Impact of preexisting immune profile in elderly on influenza vaccine response

The decline in immunity with age results in poor responses to vaccines and novel pathogens. Pneumonia and influenza are the most common causes of infectious hospitalization and death in people who are > 65-years of age and yet the effectiveness of influenza vaccine lessens with age. An effective immune response requires the

appropriate interaction between the innate and the adaptive arms of the immune system and the proper balance of activation and regulation. Aging affects multiple components of the immune system and we propose that the cumulative defects and imbalances in the aging immune system that exist before vaccination contribute to

vaccine outcomes. This application will examine immune phenotypes in elderly and young participants before annual influenza vaccination and determine how these phenotypes affect the B cell and T cell responses to seasonal influenza vaccine. Aim 1 will determine whether older age, lower naïve T cell number or dysfunctional

naïve T cells prior to vaccination is associated with development of host T and B cell response to seasonal influenza vaccine. We will evaluate age and naïve T cell phenotype in PBMC samples before vaccination to determine whether these parameters correlate with host influenza specific T cell responses by ELISPOT (IFNγ

and IL2) and antibody responses by ELISA and hemagglutination inhibition assay (HAI). We will pay special attention to a novel subset of T cells that are expanded in elderly, memory T cells with a naïve phenotype (Tmnp). These cells express the lymph node homing receptor CCR7 but are transcriptionally and functional distinct from

naïve cells. In Aim 1a we will determine the antigen specificity of Tmnp cells in elderly by examining their specificity to common viral antigens from influenza, CMV, and EBV using tetramers. In Aim 2, we will examine the contribution of preexisting monocyte/macrophage phenotypes in elderly to influenza vaccine responses. We will

examine the phenotype of peripheral monocytes in elderly patients directly ex vivo using flow cytometry and determine if the phenotype before vaccination is associated with the T and B cell response to influenza vaccine. We will examine the systemic environment by measuring plasma levels of both inflammatory and anti-

inflammatory cytokines. Aim 2a will examine the influence of the elderly systemic microenvironment on monocyte derived macrophage differentiation. We will generate monocyte-derived macrophages (MDM) in the presence of autologous serum and then analyze the development of inflammatory (M1) or alternatively activated (M2)

macrophages and compare elderly and young MDM. In Aim 3 we will determine if T regulatory (Treg) or dysfunctional T regulatory (TregDys) cell frequencies prevaccination are associated with impaired response to influenza vaccine in the elderly. Although previous studies suggest there are elevated plasma levels of TGFβ

and an accumulation of Tregs with age, this contradicts the well-established observation of inflamaging. In Aim 3a we will test an alternative hypothesis that M2 monocytes drive the development of Tregs, but because of the high levels of IL-6 in elderly, these Tregs are dysfunctional (TregDys). We propose that elevated levels of IL-6 drive the

development of TregDys and that this contributes to persistent chronic inflammation in the elderly. To this end, we will use in vitro assays with autologous serum and IL-6 blockade to investigate the mechanistic role of IL-6 in promoting TregDys cells. Results from this proposal will provide insight into the immunologic phenotype that

precedes influenza vaccination in elderly and is predictive of poor vaccine response. Immunologic parameters of elderly and young preceding vaccination will permit us to propose improvements to current vaccine practices in the elderly.