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Immunology Letters 162 (2014) 346353

Contents lists available at ScienceDirect

Immunology Letters
journal homepage: www.elsevier.com/locate/immlet

Immunosenescence and vaccine failure in the elderly: Strategies for


improving response
Diana Boraschi a, , Paola Italiani b,1
a
b

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.

societal burden, as aged people may be in need of continuous


assistance with great nancial and psychological cost for the public health system and for the families. Ensuring healthy ageing
(adding life to years) is therefore a major public health issue.
Increased susceptibility to diseases in the elderly is mainly due
to immunosenescence, i.e., the diminished effectiveness of the
immune response. Thus, prevention of age-related immunological
defects becomes a central issue for ensuring the individual wellbeing.
Among the consequences of immunosenescence, the increased
susceptibility to infectious diseases is a major threat and cause
of death also in developed countries. Vaccination has been the
most successful preventive tool in preventing infections and infant
death. However, the vaccination strategies that are currently and
successfully used may not be suited for efciently protecting
the elderly population. The aged immune system does not react
with the same rules as that of a child or a younger adult, thus
current vaccines are in general less immunogenic and therefore
less efcient in the elderly. Research on immunological ageing
is addressing the ne mechanisms of age-related change in the
immune regulation, aiming at providing the basis for designing
efcient strategies for immune rejuvenation and for effective vaccines. However, it should be noted that most of these studies are
performed in the mouse. The evolutionary distance between mice
and men has introduced differences that do not always allow simple extrapolation of ndings. This concept is particularly relevant if

D. Boraschi, P. Italiani / Immunology Letters 162 (2014) 346353

we consider the immunological differences between species [3,4],


including their immunosenescence features [5]. Future studies
should therefore focus more on investigating age-related immunological changes in humans, to generate hypotheses that could be
tested further in animal models [6].
We are just starting to understanding how the immune system
ages in humans and identifying molecular pathways that can be
targeted to specically improve the responses to vaccination in the
elderly. In this perspective, this review will give a brief overview
on novel vaccination strategies aiming at improving efcacy in the
elderly.

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

3. Current immunisation approaches in the elderly


It is important to assess, in a vaccine for the elderly, not only
the vaccine efcacy, i.e. the ability of a vaccine to confer protection against a specic infection, but also its effectiveness, i.e. the
ability of avoiding other related diseases. For instance, the seasonal inuenza vaccine, by avoiding infection with the inuenza
virus, also decreases the incidence of respiratory and cardiac diseases consequent to inuenza. The value of vaccines for the elderly
therefore relies not only on efcacy but also on effectiveness, i.e.
in the capacity of generally improving the health status of the old
individual.
In developed countries, four main vaccines are recommended
for the elderly, in order to protect them from the most common infections: the seasonal inuenza vaccine, the pneumococcal
vaccine (against Streptococcus pneumoniae), the vaccine against
tetanus, diphtheria and pertussis (booster every 10 years), and the
vaccine to prevent reactivation of Varicella Zoster Virus (VZV).
These infections still represent a cause of signicant morbidity
and mortality in the elderly (65 and 85 years), who are more
susceptible to them compared to young adults [7072]. Table 2
summarises the features of vaccines against these infections and
their effects on the elderly immune system.
Of the four vaccines mentioned above, only the Tdap vaccine
(tetanus toxoid, reduced diphtheria toxoid and acellular pertussis) gives a satisfactory although diminished protective antibody
response in the elderly compared to adults [73]. In contrast, vaccines against inuenza or pneumococcal infections do not induce
protective immunity in a large proportion of the elderly population,
although they can mitigate the disease to some degree [74]. Similarly, vaccination with the live vaccine against VZV is only partially
active in preventing reactivation of herpes zoster or attenuating the
severity of post-herpetic neuralgia [75].
To understand why these vaccines are not fully effective in the
elderly, one must take into account the following considerations:

1. these vaccines have been developed for preventing infections


mainly in childhood and in immunologically competent individuals, and therefore they may not be optimally effective in the
elderly that are immunologically different;
2. assessing vaccine efciency in the elderly has been often difcult because of little consensus between studies (lack of study
protocol standardisation), the use of outcome measures with
low sensitivity (inuenza-like illness rather than laboratory conrmed inuenza), and insufcient consideration of frailty and
study bias, varying cohorts and variable epidemiological factors
(e.g., in the case of inuenza, prevalence of the virus, virulence
of the circulating strain and matching of vaccine and circulating
viral strain);
3. the extent of the immune response depends on intrinsic
immunosenescent defects as well as on the history of natural
exposure to pathogens or previous vaccines, both contributing
to the baseline immune status of an older individual [76].

Optimising vaccination for the elderly is therefore a major


task in immunological research [77]. The strategies to address the
limitations of the current vaccines in protecting the elderly are
illustrated in Table 3. We will briey discuss them hereafter, taking the vaccine against seasonal inuenza as an example, given the
abundance of available data for this vaccine.
Since the understanding of the mechanistic basis of immune
senescence is still partial, no current vaccination strategy is based
on such knowledge and the approaches have been exclusively
empirical. The most developed approaches include the use of higher

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D. Boraschi, P. Italiani / Immunology Letters 162 (2014) 346353

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

-Increased MDSC (myeloid


derived suppressor cells) in
blood
Innate immunity
-Fewer circulating monocytes
and DC, and
tissue-associated DC
-Increased splenic DC
-Reduced pDC and normal
mDC
-Normal tissue macrophages

Cause

Effect

Reference

-Epigenetic changes
-DNA damage
-Telomere shorting
-Exposure to chronic age-related
inammation
-Infections and cancer

-Fewer circulating lymphocytes


-Increased susceptibility to
anaemia
-Increased pyogenic bacterial
infection
-Lower capacity to clear the
infection

[9,3034]

-Changes in myeloid progenitors


-mDC and pDC constitutively activated
-Changes in surface receptor
expression
-Reduced ability to migrate to local
lymph nodes

-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]

-Decreased TLR signalling

-Decreased TLR expression


-Unresponsiveness of TLR to challenge

-Inamm-ageing (chronic
inammation, enhanced
level of basal inammatory
activation)

-Increased leakage in the gut


-Chronic viral infection (e.g.,
Cytomegalovirus)
-Increased lifespan of tissue
macrophages

Adaptive immunity
-Lack of nave T cell in
peripheral blood and
lymphoid organs

-Reduced nave B cells (extent


unknown)

-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

-Reduced output of lymphoid


precursors from the bone marrow (?)
-Conicting ndings on B cellintrinsic
defects in class-switch recombination
and somatic hypermutation
-Defective responses of memory CD4+
or CD8+ T cells, inability to provide
help to B cells in part due to higher
DUSP4 expression

and repeated antigen doses, the choice of different administration


routes, and the use of adjuvants.
4. How to improve reduced response to vaccination in the
elderly
4.1. Increasing the vaccine antigen dosage
Immunogenicity of inuenza vaccine is generally measured
based on the levels of antibodies inhibiting haemagglutination
caused by the virus. The haemagglutination inhibition (HAI) assay,
used for over 80 years, gives a measure of vaccine efcacy by

[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

D. Boraschi, P. Italiani / Immunology Letters 162 (2014) 346353


Table 2
Current vaccines recommended for the elderly.
Vaccine

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

D. Boraschi, P. Italiani / Immunology Letters 162 (2014) 346353

Table 3
New strategies of vaccination and associated immunological targets.
Goal

Strategies

Target

Vaccine

Improving vaccine delivery

High-dose antigen

To increase antigen delivery from APC


to B cells (antigen presentation),
eliciting a greater antigen-specic
antibody response
-To increase the immunogenicity of
vaccine, exploiting the notion that the
skin harbours a variety of immune cells
(e.g., DCs, monocytes and
macrophages) and accessory cells (e.g.,
keratinocytes)

-TIV (Inactivated Inuenza Vaccine)


(60 g instead of the standard 15 g of
HA)

Route of administration:
intradermal vs. intramuscular
vaccination

Amplication of immune
system

Adjuvants

-To enhance innate immune response,


especially the inux and activation of
APCs at the site of vaccination
-To increase inammatory
(immunostimulatory cytokine
production
-To improve proliferation and
activation of T and B cells

Vector-based vaccines

-To improve antigen delivery


-To enhance CD8+ T and CD4+ T cells
response overcoming reduced TCR
sensitivity and repertoire restriction

and protection, although the intradermal route was preferable for


high-dose vaccination in the elderly [104].
4.4. Amplication of the immune response: adjuvants and
vector-based vaccines
The principle of adjuvanticity implies the amplication of the
antigen-specic immune response by non-specic immunostimulation strategies. Among the most efcient approaches, we will
consider the use of novel adjuvants such as TLR agonists, able to
trigger innate immunity, and the use of vector-based vaccines, able
to amplify and polarise the induction of adaptive immunity.
4.4.1. Adjuvants
The use of adjuvants is the best way to enhancing the immune
response to vaccines. Adjuvants are molecules or strategies that
stimulate the non-specic, innate immune response, inducing the
recruitment and activation of APC at the site of vaccination [105].
This reaction is in turn responsible of the quality and magnitude of
the following adaptive immune response.
The majority of vaccines currently on the market contain adjuvants. The most used adjuvant, and the rst one licensed for
human use, is based on aluminium salts (aluminium hydroxide or
aluminium phosphate). Vaccine antigens are adsorbed on the aluminium particles, and their immunogenicity is increased both by
the slower release/higher persistence of the antigens and by the
innate immunity enhancement induced by the particulate agent.
The second licensed adjuvant, the rst used in TIV, is an
oil-in-water emulsion, MF59, that includes a low amount of oil
(45% vs. the 50% of the old mineral oil emulsions) and uses
the physiological oil squalene (a precursor of cholesterol, steroid
hormones and vitamin D) [106]. MF59 increases the chemokinedependent recruitment of APC (DC, monocytes and macrophages)
[107]. It is noteworthy that MF59-adjuvanted inuenza vaccines
demonstrated good immunogenicity and safety in older individuals
[108,109].
In a genome-wide microarray analysis in the mouse, MF59
upregulated a large number of genes involved in the initiation of
the innate/inammatory reaction, including the Il1b gene, and also

-Patch with arrays of antigen-coated


microneedles
-Cyanoacrylate skin surface stripping
-Immunostimulatory patches coated
with heat-labile enterotoxin from
E. coli
-Oil-in-water emulsions (e.g., MF59,
AS03)
-Liposomes (e.g., virosomes)
-Saponines (e.g., Matrix-MTM )
-TLR agonists (e.g., agellin, poly I:C,
CpG 7909, Pam3Cys, Monophosphoryl
lipid A) (not licensed for use)
-Combination (e.g., AS01, Iscomatrix,
CAF01)
-Cytokines (e.g., IL-7, IL-2,
IL-1/IL-6/TNF-) (not licensed for use)
-Modied Vaccinia Virus Ankara
(MVA) as a vector for highly conserved
inuenza proteins nucleoprotein (NP)
and matrix protein 1 (M1)

a set of genes responsible for the down-regulation of inammation


[110]. The enhancement of innate/inammatory activities together
with the concomitant expression of regulatory factors leads to the
hypothesis that MF59 can induce a potent innate/inammatory
reaction (which is fundamental for the adjuvant effect), but that
it can efciently control its development and termination. This
would achieve optimal efcacy and concomitantly avoid the risk
of persistent pathological inammation.
It has been shown that the MF59-adjuvanted inuenza vaccine
can provide a protective effect over the non-adjuvant vaccines in
the elderly [111], and it could also generate 4-fold higher specic antibody titres and also cross-protection against heterologous
inuenza strains of inuenza, as compared to the split or the virosomal vaccines [112,113].
TLR agonists are currently evaluated as potential adjuvants for
various vaccines [114,115]. The adjuvant potential of TLR agonists
is based on the notion that TLR triggering can induce the production
of inammatory cytokines by APC [116], and also promote germinal
centre antibody production [117]. In humans, there is evidence that
age-related variations in cytokine production are specic for cell
type and TLR type, and do not depend on a general alteration of TLR
signalling [46].
TLR
agonists
that
can
induce
innate/inammatory
chemokines/cytokines and type I interferons (thus good candidates as adjuvants in an anti-viral vaccine) are the lipopeptides
Pam2Cys and Pam3Cys (activating TLR2), the double-stranded
RNA analogue poly:IC and its derivatives (for TLR3), monophosphoryl lipid A and other TLR4 agonists, the TLR5 agonist agellin,
imidazoquinolines (TLR7/8) and CpG oligodeoxynucleotides
(TLR9).
Thus far, the use of TLR agonists as adjuvants in vaccines for
the elderly has provided encouraging results in the mouse model,
but much more work will be required in order to show their efcacy in human vaccines. Experiments on humans are still limited.
An increase of T cell cytotoxic response after stimulation with TLR
agonists has been observed in vitro [118]. A trial aiming at evaluating the efciency of a recombinant HA-agellin fusion vaccine
(VAX125) in the elderly showed a dose-dependent increase in the
HIA titre [119,120].

D. Boraschi, P. Italiani / Immunology Letters 162 (2014) 346353

4.4.2. Vector-based vaccines


An issue raised by the current inuenza vaccine is that there is no
correlation between specic antibody production and protection in
older individuals, in which protection seems to be closely associated with the T cell response [121]. Generally, inactivated vaccines
induce a good CD4+ T cell response, while CD8+ T cell activation
is only induced by a natural infection. A recent study has demonstrated that CD8+ T cell responses against different viruses remain
intact in the elderly [7]. This fact has driven researchers to reconsider vector-based vaccines, and to develop one by using Modied
Vaccinia Virus Ankara (MVA) as vector for highly conserved nucleoprotein (NP) and matrix protein 1 (M1) (MVA-NP+M1) [122]. The
inuenza NP contains immunodominant epitopes for both CD4+
and CD8+ T cells [123], suggesting that this vaccine can generate
both antibodies and good T cell immunity. As compared to TIV,
MVA-NP+M1 has the advantage of targeting CD8+ T cell response
using antigens that are common to all inuenza strains, thus eliminating the need for the serotype matching needed each year for the
seasonal TIV vaccine. This vaccine was shown to be immunogenic
as it could induce specic CD8+ T cells in people aged 5085 years
as well as in younger individuals [124], but its capacity to induce
antibody production was not determined.
5. Conclusions
Considering the changes in the elderly immune response (frequency, repertoire diversity, activation, and differentiation of cell
subsets including DC, T cells and B cells), the success of new vaccines specically tailored for the aged population will come from
a deep knowledge on the mechanisms of protective immunity in
the elderly, in particular in the presence of concurring conditions
(chronic diseases, malnutrition, etc.). This is not a simple challenge
for vaccinologists, also in light of the fact that immune response in
aged people is signicantly driven by the individual past history of
exposure and immunity.
The current strategies for formulating effective vaccines for
the ageing population will likely include a combination of the
approaches that are currently available and briey reported herein,
as well as altering vaccine schedule, targeting at-risk population,
and sustain herd immunity, in order to reduce the probability that
unvaccinated individuals contract disease [125].
Funding
The authors are supported by the EU FP7 grant HUMUNITY
(PITN-GA-2012-316383) and by the grant 2011-2114 of Fondazione
Cariplo, Milano, Italy.
Conict of interest
The authors declare no conicts of interest.
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Diana Boraschi is an immunologist that has worked
both in academy and industry, in Italy and in the USA.
She served as director of fellowships at HFSPO in Strasbourg, and as expert evaluator for the EU research
programmes and other international funding agencies.
She is research director at the Italian National Research
Council. Her studies focus on the role of macrophages in
the innate/inammatory response against infections and
tumours. Her main interests are in macrophage biology
and IL-1R family receptors and their cytokine ligands. She
is currently studying the pathogenic role of inammation
in autoimmune and degenerative diseases.

Paola Italiani has a specialisation degree in clinical


biochemistry and a PhD in molecular medicine. From
2006 she has been working as immunopharmacologist at the National Research Council, focussing on the
effects of novel adjuvants derived from plant polysaccharides on human macrophages, broblasts, and epithelial
cells, and on the mechanisms of the activation of innate
defence cells in physiological conditions and pathological derangements. In this context, she is studying the
role of human monocytes/macrophages in the development of the inammation. In human diseases, she is
focussing on the cross-regulation of the IL-1/IL-18 family
in chronic inammatory, autoimmune and degenerative
pathologies.