key: cord-016903-z2vqfq98
authors: Herndler-Brandstetter, Dietmar; Grubeck-Loebenstein, Beatrix
title: The Efficacy of Vaccines to Prevent Infectious Diseases in the Elderly
date: 2007
journal: Immunosenescence
DOI: 10.1007/978-0-387-76842-7_10
sha: 
doc_id: 16903
cord_uid: z2vqfq98

Infectious diseases still represent a major challenge to human progress and survival. Especially elderly persons are more frequently and severely affected by infectious diseases and they display distinct features with respect to clinical presentation and treatment. Although vaccinations are considered a vital medical procedure for preventing morbidity and mortality caused by infectious diseases, the protective effect of vaccinations is abrogated in elderly persons. This is due to a decline in the functions of the immune system referred to as immunosenescence. The first part of this chapter will therefore summarize the status quo of the efficacy of vaccines in preventing morbidity and mortality caused by typical infectious diseases in the elderly, such as influenza, pneumonia and tuberculosis. The second part will then elucidate the underlying age-related mechanisms which may contribute to the decreased efficacy of vaccines. Based on the complex mechanisms involved in immunosenescence, strategies will be outlined which may be succesfful in enhancing protective immune responses following vaccination in elderly persons.

With respect to the current demographic development in many countries, including the European Union and the United States of America, infectious diseases in geriatric patients are becoming an increasingly important issue. Infections in elderly persons are not only more frequent and more severe, but they also have distinct features regarding clinical presentation, microbial epidemiology and treatment. Urinary tract infections, lower respiratory tract infections, skin and soft tissue infections, infective endocarditis, bacterial meningitis, tuberculosis and herpes roster appear to have a higher prevalence in elderly persons. In developed countries like the United States, pneumonia, influenza and septicemia are ranked among the ten major causes ofdeaths in people aged 6S years and older. 1 The reasons for the increased susceptibility to infectious diseases include epidemiological elements, imrnunosenescence, malnutrition and age-dependent anatomical alterations.

Infectious diseases still represent a major challenge to human progress and survival as they are responsible for about 20% ofall deaths in the world. This is not only related to microbial and viral factors but also to social and environmental determinants, such as social upheaval, urbanization, air travel, natural disasters and climate change.' Newly emerging infectious diseases include acquired immune deficiency syndrome (AIDS), hepatitis C, several hemorrhagic fevers, severe acute respiratory syndrome (SARS) and avian influenza. The resurgence ofseveral other infectious diseases is supported by the increased occurrence ofmultiple drug-resistant microorganisms such as Staphylococcus aureus, Mycobacterium tuberculosis, Escherichia coli and Streptococcuspneumoniae. *Corresponding Author: Beatrix Grubeck-Loebenstein-Institute for Biomedical Aging Research, Austrian Academy of Sciences, Rennweg 10, 6020 Innsbruck, Austria. Email: beatrix.grubeck-loebenstein@oeaw.ac.at Immunosenescence, edited by Graham Pawelec. ©2007 Landes Bioscience and Springer Science+Business Media.

Altogether, this represents an enormous economic burden on health care systems all over the world. For instance, the annual costs ofmedical care for treating infectious diseases in the United States alone is about $120 billion and for treating antimicrobial-resistant infections it may be as high as $5 billion. ' A great success story was the implementation oflarge-scale vaccination strategies that led to the eradication of smallpox in 1980 4 and to a drastic reduction ofpoliomyelitis, tetanus, diphtheria, measles, pertussis and meningitis. Presently, vaccinations are still considered the most cost-effective medical procedure for preventingmorbidity and mortality caused by infectious diseases. 26 different infectious diseases can be prevented by vaccinations and 61 vaccines are being developed according to a 2004 survey by the Pharmaceutical Research and Manufacturers ofAmerica," The new candidate vaccines are intended to provide protection against diseases caused by rotavirus, herpes zoster and papilloma virus and will be available from 2007 onwards ( Table 1) . But also improved vaccines against influenza, pneumonia and tuberculosis are currently being tested in clinical trials ( Table 1 ). This chapter now outlines the relevance ofvaccines to fight infectious diseases in old age and how age-related changes within the immune system contribute to the decreased efficacy of vaccines. It also discusses the progress made in the development of vaccines with improved immunogenicity in elderly persons.

Outbreaks of deadly infectious diseases such as Ebola, Marburg, SARS or the H5Nl avian influenza regularly alert the world, whereas there is not much public attention paid to infectious diseases that cause substantial morbidity and mortality among the elderly population. For instance, influenza, invasive Streptococcus pneumoniae infection, urinary tract and skin infections have a higher prevalence in elderly persons," Old individuals may also fail to respond sufficiently to therapy and frequently suffer from opportunistic infections, recurrent infections with the same pathogen or reactivation oflatent diseases, such as those caused by Mycobacterium tuberculosis or the Varicella zoster virus. There are no vaccines available for many infectious pathogens that are frequent in elderly subjects and existing vaccines are underused and often do not assure such an effective protection as in young subjects. The following paragraphs will highlight the most important infectious diseases which threaten the elderly population and will provide information on epidemiology, vaccine availability and efficacy,vaccination coverage and general health authority recommendations.

Influenza is a highly contagious, acute viral respiratory disease that causes significant morbidity and mortality. The annual outbreaks affect approximately 5-20% ofthe population worldwide with 3-5 million cases ofsevere illness and up to one million deaths each year. Especially elderly people and persons that are chronically ill or otherwise immunocompromised are at enhanced risk. For example, during influenza epidemics, Barker and Mullooly reported two deaths per 100,000 healthy people below 65 years ofage compared with 797 per 100,000 in those over 65 with two or more high-risk conditions? In contrast to measles, smallpox and poliomyelitis, influenza is caused by viruses that undergo continuous antigenic variation and possess an animal reservoir. Therefore, we are recognizingannual epidemics that have been interruptedby three pandemics (Spanish influenza, HINl, 1918-1919; Asian influenza, H2N2, 1957-1958 andHongKonginfluenza,H3N2, 1968), caused by new influenza virus strains with increased virulence.

Influenza viruses are enveloped viruses containing eight single-stranded RNA segments which encode for viral proteins, such as hemagglutinin (HA), neuraminidase (NA), matrix protein (Ml) and nucleoprotein (NP) (Fig. 1) . Influenza viruses belong to the family Orthomyxoviridae and are divided into three genera, influenza virus A, B and C, based on antigenic differences in two oftheir structural proteins, M and NP. Disease symptoms caused by Influenza C are rare whereas Influenza B often causes sporadic outbreaks, especially in residential communities like nursing homes. Influenza A viruses are further divided into subtypes according to the antigenicity oftheir major envelope glycoproteins, HA and NA. With at least IS different hemagglutinin and 9 different neuraminidase subtypes, there is con siderable antigenic variation among influenza viruses. The human influenza viruses are currently limited to three hemagglutinin (H I, H2 and H3) and two neuraminidase subtypes (N 1 and N2), whereas birds are the predominant hosts for the other subtype strains. HA initiates viral infection by binding to sialic acid residues on the carbohydrates ofglycoproteins present on epithelial cells ofthe respiratory trace. Therefore, high-affinity IgA and

IgG antibodies against HA may preven t infection from influenza virus. In contrast, NA cleavesthe sialic acid from viral and cellular proteins to promote the release of newly synthesized influenza viruses from the infected host's plasma membrane. Although antiviral drugs with moderate efficacy are available, active immunization represents the most vital element in th e prophylaxis ofinfluenza disease. However, the frequently occurring antigenic driftrequires an annual modification ofthe vaccinecomponents according to the recommendations ofthe WHO. Therefore, vaccination has to be repeated annually to ensure protection against the circulating influenza strains. But vaccination coveragediffers largelywithin European countries. In 2002, the rate ofvaccinedistribution washighest in Spain, Belgium,The Netherlands, United Kingdom and Germany (between 18.1 and 20.3%) and lowest in Poland, Czech Republic, Lithuania and Latvia (between 1.9 and 7.1%). Canada and the United States had the highest rate ofvaccine distribution, being 32.8 and 28.9%, respectively. Remarkably,70% ofUS citizens aged 65 and abovehave been vaccinated against Influenza."Although there are severalvaccinesavailable, the efficacyofmanyvaccinesin preventing influenza diseasein elderlypersons isonly around 56%.9 Especiallyveryold and frail persons show a decreased response to influenza vaccines.P'Ihe reduced vaccine efficacyis due to low levelsofIgA and IgGantibodies, delayed peak antibody titers and shortened maintenance of titers after vaccination. Nevertheless, immunization in elderly people has been shown to be safe,cost-effective and associated with reduced rates ofhospitalization and influenza-relateddeaths.I1,12In particular, the efficacyofinfluenzavaccination to reduce mortality in elderlypeople is greater after repeated annual vaccination than after first administration. 13Presently, Influenza vaccines can be classifiedin split-virus, subunit, virosomal and live-attenuated vaccines ( Table 2 ). Split-virus vaccines are used since the 1980s, are cheap and offer a good protection for children above 6 months of age and adults. Recently, subunit vaccines with new adjuvants have been developed (FluadO, Addigrip') that show an increased immunogcnicity, a favorable safety profile and may be more suitable for the vaccination of elderly persons.'! Additionally, invariant antigens, such as M 1 and NP, may also play an important role in protection and could be used in vaccines to induce long-lasting immunity to a variety of different influenza strains. Another strategy to enhance immunogenicity may the use ofvirosomes that are nontoxic , biodegradable lipid-basedantigen-presentation systems." Virosomal influenzavaccines, such asInflexalV', InfIuvac Plus'and Invivac'have been on the market in several European countries for a number of years. They display a high immunogenicity and a similar safety profile in elderly persons compared with inactivated influenza vaccines.F" Furthermore, new live-attenuated and subunit influenza vaccines ate currently in clinical trials that promise to have an increased efficacy ofprotection (Table  1) . Especially live-attenuated influenza vaccines ate believed to elicit strong Tcel! responses and should be able to enhance antibody levels after vaccination. Importantly, before administration of live-attenuated vaccines to elderly or immunocompromised persons, an acceptable safety profile has to be demonstrated. Irrespective ofthe improvement ofinfluenza vaccines for elderly persons, vaccination of children is clinically effective'" and high vaccination coverage among pupils has demonstrated to induce herd immunity and to reduce mortality in older adults.

Streptococcus pneumoniae is an important cause of invasive clinical manifestations such as bacterial pneumonia, meningitis and septicemia, particularly in young children and the elderly. 80 to 90% ofdeaths associated with Streptococcus pneumoniaeinfection occur in people aged 60 years and above. Several further groups at higher risk ofinvasive pneumococcal disease have been defined, including individuals with splenic dysfunction, immunosuppression, chronic pulmonary or cardiac disease, diabetes mellitus and chronic liver disease. Generally, antibiotic therapy has to be initiated as soon as possible to reduce the risk ofcomplications due to pneumonia, meningitis or sepsis. Nonetheless, 50% ofall deaths occur within the first 48 hours despite adequate antibiotic therapy. This may be due to the increased occurrence of multiple drug-resistant pneumococcal strains. In 2002, the proportion ofpenicillin-resistant Streptococcus pneumoniaewas reported to be 53% in France and more than 25% in Israel, Poland, Romania and Spain." After recovering from pneumococcal infection, people are not necessarily immune, because there are about 90 different serotypes and immunity will be guaranteed only to the strain that has caused the infection.

Currently, pneumococcal vaccines are available that include up to 23 strains which are responsible to cause disease in almost 90% ofall cases ( Table 2 ). These vaccines offer protection against invasive pneumococcal disease in 65% of the general elderly population 22.23whereas in elderly persons with high risk factors, the protective effect of vaccination seems to be only moderate. Although many European countries recommend the administration of pneumococcal vaccines to all those >65 years ofage, vaccination coverage among the elderly population is very low. This may be due to the high costs ofthe vaccine and its unsatisfying efficacy in elderly people. But more immunogenic vaccines are currently in different phases ofclinical trials (Table 1 ) and promise to be more efficient in old age. Additionally, implementing pneumococcal vaccination for children may decrease the incidence ofpneumococcal disease in the elderly by reducing transmission and possibly accomplishing herd immunity.-"

Each year, about 8 million people are infected worldwide with the tubercle bacillus Mycobacterium tuberculosis and 1.6 million ofthem die. The EU25 has a tuberculosis (TB) burden ofmore than50,000 new casesper year,with the highest incidences in Latvia, Lithuania and Estonia (50-100 cases/ 100,000). The risk ofdeveloping a disease following TB infection is about 5-10% during lifetime and individuals above 65 years ofage have a four-fold increased risk ofdeveloping TB than the average population," TB is also frequently diagnosed with delay due to an atypical manifestation in old age. This may lead to an increased morbidity and mortality and to a spreading ofthe disease, in particular within institutionalized elderly persons.P Further difficulties include the increased emergence of new, multiple drug-resistant strains with higher rransmissibiliry," the poor efficacy of the current bacille Calmette Guerin (BCG) vaccine in protecting adults and elderly people from pulmonary Infection" and the increased risk ofTB co-infection in HIV positive patients." However, in the past few years, several TB vaccine candidates have entered phase I clinical trials, including adjuvanted subunit vaccines as well as improved live recombinant strains of the current BCG vaccine (Table 1 ). All these vaccine candidates are supposed to induce an effective and sustainable cellular immune response which is thought to be crucial to protect the host from an intracellular pathogen such as Mycobacterium tuberculosis. 30 

Primary infection with the Varicella zoster virus (VZV) causes chickenpox which is usually a mild disease in childhood. The virus then persists in a latent form in sensory ganglia until its reactivation which results in the clinical manifestation of herpes zoster (shingles). Between 13 and 26% ofpersons with herpes zoster develop complications, such as postherpetic neuralgia." Postherpetic neuralgia also increases with age with a prevalence of 50% in people aged 70 years and above. The incidence and severity ofherpes zoster increase with age, because VZV reactivation is associated with a progressive decline in cell-mediated immunity to VZVY.·33 Routine vaccination ofchildren using a tetravalent vaccine that protects against measles, mumps, rubella and varicella will soon be available (Table 1 ) and may reduce the incidence of chickenpox as well as the reactivation ofVZV in later life. Since 1995, a live-attenuated Oka strain VZV vaccine is on the market that has shown clinical efficacy in preventing children from chickenpox." However, the currently available VZV vaccines have not been proven to adequately boost T-cell responses in older adults and to prevent reactivation ofherpes zoster. Recently, a vaccine that may prevent herpes zoster virus reactivation has been submitted for registration. This live-attenuated VZV vaccine has been developed to prevent reactivation of herpes zoster in the elderly.3s.36This is of particular importance, because the elderly population has not been vaccinated against but may have been frequently infected by Vzv. For instance, more than 90% ofadults in the United States have had chickenpox. As a consequence, it is estimated that up to 800,000 people in the United States suffer from shingles each year and the incidence is expected to increase as the population ages. Thus, reactivation ofherpes zoster and its clinical manifestations represents a serious health burden to the growing elderly population and could be counteracted by potent vaccines.

The cytomegalovirus (CMV), a B-herpesvirus, has also been shown to persist throughout life until its reactivation as a result ofimmune suppression or deficiency. CMV infection is quite common and affects 60-100% ofthe adult population, dependingon the area. The CMVis transmitted via person-to-person contacts but immunocompetent subjects mostly do not recognize infection as it causes no or few unspecific symptoms. However, a CMV infection represents a severe health problem in immunocompromised persons (e.g.,due to immunosuppressive disease, chemotherapy or transplantation) or in a fetus as a result of congenital infection. Research results over the past decade suggest that CMV favors an accelerated aging of the immune system as CMV infection is chronic and the organism is forced to continuously prevent virus reactivation.F'" Despite the high frequency of CMV-specific CD8+ Tscells, the virus usually can not be eliminated by the immune system. This is because the virus has evolved several mechanisms to escape the host's immune defense." For instance, CMV encodes for a type ofproteins called immunoevasins that modulate the presentation ofviral peptides or directly suppress cellular immune responses. Hence, the accumulation of CMV-specific T-cells substantially constricts the diversity of the T-cell repertoire" and leads to the production ofproinflammatory cytokines, such as gamma interferon and tumor necrosis factor alpha.'? This imbalance in the cytokine production profile may not only promote the pathogenesis of age-related diseasesf but leads to a decreased production of antibodies following influenza vaccination in elderly persons.fA few antiviral substances including ganciclovir, valganciclovir, foscarnet and cidofovir are available to prevent CMV infection in immunocompromised patients. But antiviral therapy is limited by its severe adverse reactions, such as neutropenia, nephrotoxicity, hypocalcemia and seizures. Another strategy is the adoptive transfer ofdonor-derived CMV-specific CD4+ and CD8+ T-cells that may restore the host's immunity against CMV. 44 Despite the need ofa safe and potent vaccine that prevents CMV disease, no vaccine candidate has yet entered the market. A few vaccines against CMV are currently in phase IIII clinical trials (Table 1) . Active immunization against CMV could reduce the incidence ofneonatal infections as well as complications in immunocompromised persons and may prevent CMV-associated premature aging ofthe immune system when applied early in life.

Pertussis (whooping cough) is a highly contagious respiratory system infection caused by the bacterium Bordetella pertussis and rarely by B.parapertussis, B. bronchiseptica or other pathogens.

Each year, more than 20 million cases ofpertussis are reported worldwide, 90% ofwhich occur in developing countries, with an estimated 200,000 to 300,000 fatalities. The implementation of routine childhood vaccination against pertussis has reduced the high mortality rate among children. Although most infants are being immunized against pertussis in industrialized countries, immunity usually fades during adolescence. Consequently, a significant rise in pertussis incidence has been noticed in adolescents and adults." However, the reported pertussis cases in adults and elderly people are likely to be underestimated because symptoms ofdisease may be characterless and make clinical diagnosis difficult. Among nonvaccinated elderly people the attack rate ofpertussis is high (53%) and up to 10% ofelderly persons may die from intracranial bleeding while they are symptomatic for pertussis." Regular booster immunizations should thus be considered for adults and elderly persons, which is indispensable to remain protected from disease.

Tetanus is acquired via environmental exposure to the spores of Clostridium tetani,which are present in soil worldwide. The disease is caused by a potent neurotoxin produced by the bacterium in dead tissue, e.g.,dirty wounds. Diphtheria is a bacterial disease caused by Corynebacterium diphtheriac and is transmitted from person to person through close physical contact. The public health burden ofboth diseaseshas been low in developed countries due to routine immunization. However, outbreaks ofdiphtheria have been reported in the independent states ofthe former Soviet Union, Algeria, China, Iraq, Sudan, Thailand and other countries. Thus, maintaining high vaccination coverage is important to prevent the outbreak of new diphtheria epidemics. Although vaccines that prevent from tetanus and diphtheria have been used for routine immunization for a long time all over the world, few studies exist that document their efficacyin elderly people. The vaccination coverage among elderly subjects is decreasing in several European countries and up to 40% of appropriately vaccinated elderly persons do not have protective tetanus-specific antibody concentrations. 47-49Therefore, public health authorities ofsome European countries have recommended five instead often year booster vaccination intervals for people over 60 years ofage. Additionally, strategies should be developed to draw public attention to the problem ofimmunizations in the elderly, to inform general practitioners and to increase vaccination acceptance.

The increasing mobility ofelderly persons recognized worldwide is accompanied by an enhanced risk to encounter new antigens. This may be ofconcern because elderly persons possess a limited T-cell repertoire that may not guarantee full responsiveness to a wide variety ofnew antigens (see below for details). Nevertheless, in vitro experiments have demonstrated that naive T-cells from elderly persons can still be stimulated by neoantigens, at least to the recombinant Etr protein of TBE virus and rabies virus." Based on an assessment of the risks for travel-related diseases, including the destination, the type of journey and the duration, vaccination is recommended to protect from typhoid and yellow fever, hepatitis A and B, Japanese encephalitis, tick-borne encephalitis (TBE) or rabies. But elderly persons should also check whether they have followed the recommended booster intervals of routine immunizations, e.g., against tetanus, diphtheria, poliomyelitis, measles or influenza.

TBE is caused by a virus that is primarily transmitted to humans by infected ticks. There are three genetically closely related subtypes of the TBE virus known (European, Siberian and Far Eastern subtype). TBE is among the most dangerous neuro-infectious diseases in Europe and Asia and is responsible for up to 12,000 casesofTBE annually, most ofthem occurring in Russia, Czech Republic and the Baltic states." Up to 30% ofadults with clinically confirmed TBE infection develop meningitis or meningoencephalitis and the lethality ofTBE in Europe is up to 1%.Yet,there is no specific therapy available and, therefore, active immunization with inactivated whole virus provides the only efficient protection from TBE disease ( Table 2 ).52 Importantly, more and more TBE cases are reported in people over 50 years ofage and vaccination coverage in this population is lower than average. Therefore, future strategies should increase the vaccination coverage among elderly persons and assure that they stick to regular booster intervals. Anyhow, regular boosters should be given throughout life as this may favor the maintenance oflong-lastinghumoral immunity against TBE53and may decrease the risk ofimmunization failures in the elderly.

Hepatitis A is an acute disease ofthe liver caused by the hepatitis A virus (HAY), a nonenveloped virus belonging to the Picornaviridae family. Each year, an estimated 1.5 million cases ofhepatitis A occur worldwide. HAY infection induces life-long immunity and is usually asymptomatic in young children, whereas adults frequently experience symptomatic disease. HAY is acquired directly from infected persons by close contact or by the consumption ofcontaminated drinking water, vegetables, fruits or shells. HAY vaccination is recommended when traveling to tropic and subtropic countries that have an increased risk of infection. For instance, the risk ofhepatitis A infection ofpersons traveling to developing countries was estimated to be 3 to 20 cases per 1000 persons per month ofstay,varying with destination, living conditions and age." Improved sanitary standards in developed countries have reduced the opportunity for environmental exposure to HAY and have lowered the overall incidence ofinfection. Paradoxically, susceptibility to the virus increased because of the decrease in natural immunity. Consequently, less than 20% ofpersons born after 1945 have a natural immunity against HAy'54 In contrast to hepatitis B and C that may lead to the manifestation of a chronic infection, clinical illness after hepatitis A infection is usually mild in young individuals. But increasing age represents an enhanced risk ofsevere infection and mortality rates are about 2% for persons over 40 and 4% for those over 60 years ofage." Several vaccines against hepatitis A are available (Table 2 ) and a study of773 adults showed that immunogenicity and safety profiles between 'Iwinrix' and Havrix' are comparable.56 But there is some evidence oflower antibody titers with advanced age. For instance, the seroconversion rates 8 months after two doses ofHavrix' were found to be 85% and 60% for adults < 35 years and >35 years, respectively.57After the recommended immunization schedule with Twinrix'.seroprotection was 92% and 63% for adults <40 years and >60 years, respectively.58 Therefore, it may be useful to measure HAY antibodies in elderly persons, as in the case ofvaccination failure, boosters have shown to be effective." It is further recommended that the vaccine is given at least 3 to 4 weeks before travel due to a slower onset ofthe antibody response in elderly individuals. 59 Another travel vaccine is directed against yellow fever (YF), which is endemic in tropic regions ofAfrica and South America. YF is transmitted by the bite ofinfective Aedes aegypti and other mosquitoes that bite during daylight hours in regions below 2500 meters ofaltitude. Most infections lead to an acute illness characterized by fever, muscular pain, headache, anorexia, nausea and/or vomiting, often with bradycardia. After a few days, about 15% ofpatients progress to a second phase, with resurgence offever,development ofjaundice, abdominal pain and haemorrhagic manifestations. Halfofthese persons die 10-14days after the onset ofillness. The WHO estimates that a total of200,000 cases ofYF occur each year, with about 30,000 deaths. 6oYF also represents a significant risk to more than 3 million travelers that visit YF-endemic areas each year. Neonates and elderly individuals demonstrate the highest mortality when infected by the YF virus. As there is no specific antiviral treatment against YF available yet, vaccination is the only way to protect persons from YF disease. The currently available vaccine contains a live-attenuated 17D strain virus ( Table 2 ) and has been shown to be safe and highly potent." However, due to the increased use in international travelers, it has become evident that advanced age might be a risk factor for serious adverse effects and even deam. 62 Compared with persons aged 25-44 years, individuals aged <75 had an 18-fold greater risk to experience serious adverse events after vaccination. The rate for systemic illness requiring hospitalization or leading to death after YF vaccination was reported to be 3.5 per 100,000 among people 65 to 75 years of age and 9.1 per 100,000 for people more than 75 years. Furthermore, there are no studies available that demonstrated the efficacy of the YF vaccine in elderly persons. Accordingly, recommendations and manufacturing standards have been modified to increase vaccine safety in elderly persons. Although the benefit-risk ratio still favors the vaccination ofpeople at high risk for infection and outlines the vaccine's fundamental role in disease prevention and control, efforts to improve safety and to ensure vaccine efficacy in elderly persons are ofurgent need.

The term immunosenescence refers to a complex remodeling ofthe immune system in old age and may contribute significantly to morbidity and mortality in the elderly. Thymic involution, telomere shortening, T-cell signal transduction changes, alterations in the interaction of the innate and adaptive immune response, impaired DNA repair and antioxidant mechanisms as well as persistent antigenic stress may all be factors contributing to immunosenescence. Although perturbations ofinnate immune system components have been described, much ofthe decrease in immunoresponsiveness seen in elderly people is associated with changes in T-cell responses. This is due to the continuous loss offunctional thymic tissue with increasing age. 63.64The thymus, the central lymphoid organ, is responsible for the maturation and selection ofso-called naive T-cells that regenerate the peripheral Tcell pool and retain the capability ofthe immune system to respond to a variety ofdifferent pathogens. In old age, the number ofnaive T-celIs decreases while the number ofantigen-experienced 'Tcells increases. 65 .66 These antigen-experienced T-celIs include a substantial proportion of senescent memory-effector T-cells that accumulate in elderly persons. Senescent memory-effector TcelIs display phenotypic (loss ofcostimulatory molecules such as CD28 and CD40L) as well as functional changes (altered cytokine production profile, decreased proliferative response, shortened telomeres, increased resistance to programmed cell-death and restricted T-cell diversity).67.68Ofparticular importance, the senescent CD8+CD28-memory-effector T-cell population predominantly produces the pro-inflammatory cytokine gamma interferon (IFNy), but does not produce interleukin 2 (IL-2) and the anti-inflammatory, B-cell stimulating cytokine IL-4. 43 Recent data also support the hypothesis that chronic infection with the cytomegalovirus, ã -herpesvirus, may lead to a decrease in the size ofthe naive and early memory CD8+ T-cell pool, but to an increase in the number of dysfunctional, IFNy-producing CD8+CD28-memory-effector Tvcells (Fig. 2) , 37 One clinical consequence of the accumulation of CD8+CD28-T-cells is an impaired generation of protective antibody levels after vaccination. 43.69 Furthermore, the age-dependent increase in the level ofpro-inflammatory cyrokines may lead to ubiquitous chronic inflammatory responses in old age 42 and may therefore support the development of age-related chronic diseases, such as atherosclerosis," rheumatoid arthritis" and Alzheimer's disease. 72, 73 Although individuals maintain a relatively constant total number ofperipheral B-celIs during aging, each B-cell subset comprises severeperturbations in size,dynamics and repertoire. The alterations affecting the Bvcell subsets are due to a decreased generation ofB-cell precursors, such asearly lymphoid precursors and pro-Bvcells, Cell-intrinsic as well as micro-environmental disturbances are both likely to contribute to the decreased output ofpro-Bscells. Furthermore, alterations in environmental factors also impair overall V(D)J recombinase activity among pro-Bvcellst'whlch accounts for the limited B-cell repertoire frequendy detected in elderly persons." Although no decrease in overall serum immunoglobulin levels have been observed during aging, the antibodies generated in old age are oflower affinity due to a shift in antibody isotypes from IgG to IgM,76 Of particular importance, B-celIs from elderly individuals are stimulated 70% less efficiendy by follicular dendritic cells than Bvcells from young subjects," suggesting loss ofB-cell function, in part due to the decreased expression ofcostimulatory molecules, such as CD40 or CD27,78 Impaired T-cell-mediated immunity as well as defects in antigen presentation by antigen presenting cells 

There is a tremendous need to increasethe protective effect ofvaccines in the elderly. Research of the last decade has provided new insights into the molecular mechanisms ofthe immune response in old age, which can now be used for th e development of potent vaccines. In the past, vaccines were primarily designed to elicit a strong humoral immune response . However, vaccines in elderly persons may be more effective ifthe stimulate innate immune components and the generation of long-lived memory T-cells. Currently,severalstrategies are being pursued to increase immunogeniclry, to minimize adverse side effects and to increase vaccine acceptance by introducing needle-free injection devices. Proven and promisingvaccine technologies are used to design conjugate, subunit, live vector, DNA and live-attenuated vaccines (Table 3) .80 While live-attenuated vaccines (e.g.• against varicella, measles or yellow fever) stimulate numerous immune components and display enhanced immunogenicity, conjugate and subunit vaccines (e.g., against influenza) are often supplemented with adjuvants" to ensure their protective effect. Generally, adjuvants can be divided into antigen delivery systems (cationic microparticles, proteasomes and virus-like particles) and immune potentiators (e.g.• cytokines). These adjuvants may overcome the proposed age-related functional decline ofinnate immune responses by targeting pattern-recognition receptors, such as the recently identified toll-like receptors or nucleotide-bindingoligomerization domain proteins." The enhanced activation ofthe innate immune system may also improve antigen processing and presentation leading to more potent T and B-cell responses and to sustained immunological memory. Vaccines supplemented with the DNA of cytokines (e.g., IL-2 , IL-? IL-I2, IL-IS or IL-21 ), chemokines or costirnulatory molecules may magnify immune responses by generating more and long-lived memory T_ceIIs83-85and may overcome immunodominance.'"

In addition to improve vaccine efficacy, a modification of vaccination strategies for elderly persons has been supported by the results of several vaccination trials. For instance, a decreased response and a shortened duration ofprotective immunity following booster immunization is a characteristic feature of old age. 87Thus , several European health authorities have recommended five-year vaccination intervals for tetanus, diphtheria, pertussis and pneumonia. Increased public awareness of regular booster vaccinations in adults should be enforced, as these immunization regimes may be essential to maintain the ability to respond to recall antigens in old age. Recent result s also indicate that long-lasting protection but also a good booster effect can be expected even a long time after the last vaccination, when a live-attenuated vaccine (e.g., polio vaccine) is used for primary immunization in early life. New delivery systems that make use oftiny micro-needles or non-injectable application devices (nasal , oral, transcutaneous) may further increase vaccination acceptance, especially in the case of influenza as this vaccination has to be repeated annually.

Infectious diseases in elderly persons are becoming an increasingly importan t issue. An utmost need represents the development ofmore immunogenic vaccines for the elderly. The improvement of specific vaccine types regarding immunogenicity and tolerability, th e addition of adjuvants. the design ofnew delivery systems as well as specific immunization regimes should all contribute to an enhanced efficacy ofvaccines in elderl y persons. Further improvements may comprise the adjustment ofvaccination intervals in old age, the increase in vaccine acceptance and vaccination coverage as well as raising people's awareness to stick to the recommended booster vaccination intervals throughout life. In the distant future, vaccines may also play an important role in treating non-infectious diseases such as allergy, autoimmunity, Alzheimer's disease and cancers.

Deaths: leading causes for 2002

Social and environmental risk factors in the emetgence of infectious diseases

A successful eradication campaign. Global eradication of smallpox

Survey: New Medicines in development for Infectious diseases

Ageing and infection

Pneumonia and influenza deaths during epidemics: implications for prevention

Influenza and pneumococcal vaccination coverage among persons aged> or =65 years and persons aged 18-64 years with diabetes or asthma-United States

The efficacy of influenza vaccine in elderly persons. A meta-analysis and review of the literature

Immunity and immunization in elderly

The efficacy and cost effectiveness of vaccination against influenza among elderly persons living in the community

Influenza vaccination programs for elderly persons: cost-effectiveness in a health maintenance organization

Reduction in mortality associated with influenza vaccine during 1989-90 epidemic

Evidence of increased clinical protection of an MF59-adjuvant influenza vaccine compared to a non-adjuvant vaccine among elderly residents of long-term care facilities in Italy

Immunogenicity of new virosome influenza vaccine in elderly people

Immunogenicity of trivalent subunit versus virosome-formulated influenza vaccines in geriatric patients

randomized study to compare the immunogenicity and reactogenicity of an influenza split vaccine with an MF59adjuvanted subunit vaccine and a virosome-based subunit vaccine in elderly

Clinical experience with inactivated, virosomal influenza vaccine

Inactivated influenza virus vaccines in children

The Japanese experiencewith vaccinating schoolchildren against influenza

The 23-valent pneumococcal polysaccharide vaccine. Part 1.Efficacyof PPV in the elderly: a comparison of meta-analyses

Impact of pneumococcal vaccination on morbidity and mortality of geriatric patients: a case-controlled study

Changing epidemiology of invasivepneumococcal disease among older adults in the era of pediatric pneumococcal conjugate vaccine. lama

Stead ww: Tuberculosis

Tuberculosis in the elderly

AntiTB drug resistance in the world

Efficacy of BCG vaccine in the prevention of tuberculosis. Meta-analysis of the published literature

Colnfection with HIV and TB: double trouble

lnununology of tuberculosis

Population-based study of herpes zoster and its sequelae

Varicella-Zoster virus: pathogenesis, immunity and clinical management in hematopoietic cell transplant recipients

Stress-induced subclinical reactivation of varicella zoster virus in astronauts

Live attenuated varicella vaccine

Vaccination boosts adult immunity to varicella zoster virus

A vaccine to prevent herpes zoster and postherpetic neuralgia in older adults

Long-term cytomegalovirus infection leads to significant changes in the composition of the CD8+ T-cell repertoire, which may be the basis for an imbalance in the cyrokine production profile in elderly persons

Human immunosenescence: is it infectious?

Dysfunctional CMV-specific CD8 +T-cells accumulate in the elderly

Cytomegalovirus misleads its host by priming of CD8 Tvcclls specific for an epirope not presented in infected tissues

Cytomegalovirus seropositivity drives the CD8 T-cell repertoire toward greater clonaliry in healthy elderly individuals

Inllamm-aging. An evolutionary perspective on immunosenescence

Lack of antibody produ ction following immunization in old age: association with CD8 +CD28' T-cell clonal expansions and an imbalance in the production of Thl and Th2 cyrokines

Restoration of viral immunity in immunodeficient humans by the adoptive transfer ofT-cell clones

The epidemiology of pertussis: a comparison of the epidemiology of the disease pertussis with the epidemiology of Bordetella pertussis infection

An epidemic of pertussis among elderly people in a religious institution in The Netherlands

Vaccination against tetanus in the elderly: do recommended vaccination strategies give sufficient protection

No immunity for the elderly

A population-based serologic survey of immunity to tetanus in the United States

T-cells from elderly persons respond to neoantigenic stimulation with an unimpaired IL-2 production and an enhanced differentiation into effector cells

Epidemiology and ecology of TBE relevant to the production of effectivevaccines

TBE vaccination and the Austrian experience Vaccine

Immunogenicity and safety of a booster vaccination against tick-borne encephalitis more than 3 years following the last immunisation

Epidemiology and prevention of hepatitis A in travelers

Hepatitis A and hepatitis B: risks compared with other vaccine preventable diseases and immunization recommendations

A prospective,randomized, comparative US trial of a combination hepatitis A and B vaccine (Twinrix) with corresponding monovalent vaccines (Havrix and Engerix-B) in adults

Immunogenicity of an inactivated hepatitis A vaccine in Dutch United Nations troops

Immunogenicity of combined hepatitis A and B vaccine in elderly persons

The effect of age and weight on the response to formalin inactivated, alum-adjuvanted hepatitis A vaccine in healthy adults

District guidelines for yellow fever surveillance

Persistence of neutralizing antibody 30-35 years after immunization with 17D yellow fever vaccine

Advanced age a risk factor for illness temporally associated with yellow fever vaccination

Thymic involution in aging

Thymic involution with ageing: obsolescence or good housekeeping?

Age-related loss of naive T-cells and dysregulation of T'-cell/ B-cell interactions in human lymph nodes

Marked increase with age of type 1 cytokines within memory and effector/cytotoxic CD8+ T-cells in humans: a contribution to understand the relationship between inflammation and immunosenescence

The aging of the immune system

CD8 T-cells and aging

Value of immunological markers in predicting responsiveness to influenza vaccination in elderly individuals

Artherosclerosis as an infectious, inflammatory and autoinunune disease

Role of the immune system in the pathogenesis, prevention and treatment of Alzheimer's disease

How chronic inflammation can affect the brain and support the development of Alzheimer's disease in old age: the role of microglia and astrocytes

Bone marrow microenvironmental changes underlie reduced RAG-mediated recombination and Bvcell generation in aged mice

The effect of age on the B-cell repertoire

Ageing, autoimmunity and arthritis: senescence of the B-cell compartment -implications for humoral immunity

Age-related depression of FDC accessory functions and CD21 ligand-mediated repair of costimulation

B-cells in the aged: CD27, CDS and CD40 expression

Ineffective humoral immunity in the elderly

Vaccine development strategies for improving immunization: the role of modem immunology

Survey of human-use adjuvants

Targeting the innate immune response with improved vaccine adjuvants

Augmentation and suppression of immune responses to an HIV-l DNA vaccine by plasmid cytokine/Ig administration

Coimmunization with an optimized IL-15 plasmid results in enhanced function and longevity of CD8 T-cells that are partially independent of CD4 T-cell help

IL-21 influences the frequency, phenotype and affinity of the antigen-specific CD8 T-cell response

Adjuvant IL7 or IL-15 overcomes immunodominance and improves survival of the CD8+ memory cell pool

Insufficient protection for healthy elderly adults by tetanus and TBE vaccines

Immunizations in the elderly: do they live up to their promise

The authors wish to acknowledge the support ofthe Austrian Science Fund and the Austrian Green Cross Society for Preventive Medicine.