SBIR-STTR Award

?Respiratory infections with influenza viruses cause severe morbidity and mortality in humans and animals worldwide. Importantly, in humans, the majority of morbidity and mortality following flu infection is seen in older individuals (> 65 year old). Yet, clear understanding of how aging impacts on innate immune responses, and how to improve vaccine design in this age group is lacking. Restimulating preexisting memory T cells against conserved epitopes in influenza virus by a vaccine might confer protective immunity in this age group. An ideal vaccine for elderly should therefore engage pattern recognition receptors (PRRs) that activate antigen-presenting cells (APCs), generate conserved antigenic epitopes, while avoiding overt inflammatory responses. In this proposal we will test the hypothesis that engaging non-inflammasome dependent innate pathways by M2SR virus results in robust restimulation of memory CD4 and CD8 T cells in older humans without causing pathological inflammation. Aim 1. To examine the transcriptome signature following infection with M2SR vaccine in dendritic cells from old vs. young adults. Aim 2: To examine ex vivo efficacy of M2SR in restimulating functional anti-influenza CD8 and CD4 memory T cells in the elderly. Aim 3: To determine the adjuvants that enhance the capacity of M2SR to restimulate flu- specific memory T cells in APCs from older adults. These experiments are aimed at improving protection of older humans from influenza-mediated disease, by understanding the fundamental innate immune defects that contribute to failure to mount protective immunity. The outcome of the experiments is expected to have high impact, both with respect to the fundamental understanding of the underlying mechanism of flu-related illnesses in the susceptible elderly population, and in providing a basis with which to design vaccine and immunotherapeutic interventions.

Public Health Relevance Statement:


Public Health Relevance:
Respiratory infections with influenza viruses cause severe morbidity and mortality in humans and animals worldwide. Importantly, in humans, the majority of morbidity and mortality following flu infection is seen in older individuals (> 65 years old). Yt, clear understanding of how aging impacts on innate immune responses, and how to improve vaccine design in this age group is lacking. In this proposal we will test the hypothesis that engaging non-inflammasome dependent innate pathways by M2SR virus results in robust restimulation of memory CD4 and CD8 T cells in older humans without causing pathological inflammation.

Project Terms:
adaptive immunity; Adjuvant; Age; age group; aged; Aging; Animals; anti-influenza; Antibodies; Antibody Response; Antigen-Presenting Cells; base; CD4 Positive T Lymphocytes; CD8B1 gene; Cells; Complex; cytokine; Data; Defect; Dendritic Cells; differential expression; Disease; Elderly; Epitopes; Failure (biologic function); flu; Flushield; Gene Expression Profile; Generations; Granzyme; Human; human old age (65+); Immune; immune function; Immune response; Immunity; Immunization; Immunotherapeutic agent; improved; in vivo; Individual; Infection; Inflammation; Inflammatory; Inflammatory Response; Influenza; Influenza virus vaccine; influenzavirus; Interferons; Interleukin-10; Intervention; Ion Channel; Knock-out; Life; Lymphocyte; Mediating; Memory; memory CD4 T lymphocyte; monocyte; Morbidity - disease rate; Mortality Vital Statistics; Mus; novel; Outcome; Pathway interactions; Pattern recognition receptor; Peptides; Peripheral Blood Mononuclear Cell; Population; prevent; programs; public health relevance; Regulator Genes; research study; Respiratory Tract Infections; response; T cell response; T memory cell; T-Lymphocyte; Testing; TimeLine; transcriptome sequencing; Vaccinated; Vaccination; vaccine candidate; Vaccine Design; vaccine response; Vaccines; Virus; young adult

Respiratory infections with influenza viruses cause severe morbidity and mortality in humans and animals worldwide. Importantly, in humans, the majority of morbidity and mortality following flu infection is seen in older individuals (> 65 years old). Yet, clear understanding of how aging impacts on innate immune responses, and how to improve vaccine design in this age group is lacking. Restimulating preexisting memory T cells against conserved epitopes in influenza virus by a vaccine might confer protective immunity in this age group. An ideal vaccine for elderly should therefore engage pattern recognition receptors (PRRs) that activate antigen-presenting cells (APCs), generate conserved antigenic epitopes, while avoiding overt inflammatory responses. In Phase I, we showed that M2SR virus results in robust restimulation of memory CD4 and CD8 T cells in older humans without causing pathological inflammation by engaging non-inflammasome dependent innate pathways. In this Phase II proposal, we will explore how M2SR stimulates antiviral immune responses in older subjects in the following aims: Aim 1. Examine dendritic cell survival and function in response to M2SR infection. Aim 2: Determine the molecular mechanism of interferon stimulated gene expression regulation in dendritic cells. Aim 3: Evaluate the early immune response in human subjects vaccinated with M2SR. These experiments are aimed at improving protection of older humans from influenza-mediated disease, by understanding the fundamental innate immune defects that contribute to failure to mount protective immunity. The outcome of the experiments is expected to have high impact, both with respect to the fundamental understanding of the underlying mechanism of flu-related illnesses in the susceptible elderly population, and in providing a basis with which to design vaccine and immunotherapeutic interventions.

Public Health Relevance Statement:
Respiratory infections with influenza viruses cause severe morbidity and mortality in humans and animals worldwide. Importantly, in humans, the majority of morbidity and mortality following flu infection is seen in older individuals (> 65 years old). Yet, clear understanding of how aging impacts on innate immune responses, and how to improve vaccine design in this age group is lacking. In this proposal we will investigate the molecular mechanism of how M2SR vaccine results in robust restimulation of memory CD4 and CD8 T cells in older humans without engaging inflammasome dependent innate pathways.

Project Terms:
Accounting; adaptive immune response; adaptive immunity; Affect; Age; age group; aged; Aging; Aging-Related Process; Animals; Antibody Response; Antibody titer measurement; Antigen-Presenting Cells; Antiviral Agents; B-Lymphocytes; CD8-Positive T-Lymphocytes; Cell Death; Cell physiology; Cell Survival; Cells; Cessation of life; Chronic Disease; Clinical; Clinical Research; cytokine; Data; Defect; Dendritic Cells; disability; Disease; Down-Regulation; Elderly; Epitopes; Exhibits; experimental study; Failure; flu; FluMist; Gene Expression; Gene Expression Regulation; Genes; genetic signature; Hospitalization; Human; human old age (65+); human subject; Immune; immune function; Immune response; Immune system; Immunity; Immunization; immunogenicity; immunosenescence; Immunotherapeutic agent; Impairment; improved; In Vitro; in vivo; Inactivated Vaccines; Individual; Infection; Inflammasome; Inflammation; Inflammatory Response; Influenza; Influenza A virus; Influenza prevention; Influenza virus vaccine; influenzavirus; Innate Immune Response; insight; Interferon Type I; Interferons; Interleukin-1; Interleukin-18; Intervention; Ion Channel; Lung diseases; M2 protein; Mediating; Memory; Methods; Molecular; monocyte; Morbidity - disease rate; mortality; Natural Immunity; novel; Outcome; Pathologic; Pathway interactions; Pattern recognition receptor; Peripheral Blood Mononuclear Cell; Phase; Phenotype; Population; Predisposition; prevent; Production; protein expression; Receptor Signaling; Research; Respiratory Tract Infections; response; Retinoic Acid Receptor; Risk; Sampling; Signal Transduction; T cell response; T memory cell; T-Cell Activation; T-Lymphocyte; Testing; Time; transcriptome; Tretinoin; Vaccinated; Vaccination; vaccine candidate; Vaccine Design; vaccine response; Vaccines; Viral Load result; Virus; Virus Diseases; Vulnerable Populations; Work