REVIEW 10.1111/j.1469-0691.2012.03944.

Vaccines for the elderly

B. Weinberger and B. Grubeck-Loebenstein

Institute for Biomedical Aging Research, Austrian Academy of Sciences, Innsbruck, Austria

Abstract

Vaccination is the most efficient strategy to prevent infectious disease. The increased vulnerability to infection of the elderly makes
them a particularly important target population for vaccination. However, most vaccines are less immunogenic and efficient in the
elderly because of age-related changes in the immune system. Vaccination against influenza, Streptococcus pneumoniae and varicella zoster
virus is recommended for the elderly in many countries. Various strategies such as the use of adjuvants and novel administration routes
are pursued to improve influenza vaccination for the elderly and recent developments in the field of pneumococcal vaccination led to
the licensure of protein-conjugated polysaccharide vaccines containing up to 13 serotypes. As antibody titres are generally lower in the
elderly and—particularly for inactivated vaccines—decline fast in the elderly, regular booster immunizations, for example against tetanus,
diphtheria and, in endemic areas, tick-borne encephalitis, are essential during adulthood to ensure protection of the elderly. With
increasing health and travel opportunities in old age the importance of travel vaccines for persons over the age of 60 is growing. How-
ever, little is known about immunogenicity and efficacy of travel vaccines in this age group. Despite major advances in the field of vacci-
nology over the last decades, there are still possibilities for improvement concerning vaccines for the elderly. Novel approaches, such
as viral vectors for antigen delivery, DNA-based vaccines and innovative adjuvants, particularly toll-like receptor agonists, will help to
achieve optimal protection against infectious diseases in old age.

Keywords: Adjuvant, elderly, herpes zoster, influenza, Streptococcus pneumoniae, travel vaccines, vaccination
Original Submission: 17 January 2012; Revised Submission: 30 January 2012; Accepted: 31 January 2012
Editor: M. Paul
Clin Microbiol Infect 2012; 18 (Suppl. 5): 100–108
Corresponding author: B. Grubeck-Loebenstein, Institute for Bio-
medical Aging Research, Austrian Academy of Sciences, Rennweg 10,
6020 Innsbruck, Austria
E-mail: beatrix.grubeck@oeaw.ac.at
Introduction
Life expectancy has risen dramatically over the last century
and population projections foresee that the European popu-
lation will continue to age in future decades. Between 1990
and 2010 the percentage of persons aged 65 years or over
has risen from 13.9% to 17.4% in the European population
(EU-27) and is estimated to reach 30% by 2060 (European
Commission, Demography Report 2010. http://ec.europa.eu/
eurostat). This development confronts societies with a signif-
icant socioeconomic challenge and will put tremendous pres-
sure on health systems. Keeping people healthy in old age is
one of the most important strategies to respond to these
challenges.
Vaccination is the most efficient measure to prevent infec-
tious disease, as shown for many childhood vaccines that led
to a dramatic decrease of infections in children. As severity
and incidence of infections increase with age [1], the elderly
are a particularly important target population for vaccination.
However, it has been shown that most vaccines are less
immunogenic and therefore less efficient in the elderly
because of age-related changes of the innate and adaptive
immune system, collectively termed immunosenescence. A
schematic overview of the innate and adaptive immune sys-
tem is shown in Fig. 1 and processes that are affected by im-
munosenescence are highlighted with roman numerals. With
increasing age haematopoietic stem cells differentiate prefer-
entially into myeloid progenitors at the expense of the lym-
phoid lineage. Therefore, the numbers of innate immune
cells of the myeloid lineage do not decrease with age. The
number of natural killer cells is even increased with age,
however, natural killer cell functions, for example cytotoxic-
ity (I) and cytokine production (II), decrease on a per cell
basis. Chemotaxis is disturbed in neutrophils, monocytes/
macrophages and dendritic cells and impaired microbicidal

ª2012 The Authors

Clinical Microbiology and Infection ª2012 European Society of Clinical Microbiology and Infectious Diseases
CMI Weinberger and Grubeck-Loebenstein Vaccines for the elderly 101

produc on of
[II]
cytokines NK cell

elimina on of
[I]
infected cells

elimina on of
infected cells
produc on of
cytokines
[VII]
immature DC naïve
phagocytosis mature DC CD8+ T cell memory/effector
T cells [VIII]
[V]
pathogen
produc on of an gen presenta on
cytokines migra on
[VI]
naïve
phagocytosis CD4+ T cell follicular DC
[VII]
[IV]
pathogen moncyte/macrophage

elimina on of
[III] T cell help
pathogen
[IX]
s mula on of T cells and innate immunity
phagocytosis naïve B cell
produc on of [X]
[IV]
cytokines
pathogen neutrophil

an body producing cell

isotype switch
[XI] IgM
an body producing cell

IgG, IgA or IgE

FIG. 1 Schematic representation of the innate and adaptive immune system. Cell types and cellular functions affected by aging are marked with
red roman numbers.

function (III) as a consequence of reduced phagocytosis (IV)
and superoxide production can also be observed in neu-
trophils as well as monocytes/macrophages. Reduced phago-
cytic capacity of dendritic cells (V) also leads to impaired
antigen presentation and activation of adaptive immune
responses (VI). In addition, there are also age-related altera-
tions in toll-like receptor (TLR) -signalling, which are of par-
ticular interest in the context of vaccination, as many novel
adjuvants target different TLRs. One of the hallmarks of im-
munosenescence is the gradual replacement of functional
thymic tissue by fat, leading to a dramatically reduced output
of newly generated naive T cells, which is reflected by low
numbers of naive T cells in peripheral blood and lymphoid
organs (VII). Concomitantly, antigen-experienced T cells
accumulate (VIII). With increasing age the T-cell compart-
ment is skewed more towards highly differentiated effector
T cells bearing large clonal expansions and thereby limiting
the T-cell repertoire. Highly differentiated effector T cells
produce less interleukin-2 and more proinflammatory cyto-
kines such as interferon-c and tumour necrosis factor-a con-
tributing—together with cells of the innate immune
system—to the low-grade proinflammatory background
observed in the elderly. Elderly persons often lack high-affin-
ity antibody responses to infectious agents and vaccination,
which can partly be explained by defects in T-cell help (IX),
but is also the result of intrinsic defects within the B-cell
pool. It has been demonstrated that B-cell generation in the
bone marrow is affected at several developmental stages
leading to a decreased output and therefore diminished num-
bers of naive B cells (X) in mice, and that antigen-experi-
enced B cells accumulate at the same time. However,
changes of B-cell subpopulations with age are more contro-
versially discussed for humans. Defects in class-switch
recombination and somatic hypermutation (XI) have been
described and molecularly characterized in old mice, but are
mechanistically less clear for humans. Sequence analysis dem-
onstrated that the B-cell repertoire reflected by the diversity
of B-cell receptors is limited in old age and is associated with
frailty. The concept of immunosenescence has been reviewed
in detail by our group and others [2–9].
Several vaccines, such as influenza and pneumococcal vac-
cines, are specifically recommended for the elderly. Vaccine
recommendations vary in individual countries and Table 1
summarizes official recommendations for adults and for the
elderly in the USA and in Germany, as an example of a Euro-
pean country. There are initiatives for harmonized European

ª2012 The Authors

Clinical Microbiology and Infection ª2012 European Society of Clinical Microbiology and Infectious Diseases, CMI, 18 (Suppl. 5), 100–108
102 Clinical Microbiology and Infection, Volume 18 Supplement 5, October 2012
TABLE 1. Official vaccination recommendations for the
USA and for Germany for the year 2011
Germany USA
Tetanus Every 10 years Every 10 years
Diphtheria Every 10 years Every 10 years
Pertussis (acellular) Once during adulthood Once during adulthood
Tick-borne encephalitis In risk areas –
Streptococcus pneumoniaea Once over 60 Once over 65b
Influenza Annual over 60 Annual
Varicella zoster virus – Once over 60
Included are vaccines that are recommended for all adults including the elderly
(white) or for specific age-groups only (shaded). Recommendations for specific
target groups, such as persons with underlying diseases or occupational risks
are not listed here. Data from http://www.rki.de Epidemiologisches Bulletin 30/
2011.
a
23-valent polysaccharide vaccine.
b
Repeated vaccination is recommended for risk groups.
vaccine recommendations for the elderly, which have been
summarized by Michel et al. [10].
This review will introduce vaccines that are recommended
in the elderly with a particular focus on the effect of age on
immunogenicity and efficacy, and will give an outlook on
novel strategies aiming to improve protection of the elderly.
Influenza vaccine
Infections with seasonal influenza virus are a major cause of
vaccine-preventable disease mortality with 25–50 million
cases of influenza estimated to occur in the USA resulting in
30 000–50 000 deaths, mainly in the elderly population [11].
The primary strategy for prevention of influenza disease is
vaccination. Annual vaccination against influenza with an inac-
tivated trivalent vaccine is generally recommended for per-
sons with underlying chronic diseases such as pulmonary,
renal, coronary or heart disease, those who are immunosup-
pressed and for elderly individuals with different age limits in
individual countries. A live-attenuated nasal vaccine is
licensed in the USA for use in healthy children above the age
of 2 years and healthy adults under the age of 50 years
[12,13]. A recent meta-analysis of randomized controlled tri-
als showed a decrease of influenza symptoms (risk difference
3%, 95% CI 2–5; well-matched circulating virus) in vaccinated
adults under the age of 65 years, but no significant effect of
influenza vaccination on complications and hospitalizations in
this age group [14]. Unfortunately, most studies in elderly
cohorts are not randomized controlled trials but rely on
observational data. The assessment of clinical efficacy of
influenza vaccination is difficult and comparison of different
studies is complicated by different outcome parameters,
varying cohorts and variable epidemiological factors such as
prevalence of the virus, virulence of the circulating strain and
ª2012 The Authors
Clinical Microbiology and Infection ª2012 European Society of Clinical Microbiology and Infectious Diseases, CMI, 18 (Suppl. 5), 100–108
CMI
matching of vaccine and circulating viral strains. Despite
these uncertainties, several systematic reviews and meta-
analyses demonstrate clinical efficacy of influenza vaccination,
as hospitalization as a consequence of influenza and overall
deaths are reduced in vaccinated elderly cohorts [15–19].
Immunogenicity of influenza vaccines is generally measured
based on haemagglutination inhibition (HAI) antibody con-
centrations. Antibody responses after vaccination are lower
in the elderly compared with young adults and are even fur-
ther decreased in the very old. Most studies additionally
investigate rates of seroprotection (HAI ‡1:40) and serocon-
version (titre increase at least four-fold), which are fre-
quently also lower in the elderly. Goodwin et al. [20]
performed a meta-analysis of 31 studies and demonstrated
unadjusted odds ratios (OR) of 0.48 (95% CI 0.41–0.55;
H1N1), 0.63 (0.55–0.73; H3N2), and 0.38 (0.33–0.44; B) for
seroconversion and 0.47 (0.40–0.55; H1N1), 0.53 (0.45–0.63;
H2N3), and 0.58 (0.50–0.67; B) for seroprotection in a com-
parison of old and young adults. However, HAI titres are
imperfect correlates of protection because laboratory-con-
firmed influenza infections have been documented despite
the presence of HAI titres ‡1:640 [21]. It has been demon-
strated that the quality of antibody responses, namely the
repertoire and affinity of antibodies, are altered in the
elderly [22,23], corroborating that HAI titres alone are not
sufficient for evaluation of vaccine immunogenicity. This
should also be taken into account when validating new vac-
cines or vaccination strategies. Generally, viral vaccines are
believed to promote protection by inducing neutralizing anti-
body responses; however, cell-mediated immunity also plays
an important role in controlling viral infections. Similar to
the humoral immune response, cell-mediated immunity after
vaccination is lower in the elderly compared with young
adults [24–26].
Optimizing influenza vaccination for the elderly is a major
task, and to make the most of existing vaccines, strategies
that offer indirect protection of the elderly by vaccination of
other populations are a promising option. Vaccination of
healthy children could decrease the incidence of influenza in
the elderly, because children are very efficient transmitters
of the virus [27,28]. In addition, vaccination of healthcare
workers, particularly in long-term care facilities, can be a
successful strategy to reduce patient mortality [29,30].
Despite a general recommendation for vaccination of health-
care workers in many European countries, vaccination cover-
age is disappointingly low in this group [31]. Increased
antigen dosage [32,33] and two-dose schedules [34,35] gave
conflicting results with regard to antibody titres and the
benefit, which can be achieved by higher antigen doses
and booster vaccinations, seems to depend on the specific
CMI
vaccinee cohort and on the timing of booster intervals.
These limitations need to be kept in mind for further studies.
Recently, a high-dose inactivated influenza vaccine has been
licensed in the USA for use in the elderly [33]. Two adju-
vanted influenza vaccines, one subunit vaccine adjuvanted
with MF59 (oil-in-water-emulsion) [36] and a virosomal [37]
vaccine, were registered in several countries and shown to
induce higher anti-haemagglutinin antibody titres compared
with non-adjuvanted vaccines in several studies [37–39],
although others did not confirm the increased immunogenic-
ity [40,41]. Further investigations are required to clarify this
issue and to confirm the clinical benefits of adjuvanted influ-
enza vaccines.
Pneumococcal vaccine
Infections with Streptococcus pneumoniae account for 25–35%
of bacterial pneumonias requiring hospitalization and are a
significant cause for morbidity and mortality in the elderly
[42]. The current pneumococcal vaccine contains polysaccha-
rides of 23 pneumococcal serotypes (PPV) and is recom-
mended for the elderly in several countries. As PPV is a
polysaccharide vaccine, it elicits only T-cell-independent anti-
body responses, induces no immunological memory and does
not show a booster effect upon repeated vaccination. The
efficacy of PPV to prevent pneumococcal disease is contro-
versial. A meta-analysis of 22 studies demonstrated that vac-
cination with PPV reduces the risk of invasive pneumococcal
disease (OR 0.26; 95% CI 0.15–0.46) and to a lesser extent
all-cause pneumonia (OR 0.71; 95% CI 0.52–0.97) in adults
[43]. However, efficacy of PPV against pneumococcal pneu-
monia in the elderly is often doubted. In their meta-analysis
Melegaro and Edmunds [44] report a non-significant vaccine
efficacy of 16% (95% CI )50 to 53) against pneumonia in
healthy elderly. In contrast to these data, a recent random-
ized placebo-controlled study in nursing homes showed a
63.8% (95% CI 32.1–80.7) reduction of pneumococcal pneu-
monia in vaccinated institutionalized elderly [45] and Vila-
Corcoles et al. [46] demonstrated a reduced incidence of all
pneumococcal pneumonia (OR 0.52; 95% CI 0.37–0.73), bac-
teraemic pneumococcal pneumonia (OR 0.34; 95% CI 0.27–
0.66) and non-bacteraemic pneumococcal pneumonia (OR
0.58; 95% CI 0.39–0.86) in persons over the age of 50 years.
Meta-analyses of vaccine efficacy are complicated by hetero-
geneous study populations, such as institutionalized versus
community-dwelling elderly as well as varying read-out
parameters (pneumococcal pneumonia, all-cause pneumonia,
hospitalization due to pneumonia). Serotype-specific antibody
concentrations, which are accepted as correlates of protec-
Clinical Microbiology and Infection ª2012 European Society of Clinical Microbiology and Infectious Diseases, CMI, 18 (Suppl. 5), 100–108
Weinberger and Grubeck-Loebenstein Vaccines for the elderly 103
tion, are lower in the elderly and in individuals with underly-
ing disease [42,47]. A heptavalent, protein-conjugated
pneumococcal vaccine (PCV7), which has been used for
childhood vaccination, is capable of eliciting memory
responses in children and allows booster vaccinations. PCV7
is also more immunogenic in the elderly compared with PPV
and shows a booster effect following a second vaccination
1 year later [48]. Vaccination of children with PCV decreases
the transmission of S. pneumoniae to the elderly and thereby
provides indirect protection against the seven serotypes
included in the vaccine [49]. Recently, conjugated vaccines
containing up to 13 different serotypes have been developed
and replaced PCV7 for childhood vaccination in some coun-
tries [50]. PCV13 has also been licensed for persons over
the age of 50 years. Current vaccination recommendations
still include the polysaccharide vaccine for the elderly, but
future updates will probably consider recommendations for
the use of PCV13 in the elderly.
Herpes zoster vaccine
The incidence of herpes zoster increases with age and rises
from 1.1–2.9 per 1000 in persons under 50 years to 10.9
per 1000 in persons over 80 years [51]. The lifetime risk for
herpes zoster is c.50% among those who reach 85 years of
age [52]. The most common complication of herpes zoster
is postherpetic neuralgia, which is characterized by persistent
pain for months after acute herpes zoster. Especially in the
elderly, postherpetic neuralgia can have a dramatic impact on
activities of daily living and these restrictions can lead to loss
of independence and institutionalization [53]. It is not clear
what induces reactivation of the virus, but it has been postu-
lated that reactivation occurs once T-cell-mediated immunity
against varicella zoster virus falls below a crucial level
because—compared with young adults—fewer varicella zos-
ter virus-specific T cells are detectable in the elderly [54,55].
Vaccination of elderly persons with the live attenuated Oka-
strain, which is also used for childhood vaccination against
chickenpox, leads to increased numbers of varicella zoster
virus-specific T cells [56] persisting for several years [57].
In 2006 a vaccine containing a high dose of this attenuated
varicella zoster virus Oka-strain has been licensed for vacci-
nation of the elderly. This vaccine has been shown to
induce antibody and T-cell responses in the elderly [58]
and in a large study proved to be clinically efficient because
vaccination reduced the incidence of herpes zoster by
51.3% (95% CI 44.2–57.6) in the total population. However,
efficacy was only 37.6% in persons over 69 years. The inci-
dence of postherpetic neuralgia was reduced by 66.5% (95%
ª2012 The Authors
104 Clinical Microbiology and Infection, Volume 18 Supplement 5, October 2012
CI 44.5–79.2) in the total study cohort independent of age
[59].
Other vaccines
Vaccines, not specifically recommended for the elderly, but
administered to all adults, should also be evaluated in per-
sons older than 60 years. Vaccination against tetanus (Clos-
tridium tetani), diphtheria (Corynebacterium diphtheriae) and
pertussis (Bordetella pertussis) is recommended every
10 years in many countries. Although these diseases have
become less frequent as a result of successful vaccination,
they have not disappeared. In endemic areas, which include
regions in 27 European states, vaccination against tick-borne
encephalitis and booster immunizations every 5 years are
recommended with an inactivated vaccine. For persons living
outside areas where the disease is endemic immunization
against tick-borne encephalitis can be of importance as a tra-
vel vaccination. It has been shown that time since the last
vaccination, as well as age, has an impact on antibody titres
against tetanus and tick-borne encephalitis. At all time-points
antibody titres are lower in the elderly compared with young
adults, and antibody titres are negatively correlated with the
time since the last vaccination [60]. Similar data for diphthe-
ria and pertussis are still missing. Pre-booster antibody ti-
tres against tetanus, diphtheria and TBE are positively
correlated with the respective post-booster antibody titres
[61]. These findings indicate that the success of booster
immunizations depends on the existence of residual antibod-
ies and suggest a role for memory B cells and long-lived
plasma cells in the maintenance of immunological protec-
tion. Regular booster immunizations throughout adulthood
ensure sustained protection and are crucial for successful
vaccination in old age.
As a consequence of the increased life expectancy and
mobility of elderly persons, a substantial fraction of travellers
in tropical areas are currently of advanced age (e.g. 14% over
65 years in the USA) [62], and travel vaccines are therefore
an emerging issue in the context of vaccination of the
elderly. Vaccination against diseases such as typhoid and yel-
low fever, Japanese encephalitis and rabies will be a first con-
tact with neo-antigen for most elderly travellers. However,
hepatitis A, hepatitis B and tick-born encephalitis can also
represent new antigens for travellers who have never had
contact with the disease or the vaccine. As the number of
antigen-inexperienced naive T and B cells, and thereby the
immunological repertoire, is reduced in the elderly it can be
hypothesized that elderly persons will not fully respond to
neo-antigens in the context of vaccination. General immuni-
ª2012 The Authors
Clinical Microbiology and Infection ª2012 European Society of Clinical Microbiology and Infectious Diseases, CMI, 18 (Suppl. 5), 100–108
CMI
zation guidelines for travel vaccines are relying primarily on
data from studies with young adults.
Several studies have shown lower antibody titres and
seroconversion rates as well as slower antibody responses in
middle-aged compared with young adults after vaccination
against hepatitis A virus. However, only limited data are
available on the immunogenicity and efficacy of hepatitis A
vaccine in the elderly (>60 years) [63–66]. It is therefore
crucial to vaccinate early enough before travelling to allow
for the development of an adequate antibody response, for
titre controls, and eventually for booster vaccination, if there
is no adequate protection. Hepatitis B vaccination is recom-
mended for elderly persons with selected risk factors.
Besides travellers to high-risk regions this includes healthcare
workers, haemodialysis patients and house-hold contacts of
hepatitis B virus-infected persons. Antibody titres against the
hepatitis B surface antigen are lower and the percentage of
non-responders without protective antibody concentrations
increases with age [67,68]. To improve hepatitis B vaccina-
tion for the elderly and for immunocompromised adults,
alternative routes of administration, such as intradermal
injection, higher doses of hepatitis B surface antigen, altera-
tions in the immunization schedule and an increased number
of doses have been suggested. However, these different
approaches have not yet been evaluated sufficiently in ran-
domized trials. New adjuvant technology to replace the cur-
rently used aluminium salts led to promising results in
healthy adults but has not yet been tested in the elderly [69].
Despite the fact that yellow fever is relatively rare in trav-
ellers, vaccination with a live-attenuated vaccine is recom-
mended for journeys in endemic areas and several African
and South American countries require documented yellow
fever vaccination within the last 10 years for official entry.
Seroconversion rates are very high in young adults [70], but
few data are available on seroconversion rates, antibody ti-
tres, timing of antibody responses or clinical efficacy of vacci-
nation for elderly persons. However, there have been
reports that severe adverse effects, including hospitalization
and death, are more frequent in the elderly [71,72]. Little
information is available on vaccination of the elderly against
other diseases such as for instance Japanese encephalitis and
typhoid fever. Incidence and severity of both infections is
increased in old age [73,74]. Parenteral vaccines based on
bacterial polysaccharides as well as an oral live-attenuated
vaccine are available against Salmonella typhi. Recently, a new
cell-culture-derived inactivated vaccine against Japanese
encephalitis has been licensed [75] in addition to the tradi-
tional vaccine, which is purified from mouse brain. However,
most studies on efficacy involve vaccinees in endemic areas
[76–78]. These data cannot be extrapolated to a naive popu-
CMI
lation of travellers, because vaccination in endemic areas is
likely to elicit booster responses of already existing immunity
after natural contact.
Future challenges
Despite major advances in the field of vaccinology over the
last decades, there are still possibilities for improvement,
particularly concerning vaccines for the elderly. As described
above, most existing vaccines are less immunogenic in the
elderly and many different strategies are currently pursued
to optimize vaccine efficacy in the elderly. Several new
approaches for influenza vaccines are under investigation,
including the use of live recombinant viral vectors for the
delivery of influenza antigens, proteosome vaccines and
DNA-based vaccines (summarized in ref. [79]). Cutaneous
administration of influenza vaccination is a highly attractive
alternative to intramuscular vaccination as the skin harbours
a variety of immune cells including dendritic cells, monocytes,
macrophages and also accessory cells such as keratinocytes
[80]. Several different technical approaches for cutaneous
vaccination such as patches with arrays of antigen-coated mi-
croneedles [81,82], cyanoacrylate skin surface stripping [83]
and immunostimulatory patches, coated with heat-labile
enterotoxin from Escherichia coli [84] are currently under
investigation. The first intradermal influenza vaccine is based
on an inactivated split-vaccine without adjuvant and is deliv-
ered in ready-to-use microinjection devices, which ensure
intradermal delivery of the vaccine. Immunogenicity of the
intradermally administered vaccine has been shown to be
increased in the elderly in the first clinical trials compared
with intramuscular injection of the same antigen dose and
the vaccine has been licensed in Europe for the 2009/10
influenza season. For S. pneumoniae a universal pneumococcal
vaccine covering all serotypes and providing broader protec-
tion in the elderly is desirable. Several protein-based vaccine
candidates are currently developed and mainly focus on
pneumolysin and surface proteins as antigens. Studies in ani-
mal models show varying effectiveness against bacterial chal-
lenge. However, individual studies are difficult to compare
because study design, route of administration, use of adju-
vants and challenge protocols differ greatly [85]. Further
research to optimize pneumococcal vaccines is required.
Recent research focuses on the development of novel ad-
juvants, which enhance or modulate vaccine-induced immune
responses and could be useful to improve the immunogenic-
ity of various antigens in the elderly. Substances targeting
TLRs such as the lipopeptides Pam2Cys and Pam3Cys
(TLR2), the double-strand RNA analogue poly:IC and its
Clinical Microbiology and Infection ª2012 European Society of Clinical Microbiology and Infectious Diseases, CMI, 18 (Suppl. 5), 100–108
Weinberger and Grubeck-Loebenstein Vaccines for the elderly 105
derivatives (TLR3), monophosphoryl lipid A and other TLR4
agonists, the TLR5 agonist flagellin, imidazoquinolines (TLR7/
8) and CpG oligodeoxy nucleotides (TLR9) aim to induce
proinflammatory chemokines/cytokines and type I interferons.
Detailed reviews summarizing the use of TLR agonists as adju-
vants and giving an overview on current clinical development
have recently been published [86,87]. However, one has to
keep in mind that there are age-related alterations in TLR-sig-
nalling. Surface expression of TLR1 is reduced on the mono-
cytes of elderly persons [88] leading to decreased production
of interleukin-6 and tumour necrosis factor-a following TLR1/
2 engagement, upregulation of the co-stimulatory molecule
CD80 is impaired after stimulation of various TLRs such as
TLR1, TLR2, TLR 4, TLR5, TLR6 and TLR-induced alterations
of CD80 expression have been shown to be associated with
antibody responses after influenza vaccination [89]. Age-
related changes of TLR function have also been described for
dendritic cells, but are controversial. A recent study using pri-
mary myeloid and plasmacytoid dendritic cells showed that
there is an age-related defect in the production of several
cytokines after stimulation via almost all TLRs tested, which is
correlated with the generation of protective antibodies after
influenza vaccination [90]. Therefore, it seems essential to
test these substances specifically in the elderly to ensure ade-
quate adjuvanticity also in this age group. Several other types
of adjuvants such as oil-in-water emulsions (e.g. MF59), lipo-
somes or saponins are also in use or under development.
Novel adjuvant strategies often also rely on combinations of
different substances, for example alum plus monophosphoryl
lipid A (AS04), KLK peptide plus TLR9 agonist (IC31), immu-
nostimulatory complexes based on 40 nm cage-like particles
(ISCOM, cholesterol plus phospholipids plus saponin), lipo-
somes or oil-in-water emulsions plus monophosphoryl lipid A
plus saponin (AS01/AS02) (reviewed in refs [91,92]).
Currently, no vaccines are available against nosocomial
bacterial infections. In view of increasing resistance to antibiot-
ics, vaccination could be a very efficient strategy to reduce the
burden of hospital-acquired infections. As elderly persons are
hospitalized more frequently they could be a primary target
for those vaccines. However, little research is currently deal-
ing with these issues. Staphylococcus aureus, particularly methi-
cillin-resistant strains, Clostridium difficile, E. coli, Klebsiella
pneumoniae and—albeit not a bacterial infection—Candida spp.
could be considered as targets for vaccine development [93].
Conclusion
Immunosenescence contributes to decreased immune
responses after vaccination of elderly individuals. Nevertheless,
ª2012 The Authors
106 Clinical Microbiology and Infection, Volume 18 Supplement 5, October 2012
vaccination is the most effective strategy to prevent infec-
tious diseases. Public awareness is needed that not only chil-
dren, but also adults, and in particular the elderly, benefit
from vaccination. Further research to gain deeper insight
into basic mechanisms of immunosenescence, investigation of
licensed vaccines in the elderly, adaptation of vaccination
strategies and development of new vaccines, modes of
administration and adjuvants will help to achieve optimal pro-
tection in old age.
Conflicts of interest
BW has received speakers ‘fees from Sanofi Pasteur MSD,
Pfizer Inc and Novartis Vaccines.
BGL has received speakers’ fees from Sanofi Pasteur MSD,
Pfizer Inc and Novartis Vaccines and consultant fees from
Intercell and Pfizer Inc.
References
1. Gavazzi G, Krause KH. Ageing and infection. Lancet Infect Dis 2002; 2:
659–666.
2. Weinberger B, Herndler-Brandstetter D, Schwanninger A, Weiskopf
D, Grubeck-Loebenstein B. Biology of immune responses to vaccines
in elderly persons. Clin Infect Dis 2008; 46: 1078–1084.
3. Panda A, Arjona A, Sapey E et al. Human innate immunosenescence:
causes and consequences for immunity in old age. Trends Immunol
2009; 30: 325–333.
4. Ademokun A, Wu YC, Dunn-Walters D. The ageing B cell popula-
tion: composition and function. Biogerontology 2010; 11: 125–137.
5. Shaw AC, Joshi S, Greenwood H, Panda A, Lord JM. Aging of the
innate immune system. Curr Opin Immunol 2010; 22: 507–513.
6. Agrawal A, Gupta S. Impact of aging on dendritic cell functions in
humans. Ageing Res Rev 2011; 10: 336–345.
7. Brunner S, Herndler-Brandstetter D, Weinberger B, Grubeck-Loe-
benstein B. Persistent viral infections and immune aging. Ageing Res
Rev 2011; 10: 362–369.
8. Arnold CR, Wolf J, Brunner S, Herndler-Brandstetter D, Grubeck-
Loebenstein B. Gain and loss of T cell subsets in old age – age-related
reshaping of the T cell repertoire. J Clin Immunol 2011; 31: 137–146.
9. Frasca D, Blomberg BB. Aging affects human B cell responses. J Clin
Immunol 2011; 31: 430–435.
10. Michel JP, Chidiac C, Grubeck-Loebenstein B et al. Advocating vacci-
nation of adults aged 60 years and older in Western Europe: state-
ment by the Joint Vaccine Working Group of the European Union
Geriatric Medicine Society and the International Association of Ger-
ontology and Geriatrics-European Region. Rejuvenation Res 2009; 12:
127–135.
11. Thompson WW, Shay DK, Weintraub E et al. Mortality associated
with influenza and respiratory syncytial virus in the United States.
JAMA 2003; 289: 179–186.
12. Harper SA, Fukuda K, Cox NJ, Bridges CB. Using live, attenuated
influenza vaccine for prevention and control of influenza: supplemen-
tal recommendations of the Advisory Committee on Immunization
Practices (ACIP). MMWR Recomm Rep 2003; 52: 1–8.
ª2012 The Authors
Clinical Microbiology and Infection ª2012 European Society of Clinical Microbiology and Infectious Diseases, CMI, 18 (Suppl. 5), 100–108
CMI
13. Fiore AE, Shay DK, Broder K et al. Prevention and control of influ-
enza: recommendations of the Advisory Committee on Immunization
Practices (ACIP), 2008. MMWR Recomm Rep 2008; 57: 1–60.
14. Jefferson T, Di PC, Rivetti A, Bawazeer GA, Al-Ansary LA, Ferroni E.
Vaccines for preventing influenza in healthy adults. Cochrane Database
Syst Rev 2010; 7: CD001269.
15. Gross PA, Hermogenes AW, Sacks HS, Lau J, Levandowski RA. The
efficacy of influenza vaccine in elderly persons. A meta-analysis and
review of the literature. Ann Intern Med 1995; 123: 518–527.
16. Vu T, Farish S, Jenkins M, Kelly H. A meta-analysis of effectiveness of
influenza vaccine in persons aged 65 years and over living in the com-
munity. Vaccine 2002; 20: 1831–1836.
17. Jefferson T, Rivetti D, Rivetti A, Rudin M, Di PC, Demicheli V. Effi-
cacy and effectiveness of influenza vaccines in elderly people: a sys-
tematic review. Lancet 2005; 366: 1165–1174.
18. Rivetti D, Jefferson T, Thomas R et al. Vaccines for preventing influ-
enza in the elderly. Cochrane Database Syst Rev 2006; 19:
CD004876.
19. Nichol KL, Nordin JD, Nelson DB, Mullooly JP, Hak E. Effectiveness
of influenza vaccine in the community-dwelling elderly. N Engl J Med
2007; 357: 1373–1381.
20. Goodwin K, Viboud C, Simonsen L. Antibody response to influenza
vaccination in the elderly: a quantitative review. Vaccine 2006; 24:
1159–1169.
21. Gravenstein S, Drinka P, Duthie EH et al. Efficacy of an influenza
hemagglutinin-diphtheria toxoid conjugate vaccine in elderly nursing
home subjects during an influenza outbreak. J Am Geriatr Soc 1994;
42: 245–251.
22. van Dijk-Hard I, Soderstrom I, Feld S, Holmberg D, Lundkvist I. Age-
related impaired affinity maturation and differential D-JH gene usage
in human VH6-expressing B lymphocytes from healthy individuals. Eur
J Immunol 1997; 27: 1381–1386.
23. Wang X, Stollar BD. Immunoglobulin VH gene expression in human
aging. Clin Immunol 1999; 93: 132–142.
24. Bernstein ED, Gardner EM, Abrutyn E, Gross P, Murasko DM. Cyto-
kine production after influenza vaccination in a healthy elderly popu-
lation. Vaccine 1998; 16: 1722–1731.
25. Bernstein E, Kaye D, Abrutyn E, Gross P, Dorfman M, Murasko DM.
Immune response to influenza vaccination in a large healthy elderly
population. Vaccine 1999; 17: 82–94.
26. Murasko DM, Bernstein ED, Gardner EM et al. Role of humoral and
cell-mediated immunity in protection from influenza disease after
immunization of healthy elderly. Exp Gerontol 2002; 37: 427–439.
27. Munoz FM. The impact of influenza in children. Semin Pediatr Infect
Dis 2002; 13: 72–78.
28. Jordan R, Connock M, Albon E et al. Universal vaccination of children
against influenza: are there indirect benefits to the community? A sys-
tematic review of the evidence Vaccine 2006; 24: 1047–1062.
29. Potter J, Stott DJ, Roberts MA et al. Influenza vaccination of health
care workers in long-term-care hospitals reduces the mortality of
elderly patients. J Infect Dis 1997; 175: 1–6.
30. Carman WF, Elder AG, Wallace LA et al. Effects of influenza vaccina-
tion of health-care workers on mortality of elderly people in long-
term care: a randomised controlled trial. Lancet 2000; 355: 93–97.
31. Mereckiene J, Cotter S, Nicoll A et al. National seasonal influenza
vaccination survey in Europe, 2008. Euro Surveill 2008; 13: 19017.
32. Roos-Van Eijndhoven DG, Cools HJ, Westendorp RG, Ten Cate-
Hoek AJ, Knook DL, Remarque EJ. Randomized controlled trial of se-
roresponses to double dose and booster influenza vaccination in frail
elderly subjects. J Med Virol 2001; 63: 293–298.
33. Keitel WA, Atmar RL, Cate TR et al. Safety of high doses of influenza
vaccine and effect on antibody responses in elderly persons. Arch
Intern Med 2006; 166: 1121–1127.
CMI Weinberger and Grubeck-Loebenstein
34. Tanzi E, Amendola A, Pariani E et al. Lack of effect of a booster dose
of influenza vaccine in hemodialysis patients. J Med Virol 2007; 79:
1176–1179.
35. Cools HJ, Gussekloo J, Remmerswaal JE, Remarque EJ, Kroes AC.
Benefits of increasing the dose of influenza vaccine in residents of
long-term care facilities: a randomized placebo-controlled trial. J Med
Virol 2009; 81: 908–914.
36. De Donato S, Granoff D, Minutello M et al. Safety and immunogenic-
ity of MF59-adjuvanted influenza vaccine in the elderly. Vaccine 1999;
17: 3094–3101.
37. Conne P, Gauthey L, Vernet P et al. Immunogenicity of trivalent sub-
unit versus virosome-formulated influenza vaccines in geriatric
patients. Vaccine 1997; 15: 1675–1679.
38. Gluck R, Mischler R, Finkel B, Que JU, Scarpa B, Cryz SJ Jr. Immuno-
genicity of new virosome influenza vaccine in elderly people. Lancet
1994; 344: 160–163.
39. Podda A. The adjuvanted influenza vaccines with novel adjuvants:
experience with the MF59-adjuvanted vaccine. Vaccine 2001; 19:
2673–2680.
40. Ruf BR, Colberg K, Frick M, Preusche A. Open, randomized study to
compare the immunogenicity and reactogenicity of an influenza split
vaccine with an MF59-adjuvanted subunit vaccine and a virosome-
based subunit vaccine in elderly. Infection 2004; 32: 191–198.
41. de Bruijn I, Meyer I, Gerez L, Nauta J, Giezeman K, Palache B. Anti-
body induction by virosomal, MF59-adjuvanted, or conventional influ-
enza vaccines in the elderly. Vaccine 2007; 26: 119–127.
42. Centers for Disease Control and Prevention. Prevention of pneumo-
coccal disease: recommendations of the Advisory Committee on
Immunization Practices (ACIP). MMWR Recomm Rep 1997; 46: 1–24.
43. Moberley SA, Holden J, Tatham DP, Andrews RM. Vaccines for pre-
venting pneumococcal infection in adults. Cochrane Database Syst Rev
2008; 1: CD000422.
44. Melegaro A, Edmunds WJ. The 23-valent pneumococcal polysaccha-
ride vaccine. Part I. Efficacy of PPV in the elderly: a comparison of
meta-analyses. Eur J Epidemiol 2004; 19: 353–363.
45. Maruyama T, Taguchi O, Niederman MS et al. Efficacy of 23-valent
pneumococcal vaccine in preventing pneumonia and improving sur-
vival in nursing home residents: double blind, randomised and pla-
cebo controlled trial. BMJ 2010; 340:c1004.
46. Vila-Corcoles A, Salsench E, Rodriguez-Blanco T et al. Clinical effec-
tiveness of 23-valent pneumococcal polysaccharide vaccine against
pneumonia in middle-aged and older adults: a matched case-control
study. Vaccine 2009; 27: 1504–1510.
47. Kumar R, Burns EA. Age-related decline in immunity: implications for
vaccine responsiveness. Expert Rev Vaccines 2008; 7: 467–479.
48. de RA, Schmole-Thoma B, Siber GR et al. Comparison of pneumo-
coccal conjugate polysaccharide and free polysaccharide vaccines in
elderly adults: conjugate vaccine elicits improved antibacterial immune
responses and immunological memory. Clin Infect Dis 2008; 46: 1015–
1023.
49. Lexau CA, Lynfield R, Danila R et al. Changing epidemiology of inva-
sive pneumococcal disease among older adults in the era of pediatric
pneumococcal conjugate vaccine. JAMA 2005; 294: 2043–2051.
50. Nuorti JP, Whitney CG. Prevention of pneumococcal disease among
infants and children – use of 13-valent pneumococcal conjugate vac-
cine and 23-valent pneumococcal polysaccharide vaccine – recom-
mendations of the Advisory Committee on Immunization Practices
(ACIP). MMWR Recomm Rep 2010; 59: 1–18.
51. Insinga RP, Itzler RF, Pellissier JM, Saddier P, Nikas AA. The incidence
of herpes zoster in a United States administrative database. J Gen
Intern Med 2005; 20: 748–753.
52. Katz J, Cooper EM, Walther RR, Sweeney EW, Dworkin RH. Acute
pain in herpes zoster and its impact on health-related quality of life.
Clin Infect Dis 2004; 39: 342–348.
Clinical Microbiology and Infection ª2012 European Society of Clinical Microbiology and Infectious Diseases, CMI, 18 (Suppl. 5), 100–108
Vaccines for the elderly 107
53. Schmader K, Gnann JW Jr, Watson CP. The epidemiological, clinical,
and pathological rationale for the herpes zoster vaccine. J Infect Dis
2008; 197 (Suppl 2): S207–S215.
54. Burke BL, Steele RW, Beard OW, Wood JS, Cain TD, Marmer DJ.
Immune responses to varicella-zoster in the aged. Arch Intern Med
1982; 142: 291–293.
55. Levin M. Immunization against herpes zoster. 2000; 500–519.
56. Levin MJ, Murray M, Rotbart HA, Zerbe GO, White CJ, Hayward
AR. Immune response of elderly individuals to a live attenuated vari-
cella vaccine. J Infect Dis 1992; 166: 253–259.
57. Levin MJ, Barber D, Goldblatt E et al. Use of a live attenuated vari-
cella vaccine to boost varicella-specific immune responses in seropos-
itive people 55 years of age and older: duration of booster effect. J
Infect Dis 1998; 178: S109–S112.
58. Levin MJ, Oxman MN, Zhang JH et al. Varicella-zoster virus-specific
immune responses in elderly recipients of a herpes zoster vaccine. J
Infect Dis 2008; 197: 825–835.
59. Oxman MN, Levin MJ, Johnson GR et al. A vaccine to prevent herpes
zoster and postherpetic neuralgia in older adults. N Engl J Med 2005;
352: 2271–2284.
60. Hainz U, Jenewein B, Asch E, Pfeiffer KP, Berger P, Grubeck-Loeben-
stein B. Insufficient protection for healthy elderly adults by tetanus
and TBE vaccines. Vaccine 2005; 23: 3232–3235.
61. Kaml M, Weiskirchner I, Keller M et al. Booster vaccination in the
elderly: their success depends on the vaccine type applied earlier in
life as well as on pre-vaccination antibody titers. Vaccine 2006; 24:
6808–6811.
62. Hill DR. Health problems in a large cohort of Americans traveling to
developing countries. J Travel Med 2000; 7: 259–266.
63. Stoffel M, Lievens M, Dieussaert I, Martin I, Andre F. Immunogenicity
of Twinrix in older adults: a critical analysis. Expert Rev Vaccines 2003;
2: 9–14.
64. Wolters B, Junge U, Dziuba S, Roggendorf M. Immunogenicity of
combined hepatitis A and B vaccine in elderly persons. Vaccine 2003;
21: 3623–3628.
65. D’Acremont V, Herzog C, Genton B. Immunogenicity and safety of a
virosomal hepatitis A vaccine (Epaxal) in the elderly. J Travel Med
2006; 13: 78–83.
66. Genton B, D’Acremont V, Furrer HJ, Hatz C, Louis L. Hepatitis A
vaccines and the elderly. Travel Med Infect Dis 2006; 4: 303–312.
67. Roome AJ, Walsh SJ, Cartter ML, Hadler JL. Hepatitis B vaccine
responsiveness in Connecticut public safety personnel. JAMA 1993;
270: 2931–2934.
68. Fisman DN, Agrawal D, Leder K. The effect of age on immunologic
response to recombinant hepatitis B vaccine: a meta-analysis. Clin
Infect Dis 2002; 35: 1368–1375.
69. Vandepapeliere P, Horsmans Y, Moris P et al. Vaccine adjuvant sys-
tems containing monophosphoryl lipid A and QS21 induce strong
and persistent humoral and T cell responses against hepatitis B
surface antigen in healthy adult volunteers. Vaccine 2008; 26: 1375–
1386.
70. Lang J, Zuckerman J, Clarke P, Barrett P, Kirkpatrick C, Blondeau C.
Comparison of the immunogenicity and safety of two 17D yellow
fever vaccines. Am J Trop Med Hyg 1999; 60: 1045–1050.
71. Martin M, Weld LH, Tsai TF et al. Advanced age a risk factor for ill-
ness temporally associated with yellow fever vaccination. Emerg Infect
Dis 2001; 7: 945–951.
72. Wilson ME. Travel-related vaccines. Infect Dis Clin North Am 2001; 15:
231–251.
73. Taylor DN, Pollard RA, Blake PA. Typhoid in the United States and
the risk to the international traveler. J Infect Dis 1983; 148: 599–602.
74. Hennessy S, Liu Z, Tsai TF et al. Effectiveness of live-attenuated Japa-
nese encephalitis vaccine (SA14-14-2): a case-control study. Lancet
1996; 347: 1583–1586.
ª2012 The Authors
108 Clinical Microbiology and Infection, Volume 18 Supplement 5, October 2012
75. Tauber E, Kollaritsch H, Korinek M et al. Safety and immunogenicity
of a Vero-cell-derived, inactivated Japanese encephalitis vaccine: a
non-inferiority, phase III, randomised controlled trial. Lancet 2007;
370: 1847–1853.
76. Oya A. Japanese encephalitis vaccine. Acta Paediatr Jpn 1988; 30: 175–
184.
77. Hoke CH, Nisalak A, Sangawhipa N et al. Protection against Japanese
encephalitis by inactivated vaccines. N Engl J Med 1988; 319: 608–614.
78. Guzman CA, Borsutzky S, Griot-Wenk M et al. Vaccines against
typhoid fever. Vaccine 2006; 24: 3804–3811.
79. Tosh PK, Poland GA. Emerging vaccines for influenza. Expert Opin
Emerg Drugs 2008; 13: 21–40.
80. Nicolas JF, Guy B. Intradermal, epidermal and transcutaneous vacci-
nation: from immunology to clinical practice. Expert Rev Vaccines
2008; 7: 1201–1214.
81. Koutsonanos DG, del Pilar MM, Zarnitsyn VG et al. Transdermal
influenza immunization with vaccine-coated microneedle arrays. PLoS
One 2009; 4: e4773.
82. Zhu Q, Zarnitsyn VG, Ye L et al. Immunization by vaccine-coated mi-
croneedle arrays protects against lethal influenza virus challenge. Proc
Natl Acad Sci U S A 2009; 106: 7968–7973.
83. Vogt A, Mahe B, Costagliola D et al. Transcutaneous anti-influenza
vaccination promotes both CD4 and CD8 T cell immune responses
in humans. J Immunol 2008; 180: 1482–1489.
ª2012 The Authors
Clinical Microbiology and Infection ª2012 European Society of Clinical Microbiology and Infectious Diseases, CMI, 18 (Suppl. 5), 100–108
CMI
84. Frech SA, Kenney RT, Spyr CA et al. Improved immune responses to
influenza vaccination in the elderly using an immunostimulant patch.
Vaccine 2005; 23: 946–950.
85. Tai SS. Streptococcus pneumoniae protein vaccine candidates: properties,
activities and animal studies. Crit Rev Microbiol 2006; 32: 139–153.
86. Duthie MS, Windish HP, Fox CB, Reed SG. Use of defined TLR ligands
as adjuvants within human vaccines. Immunol Rev 2011; 239: 178–196.
87. Steinhagen F, Kinjo T, Bode C, Klinman DM. TLR-based immune ad-
juvants. Vaccine 2011; 29: 3341–3355.
88. van DD, Mohanty S, Thomas V et al. Age-associated defect in human
TLR-1/2 function. J Immunol 2007; 178: 970–975.
89. van DD, Allore HG, Mohanty S et al. Prevaccine determination of the
expression of costimulatory B7 molecules in activated monocytes
predicts influenza vaccine responses in young and older adults. J Infect
Dis 2007; 195: 1590–1597.
90. Panda A, Qian F, Mohanty S et al. Age-associated decrease in TLR
function in primary human dendritic cells predicts influenza vaccine
response. J Immunol 2010; 184: 2518–2527.
91. Coffman RL, Sher A, Seder RA. Vaccine adjuvants: putting innate
immunity to work. Immunity 2010; 33: 492–503.
92. Rappuoli R, Mandl CW, Black S, De GE. Vaccines for the twenty-first
century society. Nat Rev Immunol 2011; 11: 865–872.
93. Cross AS, Chen WH, Levine MM. A case for immunization against
nosocomial infections. J Leukoc Biol 2008; 83: 483–488.