Vaccines for Older Adults: Current Practices and Future Opportunities

B. Weinberger

• Éditeur: S. Karger
• Année: 2020
• ISBN:
  9783318066784
• Sujet: Medicina
• Sous-sujet: Geriatria

Many infectious diseases are more frequent and are associated with high morbidity and mortality in older adults. Vaccination is the most efficient strategy to prevent infections, and older adults are an important target population for vaccination in order to promote health in this age group. Age-related changes in the immune system as well as other factors, such as comorbidities, obesity or frailty, influence vaccine-induced immune responses in old age. Awareness that vaccines developed for children might not be optimal for adults, and particularly for the older population, has only arisen in the recent past. Vaccination against influenza, pneumococcal disease, and herpes zoster is specifically recommended for older adults in many countries, and various strategies have been pursued in order to optimize these vaccines. However, there are still many pathogens, which severely affect the older population, but for which no vaccines are currently available. Extensive research and development are ongoing to further improve existing vaccines and to design novel vaccines in order to provide protection for this vulnerable age group. In order to exploit the full protective potential of vaccines it is essential to improve vaccine uptake and overcome vaccine hesitancy by providing information and education to stakeholders, health care professionals, and the general public. This book is relevant for researchers working on age-related changes in the immune system or on vaccine development, for health care professionals treating older patients, and for the stakeholders and decision makers involved in vaccination recommendations and implementation.

Immunosenescence and Other Risk Factors Affecting Vaccination Success in Old Age

Weinberger B (ed): Vaccines for Older Adults: Current Practices and Future Opportunities. Interdiscip Top Gerontol Geriatr. Basel, Karger, 2020, vol 43, pp 1–17 (DOI:10.1159/000504480)

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How Inflammation Blunts Innate Immunity in Aging

Emily L. Goldberg^a Albert C. Shaw^b Ruth R. Montgomery^b

^aDepartment of Comparative Medicine, Yale University School of Medicine, New Haven, CT, USA; ^bDepartment of Internal Medicine, Yale University School of Medicine, New Haven, CT, USA

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Abstract

The collective loss of immune protection during aging leads to poor vaccine responses and an increased severity of infection for the elderly. Here, we review our current understanding of effects of aging on the cellular and molecular dysregulation of innate immune cells as well as the relevant tissue milieu which influences their functions. The innate immune system is composed of multiple cell types which provide distinct and essential roles in tissue surveillance and antigen presentation as well as early responses to infection or injury. Functional defects that arise during aging lead to a reduced dynamic range of responsiveness, altered cytokine dynamics, and impaired tissue repair. Heightened inflammation influences both the dysregulation of innate immune responses as well as surrounding tissue microenvironments which have a critical role in development of a functional immune response. In particular, age-related physical and inflammatory changes in the skin, lung, lymph nodes, and adipose tissue reflect disrupted architecture and spatial organization contributing to diminished immune responsiveness. Underlying mechanisms include altered transcriptional programming and dysregulation of critical innate immune signaling cascades. Further, we identify signaling functions of bioactive lipid mediators which address chronic inflammation and may contribute to the resolution of inflammation to improve innate immunity during aging.

© 2020 S. Karger AG, Basel

Inflammation and Aging

Aging is the single greatest risk factor for developing chronic disease. Compared to younger adults, the elderly are at increased risk of infection and experience greater morbidity and mortality upon infection [1]. Similarly, the elderly also have poor vaccine responses, making them more susceptible to vaccine-preventable disease such as influenza or varicella zoster (causative agent in chickenpox and shingles) viruses, even when they have been vaccinated [2]. Central to this susceptibility is the functional deterioration of systemic immunity, or “immune senescence.” This term encompasses the collective loss of immune protection during aging and includes atrophy of the thymus leading to decreased naïve T cell output, an increased proportion of experienced lymphocytes contributing to adaptive immune memory but limiting responses to novel targets, an increased proportion of myeloid cells released from the bone marrow, and impaired functions of multiple existing immune cell types. Immune senescence is also characterized by functional dysregulation in immune cells at the cellular and molecular levels, ultimately leading to increased infection susceptibility and poor vaccination responses in the elderly as discussed in detail throughout this chapter.

Underlying many deficiencies in immunity is a chronic proinflammatory state. Many age-related diseases are driven by and promote increased inflammation, and elevated circulating inflammatory markers such as CRP, TNFα, and IL-6 correlate with age-related conditions including atherosclerosis [3] and frailty [4]. Importantly, even clinically healthy elderly individuals exhibit elevated inflammatory cytokines in serum [5]. While the precise source and cause of inflammation during aging is still unknown, this so-called “inflammaging” state contributes to the onset of multiple comorbidities in the elderly, including but not limited to Alzheimer’s disease, cardiovascular disease, muscle wasting, and immune senescence [6], making older adults a uniquely challenging patient population. Here, we will focus on the impact of inflammation on dysregulation of innate immune responses and relevant tissue microenvironments that influence immune cellular function.

Critical Functions of Innate Immunity

The innate immune system is responsible for initial control of pathogens by directly eliminating infections, engaging nearby cells, and recruiting adaptive immune cells. In contrast to the adaptive immune system, which requires training and is exquisitely specific to particular pathogens, the innate immune system senses and responds to numerous infections directly. The innate immune system is composed of multiple cell types with distinct critical functions both in the circulation and following infiltration into tissues to provide early responses to infection or injury. Innate immune cells such as neutrophils and monocytes circulate throughout the body and are capable of rapidly infiltrating tissues; macrophages and dendritic cells (DCs) reside within tissue and have important roles in tissue surveillance and antigen presentation. Innate immune cells rely on a variety of pattern recognition receptors (PRRs) to sense tissue disturbance and also recognize pathogenic invasion. Membrane-associated Toll-like receptors (TLRs) on the cell surface and within endosomes sense diverse structural patterns associated with pathogens such as lipoproteins, lipopolysaccharide, flagellin, and nucleic acids. Numerous studies have reported diminished responsiveness to TLR ligands in innate immune cells from elderly donors as compared to younger donors and are discussed in more detail in the sections below. Nod-like receptors and retinoic acid-inducible gene-I (RIG-I)-like receptors are cytosolic sensors that respond to bacterial or viral molecular components to initiate inflammatory responses that limit pathogen spread. While aging affects each of these cell types and functional responses differently, some unifying mechanistic alterations offer insights to immune dysfunction in aging.

Neutrophils

Peripheral blood polymorphonuclear leukocytes (PMNs), the most abundant circulating white blood cells, account for 45–75% of circulating leukocytes. An estimated 10¹¹ PMNs are released from the bone marrow daily to maintain a continuous supply of these crucial yet short-lived terminally differentiated cells. PMNs circulate throughout the body and therefore can potentially impact every tissue. They are rapid early responders to sites of infection or tissue injury and have high phagocytic and inflammatory capacity to limit pathogen spread. PMNs also contribute to chronic sterile inflammatory diseases such as gout in which they periodically accumulate and reactivate in afflicted joints causing debilitating pain in patients [7].

Despite their abundance and high inflammatory capacity, PMNs are less well characterized in the field of aging immunology. PMNs from older donors have lower TLR1 expression that correlates with reduced activation of TLR1-dependent IL-8, CD11b, and glucose uptake [8]. While PMNs from healthy elderly donors have reduced phagocytic (FITC-labeled E. coli) capacity and increased superoxide in response to fMLP and PMA [9, 10], generalization of these findings has been complicated by differences noted from different stimuli and experimental conditions [11]. PMNs from elderly individuals also show reduced actin polymerization [12, 13], suggesting impairments in chemotaxis. Indeed, in support of this possibility, PMNs isolated from aged mouse bone marrow exhibited reduced chemotaxis [14]. In the aged, poor chemotaxis is proposed to prolong PMN presence in tissue, causing collateral tissue damage [14, 15].

PMNs can undergo a novel form of cell death, NETosis, in which DNA content containing digestive and inflammatory enzymes is extruded from the cell. NETosis is a unique method to control pathogenic spread but is also recently implicated in sterile inflammation [16–18]. PMNs from old mice have impaired ability to undergo NETosis in response to in vivo cecal ligation and puncture-induced model of sepsis and also in vitro after stimulation with TLR2 ligands, suggesting a cell-intrinsic defect in signaling to induce NET formation and/or extrusion [19, 20]. In parallel with these impairments, however, human PMNs from healthy older donors maintain their ability to activate the NLRP3 inflammasome when stimulated in vitro [21]. Despite certain PMN functions being retained during aging, the accumulated defects that have been identified outnumber them, and these multiple defects in critical early responding cells allow more rapid pathogenic spread early after infection, putting the elderly host at increased susceptibility to infection and morbidity.

Monocytes

Monocytes are a heterogeneous subset of circulating myeloid cells that can infiltrate tissues and differentiate into macrophages or DCs. Their normal functions include phagocytosis, antigen presentation, and cytokine production. Multiple subsets of monocytes can be found in human blood at different stages of differentiation and maturity that are distinguishable by CD14 and CD16 expression [22]. Monocytes from older subjects have reduced production of cytokines after TLR1/2 stimulation that was associated with reduced surface TLR1 expression [23]; a generalized alteration in TLR-induced CD80 and CD86 expression correlates with reduced responses to influenza vaccination [24]. Monocytes from older subjects also have significantly diminished IFN-α/β responses to RIG-I stimulation [25]. Interestingly, these same monocytes retain the ability to produce proinflammatory cytokines upon stimulation, suggesting that aging may lead to cell-intrinsic dysregulation specifically in the IFN arm of this response [25, 26]. As there is no evidence of altered basal IFN expression with age, impaired IFN induction is representative of a model of age-related reduced dynamic range distinct from that of TLR-mediated proinflammatory cytokine induction. However, a significantly hi...