Immunology Letters
journal homepage: www.elsevier.com/locate/immlet
Institute of Protein Biochemistry, National Research Council (CNR), 80131 Naples, Italy
Institute of Biomedical Technologies, CNR, 20090 Segrate, Italy
a r t i c l e
i n f o
Article history:
Available online 21 June 2014
Keywords:
Vaccination
Elderly
Immunosenescence
a b s t r a c t
The immune system of the elderly is particularly susceptible to infectious diseases and displays reduced
response to vaccination. The current vaccines, designed for young and adult individuals, proved less
effective and less protective in old people. The world population is rapidly ageing, and consequently
preventing infectious diseases in the elderly have become an important public health issue. To this end,
it is necessary to develop novel vaccines especially suited to raising protective immunity in the ageing population. Approaches in this direction include high-dose vaccines, booster vaccinations, different
immunisation routes, and use of new adjuvants. These approaches, still empirical, must be supported by
intensive research to unravel the biological and molecular mechanisms underlying immunosenescence.
Only this knowledge would allow us to design approaches to immune rejuvenation and more effective
vaccines for protecting the elderly.
2014 Elsevier B.V. All rights reserved.
1. Introduction
Life expectancy has impressively increased during the last
century worldwide, and is equally evident in developed and in
developing countries. The United Nations expect that by 2050 about
25% of the world population will be >65 years of age, and that 75%
of this elderly population will be living in developing countries [1].
One of the aspects that contributed to prolong life expectancy
is the signicant decrease in infectious diseases burden at young
age, thanks to better nutrition, health care and effective preventive
measures [2].
The elderly population is generally immunologically frail, and
more susceptible to developing diseases. This becomes a major
Abbreviations: DC, dendritic cells; TLR, Toll-like receptors; TCR, T cell receptor; VZV, Varicella Zoster Virus; HIA, haemagglutination inhibition antibodies; HA,
haemagglutinin; Tdap, tetanus/diphteria/acellular pertussis vaccine; TIV, trivalent
inactivated inuenza virus vaccine; APC, antigen-presenting cells; MVA, Modied
Vaccinia Virus Ankara; NP, nucleoprotein; M1, matrix protein 1.
Corresponding author at: Institute of Protein Biochemistry, CNR Area della
Ricerca di Napoli 1, Via Pietro Castellino 111, 80131 Naples, Italy.
Tel.: +39 081 6132623; fax: +39 081 6132277.
E-mail addresses: d.boraschi@ibp.cnr.it, diana.boraschi@gmail.com,
boraschi@altaweb.eu (D. Boraschi), p.italiani@ibp.cnr.it (P. Italiani).
1
Present address: Institute of Protein Biochemistry, CNR Area della Ricerca di
Napoli 1, Via Pietro Castellino 111, 80131 Naples, Italy.
http://dx.doi.org/10.1016/j.imlet.2014.06.006
0165-2478/ 2014 Elsevier B.V. All rights reserved.
2. Immunosenescence
Immunosenescence is not synonymous with immunodeciency. Although a decline of immunological functions is evident,
there are elements of the system that are preserved (e.g., CD8+
T cell poly-functionality, number of resident macrophages) [7],
while others are even increased (e.g., innate/inammatory cytokine
production by macrophages) [8]. Therefore, it has been suggested
replacing the term immunosenescence with senescent immune
remodelling [9], which better implies the plasticity of the ageing
immune system.
In addition to age-related remodelling, the metabolic changes
of the ageing body (e.g., increased presence of apoptotic cells)
induce the immune system to change its quiescent state to
a different level of basal activation. Consequently, the immune
reactivity of healthy elderly people is qualitatively and quantitatively different from that of healthy adults. Thus, different
normal thresholds should be considered in the healthy ageing
population [10].
The elderly population is more susceptible than young adults to
cancer, chronic diseases and infectious diseases, with a slower and
less efcient recovery [11,12]. The reduced responsiveness of the
aged immune system is responsible of both the reduced response
to infectious and pathological events, and the suboptimal response
to vaccination.
Both innate and adaptive immunity are affected by age. The
changes in the immune response of the elderly are due to intrinsic defects within immune cells (that show altered phenotype
and function [1315]), and possibly to defects in the bone marrow and thymic stroma microenvironment [16]. Other inuencing
factors encompass changes occurring in the ageing body, such as
increased cellular death [17], increased oxidative stress events [18],
nutritional status [19,20], hormonal dysregulation [21], comorbidities [22], and chronic diseases (e.g., diabetes, cardiovascular
diseases) [23]. All these factors contribute to generate a basal
chronic low-grade inammation, termed inamm-ageing that
maintains innate immune cells, such as macrophages, in a permanent low-grade activation state [24]. This may cause excessive
inammation and tissue damage upon infectious challenges. The
functions of dendritic cells (DC) also appear to be constitutively
activated in people >65 years of age, although these cells are less
reactive to challenges that activate the innate Toll-like receptors
(TLR) [25].
Cells of the adaptive immune system are also less functional
[5]. Both nave T and B cells are still able to undergo renewal,
but a preponderance of memory T and B cells has been observed
[26,27]. Memory B cells show a limited repertoire diversity [28], so
that in elderly individuals the antibody response to new antigens
is quantitatively decreased, less efcient and with lower avidity
[29]. Table 1 summarises the main current knowledge on agerelated immunological changes. The different processes involved
in immunosenescence have been excellently reviewed recently
[52,6769].
347
348
Table 1
Causes and effects of the main age-associated changes in the immune system.
Changes
Haematopoietic stem cell
-Skewing of bone marrow
progenitors towards the
myeloid lineage
Cause
Effect
Reference
-Epigenetic changes
-DNA damage
-Telomere shorting
-Exposure to chronic age-related
inammation
-Infections and cancer
[9,3034]
-Increased incidence of
autoimmune disease
-Impaired antigen-presenting
capacity
-Reduced capacity to phagocytose
antigens
-Inamm-ageing
-Impaired ability to respond to
infections
-Reduced TLR-mediated activation
of DC and macrophages
-Reduced cytokine production
-Increased concentration of
inammatory cytokines (e.g.,
TNF-) in serum
-Increased apoptotic cells
-Increased oxidative stress
-Desensitised myeloid cells
(reduced cytokine production by
myeloid cells upon stimulation
with TLR ligands and reduced
antigen presentation)
[24,35,3745]
-Highly differentiated
effector/memory T cells (e.g., CD8+
T cells)
-Large clonal expansions
-Limited T cell repertoire
-CD8+ T cell-mediated responses
remain intact
-Impaired ability to respond to
new antigens
-T cell generation via peripheral
proliferation maintains a diverse
nave CD4+ T cell compartment up
to the eighth decade of life
-Impaired TCR sensitivity due to
loss of miR-181a and more DUSP6
in naive CD4+ T cells
-Increased memory-like B cells
-Increased lifespan and
homeostatic expansion of mature B
cell
-Homogeneous and less
antigen-specic population
-Reduced production of antibodies
in response to vaccination
[38,5762]
-Inamm-ageing (chronic
inammation, enhanced
level of basal inammatory
activation)
Adaptive immunity
-Lack of nave T cell in
peripheral blood and
lymphoid organs
-Thymic involution
-Reduced output of lymphoid
precursors from the bone marrow
-Defects in T cell receptor
(TCR)/CD3-mediated phosphorylation
events or aberrant regulation of
TCR-associated tyrosine kinase
associated with the TCR
-Decreased TCR repertoire
[35,36]
[25,4649]
[8,9,32,5056]
[6366]
assessing the presence of IgG antibodies against the haemagglutinin (HA) moiety on the viral capsule, with positive immunisation
indicated by HAI titres 1:40 [78]. The vaccine currently recommended for the elderly is the trivalent inactivated inuenza
vaccine (TIV), containing split virus from the circulating strains of
inuenza A (H1N1 and H3N2) and B. A recent meta-analysis indicated that clinical efcacy of TIV in healthy adults is around 60%
[79], whereas the same vaccine has been shown to induce signicantly lower serum HAI titres in the elderly, with estimates ranging
from 17% to 53% [80]. Considering that one of the immune defects
reported with ageing is the reduced formation of the immunological synapse, leading to reduced antigen presentation, a simple
Target
Strategies
Goal
TIV
Inactivated
trivalent vaccine,
split virus from
circulating
strains of
inuenza A
(H1N1 and
H3N2) and B
PPSV-23
Capsular
polysaccharides
from 23 bacterial
serotypes
PCV-13
Capsular
polysaccharides
from 13 bacterial
serotypes
Oka/Merck
Live, attenuated
VZV strain
Tdap vaccine
Tetanus toxoid,
reduced
diphtheria toxoid
and acellular
pertussis
Inuenza virus
Inactivated
virus
Increase of
neutralising
antibody
response
Streptococcus
pneumoniae
Polysaccharides
puried from
the bacterial
capsule
Streptococcus
pneumoniae
Protein carrierconjugated
bacterial
polysaccharides
Live or
attenuated
virus
Toxins puried
from bacteria
Induction of a T
cellindependent
antibody
response
Induction of a T
cell-dependent
antibody
response
Varicella Zoster
Virus
Diphtheria
Tetanus
Pertussis
Induction of
antibody and T
cell responses
Increase of
antibody
production
approach to increasing vaccine efcacy in the elderly is the administration of higher vaccine doses. Thus, high-dose vaccines are used
to overcome the defects in antigen presentation, in the attempt
to increasing antigen delivery from antigen-presenting cells (APC;
e.g., DC) to B cells, thereby eliciting a greater antigen-specic antibody response [81]. Moreover, it is old knowledge that the HAI titre
increases by increasing the dose of antigen in the vaccine inoculum
[82,83], although it is not clear whether this increase has clinical
signicance. This strategy has been already tested, showing that a
4-fold dose increase (60 g of HA vs. 15 g as in the normal vaccine)
could improve the immune response in old people [84], however
without reaching the protection level achieved in young adults with
the regular dose of 15 g [85]. Thus, increasing the antigen dosage
may improve response, but it does not seem to be sufcient for
reaching optimal vaccine efcacy in the elderly.
4.2. Booster vaccination
During a primary exposure to an antigen in young and adult
people, nave (or antigen-inexperienced) T cell are activated and
differentiate into effector and memory cells. Likewise, nave B
cells can be stimulated by T cells and differentiate into antibodysecreting and memory cells. On booster vaccination or subsequent
infection, pre-existing memory T cells recognise the antigen on DC,
and rapidly expand and differentiate into effector T cells, resulting
in a faster and stronger response. Accordingly, also pre-existing
memory B cells are able to mounting a more rapid response.
As previously mentioned, one of the aspects of immunosenescence is an impaired number and repertoire of nave T and B cells
[86], a situation that implies inadequate capacity of mounting an
optimal protective response. Thus, although elderly people are able
to mount a T cell response after vaccination, they also exhibit an
impaired long-term immune response [87]. Also, the antibody titres
decline faster in the elderly [88], and they often do not reach protective antibody concentrations upon recall antigens.
The time elapsed since the last vaccination has a signicant
effect on the antibody titres and can be essential for a protective
response [88]. In addition, intact immunological memory in old age
349
can be achieved upon early primary immunisation [87]. In this context, the use of booster vaccinations at different ages can reduce the
individual morbidity and is one of the strategies to improve vaccine
efcacy in old age.
Optimal response to some vaccines (including inactivated
vaccines, toxoids, recombinant subunit vaccines, polysaccharide
conjugate vaccines, and some live vaccines) requires two or more
doses to elicit an adequate antibody response. Tetanus and diphtheria toxoids require booster doses to maintain protective antibody
concentrations.
Effective protection over decades and a good booster effect after
a long time are expected when a live vaccine is used in the rst
vaccination. On the other hand, regular boosting is particularly
important when inactivated compound are used. The use of a live
attenuated inuenza vaccine has shown good efcacy in people
with limited prior immunity to inuenza, whereas the trivalent
inactivated inuenza vaccine was advantageous for people with
a history of frequent prior exposure [8993]. This is also true for
tetanus and polio vaccines [94].
The humoural immune response to booster immunisation
against tetanus, diphtheria and pertussis is lower in older age
than in young person [94]. However, the magnitude of the antibody response following these vaccines was greatly affected by
pre-vaccination antibody titres. In fact, post-vaccination antibody concentrations highly correlate with antibody concentrations
before vaccination [94], and it was shown that post-vaccination
antibody concentrations depended on pre-existing plasma cells
and B cell memory generated by adequate priming [95]. Overall,
these ndings suggest that consecutive booster vaccinations are an
important prerequisite for a long-term protection and their success
depend on prior exposure or vaccination.
It is noteworthy that primary immunisation with live attenuated vaccines in old age has been associated with an increased risk
of adverse effects [96], suggesting that an aged organism may not be
capable of coping with a new pathogen, even in the case of attenuated vaccine strains. This aspect strengthens the importance to
apply live attenuated vaccines as early in life as possible, followed
by booster vaccination with inactivated or adjuvanted subunit vaccines in old age in order to successful immunisation [97]. In vaccines
that should be administered yearly, such as the seasonal inuenza
vaccine, a base part of their efcacy is in fact based in re-stimulation
of memory (generated both by previous vaccination and by previous natural exposure). A booster inuenza vaccine dose 84 days
after the rst dose could signicantly increase the antibody titre in
elderly people [98].
4.3. Changing the routes of administration
The route of antigen administration has a signicant role
in determining the establishment of protective immunity. Thus,
optimising the immunisation route is one of the strategies for
improving vaccine efcacy in the elderly. Intradermal administration of the inuenza vaccine, in place of intramuscular
immunisation, is very attractive, since a variety of immunerelated cells (e.g., DC, macrophages and accessory keratinocytes)
are present in the skin. Thus, the intradermal delivery of antigens
should favour the local uptake by Langerhans cells and DC. However, a problem in the effectiveness of intradermal vaccination may
be posed by the age-related changes in skin physiology and vascular
activation [99], including the decreased number of skin APC [68].
The advantages of intradermal administration have been
recently reviewed [100].
An increased immunogenicity of antigens delivered by the intradermal route has been demonstrated in the elderly [101,102] but
not in young individuals [103]. In another study, no differences
between the two routes were evident in terms of immunogenicity
350
Table 3
New strategies of vaccination and associated immunological targets.
Goal
Strategies
Target
Vaccine
High-dose antigen
Route of administration:
intradermal vs. intramuscular
vaccination
Amplication of immune
system
Adjuvants
Vector-based vaccines
351
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