Dynamics of the Immune Responses to Repeat Influenza Vaccination Exposures

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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 evolutio...

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: A 4-year immunogenicity study with a randomized controlled design among 820 adults who are 18-49 years of age. Participants will be randomized to 5 groups in equal proportions, where the groups will 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. All participants will receive influenza vaccination at the end of the final year. The investigators 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 peripheral blood mononuclear cell (PBMC) analysis. The investigators 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. 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.

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