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Study of the Immune Response in the Elderly: Is It Necessary to Develop a Vaccine against Neisseria meningitidis for the Aged?

Study of the Immune Response in the Elderly: Is It Necessary to Develop a Vaccine against... Hindawi Journal of Aging Research Volume 2019, Article ID 9287121, 8 pages https://doi.org/10.1155/2019/9287121 Review Article Study of the Immune Response in the Elderly: Is It Necessary to Develop a Vaccine against Neisseria meningitidis for the Aged? 1,2 1,2 Gabriela Trzewikoswki de Lima and Elizabeth De Gaspari Department of Immunology, Adolfo Lutz Institute, São Paulo, Brazil Interunits Post-Graduate Program in Biotechnology, University of São Paulo, São Paulo, Brazil Correspondence should be addressed to Elizabeth De Gaspari; elizabeth.gaspari@ial.sp.gov.br Received 15 April 2019; Accepted 1 August 2019; Published 22 August 2019 Academic Editor: Carmela R. Balistreri Copyright © 2019 Gabriela Trzewikoswki de Lima and Elizabeth De Gaspari. *is is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Literature reports the association between aging and decline in the immune system function. *e elderly have a higher risk of developing infectious diseases and are often less responsive to vaccines that are effective in the young. *e case fatality rate of invasive meningococcal disease is higher in the elderly; therefore, vaccination for this population should be evaluated. Although new vaccines have been developed against Neisseria meningitidis, there is still a need to evaluate a vaccine for those older than 60 years, as the currently licensed vaccines are not indicated for this population. recognize and react to pathogen-associated molecular pat- 1. Introduction terns (PAMPs) and damage-associated molecular patterns (DAMPs) through specific receptors and play a role in Immune responses are essential to promote the organism’s defense. However, aging seems to be associated with the eliminating invasive pathogens. Besides, the innate immune dysfunction of the immune response [1]. *is process is system possess physical barriers, such as the epidermis [6]. called immunosenescence and is associated with increased Collectively, the main characteristics of the aging process susceptibility of the elderly to developing infections, cancer, regarding the innate system are the immune stimulation in and autoimmune diseases. Moreover, the responses to the basal level on the one hand and immune paralysis when vaccines are usually reduced in the elderly [2]. specific functions are needed, such as phagocytosis, che- Aging is associated with a paradox where a state of basal motaxis, presentation of antigens, and production of cyto- chronic inflammation, prevalent even in the absence of kines and reactive oxygen species (ROS), on the other hand diseases, coexists with a state of immunodeficiency [3]. *is [7]. *e expression of pattern-recognition receptors (PRRs) persistent inflammation, commonly called inflammaging, is and costimulatory molecules also seems to be decreased in the innate immune cells [8]. possibly associated with continuous exposure to antigens, combined with the increase in the secretion of proin- *e adaptive immune system is composed of cellular and flammatory cytokines by senescent cells and oxidative stress, humoral immune responses. T cells are the main compo- which involves the production of free radicals and toxic nents of the cellular response and are basically divided into products [4]. two populations, CD4+ and CD8+, according to their *e process of aging affects both innate and adaptive functions. CD4+ T cells are also called helper T cells and immune responses; however, the first seems to be less af- regulate the function of other cells of the immune system. fected [5]. Figure 1 shows the main changes associated with CD8+ T cells, also called cytotoxic T cells, are responsible for aging in cells of the innate and adaptive immune system. eliminating infected cells. B lymphocytes have the main function of producing antibodies and, therefore, are related *e innate immune response is the body’s first line of defense against pathogens. *e innate immune cells to the humoral immune response. *e adaptive immune 2 Journal of Aging Research Innate immune cells Age-associated changes (i) Phagocytosis (ii) Chemotaxis Neutrophils (iii) Apoptosis function (iv) ROS production (i) Antigen presentation (ii) Nitric oxide and superoxide production Macrophages (iii) TLR expression and function (iv) Phagocytosis (v) Cytokine and chemokine production (i) Cytolytic activity Natural killer cells (ii) Cytokine and chemokine production (iii) CD1 expression in NKT cells (i) IFN production (ii) Antigen uptake and presentation Dendritic cells (iii) Expression of MHC class II molecules (iv) Migration to lymph nodes Adaptive immune cells (i) Naive cell number (ii) Memory cell number T cells (iii) CD8+ T cell response, cytotoxicity, and proliferation (iv) CD4+ T cell response and proliferation (v) TCR diversity (i) Naive cell number (ii) Responses to new antigens (iii) BCR diversity B cells (iv) Antibody affinity and isotype switching (v) Signal transduction (vi) Expression of MHC class II molecules Figure 1: Changes associated with aging in cells of innate and adaptive immunity. response depends on the generation of a vast repertoire of As cytokines modulate the immune response, it has been antigen receptors in these cells and their subsequent acti- proposed that changes in the cytokine production may vation and clonal expansion. *e activation of the adaptive contribute to the functional defects of T cells. With aging, there is a change in the cytokine profile, for predominantly immune response depends not only on the recognition of antigens but also on secondary signs provided by the innate IL-4 and IL-10 [13]. Furthermore, the repertoire of T-cell receptors (TCRs) immune response [6]. *ymic involution is one of the most prominent charac- present in individuals between 70 and 85 years is signifi- teristics of aging and is associated with the decline of naive cantly smaller than the one found in individuals between 20 Tcells. During the last decades, it has become increasingly clear and 35 years [10]. Senescent T lymphocytes also present that, along the adulthood, the homeostasis of T cells is main- reduced expression of cell surface receptors, such as CD28 tained primarily by the peripheral proliferation of naive and (important in lymphocyte activation) and CD27 (associated memory T cells and not by the production of new T cells [9]. with the proliferative capacity of T lymphocytes) [14, 15]. When evaluated separately, T cell subsets show a reduction *e expression of the costimulatory molecule CD40L can of two- to fivefold in the number of naive T cells in healthy also be reduced in CD4+ T cells of elderly individuals, which can affect the response in the germinal centers [16]. elderly individuals [10]. Also, naive Tcells of the elderly present decreased cytokine production, less clonal expansion, and *e number of B-cell precursors in the bone marrow of decreased expression of activation markers after the primary the elderly remains relatively stable, but there is a significant antigen presentation by antigen-presenting cells (APCs) [11]. reduction in the number of mature B cells in the peripheral Despite that the number of effector and memory T cells blood [17]. Also, there are a limited diversity of B-cell re- increases with age, the vaccination response in the elderly is ceptors (BCRs) and a decrease in the population of naive impaired, which is indicative of the gradual decline of B cells. *e intrinsic defects of B cells related to aging include functional response [12]. In fact, it is observed that senescent a decrease in the expression of activation-induced cytidine T cells present defects in activation, memory, signaling, deaminase (AID) and a decreased number of switched memory B cells [1]. *is leads to the production of short- clonal expansion, and development of antigen-specific ef- fector cells and long-lived memory cells [5]. lived, low-affinity antibodies that may have defects in isotype Journal of Aging Research 3 switching, reflecting a low ability to respond effectively conducted in Italy showed that the risk of hospitalization for against pathogens [11]. influenza or pneumonia was 25% lower in subjects vacci- nated with the adjuvanted vaccine than in those vaccinated with the nonadjuvanted vaccine [27]. Another example is the 2. Vaccination in the Elderly novel herpes zoster subunit vaccine, which contains the *e decrease in birth rate and increase in life expectancy varicella-zoster virus E glycoproteins and the AS01B adju- have caused the progressive rise of the elderly population vant, yielding 97.9% efficacy, regardless of age, unlike the worldwide [5]. *e increasing population density of those vaccine ZOSTAVAX mentioned above, which presents aged more than 65 years requires new strategies to ensure reduced efficacy in the elderly [28]. that health and well-being remain with advancing age. Infections are one of the leading causes of morbidity and 3. Meningococcal Vaccines mortality in the elderly and may present different clinical features of those observed in young adults, regarding signs, Meningococcal disease can progress very rapidly, and death symptoms, and progression, which can hinder the early can occur within 24 to 48 hours after the initial symptoms. diagnosis and impair the treatment, making their prevention *e response of B cells to meningococcal infection may not even more important [5]. occur quickly enough since immune memory will mount an *e susceptibility to infections, such as influenza virus, adequate defense against a known antigen in approximately meningococcus, group B streptococcus, pneumococcus, 2 to 7 days, and the incubation period of meningococcal respiratory syncytial virus, and varicella-zoster virus, be- disease is 3 to 4 days. *erefore, the maintenance of pro- comes higher in this age group. As such, they need more tective levels of circulating antibodies by vaccination is frequent booster vaccinations, in many cases with vaccines important in prevention against meningococcal disease [29]. specifically designed to stimulate the immune system of the Meningococcal vaccines produced from capsular poly- elderly to respond better to vaccination [18]. *erefore, saccharides were introduced in the 70s decade; however, vaccinating older people with existing vaccines or de- they are poorly immunogenic in toddlers and do not induce veloping new improved vaccines against pathogens that immunologic memory. *ese vaccines induce mainly IgM affect this population is one of the main interventions to and short-lived bactericidal antibodies. Besides, repeated prevent infections and ensure the health of the elderly. immunization with this vaccine may induce hypores- Few vaccines are recommended to the elderly, such as ponsiveness [30, 31]. *e conjugation of the capsular influenza, herpes zoster, diphtheria, tetanus, pertussis, hepa- polysaccharide to a carrier protein improves its immuno- titis, and pneumococcal vaccines [11]; however, these vaccines genicity because it allows a T-cell-dependent response, in- are less effective in the aged population than in the young [19]. ducing high-avidity antibodies, higher bactericidal activity, *e Centers for Disease Control and Prevention (CDC) immunologic memory, and responsiveness to booster doses estimates that the efficacy of the influenza vaccine in those [32]. Nowadays, polysaccharides and conjugated vaccines aged less than 65 years is 70–90%, whereas in those aged against serogroups A, C, W-135, and Y are available [33]. 65 years or older, the efficacy is 30–40% [20]. Likewise, the Polysaccharide and conjugated vaccines to serogroup B were efficacy of the attenuated virus vaccine against herpes zoster developed; however, these vaccines did not induce an ef- (ZOSTAVAX ) decreases with aging: 69.8% in individuals fective humoral response [34, 35], and this might be due to the structural similarity of the capsular polysialic acid between 50 and 59 years, 64% in people between 60 and 69 years, 41% in people between 70 and 79 years, and only α2⟶ 8 and the embryonic neural cell adhesion molecules (N-CAMs) [36]. *is similarity is a concern as it might lead 18% in individuals above 80 years [21]. *e most common approaches to improve the effec- to the development of autoimmunity. It has been reported tiveness of vaccines in the elderly include increasing the the presence of IgM antibodies is directed against embryonic antigenic content per dose, changing the route of admin- N-CAMs in the serum of patients suffering from group B istration, giving booster doses, and using adjuvants [22]. *e meningitis [37]. *e major concern in the administration of use of adjuvants has the aim to potentialize activation of this vaccine would be the risk in women who become APCs, cytokine production, and stimulation of B and Tcells. pregnant; if IgG antibodies against embryonic N-CAMs were Different routes of administration may deliver the antigen to developed after vaccination, there is a chance that these sites enriched with APCs, optimizing its activation and antibodies cross the placenta and cause damage to the fetal central nervous system [38]. *us, many researchers con- presentation of antigens. *e increase in the antigenic dose has the purpose to improve their presentation and, therefore, cluded that developing a MenB polysaccharide vaccine pre- the activation of T cells [23]. sented more risks than benefits. So, MenB vaccine Several strategies to improve the effectiveness of in- development was focused on subcapsular antigens, such as fluenza vaccines in the elderly were addressed successfully, outer membrane proteins (OMPs) and outer membrane such as the use of adjuvant MF59 [24], the increase in the vesicles (OMVs) [39]. 4CMenB (Bexsero ) and rLP2086 antigenic content from 15 μg to 60 μg per dose [25], and a (Trumenba ) are recently developed MenB vaccines, com- vaccine administered via the intradermal route rather than posed by OMPs; they are licensed in a few countries, and the the intramuscular route [26]. *ese vaccines stimulated a initial studies suggest good immunogenicity and safety [30]. higher humoral response compared to those previously In the United States, between 1998 and 2007, 14.4% of used, especially the MF59-adjuvanted vaccine. A study invasive meningococcal disease (IMD) cases occurred in 4 Journal of Aging Research individuals aged 65 years or more; at that same period, the response of the subjects older than 60 years in this study. *e case fatality rate (CFR) of this age group was 23.2%, the same occurred in the study of Ramasamy et al. [61], which compared the immunogenicity of a quadrivalent conjugate highest between any age groups [40]. Also, in the United States, between 2006 and 2015, IMD cases in subjects aged vaccine (MenACWY-CRM) with that of a quadrivalent >65 years accounted for 17.3% of total cases, and the CFR in polysaccharide vaccine (MenACWY-PS) in healthy adults those older than 85 years was higher than in any other age aged 18–70 years; both vaccines were considered immu- groups [41]. In Australia, in 2015, 20.1% of laboratory- nogenic, but again the older individuals were not evaluated confirmed cases of IMD occurred in people aged ≥65 years separately. [42]. In Japan, between 2013 and 2014, most cases of IMD *e few studies about the effectiveness of meningococcal occurred in adults older than 50 years [43]. Approximately vaccines in the elderly [56, 58] suggest that it would be 14.7% of IMD cases occurred in individuals older than possible to adapt the currently available conjugate vaccines to older individuals, which would be more viable than de- 50 years in an analysis of 25 European countries between 2004 and 2014 [44]. In France, between 2006 and 2015, 11.3% of veloping new vaccines specifically for the elderly. As de- scribed earlier in this article, some vaccines, such as IMD cases occurred in people aged 60 years or more, besides this age group presented the highest CFR [45]. Despite that FLUAD , Fluzone High-Dose , Intanza 15 μg (influenza), ® ® ® the incidence of IMD in the elderly is relatively low, the CFR and Shingrix (varicella-zoster virus), have been specifically is high, so we consider it is important to evaluate the use of designed to improve the elderly’s immune response. meningococcal vaccines to prevent disease in the elderly. However, because of the relatively low incidence of me- Table 1 presents characteristics of currently licensed ningococcal disease, it might not be interesting for the meningococcal conjugate and protein vaccines, and these pharmaceutical industry to develop a new meningococcal vaccines are not indicated to individuals over 55 years of age, vaccine targeting specifically the elderly. given the lack of studies. *e only meningococcal vaccine *e approach of expanding age indication to the already licensed to subjects older than 55 years is the plain poly- existing vaccines was used for the tetanus toxoid, diphtheria saccharide ACWY (Menomune ) [56]. In some countries, toxoid, and acellular pertussis (Tdap) and pneumococcal meningococcal vaccines are indicated for individuals over vaccines after studies indicated they were safe, well tolerated, 55 years considered at high risk (those with certain medical, and immunogenic in adults aged 65 years and older [62–65]. Furthermore, studies are being conducted to try to expand occupational, or lifestyle indications and travelers to areas with high endemic rates for the infection) [57]. the age indication of other existing vaccines, such as the Dbaibo et al. [58] evaluated the immunogenicity and rotavirus [66]. safety of a meningococcal conjugate ACWY-TT and a Further studies are required to ensure the safety and polysaccharide ACWY vaccine in adults over 55 years. After a efficacy of meningococcal vaccines in adults aged 65 years single dose of immunization, ≥93.2% of the individuals that and older, as it has been described several changes in the received the conjugated vaccine and≥93.9% of the individuals immune system of the elderly may lead to diminished that received the polysaccharide vaccine presented serum vaccine response. Furthermore, to our knowledge, there are bactericidal antibodies (rSBA) with titers ≥1 :128. *e no studies of meningococcal serogroup B vaccines such as individuals over 65 years exhibited vaccine responses lower 4CMenB (Bexsero ) and rLP2086 (Trumenba ) in in- ® ® than those aged 56–65 years. Given these results, they con- dividuals of this age group. cluded that these vaccines were immunogenic in the in- Perhaps, the vaccination of the elderly against N. dividuals evaluated. meningitidis is not considered a priority because of the low Stamboulian et al. [56] assessed the immunogenicity of a incidence of the disease. Nevertheless, we believe that given meningococcal conjugate ACWY-CRM197 and a poly- the increasing proportion of older people in the population saccharide ACWY vaccine in individuals aged 56–65 years. and the high CFR of meningococcal disease in the elderly, it *e conjugate vaccine was considered superior to the would be interesting to evaluate the insertion of these polysaccharide one, achieving a higher percentage of vaccines in the immunization programs for this age group, seroresponse for all serogroups. *e immunogenicity of especially in countries with high and intermediate endemic MenACWY-CRM was similar between the groups aged disease and during outbreaks. Also, vaccines can generate 19–55 and 56–65 years. other benefits, such as a lower overall cost of healthcare. Hutchins et al. [59] described that elderly individuals Studies are required to evaluate if introducing menin- show decreased levels of antibodies after immunization with gococcal vaccines for adults aged 65 years and older into the meningococcal ACWY polysaccharide vaccine than immunization programs is cost-effective, and in this way, young subjects and that the level of these antibodies de- health authorities can decide whether the benefit of vacci- creased more rapidly. Besides, bactericidal activity in those nating the elderly with these vaccines is worthwhile. Me- aged 60–88 years was significantly lower. ningococcal disease is one of the several infections that can Lalwani et al. [60] assessed the immunogenicity of a affect the elderly. Further studies about the burden of the meningococcal ACWY-CRM conjugate vaccine in healthy infectious diseases in the elderly are necessary to define Indian subjects aged 2 to 75 years and concluded that it public health priorities and assess the need for vaccination generated a robust immune response; however, the aged against these pathogens. subjects were included in a group of people aged 19– Given the fact that the elderly are more likely to evolve to 75 years, and so it was difficult to distinguish the specific death when infected with N. meningitidis and the lack of Journal of Aging Research 5 Table 1: Meningococcal conjugate and protein vaccines currently licensed and their composition, age indication, and immunization schemes. Age group Vaccine Pharma Composition Immunization scheme Reference indicated Meningococcal C 2–12 months: two doses with an interval oligosaccharide >2 months of GlaxoSmithKline of at least 2 months between the doses Menjugate conjugated with age, teenagers, [46] (GSK) >12 months, teenagers, and adults: a CRM197 + aluminum and adults single dose hydroxide Meningococcal A, C, 9 months 9–23 months: two doses with an interval Y, and W-135 Menactra Sanofi Pasteur through 55 years of at least 3 months between the doses [47] polysaccharides of age 2–55 years: a single dose conjugated with DT Meningococcal A 1 year of age, polysaccharide Serum Institute of adolescents, and MenAfriVac conjugated with A single dose [48] India adults up to TT + aluminum 29 years of age phosphate Meningococcal C <12 months: three doses with an oligosaccharide >6 weeks of age, interval of at least 1 month between the Meningitec Pfizer conjugated with adolescents, and doses [49] CRM197 + aluminum adults >12 months, adolescents, and adults: a phosphate single dose Meningococcal C 2–12 months: two doses with an interval oligosaccharide >2 months of of at least 2 months between the doses Meninvact Sanofi Pasteur conjugated with age, teenagers, [50] ® >12 months, teenagers, and adults: a CRM197 + aluminum and adults single dose hydroxide 2–6 months: four doses, administrated Meningococcal A, C, at 2, 4, 6, and 12 months of age Y, and W-135 >2 months 7–23 months, nonvaccinated: two doses GlaxoSmithKline Menveo oligosaccharides through 55 years with an interval of at least 3 months [51] ® (GSK) conjugated with of age between the doses CRM197 >2 years, teenagers, and adults through 55 years: a single dose Meningococcal C 2–12 months: two doses with an interval polysaccharide >2 months and of at least 2 months between the doses Neisvac-C Baxter conjugated with [52] adults >12 months, teenagers, and adults: a TT + aluminum single dose hydroxide Meningococcal A, C, Y, and W-135 >12 months and Nimenrix Pfizer A single dose [53] ® polysaccharides adults conjugated with TT 2–5 months: three doses with an interval not less than 1 month; booster dose between 12 and 15 months 3-5 months: two doses with an interval of at least 2 months between the doses; booster dose between 12 and 15 months NHBA + NadA + 6–11 months: two doses with an interval GlaxoSmithKline fHbp + OMVs from >2 months and of at least 2 months between the doses; Bexsero [54] (GSK) NZ98/254 + adults booster dose in the second year of life aluminum hydroxide 12–23 months: two doses with an interval of at least 2 months between the doses; booster dose with an interval of 12 to 23 months between primary series 2 years and adults: two doses with an interval of at least 1 month between the doses *ree-dose schedule: 0, 1–2, and 6 Wyeth fHbp + aluminum 10 to 25 years of Trumenba months [55] ® Pharmaceuticals phosphate age Two-dose schedule: 0 and 6 months CRM197: Corynebacterium diphtheriae cross-reactive material 197; DT: diphtheria toxoid; fHbp: factor H binding protein; NadA: Neisseria adhesin A; NHBA: Neisserial heparin binding antigen; OMVs: outer membrane vesicles; TT: tetanus toxoid. 6 Journal of Aging Research [12] A. 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Study of the Immune Response in the Elderly: Is It Necessary to Develop a Vaccine against Neisseria meningitidis for the Aged?

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Copyright © 2019 Gabriela Trzewikoswki de Lima and Elizabeth De Gaspari. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
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Hindawi Journal of Aging Research Volume 2019, Article ID 9287121, 8 pages https://doi.org/10.1155/2019/9287121 Review Article Study of the Immune Response in the Elderly: Is It Necessary to Develop a Vaccine against Neisseria meningitidis for the Aged? 1,2 1,2 Gabriela Trzewikoswki de Lima and Elizabeth De Gaspari Department of Immunology, Adolfo Lutz Institute, São Paulo, Brazil Interunits Post-Graduate Program in Biotechnology, University of São Paulo, São Paulo, Brazil Correspondence should be addressed to Elizabeth De Gaspari; elizabeth.gaspari@ial.sp.gov.br Received 15 April 2019; Accepted 1 August 2019; Published 22 August 2019 Academic Editor: Carmela R. Balistreri Copyright © 2019 Gabriela Trzewikoswki de Lima and Elizabeth De Gaspari. *is is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Literature reports the association between aging and decline in the immune system function. *e elderly have a higher risk of developing infectious diseases and are often less responsive to vaccines that are effective in the young. *e case fatality rate of invasive meningococcal disease is higher in the elderly; therefore, vaccination for this population should be evaluated. Although new vaccines have been developed against Neisseria meningitidis, there is still a need to evaluate a vaccine for those older than 60 years, as the currently licensed vaccines are not indicated for this population. recognize and react to pathogen-associated molecular pat- 1. Introduction terns (PAMPs) and damage-associated molecular patterns (DAMPs) through specific receptors and play a role in Immune responses are essential to promote the organism’s defense. However, aging seems to be associated with the eliminating invasive pathogens. Besides, the innate immune dysfunction of the immune response [1]. *is process is system possess physical barriers, such as the epidermis [6]. called immunosenescence and is associated with increased Collectively, the main characteristics of the aging process susceptibility of the elderly to developing infections, cancer, regarding the innate system are the immune stimulation in and autoimmune diseases. Moreover, the responses to the basal level on the one hand and immune paralysis when vaccines are usually reduced in the elderly [2]. specific functions are needed, such as phagocytosis, che- Aging is associated with a paradox where a state of basal motaxis, presentation of antigens, and production of cyto- chronic inflammation, prevalent even in the absence of kines and reactive oxygen species (ROS), on the other hand diseases, coexists with a state of immunodeficiency [3]. *is [7]. *e expression of pattern-recognition receptors (PRRs) persistent inflammation, commonly called inflammaging, is and costimulatory molecules also seems to be decreased in the innate immune cells [8]. possibly associated with continuous exposure to antigens, combined with the increase in the secretion of proin- *e adaptive immune system is composed of cellular and flammatory cytokines by senescent cells and oxidative stress, humoral immune responses. T cells are the main compo- which involves the production of free radicals and toxic nents of the cellular response and are basically divided into products [4]. two populations, CD4+ and CD8+, according to their *e process of aging affects both innate and adaptive functions. CD4+ T cells are also called helper T cells and immune responses; however, the first seems to be less af- regulate the function of other cells of the immune system. fected [5]. Figure 1 shows the main changes associated with CD8+ T cells, also called cytotoxic T cells, are responsible for aging in cells of the innate and adaptive immune system. eliminating infected cells. B lymphocytes have the main function of producing antibodies and, therefore, are related *e innate immune response is the body’s first line of defense against pathogens. *e innate immune cells to the humoral immune response. *e adaptive immune 2 Journal of Aging Research Innate immune cells Age-associated changes (i) Phagocytosis (ii) Chemotaxis Neutrophils (iii) Apoptosis function (iv) ROS production (i) Antigen presentation (ii) Nitric oxide and superoxide production Macrophages (iii) TLR expression and function (iv) Phagocytosis (v) Cytokine and chemokine production (i) Cytolytic activity Natural killer cells (ii) Cytokine and chemokine production (iii) CD1 expression in NKT cells (i) IFN production (ii) Antigen uptake and presentation Dendritic cells (iii) Expression of MHC class II molecules (iv) Migration to lymph nodes Adaptive immune cells (i) Naive cell number (ii) Memory cell number T cells (iii) CD8+ T cell response, cytotoxicity, and proliferation (iv) CD4+ T cell response and proliferation (v) TCR diversity (i) Naive cell number (ii) Responses to new antigens (iii) BCR diversity B cells (iv) Antibody affinity and isotype switching (v) Signal transduction (vi) Expression of MHC class II molecules Figure 1: Changes associated with aging in cells of innate and adaptive immunity. response depends on the generation of a vast repertoire of As cytokines modulate the immune response, it has been antigen receptors in these cells and their subsequent acti- proposed that changes in the cytokine production may vation and clonal expansion. *e activation of the adaptive contribute to the functional defects of T cells. With aging, there is a change in the cytokine profile, for predominantly immune response depends not only on the recognition of antigens but also on secondary signs provided by the innate IL-4 and IL-10 [13]. Furthermore, the repertoire of T-cell receptors (TCRs) immune response [6]. *ymic involution is one of the most prominent charac- present in individuals between 70 and 85 years is signifi- teristics of aging and is associated with the decline of naive cantly smaller than the one found in individuals between 20 Tcells. During the last decades, it has become increasingly clear and 35 years [10]. Senescent T lymphocytes also present that, along the adulthood, the homeostasis of T cells is main- reduced expression of cell surface receptors, such as CD28 tained primarily by the peripheral proliferation of naive and (important in lymphocyte activation) and CD27 (associated memory T cells and not by the production of new T cells [9]. with the proliferative capacity of T lymphocytes) [14, 15]. When evaluated separately, T cell subsets show a reduction *e expression of the costimulatory molecule CD40L can of two- to fivefold in the number of naive T cells in healthy also be reduced in CD4+ T cells of elderly individuals, which can affect the response in the germinal centers [16]. elderly individuals [10]. Also, naive Tcells of the elderly present decreased cytokine production, less clonal expansion, and *e number of B-cell precursors in the bone marrow of decreased expression of activation markers after the primary the elderly remains relatively stable, but there is a significant antigen presentation by antigen-presenting cells (APCs) [11]. reduction in the number of mature B cells in the peripheral Despite that the number of effector and memory T cells blood [17]. Also, there are a limited diversity of B-cell re- increases with age, the vaccination response in the elderly is ceptors (BCRs) and a decrease in the population of naive impaired, which is indicative of the gradual decline of B cells. *e intrinsic defects of B cells related to aging include functional response [12]. In fact, it is observed that senescent a decrease in the expression of activation-induced cytidine T cells present defects in activation, memory, signaling, deaminase (AID) and a decreased number of switched memory B cells [1]. *is leads to the production of short- clonal expansion, and development of antigen-specific ef- fector cells and long-lived memory cells [5]. lived, low-affinity antibodies that may have defects in isotype Journal of Aging Research 3 switching, reflecting a low ability to respond effectively conducted in Italy showed that the risk of hospitalization for against pathogens [11]. influenza or pneumonia was 25% lower in subjects vacci- nated with the adjuvanted vaccine than in those vaccinated with the nonadjuvanted vaccine [27]. Another example is the 2. Vaccination in the Elderly novel herpes zoster subunit vaccine, which contains the *e decrease in birth rate and increase in life expectancy varicella-zoster virus E glycoproteins and the AS01B adju- have caused the progressive rise of the elderly population vant, yielding 97.9% efficacy, regardless of age, unlike the worldwide [5]. *e increasing population density of those vaccine ZOSTAVAX mentioned above, which presents aged more than 65 years requires new strategies to ensure reduced efficacy in the elderly [28]. that health and well-being remain with advancing age. Infections are one of the leading causes of morbidity and 3. Meningococcal Vaccines mortality in the elderly and may present different clinical features of those observed in young adults, regarding signs, Meningococcal disease can progress very rapidly, and death symptoms, and progression, which can hinder the early can occur within 24 to 48 hours after the initial symptoms. diagnosis and impair the treatment, making their prevention *e response of B cells to meningococcal infection may not even more important [5]. occur quickly enough since immune memory will mount an *e susceptibility to infections, such as influenza virus, adequate defense against a known antigen in approximately meningococcus, group B streptococcus, pneumococcus, 2 to 7 days, and the incubation period of meningococcal respiratory syncytial virus, and varicella-zoster virus, be- disease is 3 to 4 days. *erefore, the maintenance of pro- comes higher in this age group. As such, they need more tective levels of circulating antibodies by vaccination is frequent booster vaccinations, in many cases with vaccines important in prevention against meningococcal disease [29]. specifically designed to stimulate the immune system of the Meningococcal vaccines produced from capsular poly- elderly to respond better to vaccination [18]. *erefore, saccharides were introduced in the 70s decade; however, vaccinating older people with existing vaccines or de- they are poorly immunogenic in toddlers and do not induce veloping new improved vaccines against pathogens that immunologic memory. *ese vaccines induce mainly IgM affect this population is one of the main interventions to and short-lived bactericidal antibodies. Besides, repeated prevent infections and ensure the health of the elderly. immunization with this vaccine may induce hypores- Few vaccines are recommended to the elderly, such as ponsiveness [30, 31]. *e conjugation of the capsular influenza, herpes zoster, diphtheria, tetanus, pertussis, hepa- polysaccharide to a carrier protein improves its immuno- titis, and pneumococcal vaccines [11]; however, these vaccines genicity because it allows a T-cell-dependent response, in- are less effective in the aged population than in the young [19]. ducing high-avidity antibodies, higher bactericidal activity, *e Centers for Disease Control and Prevention (CDC) immunologic memory, and responsiveness to booster doses estimates that the efficacy of the influenza vaccine in those [32]. Nowadays, polysaccharides and conjugated vaccines aged less than 65 years is 70–90%, whereas in those aged against serogroups A, C, W-135, and Y are available [33]. 65 years or older, the efficacy is 30–40% [20]. Likewise, the Polysaccharide and conjugated vaccines to serogroup B were efficacy of the attenuated virus vaccine against herpes zoster developed; however, these vaccines did not induce an ef- (ZOSTAVAX ) decreases with aging: 69.8% in individuals fective humoral response [34, 35], and this might be due to the structural similarity of the capsular polysialic acid between 50 and 59 years, 64% in people between 60 and 69 years, 41% in people between 70 and 79 years, and only α2⟶ 8 and the embryonic neural cell adhesion molecules (N-CAMs) [36]. *is similarity is a concern as it might lead 18% in individuals above 80 years [21]. *e most common approaches to improve the effec- to the development of autoimmunity. It has been reported tiveness of vaccines in the elderly include increasing the the presence of IgM antibodies is directed against embryonic antigenic content per dose, changing the route of admin- N-CAMs in the serum of patients suffering from group B istration, giving booster doses, and using adjuvants [22]. *e meningitis [37]. *e major concern in the administration of use of adjuvants has the aim to potentialize activation of this vaccine would be the risk in women who become APCs, cytokine production, and stimulation of B and Tcells. pregnant; if IgG antibodies against embryonic N-CAMs were Different routes of administration may deliver the antigen to developed after vaccination, there is a chance that these sites enriched with APCs, optimizing its activation and antibodies cross the placenta and cause damage to the fetal central nervous system [38]. *us, many researchers con- presentation of antigens. *e increase in the antigenic dose has the purpose to improve their presentation and, therefore, cluded that developing a MenB polysaccharide vaccine pre- the activation of T cells [23]. sented more risks than benefits. So, MenB vaccine Several strategies to improve the effectiveness of in- development was focused on subcapsular antigens, such as fluenza vaccines in the elderly were addressed successfully, outer membrane proteins (OMPs) and outer membrane such as the use of adjuvant MF59 [24], the increase in the vesicles (OMVs) [39]. 4CMenB (Bexsero ) and rLP2086 antigenic content from 15 μg to 60 μg per dose [25], and a (Trumenba ) are recently developed MenB vaccines, com- vaccine administered via the intradermal route rather than posed by OMPs; they are licensed in a few countries, and the the intramuscular route [26]. *ese vaccines stimulated a initial studies suggest good immunogenicity and safety [30]. higher humoral response compared to those previously In the United States, between 1998 and 2007, 14.4% of used, especially the MF59-adjuvanted vaccine. A study invasive meningococcal disease (IMD) cases occurred in 4 Journal of Aging Research individuals aged 65 years or more; at that same period, the response of the subjects older than 60 years in this study. *e case fatality rate (CFR) of this age group was 23.2%, the same occurred in the study of Ramasamy et al. [61], which compared the immunogenicity of a quadrivalent conjugate highest between any age groups [40]. Also, in the United States, between 2006 and 2015, IMD cases in subjects aged vaccine (MenACWY-CRM) with that of a quadrivalent >65 years accounted for 17.3% of total cases, and the CFR in polysaccharide vaccine (MenACWY-PS) in healthy adults those older than 85 years was higher than in any other age aged 18–70 years; both vaccines were considered immu- groups [41]. In Australia, in 2015, 20.1% of laboratory- nogenic, but again the older individuals were not evaluated confirmed cases of IMD occurred in people aged ≥65 years separately. [42]. In Japan, between 2013 and 2014, most cases of IMD *e few studies about the effectiveness of meningococcal occurred in adults older than 50 years [43]. Approximately vaccines in the elderly [56, 58] suggest that it would be 14.7% of IMD cases occurred in individuals older than possible to adapt the currently available conjugate vaccines to older individuals, which would be more viable than de- 50 years in an analysis of 25 European countries between 2004 and 2014 [44]. In France, between 2006 and 2015, 11.3% of veloping new vaccines specifically for the elderly. As de- scribed earlier in this article, some vaccines, such as IMD cases occurred in people aged 60 years or more, besides this age group presented the highest CFR [45]. Despite that FLUAD , Fluzone High-Dose , Intanza 15 μg (influenza), ® ® ® the incidence of IMD in the elderly is relatively low, the CFR and Shingrix (varicella-zoster virus), have been specifically is high, so we consider it is important to evaluate the use of designed to improve the elderly’s immune response. meningococcal vaccines to prevent disease in the elderly. However, because of the relatively low incidence of me- Table 1 presents characteristics of currently licensed ningococcal disease, it might not be interesting for the meningococcal conjugate and protein vaccines, and these pharmaceutical industry to develop a new meningococcal vaccines are not indicated to individuals over 55 years of age, vaccine targeting specifically the elderly. given the lack of studies. *e only meningococcal vaccine *e approach of expanding age indication to the already licensed to subjects older than 55 years is the plain poly- existing vaccines was used for the tetanus toxoid, diphtheria saccharide ACWY (Menomune ) [56]. In some countries, toxoid, and acellular pertussis (Tdap) and pneumococcal meningococcal vaccines are indicated for individuals over vaccines after studies indicated they were safe, well tolerated, 55 years considered at high risk (those with certain medical, and immunogenic in adults aged 65 years and older [62–65]. Furthermore, studies are being conducted to try to expand occupational, or lifestyle indications and travelers to areas with high endemic rates for the infection) [57]. the age indication of other existing vaccines, such as the Dbaibo et al. [58] evaluated the immunogenicity and rotavirus [66]. safety of a meningococcal conjugate ACWY-TT and a Further studies are required to ensure the safety and polysaccharide ACWY vaccine in adults over 55 years. After a efficacy of meningococcal vaccines in adults aged 65 years single dose of immunization, ≥93.2% of the individuals that and older, as it has been described several changes in the received the conjugated vaccine and≥93.9% of the individuals immune system of the elderly may lead to diminished that received the polysaccharide vaccine presented serum vaccine response. Furthermore, to our knowledge, there are bactericidal antibodies (rSBA) with titers ≥1 :128. *e no studies of meningococcal serogroup B vaccines such as individuals over 65 years exhibited vaccine responses lower 4CMenB (Bexsero ) and rLP2086 (Trumenba ) in in- ® ® than those aged 56–65 years. Given these results, they con- dividuals of this age group. cluded that these vaccines were immunogenic in the in- Perhaps, the vaccination of the elderly against N. dividuals evaluated. meningitidis is not considered a priority because of the low Stamboulian et al. [56] assessed the immunogenicity of a incidence of the disease. Nevertheless, we believe that given meningococcal conjugate ACWY-CRM197 and a poly- the increasing proportion of older people in the population saccharide ACWY vaccine in individuals aged 56–65 years. and the high CFR of meningococcal disease in the elderly, it *e conjugate vaccine was considered superior to the would be interesting to evaluate the insertion of these polysaccharide one, achieving a higher percentage of vaccines in the immunization programs for this age group, seroresponse for all serogroups. *e immunogenicity of especially in countries with high and intermediate endemic MenACWY-CRM was similar between the groups aged disease and during outbreaks. Also, vaccines can generate 19–55 and 56–65 years. other benefits, such as a lower overall cost of healthcare. Hutchins et al. [59] described that elderly individuals Studies are required to evaluate if introducing menin- show decreased levels of antibodies after immunization with gococcal vaccines for adults aged 65 years and older into the meningococcal ACWY polysaccharide vaccine than immunization programs is cost-effective, and in this way, young subjects and that the level of these antibodies de- health authorities can decide whether the benefit of vacci- creased more rapidly. Besides, bactericidal activity in those nating the elderly with these vaccines is worthwhile. Me- aged 60–88 years was significantly lower. ningococcal disease is one of the several infections that can Lalwani et al. [60] assessed the immunogenicity of a affect the elderly. Further studies about the burden of the meningococcal ACWY-CRM conjugate vaccine in healthy infectious diseases in the elderly are necessary to define Indian subjects aged 2 to 75 years and concluded that it public health priorities and assess the need for vaccination generated a robust immune response; however, the aged against these pathogens. subjects were included in a group of people aged 19– Given the fact that the elderly are more likely to evolve to 75 years, and so it was difficult to distinguish the specific death when infected with N. meningitidis and the lack of Journal of Aging Research 5 Table 1: Meningococcal conjugate and protein vaccines currently licensed and their composition, age indication, and immunization schemes. Age group Vaccine Pharma Composition Immunization scheme Reference indicated Meningococcal C 2–12 months: two doses with an interval oligosaccharide >2 months of GlaxoSmithKline of at least 2 months between the doses Menjugate conjugated with age, teenagers, [46] (GSK) >12 months, teenagers, and adults: a CRM197 + aluminum and adults single dose hydroxide Meningococcal A, C, 9 months 9–23 months: two doses with an interval Y, and W-135 Menactra Sanofi Pasteur through 55 years of at least 3 months between the doses [47] polysaccharides of age 2–55 years: a single dose conjugated with DT Meningococcal A 1 year of age, polysaccharide Serum Institute of adolescents, and MenAfriVac conjugated with A single dose [48] India adults up to TT + aluminum 29 years of age phosphate Meningococcal C <12 months: three doses with an oligosaccharide >6 weeks of age, interval of at least 1 month between the Meningitec Pfizer conjugated with adolescents, and doses [49] CRM197 + aluminum adults >12 months, adolescents, and adults: a phosphate single dose Meningococcal C 2–12 months: two doses with an interval oligosaccharide >2 months of of at least 2 months between the doses Meninvact Sanofi Pasteur conjugated with age, teenagers, [50] ® >12 months, teenagers, and adults: a CRM197 + aluminum and adults single dose hydroxide 2–6 months: four doses, administrated Meningococcal A, C, at 2, 4, 6, and 12 months of age Y, and W-135 >2 months 7–23 months, nonvaccinated: two doses GlaxoSmithKline Menveo oligosaccharides through 55 years with an interval of at least 3 months [51] ® (GSK) conjugated with of age between the doses CRM197 >2 years, teenagers, and adults through 55 years: a single dose Meningococcal C 2–12 months: two doses with an interval polysaccharide >2 months and of at least 2 months between the doses Neisvac-C Baxter conjugated with [52] adults >12 months, teenagers, and adults: a TT + aluminum single dose hydroxide Meningococcal A, C, Y, and W-135 >12 months and Nimenrix Pfizer A single dose [53] ® polysaccharides adults conjugated with TT 2–5 months: three doses with an interval not less than 1 month; booster dose between 12 and 15 months 3-5 months: two doses with an interval of at least 2 months between the doses; booster dose between 12 and 15 months NHBA + NadA + 6–11 months: two doses with an interval GlaxoSmithKline fHbp + OMVs from >2 months and of at least 2 months between the doses; Bexsero [54] (GSK) NZ98/254 + adults booster dose in the second year of life aluminum hydroxide 12–23 months: two doses with an interval of at least 2 months between the doses; booster dose with an interval of 12 to 23 months between primary series 2 years and adults: two doses with an interval of at least 1 month between the doses *ree-dose schedule: 0, 1–2, and 6 Wyeth fHbp + aluminum 10 to 25 years of Trumenba months [55] ® Pharmaceuticals phosphate age Two-dose schedule: 0 and 6 months CRM197: Corynebacterium diphtheriae cross-reactive material 197; DT: diphtheria toxoid; fHbp: factor H binding protein; NadA: Neisseria adhesin A; NHBA: Neisserial heparin binding antigen; OMVs: outer membrane vesicles; TT: tetanus toxoid. 6 Journal of Aging Research [12] A. 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