Uncovering latent factors underlying weak and robust responses to influenza vaccine in healthy and obese older adults

Summary/Abstract
Although vaccination is the most effective measure for influenza prevention, there is considerable
variation in the responses to influenza vaccines that is influenced by factors such as age, sex,
and obesity level. Major advances in predicting and analyzing the cellular and molecular basis of
vaccine responses are being made possible by the application of high-dimensional experimental
and computational approaches that comprise Systems Vaccinology. This framework is yielding
predictive molecular signatures for influenza vaccine immunogenicity and protection. However,
there remains a considerable knowledge gap in delineation of cellular and molecular pathways
that affect the responses to advanced-generation influenza vaccines in older or obese individuals.
To gain new insights into the cellular and molecular states that underlie variation of influenza
vaccine responses in older, healthy weight or obese individuals we propose to perform deep
molecular and genomic profiling of immune cell states after screening for extreme responders.
Our approach, focused on extremes of individual vaccine responses, draws upon successful prior
use of such a framework in analyzing genetic basis of extreme phenotypic variability. We propose
in Aim 1 to elucidate latent factors and B cell genomic states underlying weak or robust
immunogenicity of the advanced-generation seasonal influenza vaccine within healthy weight
older individuals using deep molecular profiling and interpretable machine learning as well as
computational genomics. Aim 2 will delineate latent factors and infer molecular mechanisms by
which obesity distinctively affects influenza vaccine immunogenicity based on high-dimensional
and multi-scale profiling of the immune responses as in Aim 1. Uncovering new molecular markers
and pathways will spur tailored vaccine design that addresses specific impairments in vulnerable
individuals. Our team brings together strong expertise in three complementary and essential
disciplines that comprise vaccinology, immunology and systems biology.

Grant Number: 5R01AI170108-04
NIH Institute/Center: NIH
Principal Investigator: John Alcorn