T-Cell Immunity to Influenza in Older Adults: A Pathophysiological Framework for Development of More Effective Vaccines

Abstract

One of the most profound public health consequences of immune senescence is reflected in an increased susceptibility to influenza and other acute respiratory illnesses, as well as a loss of influenza vaccine effectiveness in older people. Common medical conditions and mental and psychosocial health issues as well as degree of frailty and functional dependence accelerate changes associated with immune senescence. All contribute to the increased risk for complications of influenza infection, including pneumonias, heart diseases, and strokes that lead to hospitalization, disability, and death in the over 65 population. Changes in mucosal barrier mechanisms and both innate and adaptive immune functions converge in the reduced response to influenza infection, and lead to a loss of antibody-mediated protection against influenza with age. The interactions of immune senescence and reduced adaptive immune responses, persistent cytomegalovirus infection, inflammaging (chronic elevation of inflammatory cytokines), and dysregulated cytokine production, pose major challenges to the development of vaccines designed to improve T-cell-mediated immunity. In older adults, the goal of vaccination is more realistically targeted to providing clinical protection against disease rather than to inducing sterilizing immunity to infection. Standard assays of antibody titers correlate with protection against influenza illness but do not detect important changes in cellular immune mechanisms that correlate with vaccine-mediated protection against influenza in older people. This article will discuss: (i) the burden of influenza in older adults and how this relates to changes in T-cell function, (ii) age-related changes in different T-cell subsets and immunologic targets for improved influenza vaccine efficacy in older, and (iii) the development of correlates of clinical protection against influenza disease to expedite the process of new vaccine development for the 65 and older population. Ultimately, these efforts will address the public health need for improved protection against influenza in older adults and "vaccine preventable disability."

Keywords: antibody; cell-mediated immunity; immunosenescence; influenza; vaccination.

Figure 1

Multi-morbidity that is defined as the presence of two or more chronic conditions affects 50% of older people, most of whom enjoy an active life in the absence of an acute illness or injury (~70% of the over 65 population as represented by yellow stick figure). Influenza has been associated with the six leading causes of catastrophic disability. It has been postulated that the inflammatory response to the influenza virus leads to these serious complications, which are common causes of hospitalization in older adults. During periods of inactivity, older adults lose up to 5% of their functional muscle strength every day they are in bed and may never recover, thus, being identified as a frail older adult (represented by the red stick figure) at hospital discharge. Influenza vaccines that improve protection against influenza illness and related complications provide a significant public health opportunity to promote health aging and vaccine preventable disability.

Figure 2

(A) Influenza virus contains the surface glycoproteins, hemagglutinin (HA), and neuraminidase (NA), which are strain specific in directing the antibody response to influenza vaccination. The internal proteins, including nucleoprotein (NP) and matrix (M1) protein, are conserved across the different subtypes of influenza A and, thus, confer cross-protection. Subunit vaccines contain the surface glycoproteins, while split-virus vaccines contain both surface glycoproteins and internal proteins of the virus. High-dose, split-virus (HD) vaccines are designed to improve antigen presentation from antigen-presenting cells (APCs) in the lymph node, eliciting greater antigen-specific antibody responses and potentially improving the cytotoxic T lymphocyte response for improved viral clearance from the lungs. (B) Inflammation stimulated by the injection and potentially enhanced by adjuvants, such as MF59 or increased amounts of vaccine antigen (HD vaccine), facilitates the activation of the APC and uptake of inactivated virus. The APC then migrates to the local lymph node to interact with B cells, CD4⁺ T helper (Th) and T follicular helper (Tfh) cells, and CD8⁺ cytotoxic T lymphocytes (CTL). APCs present vaccine-derived peptides on MHC II stimulating Tfh and the production of strain-specific antibodies by B cells, the cross-reactivity of which is enhanced by vaccine adjuvants, such as MF59. Memory CD8⁺ T cells from prior exposure to natural influenza infection can be restimulated by vaccination, and may be enhanced by HD vaccines containing internal proteins. (C) Influenza infection in the lungs activates Th₁/Th₂/T_reg in the adjacent lymph nodes and stimulates a T_h1 response with IFNγ production to effectively activate memory CTL, which clear virus from the lungs. However, age-related changes drive a Th₂/T_reg response to infection, and IL-10 production suppresses the CTL response. A shift toward a protective T_h1 and CTL response to infection may be stimulated by increasing the amount of internal proteins and/or the use of adjuvants in vaccines targeted to improve protection against influenza in older adults.