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The intradermal vaccination route – an attractive opportunity for influenza vaccination in the elderly
European Geriatric Medicine 1 (2010) 82–87
Hot topic in geriatric medicine
The intradermal vaccination route – an attractive opportunity for influenza vaccination in the elderly M. Paccalin a,*, B. Weinberger b,1, J.-F. Nicolas c,2, P. Van Damme d,3, Y. Me´gard e,4 a
Department of Geriatrics, University Hospital La Mile´trie, 86021 Poitiers, France Institute for Biomedical Aging Research of the Austrian Academy of Sciences, Rennweg 10, 6020 Innsbruck, Austria Inserm Unit 851, UFR, centre hospitalier Lyon-Sud, universite´ Lyon 1, 69495 Pierre-Be´nite cedex, France d Centre of the Evaluation of Vaccination, Vaccine & Infectious Disease Institute, University of Antwerp, Universiteitsplein, 1, 2610 Antwerp, Belgium e Sanofi Pasteur MSD, 8, rue Jonas-Salk, 69367 Lyon cedex 07, France b c
A R T I C L E I N F O
A B S T R A C T
Article history: Received 22 February 2010 Accepted 10 March 2010 Available online 13 April 2010
An age-related decline in functioning of the innate and adaptive immune systems results in increased susceptibility to infections (e.g. influenza) and decreased responses to vaccination in elderly people. A satellite symposium held during the XIXth IAGG World Congress of Gerontology and Aging in Paris, 5–9 July 2009, considered the potential of intradermal vaccination to enhance immune responses in the elderly. The rich supply of capillary blood and lymphatic vessels in the dermis, along with its resident population of dendritic cells, make the skin an attractive site for vaccine delivery. Intanza1 15 mg is a purified, inactivated, trivalent, split-virus influenza vaccine containing 15 mg haemagglutinin/strain/ 0.1 ml dose that is administered using a novel intradermal microneedle injection system. A randomised, open-label phase III trial in 3695 people aged 60–95 years found that antibody responses to the intradermal influenza vaccine were superior to those for the same vaccine administered intramuscularly. The systemic safety profile of the intradermal vaccine was comparable with that of the intramuscular vaccine, but rates of injection-site reactions were higher with the intradermal vaccine, reflecting the close proximity of injected vaccine to the skin surface. The increased immunogenicity of Intanza1 15 mg in the elderly compared with the standard intramuscular influenza vaccine supports the concept of intradermal vaccination to enhance immune responses in elderly people. ß 2010 Elsevier Masson SAS and European Union Geriatric Medicine Society. All rights reserved.
Keywords: Elderly Immunosenescence Influenza Intradermal Vaccination
1. Introduction Aging is associated with a decline in immune function (immunosenescence) that results in increases in the incidence and severity of infectious diseases, and decreased responses to vaccination [1,2]. For example, influenza is the fourth most common cause of death in the elderly [3] and it is also associated with greater morbidity compared with the infection in younger individuals [4]. One consequence of the decline in antibody responses to vaccination in the elderly is that influenza vaccine, although effective in the elderly population, induces reduced immune responses and protection compared with vaccination in young adults [5]. Furthermore, uptake of vaccination is sub-
* Corresponding author. Tel.: +33 5 49 44 44 27; fax: +33 5 49 44 44 29. E-mail addresses: [email protected] (M. Paccalin), [email protected] (B. Weinberger), [email protected] (J.-F. Nicolas), [email protected] (P. Van Damme), [email protected] (Y. Me´gard). 1 Tel.: +43 512 583919 13. 2 Tel.: +33 4 78 86 15 72; fax: +33 4 78 86 15 28. 3 Tel.: +32 3 265 25 38; fax: +32 3 265 26 40. 4 Tel.: +33 4 37 28 45 47; fax: +33 4 37 28 44 11.
optimal. The World Health Organization (WHO) and the Council of the European Union (EU) have set targets for member states with influenza vaccination programmes to achieve vaccination coverage rates in elderly people of greater than 75% by 2010 and 2014, respectively [6,7]. Most European countries have not achieved the WHO goal [8,9]. There is therefore a need to improve the immunogenicity of influenza vaccines for use in the elderly and also to ensure greater uptake of the vaccine in this population. This contribution is based on a satellite symposium held during the XIXth International Association of Gerontology and Geriatrics (IAGG) World Congress of Gerontology and Aging in Paris, 5–9 July 2009. A faculty of European experts in immunology, dermatology and vaccines reviewed the challenge of immunosenescence and impaired responses to vaccination in the elderly. They also considered the potential of intradermal delivery of vaccines to enhance those responses. In particular, they considered the opportunity provided by the first seasonal influenza vaccine developed for intradermal delivery, Intanza1 (Sanofi Pasteur, Lyon, France), to improve the immunogenicity and coverage of influenza vaccination in the elderly. This report provides a summary of the presentations during the symposium and represents a consensus of the views of the faculty.
1878-7649/$ – see front matter ß 2010 Elsevier Masson SAS and European Union Geriatric Medicine Society. All rights reserved. doi:10.1016/j.eurger.2010.03.004
M. Paccalin et al. / European Geriatric Medicine 1 (2010) 82–87
2. Immunosenescence: age-related changes in the immune system Aging is associated with changes in the innate and adaptive immune systems. These changes may include alterations in the numbers and functions of the various types of immune cells [2]. 2.1. Age-related changes in the innate immune system Neutrophils, macrophages and natural killer cells are affected by aging, particularly in their functions and responses to cytokines [10]. However, there is also an increase in the production of proinflammatory cytokines by macrophages in elderly individuals that contributes to the subclinical pro-inflammatory state termed ‘‘inflammaging’’ [11,12]. This state is believed to be due to chronic stimulation of innate immunity by products of degradation processes, or by the inability of the aged immune system to eliminate some pathogens, resulting in chronic (yet inefficient) innate immune responses [1]. Dendritic cells are specialised antigen-presenting cells that capture and process antigens for presentation to T-cells and, in so doing, determine the quality and intensity of adaptive immune responses [13]. However, there is evidence that the number of dendritic cells in the peripheral blood of elderly individuals is significantly reduced [14]. In addition, dendritic cells from elderly people display a reduced capacity to present antigens and impaired migration to lymph nodes [15]. Such defects in the processing and presentation of antigens by cells of the innate immune system contribute to diminished activation of cells in the adaptive immune system. Furthermore, due to inflammaging, the threshold for the induction of a ‘‘danger signal’’ by vaccination may increase. 2.2. Age-related changes in the adaptive immune system and impact on influenza vaccination Due to involution of the thymus with age, the output of naive Tcells declines and the T-cell pool in later life comprises mainly memory and effector T-cells [1]. The numbers of phenotypically naive (expressing cell-surface markers CD45RA and CD28) CD8+ T-cells are depleted in the lymph nodes and circulation of people aged more than 65 years compared with people aged less than 30 years [16]. Furthermore, these phenotypically naive T-cells are not functionally naive. Instead, they display a restricted T-cell receptor repertoire and have shortened telomeres, indicating previous replication and resulting in a reduced repertoire of responses to novel antigens [17]. The ratio of memory (CD45RA CD28+) to effector (CD45RA+CD28 ) CD8+ T-cells has been shown to vary between elderly individuals [18]. Importantly, elderly individuals with higher proportions of memory T-cells were shown to have a better response to influenza vaccination than those with higher numbers of effector T-cells [19]. Further study revealed two subpopulations of memory T-cells in the elderly. Individuals with a good response to influenza vaccination had a subset of CD8+ memory T-cells that also expressed CD25 and produced large amounts of interleukin (IL)-2 and some IL-4, but little interferon (IFN)-g. In contrast, individuals with a poor response to vaccination did not have any CD25+CD8+ T-cells [18]. This suggests that accumulation of CD25+CD8+ memory T-cells in the elderly can maintain immune responsiveness in the absence of naive T-cells [20]. Chronic infections providing repeated antigenic stimulation are believed to contribute to the accumulation of highly differentiated CD28 CD8+ effector T-cells in the elderly. For example, cytomegalovirus infection is associated with a decline in naive T-cells and an increase in CD28 CD8+ T-cells in adults of all ages, but particularly in people aged more than 65 years [21].
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CD4+ T-cells, although less affected than CD8+ T-cells, also show an increased proportion of central memory cells and a reduction in the proportions of naive and effector memory cells in older adults [22,23]. Similar to the changes in the T-cell population, the number of naive B-cells is also reduced in the elderly. This appears to be due to a reduction in the number of B-cell progenitors in the bone marrow [24]. Conversely, the proportion of antigen-experienced B-cells is increased [25]. Together these changes result in a reduction in the diversity of antibody responses [26]. In addition, the class switching and somatic recombination essential for antibody diversity and production of high-affinity immunoglobulin-G antibodies are impaired in elderly individuals [27], resulting in weak and low-affinity antibody responses. Furthermore, due to changes in the function of CD4+ T-helper cells, activation of B-cells in the elderly is impaired [28]. Thus, the impaired adaptive immune responses seen in the elderly are due (at least in part) to reductions in the numbers of naive T-cells and naive B-cells, and increases in the numbers of effector and memory cells. These changes result in a decrease in the repertoire of immune cells and defects in cooperation between T-cells and B-cells that contribute to the overall age-related decline in immune function. One consequence of this decline is that immune responses to vaccination are impaired in elderly people. For example, a quantitative review of 31 vaccine antibody response studies found that the seroconversion and seroprotection rates for all three antigens in the trivalent seasonal influenza vaccine were significantly higher in younger volunteers (age, 17–59 years) than in elderly individuals (age, 58–104 years) (Fig. 1) [5]. Multivariate stepwise regression to adjust for factors that may influence response to vaccination (e.g. health status, previous vaccination, high pre-vaccination titres, living conditions) showed that the seroconversion and seroprotection responses for all three antigens were 2–4-fold higher among younger adults than in the elderly [5]. It is apparent, therefore, that influenza vaccines for elderly people need to be adapted to optimise the immune responses to vaccination, and to reduce the 40,000–220,000 excess deaths attributable to influenza in the EU each year [29], of which approximately 90% are estimated to occur among individuals aged more or equal to 65 years [30]. Several approaches have been investigated for their potential to enhance the immunogenicity of influenza vaccines in the elderly. These include the use of an adjuvant [31], increasing the doses of antigens (e.g. 60 mg haemagglutinin [HA] of each viral component compared with the standard 15-mg dose) [32,33] and using new routes of administration. With respect to the latter approach, the intradermal route has been keenly investigated and is the focus of this symposium report. 3. The intradermal route: new perspectives for vaccination The skin has several features that make it an attractive site for vaccination. First, it has a rich supply of capillary blood and lymphatic vessels, mainly in the dermis. The blood vessels enable immune cells to enter the skin, while extensive drainage by lymphatic vessels allows transport of immune cells and soluble antigens to the lymph nodes [34,35]. Second, the skin also contains a large population of immune cells, particularly resident antigenpresenting cells: Langerhans cells in the epidermis and dermal dendritic cells in the dermis [34–36]. Other immune cells present in the dermis include T-cells, macrophages and mast cells [37]. The dermis therefore represents a rich immune environment. Third, the skin is easily accessible for vaccination. Importantly, skin thickness (epidermis and dermis) is consistent at the main
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Fig. 1. Seroconversion (percentage of individuals with four-fold antibody increase) and seroprotection (percentage of individuals with antibody titres greater or equal to 40) rates after influenza vaccination in young (age, 17–59 years) and elderly (age, 58–104 years) adults. Data from a meta-analysis of 31 studies [5]. Adapted from ref. [5], Copyright (2010), with permission from Elsevier.
vaccination sites (deltoid, suprascapular regions) irrespective of age, ethnic origin and body mass index [38]. Intradermal vaccination could target three potential routes for inducing immunity. After injection of antigens into the dermis, they may be taken up by the resident dendritic cells in the skin. In addition, local inflammation generated by injection of antigens into the dermis may recruit blood macrophages and dendritic cells. After phagocytosing the antigen, resident and recruited antigenpresenting cells migrate to the draining lymph node to stimulate Tcell immunity. Finally, antigens may also migrate freely to the lymph node due to the dense network of lymphatic vessels in the dermis. In the lymph node, free antigens are captured by lymph node-resident dendritic cells to induce immune responses. Together these three pathways may lead to cooperation and synergy in immune responses [35]. Clinical experience with rabies and hepatitis-B vaccines has demonstrated the effectiveness of the intradermal route for vaccination. For example, intradermal vaccination against hepatitis-B has been found to induce protective antibody levels in individuals who failed to respond to standard intramuscular vaccination [35,39]. The available evidence suggests that vaccination via the intradermal route generates powerful immune responses, but its use has been restricted previously due to the technical challenges of carrying out intradermal injections. The standard Mantoux intradermal technique is difficult to carry out correctly and requires skilled personnel [40]. There is also evidence of poor consistency of injection depth and volume delivered using the Mantoux technique, and the procedure is painful [41,39]. However, the development of novel microneedle injection systems has provided researchers and clinicians with a new opportunity to exploit the potential of the rich immune environment in the dermis. 4. Clinical results of intradermal influenza vaccination with IntanzaW 15 mg in the elderly Intanza1 15 mg is a purified, inactivated, trivalent, split-virus influenza vaccine. Consistent with the WHO recommendations for seasonal influenza vaccines, it contains 15 mg HA per 0.1 ml dose of each of one seasonal A/H1N1 strain, one A/H3N2 strain and one B strain. The vaccine is administered using an intradermal microneedle injection system (Becton Dickinson; Franklin Lakes, NJ,
USA) designed to provide simple and reliable intradermal vaccination [41]. In a multicentre, randomised phase-II study, healthy volunteers aged more than 60 years received the intradermal vaccine (n = 369) or a trivalent split-virus vaccine (Vaxigrip1; Sanofi Pasteur, Lyon, France) containing 15 mg HA of each strain per 0.5ml dose administered by the intramuscular route (n = 368). At 21 days post-vaccination, the geometric mean titres (GMTs) of antiHA antibodies for each strain were significantly higher in the group that had received the vaccine via the intradermal route (intradermal vaccine) compared with the group that received the vaccine via the intramuscular route (intramuscular vaccine) (p < 0.0001) [42]. Increases in seroprotection rates, seroconversion rates and mean titre were also significantly higher for the intradermal vaccine (p < 0.05), with the exception of the seroprotection rate for the A/H1N1 strain. In addition, the intradermal vaccine was well tolerated. A randomised, open-label phase III trial compared the immunogenicity and safety of intradermal influenza vaccine with that of the intramuscular vaccine in 3695 elderly individuals (age, 60–95 years) over three consecutive influenza seasons [43]. Overall, the antibody response to the intradermal vaccine was superior to that for the intramuscular vaccine. At 21 days after the first vaccination, the GMTs and seroprotection rates for all three influenza strains were higher in the intradermal vaccine group than in the intramuscular vaccine group, and these differences in seroprotection rates reached statistical significance (differences versus intradermal vaccine: A/H1N1, +5.8%, p = 0.0003; A/H3N2, +5.5%, p < 0.0001; B, +6.6%, p = 0.0003) (Fig. 2) [43]. In addition, the intradermal vaccine also induced significantly higher geometric mean titre ratios (GMTRs) for all three strains (all p < 0.0001) and higher rates of seroconversion or significant increase (A strains p < 0.0001; B strain p = 0.0012) compared with the intramuscular vaccine [43]. Both vaccines met all three immunogenicity criteria set by the European Medicines Agency for people aged more than 60 years [44] for the three strains, except seroprotection for the B strain [43]. Further descriptive analyses of immunogenicity were carried out in randomly selected subgroups of participants after vaccination in Year 2 and Year 3. Seroprotection rates were consistently increased with the intradermal vaccine compared with the intramuscular vaccine against all three virus strains. Seroprotection rates against the A/H1N1, A/H3N2 and B strains in Year 2 were 93.1%, 98.1% and 59.9% after intradermal vaccination,
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Fig. 2. Comparison of immunogenicity of the intradermal influenza vaccine Intanza 15 mg and the standard intramuscular influenza vaccine 21 days post-vaccination [43]. (a) haemagglutination inhibition (1/dil); (b) seroprotection rate (percentage of participants with a post-vaccination titre greater or equal to 40); (c) GMTR: geometric mean of post-vaccination to pre-vaccination titre ratios; (d) seroconversion or significant titre increase rate (post-vaccination titre greater or equal to 40 in participants with a prevaccination titre less than 10 or a greater or equal to four-fold increase in titre after vaccination in participants with a pre-vaccination titre greater or equal to 10). *Response in the intradermal group statistically superior to that in the intramuscular group. Error bars indicate 95% confidence intervals. The dashed horizontal lines indicate the European Medicines Agency-required thresholds for adults aged greater or equal to 60 years. Reprinted from Ref. [43] , Copyright (2010), with permission from Elsevier.
and 81.8%, 95.8%, and 53.1% after intramuscular vaccination. The respective seroprotection rates in Year 3 were 80.5%, 89.6% and 66.1% for the intradermal vaccine, and 74.2%, 77.3% and 55.2% for the intramuscular vaccine [43]. The intradermal vaccine was well-tolerated with a systemic safety profile comparable with that of the intramuscular vaccine. Rates of injection-site reactions in Year 1 were higher with the intradermal vaccine than with the intramuscular vaccine (swelling 35.8% versus 8.4%; induration 37.6% versus 11.3%; erythema 70.9% versus 15.1%), but injection-site pain was comparable for the two vaccines (22.7% versus 17.2%) [43]. The increased frequency of local reactions after intradermal vaccination was not unexpected, and reflects the close proximity of the injected vaccine to the skin surface, whereas local reactions occurring deeper in the muscles after intramuscular injection are not so obvious [43]. Most local reactions occurred within 3 days after vaccination, were transient, and resolved spontaneously within 1–3 days after onset. Importantly, the safety profile of the intradermal vaccine did not
deteriorate with repeated vaccinations over consecutive years [43]. Vaccinees’ perceptions of injection-site reactions and local reactions after intradermal vaccination with the micro-injection system have been assessed using the vaccinees’ perception of injection (VAPI) questionnaire. The self-administered questionnaire consists of 21 questions comprising four multi-question dimensions (bother from injection-site reactions, six questions; arm movement, four questions; sleep, four questions and acceptability, two questions) and five individual questions (anxiety before vaccination; bother from pain during vaccination; satisfaction with the injection system; anxiety of being vaccinated next year; willingness to be vaccinated again) [45]. The questionnaire was completed 21 days after the first vaccination by participants in the phase III study with Intanza1 15 mg. The responses showed that the vaccine was well accepted by study participants. Overall, 97% of participants considered injection-site reactions to be ‘‘totally’’ or ‘‘very’’ acceptable, and
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96% of participants were ‘‘very satisfied’’ or ‘‘satisfied’’ with the injection system [46]. 5. Potential advantages of IntanzaW 15 mg and the microneedle injection system The microneedle injection system comprises a prefilled syringe fitted with a shorter needle that is also approximately ten-times thinner than that used for intramuscular vaccination. In addition, the volume of vaccine injected intradermally is fivetimes smaller than is used for intramuscular vaccination due to concentration of antigens. The microneedle injection system also includes a needle-shielding system that is activated after injection to protect against needle-stick injuries and prevent illicit re-use [41]. The microneedle injection system has several potential advantages for healthcare providers. First, there is no requirement to prepare the vaccine, thereby saving time and preventing wastage. Second, a study involving 168 general practitioners and 15 nurses found that the system is intuitive and easy to use, and that training before first use is not necessary [41]. Third, the needle-shielding system improves safety compared with conventional syringes and needles used for intramuscular injections. Fourth, the injection system has been shown to provide consistent and reliable delivery of antigen into the dermis regardless of age, sex, ethnicity, or body mass index [41]. The microneedle injection system may also have benefits for patients. The injection is less painful than the standard intradermal (Mantoux) injection technique. In one study of 654 healthy volunteers, all participants reported that placement of the microneedle into the skin was pain-free. The only pain reported was a faint burning sensation during injection of fluid into the dermis. The mean rating of pain on a visual analogue scale was 10.2 mm (95% confidence interval [CI] 8.5–11.80) with the microneedle injection system and 27.6 mm (95% CI 26.0–29.1) with the Mantoux technique (p < 0.0001) [41]. The fine needle should also help to address the fear of needles that is a barrier to vaccination in many people [47], thereby increasing the vaccination coverage rate. 6. Discussion Vaccination provides the opportunity to protect elderly people against several diseases that contribute to morbidity and mortality in this population. However, the impaired immune responses to vaccination as a result of immunosenescence represent a major challenge in improving the health of the elderly population [1,2]. Intradermal vaccination appears to be an attractive option to enhance immune responses to vaccines. This technique delivers the vaccine to a skin layer with excellent immune properties, including rich blood and lymphatic networks, and large populations of resident and recruited dendritic cells. The increased immunogenicity of Intanza1 15 mg in the elderly compared with the standard intramuscular influenza vaccine [42,43] provides support for the concept of intradermal vaccination to enhance immune responses in elderly people. A limitation of most studies investigating intradermal vaccination using various antigens has been the absence of a comparator arm in which the same dose of antigen was delivered intramuscularly. Typically, such studies have compared a reduced dose of antigen delivered intradermally with the standard intramuscular or subcutaneous dose [35,39]. In contrast, the clinical studies with Intanza1 15 mg have compared it with the same dose of seasonal influenza vaccine delivered intramuscularly [42,43], thereby providing direct evidence of the superiority of the intradermal vaccination route.
To date, experience with Intanza1 15 mg has been limited to the clinical-trial setting. Nevertheless, it is hoped that the superior immunogenicity of the intradermal over the intramuscular route, the good acceptability of the microneedle injection system for patients, and the simplicity of the system for healthcare providers will help to increase vaccine uptake and protection against influenza in the elderly. The 5–6% increase in the seroprotection rate among elderly volunteers vaccinated by the intradermal route compared with the standard intramuscular influenza vaccination may seem modest. However, when scaled-up to the proportion of vaccinees in the estimated 84 million people aged more or equal to 65 years in the EU [9,48] this would represent a substantial increase in the number of people who could be seroprotected against influenza by intradermal vaccination. 7. Conclusion In our opinion, the dermis, with its rich supply of blood and lymphatic vessels and resident populations of antigen-presenting cells, provides an excellent immune environment that can be targeted for vaccination. The evidence from clinical trials with the intradermal influenza vaccine, Intanza1 15 mg, supports the theory that intradermal vaccination can help to enhance immune responses to vaccination in the elderly. We therefore believe that Intanza1 15 mg provides an opportunity to enhance protection against influenza in the elderly population. 8. Conflicts of interest Marc Paccalin and Birgit Weinberger have received honoraria for presentations during symposia sponsored by Sanofi Pasteur MSD, Jean-Francois Nicolas has received honoraria for presentations during symposia sponsored by Sanofi Pasteur and Sanofi Pasteur MSD and was PI for clinical studies on vaccination, Pierre Van Damme acts as Chief and Principal Investigator for clinical trials conducted on behalf of the University of Antwerp, for which the University obtains research grants from vaccine manufacturers. Speakers’ fees for presentations on vaccines are paid directly to an educational fund held by the University of Antwerp and Yves Me´gard is an employee of Sanofi Pasteur MSD, Lyon, France. Acknowledgements This manuscript is based on a satellite symposium sponsored by Sanofi Pasteur MSD held during the XIXth IAGG World Congress of Gerontology and Aging in Paris, 5–9 July 2009. The authors take full responsibility for the content of the contribution but thank Communigen Limited, Oxford, UK (supported by Sanofi Pasteur MSD, Lyon, France) for their assistance in preparing the manuscript. References [1] Weinberger B, Herndler-Brandstetter D, Schwanninger A, et al. Biology of immune responses to vaccines in elderly persons. Clin Infect Dis 2008;46: 1078–84. [2] Grubeck-Loebenstein B, Della Bella S, Iorio AM, et al. Immunosenescence and vaccine failure in the elderly. Aging Clin Exp Res 2009;21:201–9. [3] Yoshikawa TT. Epidemiology and unique aspects of aging and infectious diseases. Clin Infect Dis 2000;30:931–3. [4] Gavazzi G, Krause KH. Ageing and infection. Lancet Infect Dis 2002;2:659–66. [5] Goodwin K, Viboud C, Simonsen L. Antibody response to influenza vaccination in the elderly: a quantitative review. Vaccine 2006;24:1159–69. [6] World Health Organization. 56th World Health Assembly. Prevention and control of influenza pandemics and annual epidemics. 2003 (WHA56.19). [7] Council of the European Union. Council recommendation of 22 December 2009 on seasonal influenza vaccination. Available at: http://eur-lex.europa.eu/ LexUriServ/LexUriServ.do?uri=OJ:L:2009:348:0071:0072:EN:PDF.
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[30] Thompson WW, Shay DK, Weintraub E, et al. Mortality associated with influenza and respiratory syncytial virus in the United States. JAMA 2003;289:179–86. [31] de Bruijn IA, Meyer I, Gerez L, et al. Antibody induction by virosomal MF59adjuvanted or conventional influenza vaccines in the elderly. Vaccine 2007;26:119–27. [32] Palache AM, Beyer WE, Sprenger MJ, et al. Antibody response after influenza immunization with various vaccine doses: a double-blind, placebo-controlled, multi-centre, dose-response study in elderly nursing-home residents and young volunteers. Vaccine 1993;11:3–9. [33] Couch RB, Winokur P, Brady R, et al. Safety and immunogenicity of a high dosage trivalent influenza vaccine among elderly subjects. Vaccine 2007; 25:7656–63. [34] Lambert PH, Laurent PE. Intradermal vaccine delivery: will new delivery systems transform vaccine administration? Vaccine 2008;26:3197–208. [35] Nicolas JF, Guy B. Intradermal, epidermal and transcutaneous vaccination: from immunology to clinical practice. Expert Rev Vaccines 2008;7:1201–14. [36] Glenn GM, Kenney RT. Mass vaccination: solutions in the skin. Curr Top Microbiol Immunol 2006;304:247–68. [37] Spellberg B. The cutaneaous citadel. A holistic view of skin and immunity. Life Sci 2000;67:477–502. [38] Laurent A, Mistretta F, Bottigiolo D, et al. Echographic measurement of skin thickness in adults by high frequency ultrasound to assess the appropriate microneedle length for intradermal delivery of vaccines. Vaccine 2007; 25:6423–30. [39] Mikszta JA, Laurent PE. Cutaneous delivery of prophylactic and therapeutic vaccines: historical perspective and future outlook. Expert Rev Vaccines 2008;7:1329–39. [40] World Health Organization. WHO recommendations on rabies post-exposure treatment and the correct technique of intradermal immunization against rabies. World Health Organisation 1997. Available at: www.who.int/rabies/ en/WHO_recommendation_post_exp_treatment.pdf. [41] Laurent PE, Bonnet S, Alchas P, et al. Evaluation of the clinical performance of a new intradermal vaccine administration technique and associated delivery system. Vaccine 2007;25:8833–42. [42] Holland D, Booy R, De Looze F, et al. Intradermal influenza vaccine administered using a new microinjection system produces superior immunogenicity in elderly adults: a randomized controlled trial. J Infect Dis 2008;198:650–8 [Comment in J Infect Dis 2008;198:632–4]. [43] Arnou R, Icardi G, De Decker M, et al. Intradermal influenza vaccine for older adults: a randomized controlled multicenter phase III study. Vaccine 2009; 27:7304–12. [44] Committee for Proprietary Medicinal Products. Note for guidance on harmonisation of requirements for influenza vaccines, 1997. CPMP/BWP/214/96. [45] Chevat C, Viala-Danten M, Dias-Barbosa C, et al. Development and psychometric validation of a self-administered questionnaire assessing the acceptance of influenza vaccination: the Vaccinees’ Perception of Injection (VAPI) questionnaire. Health Qual Life Outcomes 2009;7:21. [46] Reygrobellet C, Viala-Danten M, Meunier J, et al. Perception and acceptance of intradermal influenza vaccination. Patient reported outcomes from phase 3 clinical trials. Hum Vaccin 2010;6(4):1–10. [47] Johnson DR, Nichol KL, Lipczynski K. Barriers to adult immunization. Am J Med 2008;121(7 Suppl. 2):S28–35. [48] European Centre for Disease Prevention and Control (ECDC) Interim Guidance. Use of specific pandemic influenza vaccines during the H1N1 2009 pandemic. Stockholm, August 2009. Available at: http://www.ecdc.europa.eu/en/ publications/Publications/0908_GUI_Pandemic_Influenza_Vaccines_during_ the_H1N1_2009_Pandemic.pdf.
Hot topic in geriatric medicine
The intradermal vaccination route – an attractive opportunity for influenza vaccination in the elderly M. Paccalin a,*, B. Weinberger b,1, J.-F. Nicolas c,2, P. Van Damme d,3, Y. Me´gard e,4 a
Department of Geriatrics, University Hospital La Mile´trie, 86021 Poitiers, France Institute for Biomedical Aging Research of the Austrian Academy of Sciences, Rennweg 10, 6020 Innsbruck, Austria Inserm Unit 851, UFR, centre hospitalier Lyon-Sud, universite´ Lyon 1, 69495 Pierre-Be´nite cedex, France d Centre of the Evaluation of Vaccination, Vaccine & Infectious Disease Institute, University of Antwerp, Universiteitsplein, 1, 2610 Antwerp, Belgium e Sanofi Pasteur MSD, 8, rue Jonas-Salk, 69367 Lyon cedex 07, France b c
A R T I C L E I N F O
A B S T R A C T
Article history: Received 22 February 2010 Accepted 10 March 2010 Available online 13 April 2010
An age-related decline in functioning of the innate and adaptive immune systems results in increased susceptibility to infections (e.g. influenza) and decreased responses to vaccination in elderly people. A satellite symposium held during the XIXth IAGG World Congress of Gerontology and Aging in Paris, 5–9 July 2009, considered the potential of intradermal vaccination to enhance immune responses in the elderly. The rich supply of capillary blood and lymphatic vessels in the dermis, along with its resident population of dendritic cells, make the skin an attractive site for vaccine delivery. Intanza1 15 mg is a purified, inactivated, trivalent, split-virus influenza vaccine containing 15 mg haemagglutinin/strain/ 0.1 ml dose that is administered using a novel intradermal microneedle injection system. A randomised, open-label phase III trial in 3695 people aged 60–95 years found that antibody responses to the intradermal influenza vaccine were superior to those for the same vaccine administered intramuscularly. The systemic safety profile of the intradermal vaccine was comparable with that of the intramuscular vaccine, but rates of injection-site reactions were higher with the intradermal vaccine, reflecting the close proximity of injected vaccine to the skin surface. The increased immunogenicity of Intanza1 15 mg in the elderly compared with the standard intramuscular influenza vaccine supports the concept of intradermal vaccination to enhance immune responses in elderly people. ß 2010 Elsevier Masson SAS and European Union Geriatric Medicine Society. All rights reserved.
Keywords: Elderly Immunosenescence Influenza Intradermal Vaccination
1. Introduction Aging is associated with a decline in immune function (immunosenescence) that results in increases in the incidence and severity of infectious diseases, and decreased responses to vaccination [1,2]. For example, influenza is the fourth most common cause of death in the elderly [3] and it is also associated with greater morbidity compared with the infection in younger individuals [4]. One consequence of the decline in antibody responses to vaccination in the elderly is that influenza vaccine, although effective in the elderly population, induces reduced immune responses and protection compared with vaccination in young adults [5]. Furthermore, uptake of vaccination is sub-
* Corresponding author. Tel.: +33 5 49 44 44 27; fax: +33 5 49 44 44 29. E-mail addresses: [email protected] (M. Paccalin), [email protected] (B. Weinberger), [email protected] (J.-F. Nicolas), [email protected] (P. Van Damme), [email protected] (Y. Me´gard). 1 Tel.: +43 512 583919 13. 2 Tel.: +33 4 78 86 15 72; fax: +33 4 78 86 15 28. 3 Tel.: +32 3 265 25 38; fax: +32 3 265 26 40. 4 Tel.: +33 4 37 28 45 47; fax: +33 4 37 28 44 11.
optimal. The World Health Organization (WHO) and the Council of the European Union (EU) have set targets for member states with influenza vaccination programmes to achieve vaccination coverage rates in elderly people of greater than 75% by 2010 and 2014, respectively [6,7]. Most European countries have not achieved the WHO goal [8,9]. There is therefore a need to improve the immunogenicity of influenza vaccines for use in the elderly and also to ensure greater uptake of the vaccine in this population. This contribution is based on a satellite symposium held during the XIXth International Association of Gerontology and Geriatrics (IAGG) World Congress of Gerontology and Aging in Paris, 5–9 July 2009. A faculty of European experts in immunology, dermatology and vaccines reviewed the challenge of immunosenescence and impaired responses to vaccination in the elderly. They also considered the potential of intradermal delivery of vaccines to enhance those responses. In particular, they considered the opportunity provided by the first seasonal influenza vaccine developed for intradermal delivery, Intanza1 (Sanofi Pasteur, Lyon, France), to improve the immunogenicity and coverage of influenza vaccination in the elderly. This report provides a summary of the presentations during the symposium and represents a consensus of the views of the faculty.
1878-7649/$ – see front matter ß 2010 Elsevier Masson SAS and European Union Geriatric Medicine Society. All rights reserved. doi:10.1016/j.eurger.2010.03.004
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2. Immunosenescence: age-related changes in the immune system Aging is associated with changes in the innate and adaptive immune systems. These changes may include alterations in the numbers and functions of the various types of immune cells [2]. 2.1. Age-related changes in the innate immune system Neutrophils, macrophages and natural killer cells are affected by aging, particularly in their functions and responses to cytokines [10]. However, there is also an increase in the production of proinflammatory cytokines by macrophages in elderly individuals that contributes to the subclinical pro-inflammatory state termed ‘‘inflammaging’’ [11,12]. This state is believed to be due to chronic stimulation of innate immunity by products of degradation processes, or by the inability of the aged immune system to eliminate some pathogens, resulting in chronic (yet inefficient) innate immune responses [1]. Dendritic cells are specialised antigen-presenting cells that capture and process antigens for presentation to T-cells and, in so doing, determine the quality and intensity of adaptive immune responses [13]. However, there is evidence that the number of dendritic cells in the peripheral blood of elderly individuals is significantly reduced [14]. In addition, dendritic cells from elderly people display a reduced capacity to present antigens and impaired migration to lymph nodes [15]. Such defects in the processing and presentation of antigens by cells of the innate immune system contribute to diminished activation of cells in the adaptive immune system. Furthermore, due to inflammaging, the threshold for the induction of a ‘‘danger signal’’ by vaccination may increase. 2.2. Age-related changes in the adaptive immune system and impact on influenza vaccination Due to involution of the thymus with age, the output of naive Tcells declines and the T-cell pool in later life comprises mainly memory and effector T-cells [1]. The numbers of phenotypically naive (expressing cell-surface markers CD45RA and CD28) CD8+ T-cells are depleted in the lymph nodes and circulation of people aged more than 65 years compared with people aged less than 30 years [16]. Furthermore, these phenotypically naive T-cells are not functionally naive. Instead, they display a restricted T-cell receptor repertoire and have shortened telomeres, indicating previous replication and resulting in a reduced repertoire of responses to novel antigens [17]. The ratio of memory (CD45RA CD28+) to effector (CD45RA+CD28 ) CD8+ T-cells has been shown to vary between elderly individuals [18]. Importantly, elderly individuals with higher proportions of memory T-cells were shown to have a better response to influenza vaccination than those with higher numbers of effector T-cells [19]. Further study revealed two subpopulations of memory T-cells in the elderly. Individuals with a good response to influenza vaccination had a subset of CD8+ memory T-cells that also expressed CD25 and produced large amounts of interleukin (IL)-2 and some IL-4, but little interferon (IFN)-g. In contrast, individuals with a poor response to vaccination did not have any CD25+CD8+ T-cells [18]. This suggests that accumulation of CD25+CD8+ memory T-cells in the elderly can maintain immune responsiveness in the absence of naive T-cells [20]. Chronic infections providing repeated antigenic stimulation are believed to contribute to the accumulation of highly differentiated CD28 CD8+ effector T-cells in the elderly. For example, cytomegalovirus infection is associated with a decline in naive T-cells and an increase in CD28 CD8+ T-cells in adults of all ages, but particularly in people aged more than 65 years [21].
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CD4+ T-cells, although less affected than CD8+ T-cells, also show an increased proportion of central memory cells and a reduction in the proportions of naive and effector memory cells in older adults [22,23]. Similar to the changes in the T-cell population, the number of naive B-cells is also reduced in the elderly. This appears to be due to a reduction in the number of B-cell progenitors in the bone marrow [24]. Conversely, the proportion of antigen-experienced B-cells is increased [25]. Together these changes result in a reduction in the diversity of antibody responses [26]. In addition, the class switching and somatic recombination essential for antibody diversity and production of high-affinity immunoglobulin-G antibodies are impaired in elderly individuals [27], resulting in weak and low-affinity antibody responses. Furthermore, due to changes in the function of CD4+ T-helper cells, activation of B-cells in the elderly is impaired [28]. Thus, the impaired adaptive immune responses seen in the elderly are due (at least in part) to reductions in the numbers of naive T-cells and naive B-cells, and increases in the numbers of effector and memory cells. These changes result in a decrease in the repertoire of immune cells and defects in cooperation between T-cells and B-cells that contribute to the overall age-related decline in immune function. One consequence of this decline is that immune responses to vaccination are impaired in elderly people. For example, a quantitative review of 31 vaccine antibody response studies found that the seroconversion and seroprotection rates for all three antigens in the trivalent seasonal influenza vaccine were significantly higher in younger volunteers (age, 17–59 years) than in elderly individuals (age, 58–104 years) (Fig. 1) [5]. Multivariate stepwise regression to adjust for factors that may influence response to vaccination (e.g. health status, previous vaccination, high pre-vaccination titres, living conditions) showed that the seroconversion and seroprotection responses for all three antigens were 2–4-fold higher among younger adults than in the elderly [5]. It is apparent, therefore, that influenza vaccines for elderly people need to be adapted to optimise the immune responses to vaccination, and to reduce the 40,000–220,000 excess deaths attributable to influenza in the EU each year [29], of which approximately 90% are estimated to occur among individuals aged more or equal to 65 years [30]. Several approaches have been investigated for their potential to enhance the immunogenicity of influenza vaccines in the elderly. These include the use of an adjuvant [31], increasing the doses of antigens (e.g. 60 mg haemagglutinin [HA] of each viral component compared with the standard 15-mg dose) [32,33] and using new routes of administration. With respect to the latter approach, the intradermal route has been keenly investigated and is the focus of this symposium report. 3. The intradermal route: new perspectives for vaccination The skin has several features that make it an attractive site for vaccination. First, it has a rich supply of capillary blood and lymphatic vessels, mainly in the dermis. The blood vessels enable immune cells to enter the skin, while extensive drainage by lymphatic vessels allows transport of immune cells and soluble antigens to the lymph nodes [34,35]. Second, the skin also contains a large population of immune cells, particularly resident antigenpresenting cells: Langerhans cells in the epidermis and dermal dendritic cells in the dermis [34–36]. Other immune cells present in the dermis include T-cells, macrophages and mast cells [37]. The dermis therefore represents a rich immune environment. Third, the skin is easily accessible for vaccination. Importantly, skin thickness (epidermis and dermis) is consistent at the main
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Fig. 1. Seroconversion (percentage of individuals with four-fold antibody increase) and seroprotection (percentage of individuals with antibody titres greater or equal to 40) rates after influenza vaccination in young (age, 17–59 years) and elderly (age, 58–104 years) adults. Data from a meta-analysis of 31 studies [5]. Adapted from ref. [5], Copyright (2010), with permission from Elsevier.
vaccination sites (deltoid, suprascapular regions) irrespective of age, ethnic origin and body mass index [38]. Intradermal vaccination could target three potential routes for inducing immunity. After injection of antigens into the dermis, they may be taken up by the resident dendritic cells in the skin. In addition, local inflammation generated by injection of antigens into the dermis may recruit blood macrophages and dendritic cells. After phagocytosing the antigen, resident and recruited antigenpresenting cells migrate to the draining lymph node to stimulate Tcell immunity. Finally, antigens may also migrate freely to the lymph node due to the dense network of lymphatic vessels in the dermis. In the lymph node, free antigens are captured by lymph node-resident dendritic cells to induce immune responses. Together these three pathways may lead to cooperation and synergy in immune responses [35]. Clinical experience with rabies and hepatitis-B vaccines has demonstrated the effectiveness of the intradermal route for vaccination. For example, intradermal vaccination against hepatitis-B has been found to induce protective antibody levels in individuals who failed to respond to standard intramuscular vaccination [35,39]. The available evidence suggests that vaccination via the intradermal route generates powerful immune responses, but its use has been restricted previously due to the technical challenges of carrying out intradermal injections. The standard Mantoux intradermal technique is difficult to carry out correctly and requires skilled personnel [40]. There is also evidence of poor consistency of injection depth and volume delivered using the Mantoux technique, and the procedure is painful [41,39]. However, the development of novel microneedle injection systems has provided researchers and clinicians with a new opportunity to exploit the potential of the rich immune environment in the dermis. 4. Clinical results of intradermal influenza vaccination with IntanzaW 15 mg in the elderly Intanza1 15 mg is a purified, inactivated, trivalent, split-virus influenza vaccine. Consistent with the WHO recommendations for seasonal influenza vaccines, it contains 15 mg HA per 0.1 ml dose of each of one seasonal A/H1N1 strain, one A/H3N2 strain and one B strain. The vaccine is administered using an intradermal microneedle injection system (Becton Dickinson; Franklin Lakes, NJ,
USA) designed to provide simple and reliable intradermal vaccination [41]. In a multicentre, randomised phase-II study, healthy volunteers aged more than 60 years received the intradermal vaccine (n = 369) or a trivalent split-virus vaccine (Vaxigrip1; Sanofi Pasteur, Lyon, France) containing 15 mg HA of each strain per 0.5ml dose administered by the intramuscular route (n = 368). At 21 days post-vaccination, the geometric mean titres (GMTs) of antiHA antibodies for each strain were significantly higher in the group that had received the vaccine via the intradermal route (intradermal vaccine) compared with the group that received the vaccine via the intramuscular route (intramuscular vaccine) (p < 0.0001) [42]. Increases in seroprotection rates, seroconversion rates and mean titre were also significantly higher for the intradermal vaccine (p < 0.05), with the exception of the seroprotection rate for the A/H1N1 strain. In addition, the intradermal vaccine was well tolerated. A randomised, open-label phase III trial compared the immunogenicity and safety of intradermal influenza vaccine with that of the intramuscular vaccine in 3695 elderly individuals (age, 60–95 years) over three consecutive influenza seasons [43]. Overall, the antibody response to the intradermal vaccine was superior to that for the intramuscular vaccine. At 21 days after the first vaccination, the GMTs and seroprotection rates for all three influenza strains were higher in the intradermal vaccine group than in the intramuscular vaccine group, and these differences in seroprotection rates reached statistical significance (differences versus intradermal vaccine: A/H1N1, +5.8%, p = 0.0003; A/H3N2, +5.5%, p < 0.0001; B, +6.6%, p = 0.0003) (Fig. 2) [43]. In addition, the intradermal vaccine also induced significantly higher geometric mean titre ratios (GMTRs) for all three strains (all p < 0.0001) and higher rates of seroconversion or significant increase (A strains p < 0.0001; B strain p = 0.0012) compared with the intramuscular vaccine [43]. Both vaccines met all three immunogenicity criteria set by the European Medicines Agency for people aged more than 60 years [44] for the three strains, except seroprotection for the B strain [43]. Further descriptive analyses of immunogenicity were carried out in randomly selected subgroups of participants after vaccination in Year 2 and Year 3. Seroprotection rates were consistently increased with the intradermal vaccine compared with the intramuscular vaccine against all three virus strains. Seroprotection rates against the A/H1N1, A/H3N2 and B strains in Year 2 were 93.1%, 98.1% and 59.9% after intradermal vaccination,
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Fig. 2. Comparison of immunogenicity of the intradermal influenza vaccine Intanza 15 mg and the standard intramuscular influenza vaccine 21 days post-vaccination [43]. (a) haemagglutination inhibition (1/dil); (b) seroprotection rate (percentage of participants with a post-vaccination titre greater or equal to 40); (c) GMTR: geometric mean of post-vaccination to pre-vaccination titre ratios; (d) seroconversion or significant titre increase rate (post-vaccination titre greater or equal to 40 in participants with a prevaccination titre less than 10 or a greater or equal to four-fold increase in titre after vaccination in participants with a pre-vaccination titre greater or equal to 10). *Response in the intradermal group statistically superior to that in the intramuscular group. Error bars indicate 95% confidence intervals. The dashed horizontal lines indicate the European Medicines Agency-required thresholds for adults aged greater or equal to 60 years. Reprinted from Ref. [43] , Copyright (2010), with permission from Elsevier.
and 81.8%, 95.8%, and 53.1% after intramuscular vaccination. The respective seroprotection rates in Year 3 were 80.5%, 89.6% and 66.1% for the intradermal vaccine, and 74.2%, 77.3% and 55.2% for the intramuscular vaccine [43]. The intradermal vaccine was well-tolerated with a systemic safety profile comparable with that of the intramuscular vaccine. Rates of injection-site reactions in Year 1 were higher with the intradermal vaccine than with the intramuscular vaccine (swelling 35.8% versus 8.4%; induration 37.6% versus 11.3%; erythema 70.9% versus 15.1%), but injection-site pain was comparable for the two vaccines (22.7% versus 17.2%) [43]. The increased frequency of local reactions after intradermal vaccination was not unexpected, and reflects the close proximity of the injected vaccine to the skin surface, whereas local reactions occurring deeper in the muscles after intramuscular injection are not so obvious [43]. Most local reactions occurred within 3 days after vaccination, were transient, and resolved spontaneously within 1–3 days after onset. Importantly, the safety profile of the intradermal vaccine did not
deteriorate with repeated vaccinations over consecutive years [43]. Vaccinees’ perceptions of injection-site reactions and local reactions after intradermal vaccination with the micro-injection system have been assessed using the vaccinees’ perception of injection (VAPI) questionnaire. The self-administered questionnaire consists of 21 questions comprising four multi-question dimensions (bother from injection-site reactions, six questions; arm movement, four questions; sleep, four questions and acceptability, two questions) and five individual questions (anxiety before vaccination; bother from pain during vaccination; satisfaction with the injection system; anxiety of being vaccinated next year; willingness to be vaccinated again) [45]. The questionnaire was completed 21 days after the first vaccination by participants in the phase III study with Intanza1 15 mg. The responses showed that the vaccine was well accepted by study participants. Overall, 97% of participants considered injection-site reactions to be ‘‘totally’’ or ‘‘very’’ acceptable, and
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96% of participants were ‘‘very satisfied’’ or ‘‘satisfied’’ with the injection system [46]. 5. Potential advantages of IntanzaW 15 mg and the microneedle injection system The microneedle injection system comprises a prefilled syringe fitted with a shorter needle that is also approximately ten-times thinner than that used for intramuscular vaccination. In addition, the volume of vaccine injected intradermally is fivetimes smaller than is used for intramuscular vaccination due to concentration of antigens. The microneedle injection system also includes a needle-shielding system that is activated after injection to protect against needle-stick injuries and prevent illicit re-use [41]. The microneedle injection system has several potential advantages for healthcare providers. First, there is no requirement to prepare the vaccine, thereby saving time and preventing wastage. Second, a study involving 168 general practitioners and 15 nurses found that the system is intuitive and easy to use, and that training before first use is not necessary [41]. Third, the needle-shielding system improves safety compared with conventional syringes and needles used for intramuscular injections. Fourth, the injection system has been shown to provide consistent and reliable delivery of antigen into the dermis regardless of age, sex, ethnicity, or body mass index [41]. The microneedle injection system may also have benefits for patients. The injection is less painful than the standard intradermal (Mantoux) injection technique. In one study of 654 healthy volunteers, all participants reported that placement of the microneedle into the skin was pain-free. The only pain reported was a faint burning sensation during injection of fluid into the dermis. The mean rating of pain on a visual analogue scale was 10.2 mm (95% confidence interval [CI] 8.5–11.80) with the microneedle injection system and 27.6 mm (95% CI 26.0–29.1) with the Mantoux technique (p < 0.0001) [41]. The fine needle should also help to address the fear of needles that is a barrier to vaccination in many people [47], thereby increasing the vaccination coverage rate. 6. Discussion Vaccination provides the opportunity to protect elderly people against several diseases that contribute to morbidity and mortality in this population. However, the impaired immune responses to vaccination as a result of immunosenescence represent a major challenge in improving the health of the elderly population [1,2]. Intradermal vaccination appears to be an attractive option to enhance immune responses to vaccines. This technique delivers the vaccine to a skin layer with excellent immune properties, including rich blood and lymphatic networks, and large populations of resident and recruited dendritic cells. The increased immunogenicity of Intanza1 15 mg in the elderly compared with the standard intramuscular influenza vaccine [42,43] provides support for the concept of intradermal vaccination to enhance immune responses in elderly people. A limitation of most studies investigating intradermal vaccination using various antigens has been the absence of a comparator arm in which the same dose of antigen was delivered intramuscularly. Typically, such studies have compared a reduced dose of antigen delivered intradermally with the standard intramuscular or subcutaneous dose [35,39]. In contrast, the clinical studies with Intanza1 15 mg have compared it with the same dose of seasonal influenza vaccine delivered intramuscularly [42,43], thereby providing direct evidence of the superiority of the intradermal vaccination route.
To date, experience with Intanza1 15 mg has been limited to the clinical-trial setting. Nevertheless, it is hoped that the superior immunogenicity of the intradermal over the intramuscular route, the good acceptability of the microneedle injection system for patients, and the simplicity of the system for healthcare providers will help to increase vaccine uptake and protection against influenza in the elderly. The 5–6% increase in the seroprotection rate among elderly volunteers vaccinated by the intradermal route compared with the standard intramuscular influenza vaccination may seem modest. However, when scaled-up to the proportion of vaccinees in the estimated 84 million people aged more or equal to 65 years in the EU [9,48] this would represent a substantial increase in the number of people who could be seroprotected against influenza by intradermal vaccination. 7. Conclusion In our opinion, the dermis, with its rich supply of blood and lymphatic vessels and resident populations of antigen-presenting cells, provides an excellent immune environment that can be targeted for vaccination. The evidence from clinical trials with the intradermal influenza vaccine, Intanza1 15 mg, supports the theory that intradermal vaccination can help to enhance immune responses to vaccination in the elderly. We therefore believe that Intanza1 15 mg provides an opportunity to enhance protection against influenza in the elderly population. 8. Conflicts of interest Marc Paccalin and Birgit Weinberger have received honoraria for presentations during symposia sponsored by Sanofi Pasteur MSD, Jean-Francois Nicolas has received honoraria for presentations during symposia sponsored by Sanofi Pasteur and Sanofi Pasteur MSD and was PI for clinical studies on vaccination, Pierre Van Damme acts as Chief and Principal Investigator for clinical trials conducted on behalf of the University of Antwerp, for which the University obtains research grants from vaccine manufacturers. Speakers’ fees for presentations on vaccines are paid directly to an educational fund held by the University of Antwerp and Yves Me´gard is an employee of Sanofi Pasteur MSD, Lyon, France. Acknowledgements This manuscript is based on a satellite symposium sponsored by Sanofi Pasteur MSD held during the XIXth IAGG World Congress of Gerontology and Aging in Paris, 5–9 July 2009. The authors take full responsibility for the content of the contribution but thank Communigen Limited, Oxford, UK (supported by Sanofi Pasteur MSD, Lyon, France) for their assistance in preparing the manuscript. References [1] Weinberger B, Herndler-Brandstetter D, Schwanninger A, et al. Biology of immune responses to vaccines in elderly persons. Clin Infect Dis 2008;46: 1078–84. [2] Grubeck-Loebenstein B, Della Bella S, Iorio AM, et al. Immunosenescence and vaccine failure in the elderly. Aging Clin Exp Res 2009;21:201–9. [3] Yoshikawa TT. Epidemiology and unique aspects of aging and infectious diseases. Clin Infect Dis 2000;30:931–3. [4] Gavazzi G, Krause KH. Ageing and infection. Lancet Infect Dis 2002;2:659–66. [5] Goodwin K, Viboud C, Simonsen L. Antibody response to influenza vaccination in the elderly: a quantitative review. Vaccine 2006;24:1159–69. [6] World Health Organization. 56th World Health Assembly. Prevention and control of influenza pandemics and annual epidemics. 2003 (WHA56.19). [7] Council of the European Union. Council recommendation of 22 December 2009 on seasonal influenza vaccination. Available at: http://eur-lex.europa.eu/ LexUriServ/LexUriServ.do?uri=OJ:L:2009:348:0071:0072:EN:PDF.
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