Towards strengthening memory immunity in the ageing population
van der Heiden, Marieke
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van der Heiden, M. (2018). Towards strengthening memory immunity in the ageing population: Investigating the immunological fitness of middle-aged adults. Rijksuniversiteit Groningen.
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Ageing of the world population (and other challenges)
The increased life expectancy in combination with the baby boom after the Second World War leads to a rapidly ageing world population [1, 2]. The worldwide number of persons above 60 years of age is expected to be doubled in 2060, with the highest growth predicted for the oldest persons above the age of 80 [3]. This rapid ageing results in increased numbers of persons susceptible to disease and disability, causing a strong rise in health care costs [1, 2]. Of importance and in contrast with past generations, todays and future elderly are more frequently enjoying an active lifestyle, putting high demands on societal and health care facilities [4]. Furthermore, globalization and antibiotic resistance are additional challenges of the 21st century, also enhancing the infection pressure in older adults. Consequently, preventive measures, such as effective vaccination programs are of high importance to establish healthy ageing [5].
Ageing and infectious diseases
The increased susceptibility of the elderly towards infections, cancer, and autoimmune diseases, indicates that a broad range of geriatric diseases is linked to the immune system [6-10]. Importantly, the incidence of autoimmune diseases, such as rheumatoid arthritis, already strongly increases after the age of 50 [11].
Nowadays, respiratory infectious diseases cause a large disease burden in the elderly, of which influenza contributes most to morbidity and mortality [10, 12, 13]. Likewise, older adults are increasingly vulnerable to respiratory syncytial virus (RSV) [13], rhinovirus infections [10] as well as infection with Streptococcus pneumoniae. The latter pathogen is one of the major causative agents for the increasing incidence of bacterial pneumonia in the elderly [14, 15]. Along with the increased incidence of respiratory infections, the incidence of Herpes Zoster, caused by reactivation of the varicella zoster virus, is steadily increasing after the age of 50 [16]. Besides, the population herd immunity against infectious diseases in the total population may diminish as a consequence of increasing numbers of susceptible elderly [10, 17]. Consequently, protection of the elderly against infectious diseases is a prerequisite to establish healthy ageing and is therefore of high priority [18, 19].
Vaccination of the elderly
Next to the increased vulnerability of elderly persons towards infectious diseases, vaccines often induce suboptimal responses in the elderly. A vaccine routinely provided to older adults is the seasonal influenza vaccine. The effectiveness of this vaccine is strongly reduced with advancing age, resulting in an estimated efficacy of 30-50% in the elderly [23-26]. Correspondingly, lower humoral [27, 28] and altered cellular [29] vaccine responses were found in the elderly as compared to younger age groups.
Herd immunity
Herd immunity is defined as the resistance of a population to infection by infectious pathogens [20-22]. For many pathogens, susceptible individuals are indirectly protected against infection by immunization of the surrounding individuals. The proportion of individuals that needs to be immunized to induce herd immunity differs per pathogen and depends primarily on the infectivity, spreading method and viability of the pathogen. Moreover, factors such as seasonality, demographics of the population, age of the susceptible individuals, geographical area, and social habits also determine the level of herd immunity required to prevent the spread of a particular infectious disease [20, 22]. Providing herd immunity is the primary goal of national immunization programs.
Also, despite the recommendation of pneumococcal vaccination above the age of 65 [30], pneumococcal vaccine responses drop with advancing age [30-32], leaving part of the elderly unprotected. A routine vaccination program to protect against varicella zoster is another topic of debate, due to the low effectiveness of the currently available vaccine in the elderly [33, 34]. Furthermore, serological surveillance studies reveal that increasing numbers of elderly are unprotected against tetanus and diphtheria in certain European countries. An additional booster vaccination in these unprotected elderly persons induces antibodies above the protective threshold, but unfortunately this protection is of short duration [35]. Successful tetanus and diphtheria vaccination is strongly linked to the presence of high pre-vaccination antibody levels at elderly age [35]. Finally, primary vaccine responses against hepatitis B [36, 37] and yellow fever [38] are lower in the elderly. These findings indicate general reduced vaccine responsiveness in the elderly, as a consequence of immunological ageing.
Ageing of the immune system
Immunological ageing is associated with compositional changes in immune phenotype, starting already at the level of the precursors of immune cells; the hematopoietic stem cells [39]. Most importantly, with ageing, the balance between the lymphoid and myeloid lineage shifts towards the myeloid lineage, leading to fewer precursors of the lymphoid lineage [39]. Secondly, fat deposition in the bone marrow and thymus, along with thymic shrinkage, reduces the production and development of new lymphoid cells at older age even more [19, 40-45]. Maintenance of the thymic function with age differs substantially between mice and humans, underlining the importance of human studies on immune ageing [40]. In the following paragraphs the most important changes in both the adaptive and innate human immune system are discussed, of which a schematic representation is depicted in Figure 1.
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Figure 1. The effect of ageing on the immune system.
The most profound characteristics of the ageing immune system are described for both the adaptive (blue) and innate (orange) part of the immune system. The age related changes in the primary lymphoid organs (bone marrow and thymus) are indicated in red.
Ageing of the T-cell lineage and accelerating factors
Immunological ageing primarily affects the T-cell compartment, due to shrinkage of the thymus in early adulthood. Thymic function is reduced to 10% already at the age of 50 [40, 42], resulting in diminished production of naïve T-cells in both the CD4 and CD8 T-cell lineages. As a consequence, peripheral homeostatic proliferation of already existing naïve T-cells is enhanced [40, 42, 46]. This phenomenon may be related to the observation of increased numbers of CD4+CD45RA+CD25dim cells, displaying a naïve like phenotype, in healthy elderly, possibly preserving the naïve T-cell repertoire at older age [47]. Importantly, the decreased production of naïve T-cells provokes a diminished T-cell receptor (TCR) repertoire diversity, which is likely to negatively impact responses to de novo antigens [48, 49]. As a result of the antigenic pressure throughout the life-span, naïve T-cells are (antigen specifically) stimulated and differentiated into memory cells [40, 42, 46]. Subsequently, chronic antigen stimulation, for example by latent herpes viruses such as cytomegalovirus (CMV), leads to the accumulation of late-differentiated T-cells, which are mainly found in the CD8 T-cell compartment [50-55]. These late-differentiated cells possess short telomeres and might be less able to proliferate after stimulation [42, 56]. Therefore, these cells are often referred to as exhausted or senescent cells, although the exact functionality of these cells is still topic of debate and the senescent state of these cells might be reversible [57]. Currently, the clinical consequence of CMV infection at advanced age is unclear and is topic of extensive research [58].
In addition, the numbers of Treg cells increase with advancing age [59, 60] and are mainly of the memory Treg phenotype [61]. These results suggest enhanced suppression of immune responses at old age, due to disturbances in the balance between Treg and effector cells in the immune system [61]. As a side note, accelerated ageing of the T-cell lineage is observed in older males, indicating large effects of sex on the immune phenotype at old age [50-52, 62].
Ageing of the B-cell lineage
Although less pronounced than shifts in the T-cell compartment, also changes are observed in the B-cell lineage with advancing age. The main changes include a reduced production of B-cell progenitors as well as an accumulation of late-differentiated CD27- memory B-cells of limited specificity [44, 63, 64]. Secondly, reduced numbers of IgM+ B-cells are found with advancing age [63, 65], whereas the numbers of long-lived plasma cells also diminish as a result of decreased bone marrow survival niches for these cells [44, 66]. Accordingly, limited B-cell receptor (BCR) diversity is noticed in older persons [67, 68]. Moreover, aged B-cells possess a reduced capacity for proliferation [44], possibly related to diminished T-cell help to the B-cells in the germinal centres, since these meeting points for cellular interaction between B- and T-cells are found to decrease with age as well [44, 69]. Likewise, a reduced capacity for class switch recombination (CSR) [65] as well as an increased production of autoreactive antibodies [44, 68, 70] are observed in old B-cells. CMV infection is found to only minimally affect B-cell numbers and frequencies [71], whereas sex hormones, mainly estrogens, are found to positively affect (auto)antibody formation and B-cell proliferation [72].
Ageing of the innate immune system
As reviewed elsewhere [73, 74], also innate immunity, the first line of defence, undergoes changes with advancing age. Most noticeable is the remodelling process of natural killer (NK) cell phenotype and function. At first, although increases in NK cell numbers are noted with advancing age, the per cell cytotoxicity is reduced. Additionally, aged NK cells are frequently of the CD56dim phenotype, in contrast to CD56bright NK cells at younger age [73, 74]. Along with the diminished NK cell functions, neutrophils, monocytes, and macrophages show reduced functional capacity, such as chemotaxis, phagocytosis and apoptosis, whereas dendritic cells show reduced TLR signalling and a reduced capacity for antigen presentation [73, 74]. More specifically, an age-dependent reduction in the expression and activation of AIM2, crucial for innate signalling against certain bacteria and dsDNA viruses, was found [75]. Nevertheless, the absolute numbers of these cells are maintained with ageing [73, 74], likely caused by the shift towards the myeloid lineage with age [39]. Thus, although the
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numbers of innate immune cells tend to increase with ageing, the functionality of thesecells is generally less effective which may underlie reduced innate sensing and responses in immunosenescence.
In addition to the altered functionality of the innate immunity, aged innate immune cells produce increased amounts of pro-inflammatory cytokines and acute phase proteins (such as C-reactive protein (CRP)), resulting in a low-grade inflammatory state [9, 76, 77]. This so called inflammageing is thought to lead to hypo responsiveness thereby rendering innate immune cells less able to clear antigens or stimulate cells of the adaptive immune system [70, 74]. Up till now, chronic infection with CMV was not found to affect the inflammatory state [78].
Inflammageing and the senescence-associated-secretory phenotype
Inflammageing is the term used for the overall increase in (low-grade) inflammation with advancing age [9, 76, 77, 79]. This inflammageing is considered the feedback loop of life-long exposure to antigens that trigger inflammatory responses and subsequent tissue damage and production of reactive oxygen species (ROS) [9]. Alternatively, inflammageing may be the result of diminished mucosal resistance with ageing and leakage of microbial products, such as LPS, from the gut to the blood, referred to as the leaky gut syndrome [80, 81]. Also senescent cells may contribute to this low-grade inflammation, due to secretion of inflammatory mediators as a result of DNA damage, termed the senescence-associated-secretory phenotype [79].
Novel strategies for elderly vaccination
In view of the above summarized functional deterioration of the ageing immune system, referred to as immunosenescence, it is questioned at what ages specific vaccines demonstrate reduced effectivity and how the diversity of the elderly population affects vaccine responses [82]. Dedicated studies investigating the interaction between age, immune function and vaccine responses are warranted to discover alternative strategies to strengthen the memory immunity of elderly persons. Several novel approaches for elderly vaccination are proposed, such as high-dose vaccines, the use of new adjuvants, and the administration of vector based vaccines [83]. In addition, life-long vaccination schedules aiming to maintain memory immunity against infectious diseases over the entire span are a promising alternative [18, 26, 84]. We thus propose the development of life-long vaccination programs starting with childhood vaccinations, which remain extremely important to induce immunity, in combination with vaccination programs in middle-aged adults to ensure protection at a later age. Nevertheless, these vaccination programs have to be carefully considered, since some vaccines induce life-long protection after a single shot
and repeated vaccination might cause hypo responsiveness of the immune response [85]. Importantly, these life-long vaccination programs might strengthen the herd immunity in the total population [84]. Since the pace of immune ageing differs per individual [86], the development of chronological age based vaccination programs is challenging. Therefore, vaccination programmes should be based on biological age or even the ‘immunological age’ of individuals in so called personalised national immunization programs. Consequently, there is a large need for biomarkers that predict vaccine responses, preferably markers that can be measured earlier in life, to ensure that precautions can be taken before reaching old age [82, 87].
Immunosenescence
Immunosenescence is defined as the functional deterioration of the immune system due to ageing and or ageing mechanisms. This immunosenescence is often linked to increased susceptibility towards infectious diseases, cancer and autoimmunity [88, 89] and thus thought to contribute to increased morbidity and mortality in the elderly.
Predictive biomarkers for vaccine responsiveness
The discovery of predictive biomarkers for vaccine responsiveness is ongoing and proven to be challenging. At present, most information is obtained from influenza vaccine studies in the elderly. Several of these influenza studies, as well as a hepatitis B study, describe a positive association between the number of switched memory B-cells and vaccine responsiveness in the elderly [64, 90-92]. Moreover, high numbers of late-differentiated B-cells show a negative association with the humoral response to influenza vaccination [64], whereas also the level of activation-induced cytidine deaminase (AID) in stimulated B-cells, is found predictive for the vaccine response [93, 94]. Latent infection with CMV might negatively affect the B-cell responses towards influenza vaccination [95]. In addition, influenza vaccine responses are found to negatively associate with high numbers of late-differentiated CD4 and CD8 T-cells as well as memory Treg cells [61, 91]. Besides, associations between genetic signatures, innate immune functions, and miRNA expression levels with influenza vaccine responsiveness are observed [90, 96, 97]. In line with these influenza vaccine studies, several other vaccines were used in explorative biomarker studies. First of all, high numbers of Treg cells, as well as CMV specific late-differentiated CD4 T-cells negatively affect varicella zoster vaccine responses in the elderly [98]. In addition, the yellow fever vaccine is more successful in elderly participants possessing high numbers of recently produced naïve T-cells as well as high numbers of peripheral dendritic cells [38]. On the other hand, an explorative biomarker study using a booster vaccination against diphtheria and tetanus in the elderly, did not reveal immune markers related to the vaccine response [35]. These studies might
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indicate differences in prediction between viral and bacterial vaccines. Of importance,pre-vaccination immunity often confounds the discovery of predictive biomarkers [27, 35, 92]. Similarly, sex frequently influences vaccine responses, although the exact effects of sex at advanced age are unknown. In general, stronger humoral responses are often found in females and might be caused by stimulating effects of estrogens, contrary to suppressive effects of testosterone in males [99, 100]. Therefore, sex is an important factor that has to be taken into account in biomarkers discovery studies.
The hypothesis: vaccination of middle-aged adults
The deleterious effects of immune ageing are suggested to be more pronounced for de novo vaccine responses. Due to the early appearance of the first signs of immune ageing, it is suggested that immunizations against new antigens have to be established before the onset of immunosenescence, most probably in the 5th or 6th decade of life [17]. Consequently, we propose middle-aged adults as an interesting target group for future vaccine interventions in order to strengthen the memory immunity, both by primary and recall vaccinations, before reaching old age. Subsequently, the memory immunity against infectious diseases of these future elderly might be improved until high age (Figure 2). However, knowledge on the immunological fitness of middle-aged adults, and factors affecting their immune function, is currently limited.
Figure 2. Hypothesis of this thesis; vaccination of middle-aged adults to strengthen the memory immunity of the elderly.
1). Currently, vaccine programmes for babies and children are well accepted. 2). In view of the ageing population,
prevention of the elderly against infectious diseases is a priority, but challenged by the developments of immunosenescence leading to reduced vaccine efficacy. 3). Timely vaccination of middle-aged adults might strengthen the memory immunity of the future elderly. However, knowledge on the immunological fitness of the middle-aged adults is currently limited and therefore the aim of study in this thesis.
Primary and recall vaccination
After primary vaccination, the immune system is exposed to an antigen for the first time (de novo antigen). A primary immune response thus takes time to develop and leads mainly to the production of IgM antibodies. After primary immunization, immunological memory is induced that aids a rapid and strong (IgG based) immune response after a secondary encounter with the same antigen. Active secondary immunizations by vaccination are also called recall or booster vaccinations [101].
Research aim
In this thesis, we aim to provide insight into the immunological fitness of middle-aged adults between 50 to 65 years of age. The following research questions are addressed: 1. How do sex and chronic viral infection with CMV affect the immune phenotype of
middle-aged adults?
2. How do middle-aged persons respond to a primary immunization with vaccine antigens towards which no or (very) low pre-vaccination immunity exists?
3. What is the immunogenicity of the varicella zoster vaccine in middle-aged adults? 4. Can we find predictive biomarkers for vaccine responsiveness in middle-aged adults?
Study outline
In order to answer these research questions, a clinical trial (study acronym: StimulAge study) with two different study arms was conducted in Dutch middle-aged adults (50-65 years of age). In total 255 middle-aged adults participated in this study. In blood samples from all participants a detailed immune phenotyping was performed, using absolute cell numbers of a comprehensive set of immune cell subsets.
Within the first study arm, 204 middle-aged adults were vaccinated with the tetravalent meningococcal vaccine conjugated to tetanus toxoid (MenACWY-TT). The meningococcus is used here as a model antigen, to initiate a primary immune response, without the interference of high pre-vaccination immunity obtained by natural contacts. These low levels of pre-vaccination immunity against the meningococcal groups was expected in the middle-aged adults since the circulation of meningococci C (MenC) is virtually absent after the mass vaccination campaign in 2002 and the historical circulation of meningococci W (MenW) and Y (MenY) has been low. This low historical circulation was confirmed by a large serological surveillance study, performed every ten years in the Netherlands, revealing low levels of meningococcal group specific IgG antibodies in Dutch adults (Figure 3) [102].
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0 0.5 1 1.5 2 2.5 3 3.5 Age at bloodsamplingMenA MenC MenW‐135 MenY
Figure 3. The age specific meningococcal IgG antibody concentrations in the Dutch population (2006-2007) after the Meningococcus C specific mass vaccination campaign [102].
The second study arm focusses on the responses towards an early varicella zoster vaccination in the middle-aged adults. The incidence of Herpes Zoster, caused by reactivation of the varicella zoster virus (VZV), strongly increases with age and is caused by a drop in VZV-specific cell mediated immunity (CMI) [16, 103, 104]. The implementation of the varicella zoster vaccination in national immunization programs is topic of fierce debate, due to low effectiveness of this vaccine in the elderly [33, 34]. Consequently, timely vaccination of middle-aged adults might be an alternative option to increase the VZV-specific CMI before reaching old age.
Thesis outline
The first research question is addressed in Chapter 2. In this chapter, effects of sex and latent infection with CMV, as well as the interaction between sex and CMV infection, on the absolute cell counts are investigated. This analysis provides a better understanding of the interaction between the immune phenotype and environmental factors such as CMV during the ageing process.
In Chapter 3, we investigate the immunogenicity of the primary meningococcal vaccination in the middle-aged adults, in order to answer the second research question. Additionally, the long-term protection of this vaccine is predicted using bi-exponential decay modelling. Subsequently, in Chapter 4, the primary vaccine responses in the middle-aged adults are compared with those in Dutch adolescence who received similar primary meningococcal vaccination [105]. This analysis provides information on early signs of immune ageing in the middle-aged adults.
The meningococcal polysaccharides in this vaccine are conjugated to a tetanus toxoid carrier protein in order to induce T-cell help in response to the meningococcal polysaccharides that are only recognized by B-cells. The T-cell response induced by the tetanus toxoid carrier protein in the middle-aged adults is investigated in Chapter 5. Also, the relation between the humoral vaccine response and the T-cell help towards the carrier is investigated in this chapter.
The third research question is addressed in Chapter 6 and describes the immunogenicity of a varicella zoster vaccination in middle-aged adults. In addition, predictive factors for the VZV vaccine responsiveness in middle-aged adults are described in this chapter as well. In order to answer the last research question, an explorative biomarkers study is described in
Chapter 7. In this chapter, the association between the pre-vaccination immune phenotype
and vaccine responsiveness is determined using multivariate redundancy analysis (RDA). Finally, the main findings of this thesis are summarized and remaining questions and future perspectives discussed in Chapter 8.
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