Restimulating memory T cell responses in elderly by a novel, live influenza vaccine

Respiratory infections with influenza viruses cause severe morbidity and mortality in humans and animals worldwideImportantlyin humansthe majority of morbidity and mortality following flu infection is seen in older individualsrtyears oldYetclear understanding of how aging impacts on innate immune responsesand how to improve vaccine design in this age group is lackingRestimulating preexisting memory T cells against conserved epitopes in influenza virus by a vaccine might confer protective immunity in this age groupAn ideal vaccine for elderly should therefore engage pattern recognition receptorsPRRsthat activate antigen presenting cellsAPCsgenerate conserved antigenic epitopeswhile avoiding overt inflammatory responsesIn Phase Iwe showed that M SR virus results in robust restimulation of memory CDand CDT cells in older humans without causing pathological inflammation by engaging non inflammasome dependent innate pathwaysIn this Phase II proposalwe will explore how M SR stimulates antiviral immune responses in older subjects in the following aimsAimExamine dendritic cell survival and function in response to M SR infectionAimDetermine the molecular mechanism of interferon stimulated gene expression regulation in dendritic cellsAimEvaluate the early immune response in human subjects vaccinated with M SRThese experiments are aimed at improving protection of older humans from influenza mediated diseaseby understanding the fundamental innate immune defects that contribute to failure to mount protective immunityThe outcome of the experiments is expected to have high impactboth with respect to the fundamental understanding of the underlying mechanism of flu related illnesses in the susceptible elderly populationand in providing a basis with which to design vaccine and immunotherapeutic interventions