: P+P+P+P.

*DRIVE II* A 3-year and one-month immunogenicity study with a randomized controlled design among 530 adults who are 18-45 years of age. Participants will be randomized into 4 groups in equal proportions, where the groups will receive Flublok (Sanofi Pasteur) vaccine (V) or saline placebo (P) in year 1-4: group 1: V+V+V+V; group 2: P+V+V+V; group 3: P+P+V+V; group 4: P+P+P+V.

*DRIVE I & DRIVE II* All participants will receive influenza vaccination at the end of the final year. We will collect blood samples and nasal strip samples before vaccination and various timepoints after vaccination. Whole blood samples will be collected from a subset for later PBMC analysis. We will actively monitor participants for acute respiratory illnesses throughout the follow-up period, and collect and test respiratory swabs and blood samples to identify respiratory virus infections and acute immune responses to infection.

Number of Subjects: DRIVE I: 447 enrolled in autumn and winter 2020/21. DRIVE II: 530 enrolled in autumn and winter 2021/22.

Main outcome measures: The primary outcome measures are the humoral immune responses at day 30 after vaccination measured by hemagglutinin inhibition and microneutralization assays. The investigators will also study a number of secondary outcomes, including the persistence of immune responses 91, 182, 273 and 365 days after vaccination, and the immune responses to natural laboratory-confirmed influenza virus infections, as well as immunity and immune responses to other respiratory viruses including COVID-19 (SARS-CoV- 2).

Potential implications: Our study will provide novel insight into the effects of repeat influenza vaccination and infection on the strength and breadth of immune responses to influenza, the mechanisms underlying heterogeneity in vaccine response and vaccine failure, and biological factors that could explain variation in influenza vaccine effectiveness.

Conditions

Influenza, Human

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: PREVENTION
• Blinding Strategy: TRIPLE

Study Groups

Influenza vaccination

Group Type: EXPERIMENTAL

FluBlok

Intervention Type: BIOLOGICAL

Recombinant HA quadrivalent influenza vaccine (0.5mL Flublok®, Sanofi Pasteur) containing 180μg antigen, 45μg for each influenza strain included.

Placebo

Group Type: PLACEBO_COMPARATOR

Placebo

Intervention Type: OTHER

0.5mL saline placebo.

Interventions

FluBlok

Recombinant HA quadrivalent influenza vaccine (0.5mL Flublok®, Sanofi Pasteur) containing 180μg antigen, 45μg for each influenza strain included.

Intervention Type: BIOLOGICAL

Placebo

0.5mL saline placebo.

Intervention Type: OTHER

Eligibility Criteria

Inclusion Criteria

• Aged 18-45 years at enrolment.
• Capable of providing informed consent.
• Resident in Hong Kong in the coming 2 years.

Exclusion Criteria

• Vaccinated against influenza in the past 24 months.
• Included in one of the priority groups to receive influenza vaccination in Hong Kong (priority groups include pregnant women, long-stay residents of institutions for persons with disability, persons with chronic medical problems (chronic cardiovascular, lung, metabolic or kidney diseases, obesity (body mass index 30 or above) and chronic neurological condition), healthcare workers or persons working in poultry, pig farming or pig slaughtering industry).
• With diagnosed medical conditions related to their immune system.
• Currently taking medication for any condition that impairs immune system.
• Individuals who report medical conditions not suitable to receive inactivated influenza vaccines, such as: Severe allergic reaction (e.g., anaphylaxis) after previous dose of any influenza vaccine; or to a vaccine component; moderate or severe acute illness with or without fever after any previous influenza vaccination; or a history of Guillain-Barré syndrome (GBS) within 6 weeks of previous influenza vaccination.
• Individuals, who report medical conditions not suitable to receive intramuscular injection, such as bleeding disorders; habitually taking anticoagulants (with the exception of antiplatelets such as aspirin).
• Individuals who have any medical conditions not suitable to receive inactivated influenza vaccines as determined by a clinician.

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 45 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: Yes

Sponsors

University of Chicago

OTHER

Sponsor Role: collaborator

National Institute of Allergy and Infectious Diseases (NIAID)

NIH

Sponsor Role: collaborator

The University of Hong Kong

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Locations

The University of Hong Kong

Hong Kong, , Hong Kong

Countries

Hong Kong

References

Cowling BJ, Wong SS, Santos JJS, Touyon L, Ort JT, Ye N, Kwok NKM, Ho F, Cheng SMS, Ip DKM, Peiris M, Webby RJ, Wilson PC, Valkenburg SA, Tsang JS, Leung NHL, Hensley SE, Cobey S. Preliminary Findings From the Dynamics of the Immune Responses to Repeat Influenza Vaccination Exposures (DRIVE I) Study: A Randomized Controlled Trial. Clin Infect Dis. 2024 Oct 15;79(4):901-909. doi: 10.1093/cid/ciae380.

Reference Type: DERIVED

PMID: 39041887 (View on PubMed)

Other Identifiers

1U01AI153700

Identifier Type: NIH

Identifier Source: secondary_id

View Link

BJC033

Identifier Type: -

Identifier Source: org_study_id