Aging and Vaccines

Exp Rev Immunol Vaccine Informat Volume 2 Issue 1 March 2015 Review Aging and Vaccines Liljana Stevceva* College of Medicine, California North State University, 9700 West Taron Drive, Elk Grove, CA 95757, USA * Corresponding author: Liljana Stevceva, California Northstate University College of Medicine, 9700 West Taron Drive, Elk Grove, CA 95757, USA, Phone: 916-647-0465; Fax: 916-686-7300; E-mail: [email protected] Received Date: 03 February 2015; Accepted Date: 12 March 2015; Published Date: 30 March 2015 Citation: Stevceva L. Aging and Vaccines. Exp Rev Immunol Vaccine Informat. 2015; 2(1): 54-61. Copyright: © Stevceva 2015. Article published in the journal are under open-access model distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Abstract Life expectancy had doubled since the pre-modern era resulting in increased numbers of persons over 65 years of age. This created a need to address the healthcare issues specifically affecting the aging population such as increased susceptibility to infections, cancer and autoimmune diseases. These issues are resulting from significant changes that the immune system undergoes with aging (immunosenescence). Changes in the innate immune responses are reflected by the decreased bactericidal activity of neutrophils, decreased numbers of pDCs, increased numbers of agranular NK cells, decreased phagocytosis and clearance of pathogens and others. Deposition of complement component C1q on nerve synapses and simultaneous decrease in C3 levels are also seen. Adaptive immunity is affected even more with the involution of the thymus playing a central role and resulting in decreased numbers of naïve T cells. Loss of CD28 expression and increased expression of perforin and granzyme B in T cells is also seen while decreased numbers of CD4+ T cells and loss of TCR diversity are pronounced in the seventieth decade. The numbers and function of the B lymphocytes also declines with age. Immunosenescence also decreases drastically efficacy of immunization. This further complicates the medical care for aging individuals that already need to have greater protection against infectious diseases. Novel approaches to immunization of the elderly are thus greatly needed. Keywords: Aging; Thymus; Involution; T Cells; Naïve T Cells;T Cells Homeostasis; Naïve CD4+ T Cells; CD8+ T Cells;CD8+ T Cells Diversity; CD45RA+; CCR7+ T Cells; Naïve CD8+ T Cells; MHC Class I Molecules; MHC Class II Molecules; Memory T Cells; Effectorst Cells; Memory T Cells; CD4+ CD28null T Cells; Replicative Senescence; Proliferative Activity; TCR Restriction; IL-2; IL-15; IFN ; Viral Infections; Fungal Infections; Cancer; Antibody Responses; Avidity; Naïve B Cells; Memory Long Lived B Cells; Memory Cells Survival; B Cell Depletion; Lymphopoesis; Monocyte Expansion; CD14+CD16+ Monocytes; Phagocytic Activity; Superoxide Generation; Oxidative Stress; Nitric Oxide; Complement; C1q; C3; Amyloid Plaques; Alzhaimers; Parkinsons; CD40L; CD40; CD28; CD27; Eosinophils; Dendritic Cells; Cdcs; Pdcs; IL-7; Macrophages; NK Cells; Natural Killer Cells; Exhausted; IgG; IgM; Influenza Vaccine; PCV7; PCV9; Inactivated Flavivirus Vaccine Against Tick-Borne Encephalitis; TBE; Pneumococcal Vaccine; MF59; ASO3; Matrix-M Exp Rev Immunol Vaccine Informat ISSN: 2056-7812 Vol 2 Iss 1 pp 54-61 Citation: Stevceva L. Aging and Vaccines. Exp Rev Immunol Vaccine Informat. 2015; 2(1): 54-61. Introduction Life expectancy has doubled over the years from about 30 years old in the pre-modern era (~15001800) to 80 years of age in Europe (58 in Africa) in 2011 [1]. The number of persons aged 65 years of age and more increased from 5.2% of the total population in 1950 to 8% today and is projected to increase to almost 12% by 2030 bringing the total number of living elderly from 500 million today to 1 billion in 2030 [2]. With such a rapidly increasing elderly population there is an everincreasing need to focus on their healthcare needs that are largely different from children and adult populations. Aging is associated with increased susceptibility to diseases especially, infections, increased incidence of cancer, poor responses to treatment and immunization and higher incidence of autoimmune diseases. Most of these changes are attributed to the substantial changes in immune responses that are associated with aging. Overall, the immunocompetence declines and the ability to mount an appropriate immune response to an antigen decrease and modify leading to increased susceptibility to infections and autoimmunity. Aging affects both innate and adaptive immune responses. Immunosenescence is a term that is used to describe the age-associated gradual deterioration of the immune system. Aging of the Innate Immunity There is limited number of studies looking into changes in the innate immune system with aging. Once physical and chemical barriers that represent the first line of defense against pathogens are crossed, neutrophils are one of the first cells to respond, accumulate and kill pathogens by generating reactive oxygen and nitrogen species and releasing proteolytic enzymes and microbicidal peptides from cytoplasmic granules. It has been determined that there is no decrease in numbers of neutrophils and that their ability to move(chemokinesis) is not affected by aging [3,4]. However, there was a trend in reduced ability for chemotaxis leading to delayed recruitment and accumulation in response to a pathogen [4]. In the same study the percent of phagocyting cells and the number of E. coli per neutrophil were significantly reduced with increasing age. Significant correlation was recorded between decreased phagocytic activity and the age of the participants. An age-dependent reduction in neutrophil bactericidal ability has been reported by several researchers and is largely attributed to the reduced Exp Rev Immunol Vaccine Informat ISSN: 2056-7812 superoxide anion production [5,4] and the impaired lytic enzyme activity [4,6]. Data on aging macrophages are scarce, controversial and mostly generated in mice. For example, studies in mice have shown that macrophage numbers increase with age [7]. In addition, macrophages from aged mice exhibit significantly reduced IFNγ-stimulated tyrosine phosphorylation (Y701) of the transcription factor STAT-1α and STAT-1β in comparison with macrophages from younger mice. Phagocytosis and clearance of pathogens as well as chemotactic activity decrease with aging [8]. The tissue microenvironment in which macrophages reside can influence their function. Consequently, the process of aging can modify macrophage functions progressively and continuously. In mice, there is a shift in macrophages from a proinflammatory phenotype that is found in young animals to antiinflammatory phenotype in older mice with elevated levels of IL-10 in aging playing a crucial role in this process [9]. Plasmacytoid dendritic cells (pDCs), found in peripheral blood and peripheral lymphoid organs, constitute about 0.4% of peripheral blood mononuclear cells (PBMCs) and produce large amounts of type 1 interferons (IFNα and IFNβ). Conventional or myeloid dendritic cells (cDCs) are found in peripheral tissues. Following tissue infection they become activated and migrate to the draining lymph nodes where they promote immune responses. They produce IL-12 and are major stimulators of T cell responses. Aging pDCs significantly decrease in numbers while numbers of cDCs are unaltered. Aged mouse cDCs have impaired capacity to be recruited and to migrate to the draining lymph nodes, a defect that was associated with a defect in CCR7 signal transduction. There is no consensus whether aging reduced the ability of the DCs to induce T cell responses [9]. In regards to eosinophils, degranulation in response to IL-5 but not to fMLP is suppressed in elderly asthmatics but the chemotaxis and adhesion are unchanged [9,10]. In the immune response to pathogens natural killer (NK) cells activity is crucial in removing intracellular infectious agents and tumor cells. It has been reported that the relative percentages of NK cells as well as their absolute numbers increase with aging [11]. In addition, the aged NK Vol 2 Iss 1 pp 54-61 Citation: Stevceva L. Aging and Vaccines. Exp Rev Immunol Vaccine Informat. 2015; 2(1): 54-61. cells are more likely to have a mature phenotype (CD56dim). Their function seems to be impaired as the numbers of agranular NK cells is increased with aging. Impaired ability to adhere to tumor cells has also been reported from studies in mice [12]. Reports on the ability of aged NK cells to kill tumor cells are conflicting with some authors reporting increased activity, others reporting no change and also some reporting a decreased activity [12]. Aged NK cells respond poorly to IL2 stimulation (40-60% in ability to proliferate in response to IL-2 stimulation). This is believed to be due to age-specific decrease in Ca2+ mobilization [13]. Complement components are integral part of the complement cascade, an important arm of the innate immune responses. A recently published study by Stephan et al. [14] reported as much as 300 fold age-related buildup of the complement component C1q. It appears that C1q increasingly gets deposited at the contact points between the nerve cells (synapses). The presence of such excessive amounts of C1q at these places may potentially lead to destruction of synapses and cognitive decline if C1q becomes activated by a catalytic event such as brain injury, systemic infection or series of TIAs. The regions of the brain where C1q primarily gets deposited are the hippocampus and substantia nigra, regions that are usually affected in Alzheimer’s and Parkinson’s disease. At the same time, C3 levels decrease significantly with age and are only present at very low levels in the aged brain. Low levels of C3 and factor H in the cerebrospinal fluid of patients with Alzheimer disease are thought to be related to complement activation in early stages of the disease and deposition of C3 within the amyloid plaques [15]. Aging of the T Lymphocytes Thymus is a primary lymphoid organ that is central for the proliferation and development of the T lymphocyte precursors generated in the bone marrow into mature naïve T lymphocytes. The thymic gland is the largest in the newborn and involutes with age to reach about 5% of the size in newborns in 60 years old men. In people with Down syndrome and DiGeorge syndrome, thymic involution occurs early in life. In addition, zinc deficiency and malnutrition can cause thymic atrophy. The decrease in thymic size occurs as a result of atrophic changes in the medulla and cortex of the thymus and replacement of thymic tissue with adipose tissue. With that, the functional Exp Rev Immunol Vaccine Informat ISSN: 2056-7812 role of thymus in the development of naïve mature T cells from bone marrow progenitors diminishes and this results in much lower numbers of naïve T cells (CD45RA+CCR7+CD28+CD27+) in the elderly. In young adults aged 30 years or less, there are about 300 billion T cells of which 1-2% are circulating and about 50% are naïve T cells [16]. With the involution of thymus with age, the output of new naïve T cells generated in the thymus declines to about 5% by the age of 55 years. However, decline in the total numbers of naïve T cells develops much more steadily with age as T cell maintenance is more or less maintained by direct proliferation of existing naïve T cells [17]. Simultaneously and because of frequent encounters with various pathogens during the life span, the numbers and frequency of memory effectors T cells increases. The frequency of CD28- memory T cells that are associated with aging also increases. It is a property of these cells to expand upon encountering one of the persistent pathogens such as cytomegalovirus (CMV). Up to a quarter of the CD8+ T cells may be specific for a single CMV antigen in the elderly [18]. It is believed that constant exposure to antigens (such as CMV antigens) leads to exhaustion of these cells, loss of co-stimulatory molecules such as CD28 and CD27 and terminal differentiation with expression of CD45RA and CD57 markers. The loss of CD28 is permanent, so, these cells, although capable of expanding in response to the antigen that they are specific for, are unable to proliferate and respond to any other antigens. In addition, these accumulated memory CD8+ T cells seem to be suppressing the generation and proliferation of naïve T cells. Upon release of naïve mature CD4+ T cells from the thymus into the circulation, they encounter antigens-MHC molecule complexes and differentiate into different subtypes depending predominantly on the cytokine milieu at that time. Many different subtypes of CD4+ T cells are known now and are distinguished from each other by the expression of cell surface markers and the cytokines that they secrete. Those include Th1 cells that secrete IFNγ, Th2 cells that secrete IL-4, IL-5, IL-9, IL-10 and IL-13, TH17 (produce IL-17, associated with autoimmune disease) [19], Th22 (produce IL-22, skin homeostasis) [20], follicular helper T cells (Tfh) found within B cell follicles in the lymphoid organs [21], induced regulatory T cells (iTreg) [22], regulatory T cells type 1 (Tr1) [23] and T helper 9 cells (Th9) [24]. Functionally distinct populations of T helper cells are separated Vol 2 Iss 1 pp 54-61 Citation: Stevceva L. Aging and Vaccines. Exp Rev Immunol Vaccine Informat. 2015; 2(1): 54-61. by expression of CD45RA and CCR7 into naïve CD45RA+CCR7+, central memory CD45RACCR7+, effector memory CD45RA-CCR7- and effectors memory RA+ cells CD45RA+CCR7[25]. Terminally differentiated effector T cells loose expression of CD27 first and then of CD28. Changes with aging in the helper T cells (CD4+ T cells), are not very pronounced until the age of 65. One of the early indicators that T cells are undergoing senescence is the decreased production of IL-2. The frequency of naïve CD4+ T cells decreases while the frequency of memory CD4+ T cells increases with age. There is also a decrease in CD4/CD8 T cell ratios with accumulation of dysfunctional exhausted memory CD8+ T cells. A progressive increase of the numbers of CD4+ T cells lacking CD28 co-stimulatory molecule is seen and in some individuals over the age of 65 the population of CD4+CD28- T cells can comprise as much as 50% of the total pool of CD4+ T cells. CD28 molecule is involved in activation of T cells, IL-2 production and promotion of T cell proliferation so loss of CD28 expression in the elderly is associated with a loss of immune system responsiveness [26]. CD4+CD28- T cells express NK cell receptors and have an increased expression of granzyme B and perforin that are released upon TCR stimulation (reviewed in [26]. They have a low activation threshold and this could play a role in autoimmunity. TCR diversity is drastically reduced in individuals over the 65 years of age. In addition the ratio of regulatory T cells versus effectors T cells is increased in the aging population shifting the balance toward regulatory T cells [27]. A catastrophic loss of the CD4+ T cell population occurs in the seventh decade of life [28]. CD40 ligand expression is also diminished in aging CD4+ T cells. The CD40-CD40L interaction is crucial for development of T cell dependent antibody responses. It is believed that the T helper cell via CD40-CD40L interaction provides signals to the B cell that induce proliferation, immunoglobulin switching, antibody production and rescue from apoptosis. This is why, decreased expression of CD40L in aging helper T cells this results in poor antibody responses to T cell dependent (protein) antigens. Aging of the B Lymphocytes Changes in aging B lymphocytes have not been sufficiently researched and reports have been controversial. Most of the researchers agree that the numbers and function of B lymphocytes Exp Rev Immunol Vaccine Informat ISSN: 2056-7812 declines with age. The population of naïve B cells declines more rapidly and is accompanied by appearance of more exhausted memory B cells (CD19+IgD−CD27−). These cells can be stimulated to secrete immunoglobulins but their ability to be activated by various stimuli is low [29]. The affinity of the antibodies produced also decreases because of the general isotype switch from IgG to IgM [18]. B cell clonal expansion is also reported. These large B cell clones have only been identified in patients over 70 years old. The number of B cells that are specific for autoantigens increases. Changes in Cytokines Secretion with Aging Aging is accompanied by chronic low-grade inflammation and increased levels of proinflammatory cytokines such as IL-6 and TNF-a [30]. The chronic low grade inflammation promotes atherogenic profile and correlates with increased mortality [31]. In vivo stimulation with Escherichia coli lipopolysaccharide (LPS) for 24 hours induced significantly lower concentrations of TNFα and IL-1 in the elderly compared to young patients while no difference was found in IL-6 concentrations in response to LPS. AlvarezRodriguez et al. described increased levels of IL1β in addition to IL-6 and TNFα in individuals aged 60 years and older. In the same study, increased levels of circulating IL-10 and decreased levels of IL-17 were also detected [32]. Decreased levels of IL-7 within the thymus have been reported with aging. As IL-7 is believed to be important for thymocytes survival this decrease might be contributing to thymus involution and the reduction of the naïve T lymphocytes pool in the elderly (reviewed in [16]). Aging and Immunization The above-described changes that occur in immunosenescence increase susceptibility to infections in the elderly and greatly contribute to the increased incidence of tumors in these individuals. In addition, most of the elderly individuals suffer from other chronic diseases that might influence their resistance to infections. Increased incidence is especially noted for lower respiratory tract infections, tuberculosis, intraabdominal infections (cholecystitits, diverticulitis, appendicitis, and abscesses), infective endocarditis, bacterial meningitis, urinary tract infections, skin and soft tissue infections and herpes zoster. In addition to the increased incidence, elderly individuals have 3 times greater Vol 2 Iss 1 pp 54-61 Citation: Stevceva L. Aging and Vaccines. Exp Rev Immunol Vaccine Informat. 2015; 2(1): 54-61. mortality rate than younger adults suffering from the same disease [33]. There are several factors contributing to this. First, diagnosing infections in the elderly might be a greater problem as about 25% of the seniors fail to elicit fever in response to infection. Also, the presentation of the infection may often be atypical in this population with acute confusion or delirium as a dominant finding. Coexisting chronic diseases contribute to the difficulties in overcoming the infection in this population [33]. Finally, there are a number of age-related physiological changes (especially those related to renal function) that affect the pharmacokinetics and pharmacodynamics of drugs including antibiotics in the elderly. All these factors greatly increase the need to protect the elderly against infections. For example, in the US from 1976-2007, adults aged ≥ 65 years consistently accounted for approximately 90% of all influenza-related deaths during this period. Risk of influenza-associated death is the highest among the eldest individuals rendering individuals over 85 years of age 16 times more likely to die from influenza-associated disease that those aged 65-69. Because of this, WHO recommends annual immunization against influenza in this group of people [34]. However, immunosenescence also affects responses to immunization so; efficacy of current influenza vaccines in the elderly is 17-53% as opposed to 70-90% in healthy adults [35]. As reported by the same authors, seroconversion and seroprotectionis about ¼ as strong for the H1 and B antigens of influenza vaccine and about ½ for H3 antigens compared to the one in young people. The efficacy of most of currently available vaccines is related to inducing sufficient antibody response against the vaccine antigens. Although most of the available data on immune responses in the elderly is related to T cells responses, the dysregulation of the helper T cell function does influence humoral immune responses especially those directed to protein antigens. Several of the immune players outlined above play a role in the decline of the immune responses to immunization in the elderly (Figure 1). As described in Figure 1a legend, the injected vaccine antigens are bound by the dendritic cells of the skin, a process that activates these DCs and initiates migration to the draining lymph nodes. In the elderly, this process is dysregulated as the capacity of DCs to migrate towards the draining LNs is impaired. Thus lower numbers of activated DCs carrying the antigens reach the draining LNs where they present the antigens to the already lower numbers of naïve T cells. The decreased expression of the CD40 Exp Rev Immunol Vaccine Informat ISSN: 2056-7812 ligand on T lymphocytes impairs antigen presentation by macrophages and B lymphocytes to Th1 CD4+ helper T cells. In addition, many of the naïve T cells in the elderly do not express the CD28 co-stimulatory antigen that is required for successful activation of the naïve T cell. The cumulative effect is a much lower numbers of activated T cells. These activated T cells also produce much smaller quantity of IL-2, the cytokine that is needed for T cell proliferation and differentiation into memory and effectors T cells. B cell activation is also impaired partially because of the lower numbers of naïve B cells, but also because of general immunoglobulin switch to IgM rather than IgG that contributes to the impaired immune response in the elderly. Figure 1a: Immune response at the site of vaccine injection. Injection of the vaccine results in uptake of the antigens by the conventional (myeloid) dendritic cells of the skin. The cDCs than become activated and migrate to the draining lymph nodes where they present the antigen and induce immune responses. This figure was prepared using the Biomedical-PPT-Toolkit-Suite of Motifolio Inc., USA. These are the events that most likely contribute the most to the much lower immune responses to vaccination in the elderly compared to healthy young adults (see schematic diagram in Figure 2). This was also reported in a study looking into antibody responses to vaccination with an inactivated flavivirus vaccine against tick-borne encephalitis (TBE) [36]. Although the amount of antibodies produced in response to the vaccination in the group over 50 years of age was about 1/3 of the one found in young adults, the avidity and the functional quality of the antibodies was comparable in both groups. In contrast, immune response to T cell independent antigens such as capsular polysaccharides in the 23-valent Vol 2 Iss 1 pp 54-61 Citation: Stevceva L. Aging and Vaccines. Exp Rev Immunol Vaccine Informat. 2015; 2(1): 54-61. pneumococcal vaccine was found to be satisfactory in a study conducted in Finland in people aged 65-91 years [37]. Figure 1b: Immune response in the draining lymph node after vaccine injection. In the draining lymph node, the primed cDC presents the antigen to naïve helper T cells. This interaction activates the naïve Th lymphocyte to secrete cytokines (especially IL-2 that stimulates proliferation of T lymphocytes). In order for this activation to occur two signals are needed: 1. Interaction of the Ag-MHC Class II complex with TCR receptor on the T cells and 2. A second, costimulatory signal that is generated by binding of the co-stimulatory molecule CD28 on T cells with CD80 or CD86 on the APC (DC or macrophage). Once both signals are generated and the T cell is activated, the resulting secretion of IL-2 will induce proliferation and differentiation of T cells into memory and effector T cells that are specific for the given antigen. Interaction of the helper T cell with the naïve B cells via the CD40 ligand will activate naïve B cells to proliferate and differentiate into memory and effector B cells (plasma cells) that are specific for the given antigen and produce Ag-specific antibodies. In the elderly, this process is affected by several factors such as lower numbers of available naïve T cells, decreased expression of co-stimulatory molecule CD28 that is normally needed for activation, decreased secretion of IL-2, decreased expression of the CD40 ligand that is needed for activation of B cells and finally, the general shift towards IgM antibodies with a lower percentage of IgG antibodies in the elderly. This figure was prepared using the Biomedical-PPT-Toolkit-Suite of Motifolio Inc., USA. Exp Rev Immunol Vaccine Informat ISSN: 2056-7812 Figure 2: Schematic diagram of the antibody responses to immunization in the elderly compared to healthy adults. Immunization in elderly people results in an immune response that is about ¼ of the one obtained in healthy adults. Based on the discussion presented above, the need to develop successful vaccines for our increasing aging population is greater than ever. The changes in the immune responses associated with aging though require new strategies aimed at improving the immune response. Those include using high doses of antigens such as the high dose trivalent influenza vaccine that is currently undergoing clinical trials [38]. Similarly, a dose-dependent increase in local cytokine production as well as increase in the systemic antibody titers was seen in patients given a double dose of the conjugate pneumococcal vaccine PCV7 and PCV9 [39]. Another approach is using adjuvants such as MF59 that increases antigen presentation to the B and T cells and has been in use in Europe for the influenza vaccine, ASO3 that has similar activity and the newest Matrix-M that increases traffic to the draining lymph nodes and is currently being tested in clinical trials. Improving cellular responses in the elderly could potentially be achieved by reversing thymus involution. It has been shown in animal experiments that supplementing IL-7 reverses the involution of the thymus (reviewed in [40]. Supplementation with human IL-7 in older subjects that have had chemotherapy is currently undergoing clinical trials. Removal of exhausted T cells and infusion of healthy helper T cells was also show to have a positive effect on the T cell activity. Vol 2 Iss 1 pp 54-61 Citation: Stevceva L. Aging and Vaccines. Exp Rev Immunol Vaccine Informat. 2015; 2(1): 54-61. References 1. M. Roser. Institute for New Economic Thinking. 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