Vaccination indications and limits in the elderly
Tina K. Triglav1, Mario Poljak1 h
Abstract
Infections are a major cause of morbidity and mortality in the elderly. Although vaccination is crucial for preventing infectious diseases, the ability of the elderly to establish an effective immune response to vaccination is much lower compared to the younger population. In most industrialized countries, four vaccines are now recommended for people over 60 years of age: influenza vaccine, pneumococcal vaccine, herpes zoster vaccine, and a vaccine combining tetanus toxoid, reduced diphtheria toxoid, and acel-lular pertussis. Only the last vaccine provides an adequate antibody response. The influenza and pneumococcal vaccines seem to be able to alleviate disease. The herpes zoster vaccine somewhat prevents reactivation of herpes zoster and decreases the severity of postherpetic neuralgia. Recent technological advances and novel adjuvants are providing new opportunities for improving vaccination of the elderly. Lifelong vaccination schedules should be promoted in order to achieve the herd immunity threshold. Maintaining the health of the population requires moving from a childhood-based vaccination strategy to a more balanced vaccination program throughout life.
Received: 15 July 2013 | Returned for modification: 1 August 2013 | Accepted: 30 August 2013
Introduction
Infections are a major cause of morbidity and mortality in the elderly. The diagnosis of infectious diseases is more challenging in the elderly due to subtle and non-specific clinical signs and symptoms as well as treatment, which is often complicated by multidrug resistance (1, 2). Therefore, prevention of infections in the elderly is crucial, especially in terms of vaccination.
The crucial problem connected with vaccination in the elderly is their lower ability to mount an effective immune response to vaccination than in the younger population (1-5). Namely, both innate and adaptive immune system functions are affected by aging. This process is termed immunosenescence. Immunosenescence is the main reason for lower immunogenicity and effectiveness of vaccines in the elderly (2, 5, 6). Impaired ability to respond to new antigens and unsustained memory responses are two of the cardinal features of immunosenescence that influence vaccination effectiveness (2). Other important features include impaired antigen uptake and presentation of antigen by antigen-presenting cells, lower numbers of naive T cells due to thymic involution and a lower diversity of the T cell repertoire, lower numbers of naive B cells, impaired isotype switching, and somatic hypermutation, which leads to weaker antibody responses with lower affinity (6). A summary of functions affected by aging is provided in Table 1 (5).
Another important issue is that most vaccines currently on the market were developed in a society in which the average life expectancy was 60 to 65 years (1). Today's society in most regions of the world has a much higher proportion of the elderly, and life expectancy is further increasing.
This review briefly summarizes the most recent relevant data regarding vaccination in the elderly. It encompasses current guidelines, controversies, challenges, and opinions. In most countries, four vaccines are now recommended for people over 60: influenza vaccine, pneumococcal vaccine, herpes zoster vaccine, and a vaccine combining tetanus toxoid, reduced diphtheria toxoid, and acellular pertussis (Tdap) (2). A comparison of vaccination recommendations in three selected European countries (including Slo-
venia) and the United States is presented in Table 2 (3-5).
Table 1 | A summary of main changes in the immune system due to immunosenescence.
Affected cells	Function affected by aging
NK cells	Elimination of infected cells/cytotoxicity
	Production of cytokines
Neutrophil and	Chemotaxis
monocyte/	Elimination of pathogen/microbicidal function
macrophage	Phagocytosis
	TLR-signaling
Dendritic cells	Phagocytosis
	Antigen presentation
T-cells	^ naive T cells (CD4 and CD8)
	^ antigen-experienced T cells (CD4 and CD8)
	^ T cell diversity
CD4 T-cells and	High-affinity antibody responses
B-cells	
B-cells	^ naive B cells
	Class-switch recombination, somatic hypermutation
	Reduced repertoire (^ response to neo-antigens)
Pneumococcal vaccine
The clinical spectrum of pneumococcal infections ranges from sinusitis and acute otitis media to meningitis and pneumonia (7). Streptococcus pneumoniae is the leading cause of community-acquired pneumonia.
The elderly are at substantially increased risk for pneumococcal infections. A major goal of pneumococcal vaccination in the elderly is prevention of hospitalization and death, especially due to invasive pneumococcal disease (IPD)-the condition defined by microbiological detection (mainly isolation) of S. pneumoniae from a normally sterile site.
The currently available vaccine is a 23-valent pneumococcal polysaccharide vaccine (PPV23), which is also recommended for the elderly in several countries. However, being a polysaccharide vaccine, it induces only T cell-independent antibody responses and does not induce immunological memory (5). In a recent Cochrane meta-analysis on vaccines for preventing pneumococcal
•Institute of Microbiology and Immunology, Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia. h Corresponding author: mario.poljak@ mf.uni-lj.si
infections in adults, the authors provided strong evidence supporting the recommendation for PPV to prevent IPD in adults (OR 0.26, 95% CI 0.14 to 0.45). However, there was not enough evidence to support the routine use of PPV23 to prevent all-cause pneumonia or mortality (OR 0.90, 95% CI 0.74 to 1.09) (8). The inclusion criteria were met for 25 studies: 18 randomized control trials (RCT) involving 64,852 participants and seven non-RCTs involving 62,294 participants.
A recently developed pneumococcal protein-conjugated vaccine (PCV) is more immunogenic than PPV23 and it induces a T cell-dependent immune response. Although it is also more effective in the elderly, it is mostly used for prevention of IPD and otitis media in infants and young children. An initially used heptava-lent PCV (PCV7) has mostly been replaced recently with a conjugated vaccine containing 13 different serotypes (PCV13) (5). PCV13 was approved by the U.S. Food and Drug Administration (FDA) in December 2011 for use in people 50 and older. Recently, it was also approved for extended use in the European Union for adults 18 to 49 years old and is now also approved in more than 80 countries for use in adults 50 and older (9).
In a recent randomized, modified double-blind trial of 936 adults 70 and older that had previously received PPSV23 at least 5 years before study entry and were now vaccinated with PCV13 or PPSV23, PCV13 was significantly more immunogenic than PPSV23 (10). The same group also published a study in which 60-to 64-year-olds that were initially given PCV13 received PCV13 or PPSV23, and those initially given PPSV23 received another PPSV23 (11). The authors concluded that initial vaccination with PCV13 establishes an immune state that results in recall upon subsequent vaccination. However, after initial vaccination with PPSV23, subsequent PPSV23 vaccination induces lower responses compared with the initial vaccine (11).
Using a Markov model, Smith et al. recently determined the cost-effectiveness of PCV13 and PPV23 in older U.S. adults (65 or 75 years). PPV23 vaccine was more expensive and less effective than conjugate PCV13 vaccine. Therefore, single-dose PCV13 strategies may be economically reasonable for the elderly (12).
Regular annual influenza vaccination provides an opportunity to concomitantly administer both influenza and pneumococcal vaccines. Previous studies have shown that PPV23 and trivalent influenza vaccine can be safely co-administered (13). More recently, a randomized double-blind trial evaluated the immuno-genicity and safety of PCV13 given concomitantly with trivalent influenza vaccine in the elderly. The authors confirmed acceptable immunogenicity and safety compared with either vaccine given alone (14).
Unfortunately, pneumococcal vaccine coverage is still very low in most European countries. In 2011, pneumococcal vaccine coverage in the U.S. was 62.3% (a 2.6% increase from 2010) (15), but in France only 10% of hospitalized patients over 75 received the vac-
cine (16). A recent study investigated some potential aspects of low vaccine coverage in terms of awareness of pneumococcal infection among primary care physicians and specialists from 13 western European countries (17). They found relatively low awareness of the term IPD: only 50% of physicians in primary care and 71% of specialists were able to provide a correct definition of IPD. The survey also highlighted the importance of physician recommendations for vaccination in encouraging patients to be vaccinated (17).
In conclusion, although current recommendations for vaccinating the elderly against pneumococcal infections in many countries include PPV23 only, due to recent data on immuno-genicity and the effectiveness of novel pneumococcal vaccines, future recommendations will most probably also include PCV13.
Influenza vaccine
Seasonal influenza is a public health challenge with several important economic and social implications. The best available method for prevention of influenza is vaccination. Annual vaccination against influenza is generally recommended for elderly individuals, although with different age limits in different countries (Table 2).
The effectiveness of inactivated trivalent influenza vaccine is variable in different age groups. In general, any type of influenza vaccine is less effective among the elderly than in the young population. In randomized placebo-controlled clinical trials of healthy adults, the influenza vaccine was 70 to 90% effective (8), but projected clinical efficacy in the elderly is 17 to 53% for all three antigens (18, 19). Some progress in clinical efficacy is being made with new licensed adjuvants, such as MF59 and AS03, use of higher antigen dosage, shortened booster intervals, and increased number of doses. Alternative routes of application such as intradermal or intranasal are also being explored.
The most recent Cochrane meta-analysis on vaccines for preventing influenza showed that influenza vaccines have a modest effect on reducing influenza symptoms and working days lost in adults (20). Meta-analysis found no evidence of effect on influenza-associated complications, such as pneumonia, or transmission rates. Due to the poor quality of the evidence, the authors did not draw any conclusions regarding the effects of influenza vaccines for people 65 or older (20).
In a recent study using the instrumental variable analysis method, the authors investigated the impact of influenza vaccination on all-cause mortality and tried to establish an unbiased estimate of influenza vaccine effectiveness (21). Individuals over 65 were followed for nine influenza seasons (2000/2001-2008/2009), which amounts to more than 12 million person-influenza seasons of observation. The study showed that influenza vaccination is not associated with reduction in mortality alone, but there may be an association with reductions in the composite of pneumonia and influenza hospitalizations and all-cause mortality (21).
Table 2 | Comparison of vaccination recommendations for the elderly in four countries in 2011.
Slovenia
Austria
Germany
U.S.
S. pneumoniae (polysaccharide)
Influenza
Diphtheria
Tetanus
Pertussis
Varicella-Zoster
Tick-borne encephalitis_
Once over 65
Annual over 65 Every 10 years Every 10 years Not recommended Not recommended Over 60 every 3 years
Once over 65
Annual over 50 Over 60 every 3 years Over 60 every 3 years Over 60 every 3 years
Once over 50 Over 60 every 3 years
Once over 60
Annual over 60 Every 10 years Every 10 years Once during adulthood Not recommended In risk areas only
Once over 65 (repeated vaccination recommended for risk groups) Annual Every 10 years Every 10 years Once during adulthood Once over 60 Not recommended
Recently, the MF59-adjuvanted trivalent inactivated vaccine was developed to increase the immune response of the elderly to influenza vaccination. It is considered more immunogenic than the conventional non-adjuvanted vaccine (22). A study carried out in northern Italy sought to establish its effectiveness in individuals at least 65 years old. The risk of hospitalization for influenza or pneumonia was 25% lower for the MF59-adjuvanted vaccine relative to trivalent inactivated vaccine (relative risk = 0.75, 95% CI 0.57 to 0.98) (23).
The largest randomized trial of influenza vaccine in the elderly was recently performed in 15 countries worldwide during two influenza seasons (2008-09 and 2009-10) (24). ASo3-adjuvanted inactivated trivalent influenza vaccine (TIV) was compared to non-adjuvanted TIV for seasonal influenza. The authors reported that an AS03-adjuvanted inactivated TIV has a 12% higher efficacy than the non-adjuvanted vaccine, but this difference was not significant (274 [1.27%, 95% CI 1.12-1.43] of 21,573 vs. 310 [1.44%, 1.29-1.61] of 21,482; relative efficacy 12.11%, 95% CI -3.40 to 25.29). They also suggested that the benefit of influenza vaccination in the elderly might vary depending on influenza subtypes. The greatest efficacy was against influenza A H3N2 (170 [0.79, 0.67-0.92] vs. 205 [0.95, 0.83-1.09]; post-hoc analysis relative efficacy 22.0%, 95% CI 5.68-35.49). The authors concluded that there is a benefit of use of adjuvanted vaccine for preventing death and pneumonia (24).
The average EU vaccination rate for influenza in 2010 was 45.3% for the population 65 and over. The Netherlands had the highest coverage, at 77%, whereas the lowest documented coverage was in Estonia (1%). The vaccination rate in Slovenia in 2010 was low, only 18% (25). At the EU level there was a considerable increase in vaccination rates for influenza in the elderly from 2000 to 2005 (from 45% to 54% on average), followed by a decline in vaccination in 2010. However, in Slovenia the influenza vaccination rate was similar in 2000 and 2005 (35%), followed by a decline to the 18% mentioned above in 2010 (26).
Seasonal influenza vaccine uptake in the elderly is influenced by many social determinants: structural, intermediate, and healthcare-related. Factors related to the healthcare system comprise another group of determinants of vaccination uptake. These factors include the quality, credibility, and persuasiveness of physicians' advice, accessibility, affordability, knowledge, and general attitudes toward vaccination (27). An important additional strategy of optimizing influenza vaccination in the elderly is indirect protection of the elderly through vaccination of other population groups that could come in close contact with elderly individuals. This first includes vaccination of children, who most efficiently transmit the virus, and, second, vaccination of healthcare workers, particularly in long-term care facilities.
Herpes zoster vaccine
Primary infection with the varicella zoster virus (VZV) causes chickenpox, which usually occurs in children. After the illness has resolved, the virus remains latent for life in the dorsal spinal ganglia and can be reactivated as a neurocutaneous disease, herpes zoster, when immunity to VZV declines. This painful and long-lasting condition can often significantly impair the patient's quality of life and is especially detrimental for the elderly. The reduction of cellular immunity due to immunosenescence predisposes the elderly to VZV reactivation, and therefore the incidence
of herpes zoster increases with age (28). Complications such as postherpetic neuralgia, characterized by persistent pain for prolonged periods of time, occur in almost 50% of older persons (29).
Vaccination with an attenuated live form of VZV acts by boosting declining preexisting specific cellular immunity, therefore avoiding VZV reactivation (30). Current herpes zoster and VZV vaccines both contain the same attenuated VZV Oka strain but the zoster vaccine has at least 14-times higher potency (29, 31). The zoster vaccine (Zostavax; Merck) was licensed by the FDA in 2005 and is recommended for routine use in immunocompetent adults over 60 (30). Currently it is contraindicated for use in im-munocompromised patients.
In 2005, Oxman et al. (29) determined incidence rates of post-herpetic neuralgia and herpes zoster among vaccinated and non-vaccinated older adults in a randomized, double-blind, placebo-controlled trial. Incidence rates were significantly lower among the vaccinated than in the placebo group and the researchers concluded that vaccination of immunocompetent elderly persons with the Oka strain-based vaccine decreases both morbidity associated with herpes zoster and the incidence of postherpetic neuralgia (29).
Recently, a large "real-life" cohort study on herpes zoster vaccine effectiveness and influence of vaccination on the incidence of postherpetic neuralgia was published (32). More than 750,000 eligible individuals over 65 from the U.S. were enrolled. Even though the vaccine uptake was low (3.9%), herpes zoster vaccination was associated with a significant reduction in the incidence of zoster, even among immunosuppressed individuals. Adjusted vaccine effectiveness against incident zoster was 0.48 (95% CI 0.39-0.56) and 0.37 (95% CI 0.06-0.58) for the total cohort and for immuno-suppressed individuals, respectively. Vaccine was also associated with a lower incidence of postherpetic neuralgia: effectiveness against postherpetic neuralgia was 0.59 (95% CI 0.21-0.79) (32).
In a Cochrane review of vaccines for preventing herpes zoster in adults published in 2012, eight randomized controlled trials with a total of 52,269 participants were included (31). Three studies were classified at low risk of bias. The review suggests a clear benefit in vaccinating the elderly with the herpes zoster vaccine. The vaccine is safe and well tolerated. Patients that received the vaccine had fewer confirmed cases of herpes zoster than those that received a placebo (risk ratio 0.49 (95% CI 0.43-0.56)). The benefit was greatest in participants 60 to 69 years old, although this age group was associated with more adverse events (31).
In another recent study, Morrison et al. confirmed the general safety of zoster vaccine in elderly patients with a recent history of herpes zoster (33). Serious adverse events occurred in 1.37% of all vaccinated individuals, but there were no significant differences between those with or without a prior history of herpes zoster. Their results demonstrate that the vaccine is generally safe and also well tolerated in this population. Furthermore, their results further support the U.S. Centers for Disease Control and Prevention (CDC) recommendations to administer herpes zoster vaccine to all individuals above 60 regardless of a history of recent herpes zoster (33).
Special consideration should be given to elderly patients with depression because they have diminished cell-mediated immunity responses to herpes zoster vaccine (34). If depression is left untreated, there is a higher likelihood of failure to respond to vaccination due to reduced baseline levels of VZV-specific responder cells. The risk and severity of herpes zoster thus may be increased. If patients are treated, immune responses to vaccination are normalized (34).
Td and Tdap vaccines
In many countries, tetanus and diphtheria booster doses are recommended every 10 years throughout the entire lifetime (Table 2). Booster vaccination against tetanus and diphtheria is most practically performed using combined tetanus-diphtheria vaccine or Td vaccine. Regular Td booster vaccinations throughout adulthood not only ensure sustained protection against tetanus and diphtheria, but are also crucial for successful vaccination in older age because the effectiveness of every booster vaccination depends mainly on the concentration of B memory cells and residual antibodies (5).
The tetanus toxoid, reduced diphtheria toxoid, acellular pertussis vaccine (or Tdap vaccine) is a newly designed combined vaccine against three infectious diseases: tetanus, diphtheria, and pertussis. Pertussis vaccination is currently only recommended as a single dose of Tdap across all adult age groups. It can be administered regardless of the interval since the last Td vaccine (35). In July 2011, the U.S. FDA approved expanding the age indication for Tdap to 65 or older, and a year later the U.S. Advisory Committee on Immunization Practices recommended Tdap for all adults 65 and older (35). Unfortunately, not many countries in the world (including EU countries) follow the U.S. recommendation for pertussis vaccination in the elderly, although it is well known that the incidence of pertussis in the elderly is increasing (36) and that pertussis in adults is greatly underdiagnosed and underreported (37). In our opinion, it is therefore crucial that the EU reconsider current pertussis vaccination strategies for the elderly and follow the U.S. path as soon as possible.
The safety and immunogenicity of the Tdap vaccine in adults 65 and older has been established in many studies (38, 39). A more recent study by Tseng et al. evaluated the safety of Tdap vaccine when used off-label in the elderly (40). They compared prespeci-fied adverse events in the elderly that received either the Tdap or Td vaccine in more than 119,000 vaccinees in each group. They found a slightly increased risk of inflammatory/allergic events Table 3 | Currently recommended vaccines in the elderly and future prospects.
up to 6 days following both Tdap and Td, but the risk of adverse events was comparable for both vaccines (40).
Other vaccines
An increasing number of travelers are of advanced age. There are many vaccine-preventable diseases affecting travelers, such as typhoid, yellow fever, Japanese encephalitis, hepatitis A, hepatitis B, rabies, and so on. Vaccination will be the first contact with a new antigen for most senior travelers, and so they will probably not fully respond to this antigen because the naive cell repertoire decreases with age. Furthermore, most available immunization guidelines for travel vaccines are obtained from studies including young (male) adult participants only, and so it is questionable whether derived efficacy data can also automatically be considered for the elderly population (5). Nevertheless, elderly travelers should be offered a full spectrum of vaccines against vaccine-preventable diseases before travel, but for the reasons described above in a more advance phase than for younger travelers.
Among Europe-specific vaccine-preventable diseases, tickborne encephalitis should be considered with special care. Vaccination against tick-borne encephalitis with an inactivated vaccine is recommended in 27 European countries, including Slovenia, without age restrictions (5). Booster immunizations should be given at 3-year intervals for those 50 or older (41).
Conclusions
Vaccine-preventable diseases still cause severe morbidity and mortality among the elderly. Vaccination of the elderly remains the best strategy to prevent infection, but is suboptimal because of immunosenescence. Thus, lifelong vaccination programs should be promoted in order to achieve the herd immunity threshold, moving from the current concept of childhood-based vaccination to more balanced lifelong vaccination schedules (42).
	Limits	Benefits	Prospects
Pneumococcal vaccine	PPV23 does not induce immunological memory.	PCV13 is safe, more immunogenic, and economically reasonable.	A vaccine covering all pneumococcal serotypes.
Influenza vaccine	Variable effectiveness, substantially lower in the elderly.	More immunogenic with new adjuvants, such as MF59 and AS03.	A universal pan-influenza vaccine. Live recombinant viral vectors for the delivery of influenza antigens, proteosome vaccines and DNA-based vaccines. Cutaneous or intradermal administration.
Herpes zoster vaccine	Contraindicated in immunocom-promised, less effective in elderly patients with untreated depression.	Effective, generally safe, and well tolerated.	Inactivated herpes zoster vaccine for immunocompromised patients.
Tdap vaccine		A safe and immunogenic vaccine. Can be co-administered with influenza vaccine.	Reconsidering recommendations and current vaccination strategies for pertussis.
Other vaccines			Vaccines for hospital-acquired bacterial infections.
All vaccines for the elderly			Higher dose of antigen, shorter booster intervals. Intradermal or intranasal administration. Novel adjuvants (mineral salts, oil-in-water emulsions, TLR agonists, liposomes, and combination adjuvants). Enhancing immunity in the elderly (restoring the generation of B and T cell precursors, rejuvenating thymic function).
An overview of currently recommended vaccines for the elderly and future prospects is presented in Table 3 (1, 41-43). Briefly, all four vaccines described in detail above boost preexisting immunological memory. Only the Tdap vaccine gives a satisfactory antibody response in the elderly compared to the response in young adults (39). Influenza and pneumococcal vaccine seem to be able to alleviate disease but do not induce protective immunity in a large proportion of the elderly. Herpes zoster vaccination somewhat prevents reactivation of herpes zoster and decreases the severity of postherpetic neuralgia (2).
In recent years, research in this field has mainly focused on improving existing adjuvants and designing novel ones that enhance or modulate vaccine-induced immune responses. These in-
clude combinations of novel TLR agonists, liposomes, saponins, glycolipid a-galactosylceramide, and so on, which might also improve the immunogenicity of various antigens in the elderly (1, 43). How the immune system ages and which molecular pathways can be targeted to improve responses to vaccination in the elderly are two issues we are only beginning to understand. Due to the rapid development of new technologies, we may soon be able to develop vaccines against new pathogens and, more importantly, improve the safety and efficacy of existing vaccines. Developing a universal pan-influenza vaccine, a universal pneumococcal vaccine covering all serotypes, or an inactivated herpes zoster vaccine for immunocompromised patients are some of the achievable goals in the coming years.
References
1.	Rappuoli R, Mandl CW, Black S, De Gregorio E. Vaccines for the twenty-first century society. Nat Rev Immunol. 2011;11:865-72.
2.	Goronzy JJ, Weyand CM. Understanding immunosenescence to improve responses to vaccines. Nat Immunol. 2013;14:428-36.
3.	Instructions and recommendations for vaccination [Internet]. Institute of Public Health of the Republic of Slovenia. c2011 - [cited 2013 Aug 3]. Available from: http://www.ivz.si/cepljenje/strokovna_javnost. Slovene.
4.	Official vaccination recommendations [Internet]. Oberster Sanitatsrat. c2011 -[cited 2013 Aug 3]. Available from: www.bmg.gv.at. German.
5.	Weinberger B, Grubeck-Loebenstein B. Vaccines for the elderly. Clin Microbiol Infect. 2012;18:100-8.
6.	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;46:1078-84.
7.	Blasi F, Mantero M, Santus P, Tarsia P. Understanding the burden of pneumococcal disease in adults. Clin Microbiol Infect. 2012;18(Suppl 5):7-14.
8.	Moberley S, Holden J, Tatham DP, Andrews RM. Vaccines for preventing pneumococcal infection in adults. Cochrane Database Syst Rev. 2013;1:CD000422.
9.	Pfizer receives European approval to expand use of Prevenar 13* to adults aged 18 to 49 years for the prevention of invasive pneumococcal disease [Internet]. Pfizer [cited 2013 Jul 21]. Available from: http://www.pfizer.com/news/press-release/press-release-detail/pfizer_receives_european_approval_to_expand_ use_of_prevenar_13_to_adults_aged_18_to_49_years_for_the_prevention_of_ invasive_pneumococcal_disease.
10.	Jackson LA, Gurtman A, Rice K, Pauksens K, Greenberg RN, Jones TR, et al. Immu-nogenicity and safety of a 13-valent pneumococcal conjugate vaccine in adults 70 years of age and older previously vaccinated with 23-valent pneumococcal polysaccharide vaccine. Vaccine. 2013;31:3585-93.
11.	Jackson LA, Gurtman A, van Cleeff M, Frenck RW, Treanor J, Jansen KU, et al. Influence of initial vaccination with 13-valent pneumococcal conjugate vaccine or 23-valent pneumococcal polysaccharide vaccine on anti-pneumococcal responses following subsequent pneumococcal vaccination in adults 50 years and older. Vaccine. 2013;31:3594-602.
12.	Smith KJ, Wateska AR, Nowalk MP, Raymund M, Lee BY, Zimmerman RK. Modeling of cost effectiveness of pneumococcal conjugate vaccination strategies in U.S. older adults. Am J Prev Med. 2013;44:373-81.
13.	Honkanen PO, Keistinen T, Kivela SL. Reactions following administration of influenza vaccine alone or with pneumococcal vaccine to the elderly. Arch Intern Med. 1996;156(2):205-8.
14.	Schwarz TF, Flamaing J, Rumke HC, Penzes J, Juergens C, Wenz A, et al. A randomized, double-blind trial to evaluate immunogenicity and safety of 13-valent pneumococcal conjugate vaccine given concomitantly with trivalent influenza vaccine in adults aged 265 years. Vaccine. 2011;29:5195-202.
15.	Centers for disease control and prevention (CDC). Noninfluenza vaccination coverage among adults—United States, 2011. MMWR Morb Mortal Wkly Rep. 2011;62:66-72.
16.	Rouveix E, Gherissi Cherni D, Dupont C, Beauchet A, Sordet Guepet H, Gavazzi G, et al. Streptococcus pneumoniae vaccinal coverage in hospitalized elderly patients in France. Médecine Mal Infect. 2013;43:22-7.
17.	Lode H, Ludwig E, Kassianos G. Pneumococcal infection—low awareness as a potential barrier to vaccination: Results of a European survey. Adv Ther.
2013;30:387-405.
18.	Goodwin K, Viboud C, Simonsen L. Antibody response to influenza vaccination in the elderly: a quantitative review. Vaccine. 2006;24:1159-69.
19.	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 community. Vaccine. 2002;20:1831-6.
20.	Jefferson T, Di Pietrantonj C, Rivetti A, Bawazeer GA, Al-Ansary LA, Ferroni E. Vaccines for preventing influenza in healthy adults. Cochrane Database Syst Rev. 2010;7:CD001269.
21.	Wong K. Estimating influenza vaccine effectiveness in community-dwelling elderly patients using the instrumental variable analysis method. Arch Intern Med. 2012;172(6):484.
22.	Durando P, Icardi G, Ansaldi F. MF59-adjuvanted vaccine: a safe and useful tool to enhance and broaden protection against seasonal influenza viruses in subjects at risk. Expert Opin Biol Ther. 2010;10:639-51.
23.	Mannino S, Villa M, Apolone G, Weiss NS, Groth N, Aquino I, et al. Effectiveness of adjuvanted influenza vaccination in elderly subjects in northern Italy. Am J Epidemiol. 2012;176:527-33.
24.	McElhaney JE, Beran J, Devaster JM, Esen M, Launay O, Leroux-Roels G, et al. AS03-adjuvanted versus non-adjuvanted inactivated trivalent influenza vaccine against seasonal influenza in elderly people: a phase 3 randomised trial. Lancet Infect Dis. 2013;13:485-96.
25.	Vaccination rates for influenza, EU population aged 65 and over, 2010 [Internet]. Organisation for Economic Cooperation and Development (OECD) Health Data. c2012 - [cited 2013 Jul 23]. Available from: http://www.oecd-ilibrary. org/social-issues-migration-health/health-at-a-glance-europe-2012/vacci-nation-rates-for-influenza-population-aged-65-and-over-2 010-or-nearest-year_9789264183896-graph130-en.
26.	Trends in vaccination rates for influenza, population aged 65 and over 2000-2010 [Internet]. Organisation for Economic Cooperation and Development (OECD) Health Data. c2012 - [cited 2013 Jul 23]. Available from: http:// www.oecd-ilibrary.org/social-issues-migration-health/health-at-a-glance-europe-2012/vaccination-rates-for-influenza-population-aged-65-and-over-2010-or-nearest-year_9789264183896-graph130-en.
27.	Nagata JM, Hernández-Ramos I, Kurup A, Albrecht D, Vivas-Torrealba C, Franco-Paredes C. Social determinants of health and seasonal influenza vaccination in adults 265 years: a systematic review of qualitative and quantitative data. BMC Public Health. 2013^3:388.
28.	Levin MJ. Immune senescence and vaccines to prevent herpes zoster in older persons. Curr Opin Immunol. 2012;24:494-500.
29.	Oxman MN, Levin MJ, Johnson GR, Schmader KE, Straus SE, Gelb LD, et al. A vaccine to prevent herpes zoster and postherpetic neuralgia in older adults. N Engl J Med. 2005;352:2271-84.
30.	Oxman MN. Zoster vaccine: current status and future prospects. Clin Infect Dis. 2010;51:197-213.
31.	Gagliardi AMZ, Gomes Silva BN, Torloni MR, Soares BGO. Vaccines for preventing herpes zoster in older adults. Cochrane Database Syst Rev. 2012;10:CD008858.
32.	Langan SM, Smeeth L, Margolis DJ, Thomas SL. Herpes zoster vaccine effectiveness against incident herpes zoster and post-herpetic neuralgia in an older US population: A cohort study. Plos Med. 2013;10(4):e1001420.
33.	Morrison VA, Oxman MN, Levin MJ, Schmader KE, Guatelli JC, Betts RF, et al. Safety of zoster vaccine in elderly adults following documented herpes zoster. J Infect Dis. 2013;208:559-63.
34.	Irwin MR, Levin MJ, Laudenslager ML, Olmstead R, Lucko A, Lang N, et al. Varicella zoster virus-specific immune responses to a herpes zoster vaccine in elderly recipients with major depression and the impact of antidepressant medications. Clin Infect Dis. 2013;56:1085-93.
35.	Centers for disease control and prevention (CDC). Updated recommendations for use of tetanus toxoid, reduced diphtheria toxoid, and acellular pertussis (Tdap) vaccine in adults aged 65 years and older—Advisory Committee on Immunization Practices (ACIP). MMWR Morb Mortal Wkly Rep. 2012;62:468-70.
36.	Zepp F, Heininger U, Mertsola J, Bernatowska E, Guiso N, Roord J, et al. Rationale for pertussis booster vaccination throughout life in Europe. Lancet Infect Dis. 2011;11:557-70.
37.	Ridda I, Yin JK, King C, Raina MacIntyre C, McIntyre P. The importance of pertussis in older adults: a growing case for reviewing vaccination strategy in the elderly. Vaccine. 2012;30:6745-52.
38.	Moro PL, Yue X, Lewis P, Haber P, Broder K. Adverse events after tetanus toxoid, reduced diphtheria toxoid and acellular pertussis (Tdap) vaccine administered to adults 65 years of age and older reported to the Vaccine Adverse Event Reporting System (VAERS), 2005-2010. Vaccine. 2011;29:9404-8.
39.	Weston WM, Friedland LR, Wu X, Howe B. Vaccination of adults 65 years of age and older with tetanus toxoid, reduced diphtheria toxoid and acellular pertussis vaccine (Boostrix®): Results of two randomized trials. Vaccine. 2012;30:1721-8.
40.	Tseng HF, Sy LS, Qian L, Marcy SM, Jackson LA, Glanz J, et al. Safety of a tetanus-diphtheria-acellular pertussis vaccine when used off-label in an elderly population. Clin Infect Dis. 2012;56:315-21.
41.	Weinberger B, Keller M, Fischer K-H, Stiasny K, Neuner C, Heinz FX, et al. Decreased antibody titers and booster responses in tick-borne encephalitis vaccinees aged 50-90 years. Vaccine. 2010;28:3511-5.
42.	Lang PO, Aspinall R. Immunosenescence and herd immunity: with an ever-increasing aging population do we need to rethink vaccine schedules? Expert Rev Vaccines. 2012;11:167-76.
43.	Derhovanessian E, Pawelec G. Vaccination in the elderly. Microb Biotechnol. 2012;5:226-32.