Transcriptomic Signatures of Influenza Vaccine Responses

NIH Pandemic-Era Grants

Pandemic Era Grants

2021

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Principal Investigator: Richard B Kennedy
Organization: MAYO CLINIC ROCHESTER
Fiscal Year: 2021
Award: $782,918
Funding agency: National Institute of Allergy and Infectious Diseases

ABSTRACT
The broad long-term goal of this application is to identify innate and T helper (Th) cell transcriptomic signatures
of immune response and further our understanding of sex-dependent human immune responses to two unique
influenza A/H3N2 vaccines in a population of older adult males and females. We will comprehensively
measure the spectrum of innate and adaptive (CD4+T helper cell) immune responses to the recently FDA-
licensed MF59-adjuvanted influenza subunit vaccine (MF59Flu) and the high-dose split influenza virus vaccine
(HDFlu) using a systems biology approach, combined with detailed clinical and laboratory immunophenotyping
in a well-characterized cohort (65 years of age and older). Early innate immune responses are critical to the
development of robust adaptive immunity that confers protection upon re-exposure to influenza. Likewise, Th
responses provide T cell help essential for the establishment of protective humoral immunity. Little is known
about the effect of sex on innate and Th helper responses following these influenza vaccines. In this
application, we propose two parallel Specific Aims (one focused on innate immune responses and the other on
CD4+Th responses to these two vaccines). Our Aims will test the following hypotheses: 1) that vaccine type
(MF59Flu vs HDFlu) and/or sex are associated with variations in innate and Th cell immune response; 2) that
the increased Ag dose in HDFlu results in greater activation/suppression of the genes/genesets previously
associated with immune responses to standard dose influenza vaccine; 3) that the MF59 adjuvant results in
activation/suppression of additional genes/genesets compared to HDFlu; 4) that transcriptomic signatures
(gene expression patterns associated with immune responses) mediate the association of vaccine type (or
sex) with immune outcomes; and 5) that the innate or Th cell immune outcomes and corresponding
transcriptomic signatures will predict markers of humoral immunity (HAI titer and memory B cell ELISPOT
response). Completion of these Specific Aims will allow us to dissect the molecular mechanisms by which
MF59Flu and HDFlu enhance innate and Th immune responses in older persons at high risk of influenza
disease, identify specific genesets involved in sex-based differences in immune response, and may allow the
identification of new correlates of vaccine immunogenicity.

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