Targeted Vaccine Selection in Influenza Vaccination
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Background: The main target groups for influenza vaccination are the elderly, the chronically ill, infants, and toddlers. Influenza vaccines are needed that suit the immunological particularities of each of these age and risk groups. Recent years have seen the approval of influenza vaccines that are more immunogenic than before, but whose use in Germany is limited by the restriction of reimbursement to a small number of vaccines.
Methods: The Medline database was selectively searched for pertinent literature.
Results: The suboptimal immunogenicity of conventional influenza vaccines that contain inactivated viral cleavage products and subunits can be markedly improved by the use of squalene-based adjuvant systems, by the integration of viral antigens in virosomal particles, or by intradermal administration. The vaccination of elderly persons with a vaccine containing the adjuvant MF59 was found to lower the risk of hospitalization for influenza or pneumonia by 25% compared to vaccination with a trivalent inactivated vaccine (TIV). On the other hand, the adjuvant ASO3 was found to be associated with an up to 17-fold increase in the frequency of narcolepsy among 4- to 18-year-olds. In a prospective study, a virosomal vaccine lowered the frequency of laboratory-confirmed influenza in vaccinated children by 88% compared to unvaccinated children (2 versus 18 cases per 1000 individuals). A live, attenuated influenza vaccine lowered the rate of disease in children up to age 7 by 48% compared to a TIV (4.2% versus 8.1%).
Conclusion: The newer vaccines possess improved efficacy when used for primary and booster immunization in certain age and risk groups, and they are superior in this respect to conventional vaccines based on viral cleavage products and subunits. The risk/benefit profiles of all currently available vaccines vary depending on the age group or risk group in which they are used.
Seasonal influenza vaccination is recommended in Germany as a standard procedure for all persons aged 60 and above. Moreover, vaccination is also recommended for all persons at elevated risk of serious disease, for pregnant women, and for persons exposed to a higher than usual risk of infection (e1). In April 2012, the Strategic Advisory Group of Experts (SAGE) on Immunization of the World Health Organization (WHO) recommended the extension of national vaccination recommendations to children aged 6 to 59 months. Thus, the spectrum of target groups ranges from infants to very old persons, and from healthy persons with intact immune systems to the chronically ill. There is a corresponding variety in the tasks that influenza vaccines are required to fulfill. For example, a naive immune system that has never yet been in contact with influenza virus antigens cannot be effectively stimulated by the highly purified antigens contained in conventional influenza vaccines. The generation of robust immunity after primary vaccination requires a suitable vaccine, for example, one with added adjuvant or one containing live, attenuated virus (1).
The elderly have a less effective immune system that has become accustomed to influenza virus antigens through decades of exposure to naturally occurring viruses and repeated immunizations. They therefore need a strong, age-specific immunologic stimulus to achieve lasting protection against disease due to infection with currently circulating influenza viruses. The same is true of influenza vaccines for the chronically ill.
A number of influenza vaccines with improved immunogenicity have been approved in the last few years, and others are currently being clinically tested. In this article, we present the clinically relevant differences between conventional and newer influenza vaccines for each of the target groups in which they are used, and we discuss their optimal application.
This review is based on a search in the Medline database for publications that appeared from January 2000 to February 2013 and that included the search terms “influenza vaccine,” “immunogenicity,” “efficacy,” and “effectiveness.” Particular emphasis was laid on randomized, controlled trials and meta-analyses.
Classes of vaccines
The influenza viruses that are needed for antigen production in the manufacturing process of the currently approved seasonal, pandemic, and pre-pandemic vaccines are replicated either in incubated hen’s eggs (egg-based influenza vaccines) or in permanent cell lines (cell-based influenza vaccines, made with the use of Madin-Darby canine kidney cells [MDCK] or Vero simian kidney cells). These viruses for vaccination, once they have been inactivated with formaldehyde or β-propiolactone and then purified in a multistep process, can either be incorporated whole into a vaccine (whole-virus vaccines) or else used for the extraction of the viral hemagglutinin surface glycoprotein (HA). Depending on the intensity of the purification steps that follow, the final product is designated as either a split-virus vaccine or a subunit vaccine (Table 1).
Split-virus vaccines contain larger amounts of other viral components than subunit vaccines, which have been subjected to more intense purification. These additional components, however, are neither characterized nor quantified. The more intensely a viral preparation has been purified, the better tolerated it will be when administered, but at the cost of lower immunogenicity (e2).
Both split-virus and subunit antigens can be incorporated in virosomal particles (virosomal influenza vaccines) or given in combination with adjuvant systems (adjuvanted influenza vaccines) (Table 1). Whole-virus vaccines are generally formulated without adjuvant.
Seasonal trivalent inactivated vaccines (TIV) contain antigens of subtypes A/H1N1, A/H3N2, and B-strain. In Germany, in March 2013, the first quadrivalent inactivated vaccine (QIV) against influenza was approved, containing the HA antigens of the two different genetic lines of influenza B viruses (Victoria and Yamagata) (2, e3). Inactivated influenza vaccines for protection against zoonotic (“pre-pandemic”) or pandemic influenza viruses contain only the antigen of a single, relevant viral strain and are therefore called monovalent inactivated influenza vaccines. The alternative to inactivated vaccines is represented by live attenuated influenza vaccines (LAIV), which, like the inactivated vaccines, are produced in incubated eggs—in this case, in eggs that have been very thoroughly tested for contaminating foreign material (specific-pathogen-free or SPF eggs). LAIV have been approved in trivalent (EU, USA) and quadrivalent (USA) varieties. The efficacy of influenza vaccines depends to a large degree on the correspondence between the viral strains incorporated in the seasonal vaccine and the influenza viruses that are actually circulating during the current season (e4).
Vaccines with improved efficacy
TIV with increased antigen content
For healthy adults and older children, the efficacy of conventional TIV in the prevention of laboratory-confirmed influenza infection is well documented (e5, e6). Nonetheless, for persons at increased risk, elderly persons, and children under 8 years of age, the efficacy of these vaccines is moderate at best (e5–e8). For children under 2 years of age, a TIV was not found to be any more effective than placebo (e5).
Multiple studies have shown that raising the antigen dose from 15 to 60 µg HA increases the immunogenicity of TIV, in the sense of elevating the concentration of antibodies measured in the hemagglutination inhibition test (3–5). On the other hand, the higher antigen dose is also associated with a higher frequency of moderate to severe local and systemic reactions, of which the most common types are pain (5% versus 0%) and myalgia (7% versus 1%) (4). A TIV of this type was approved in the USA in 2009 for use in persons aged 65 and above (6). A comprehensive phase IIIb trial of this high-dose vaccine was carried out during the 2009/2010 influenza season but did not yield any conclusion about its clinical efficacy, as the strain of virus for which the vaccine was designed was strongly divergent from the H1N1 pandemic virus that prevailed at that time (e9).
It remains an open question whether the currently approved non-adjuvanted TIV with higher antigen doses are suitable for the primary immunization of immunologically naive persons. Evidence that this may be the case comes from a prospective cohort study carried out in Finland, where small children are given two adult doses of 15 µg HA at a 4-week interval for primary immunization (this is not the practice in other countries) (7).
Adjuvanted trivalent influenza vaccines
Extensive studies of candidate pandemic vaccines have clearly shown the superiority of adjuvanted vaccines over conventional ones for inducing immunity to the vaccine antigens (8, e10). This holds both for primary immunization of the naive immune system and for boosters to reinforce immunity that is already present. Squalene-based adjuvant systems like AS03 and MF59 make it possible to reduce antigen content by half (to 7.5 µg) or three quarters (to 3.75 µg) without lowering the immunogenicity of the HA antigens, as measured by the titer of induced protective antibodies (9, 11). The large-scale use of pandemic H1N1 vaccines in Scandinavia and England was associated with an up to 17-fold increase in cases of narcolepsy in persons aged 4 to 18 who had received an AS03-adjuvanted vaccine (e12–e14). No such increase has yet been observed in connection with the MF59-adjuvanted pandemic vaccine (e15, e16), but the total number of children and adolescents vaccinated with this vaccine is too small for an association with narcolepsy to be definitively excluded.
As for seasonal vaccines, clinical experience with the MF59 adjuvant system goes back many years. This is an oil-in-water emulsion based on squalene, which is a natural intermediate product of human endogenous cholesterol metabolism and a cellular component. In Germany, an MF59-adjuvanted influenza vaccine (MF59-TIV) has been available since the 2000/2001 influenza season but is only approved for persons aged 65 and above. The vaccine is well tolerated aside from a somewhat higher frequency of local reactions, which are usually mild and of brief duration.
Vaccination with MF59-TIV induces an immune response in elderly and/or chronically ill persons that is 1.2 to 1.8 times stronger than that induced by a non-adjuvanted TIV (10–12). The effect is particularly strong in persons who are both elderly and chronically ill, and in persons with a low antibody titer before vaccination (10, 11). Moreover, the vaccine induces immune response to influenza A strain variants (13, 14).
Observational studies on the clinical efficacy of MF59-TIV have shown that vaccinated persons have a 68% to 87% relative risk reduction (compared to non-vaccinated persons) with respect to hospitalization for pneumonia, cerebrovascular accidents, or acute coronary syndrome (15, 16). In a further observational study on a cohort of persons aged 65 and above, MF59-TIV was found to lower the rate of hospitalization for influenza or pneumonia by 25% in comparison to TIV (17).
Immunogenicity studies in children aged 6 months to <72 months have shown that age-appropriate vaccination with MF59-TIV on two separate occasions elicited a stronger immune response than TIV did, even in very young children (18). An extensive field study on children in this age group showed that MF59-TIV lowered the rate of laboratory-confirmed influenza in comparison to conventional TIV (19). The difference in efficacy between the adjuvanted and the conventional vaccine was most marked in children under 2 years of age: in this group, the absolute efficacy of M59-TIV was 77%, while that of TIV was only 11%.
Virosomal influenza vaccines
Virosomal vaccines consist of liposomes with a virus-like structure that present HA antigens of the relevant seasonal influenza viruses on their surface. As in a natural infection, the virosomal particles bind and fuse with the host cell, leading to an increased immune response (20, 21). Virosomal influenza vaccines are considered immunogenic, well tolerated, and safe, also for children aged 6 months and above (22, 23, e17).
Two studies of the relative immunogenicity of a virosomal influenza vaccine and MF59-TIV in elderly patients have yielded conflicting results. In one study (24) the two vaccines did not differ in efficacy, while in the other study (25) MF59-TIV was found to induce a stronger immune response.
The only study to date of the clinical efficacy (i.e., protective effect) of a virosomal influenza vaccine is a prospective cohort study performed in children aged 3 to 14 years, with non-vaccinated children as a control group. The vaccine prevented 75% of influenza-like illnesses (27 versus 102 cases per 1000) and 88% of laboratory-confirmed cases of influenza (2 versus 18 cases per 1000) (26).
Influenza vaccines for intradermal administration
Because of the large number of macrophages and dendrites in the skin, intradermal vaccination is thought to be more efficacious than intramuscular or subcutaneous antigen application (e18). Novel microinjection systems are now available for practical intradermal vaccination (e19). In 2009, an influenza vaccine for intradermal administration was approved in Europe for use in persons aged 18 and over, on the basis of immunogenicity studies (e20, e21). In patients under age 60, an antigen dose of 9 µg per virus component is used; older persons are given 15 µg of antigen. A randomized, multicenter phase III study showed no difference in immunogenicity and safety between the intradermal vaccine and MF59-TIV when given to persons over age 65 (27). More recent studies have shown that intradermal vaccination also leads to the formation of antibodies against drift variants (28). No studies of clinical efficacy are available.
Live attenuated influenza vaccines
Live vaccines are based on influenza strains that are repeatedly passaged at decreasing temperatures, with the result that they replicate best at 25°C but can hardly do so any more at 37°C. Gene segments of these adapted “master” strains are then combined with gene segments that encode the hemagglutinins and neuraminidases of the currently prevalent epidemic strains. These viruses developed for the purpose of creating vaccines are highly genetically stable and do not undergo reverse mutation (e22–e24).
Given intranasally as a spray, the live viruses in the vaccine replicate in the upper respiratory tract, potentially inducing mild respiratory symptoms. Being temperature-sensitive, they do not replicate in the warmer lower portion of the respiratory tract.
A live attenuated influenza vaccine (LAIV) was approved in the European Union in 2011 for use in children and adolescents aged 2 to 17 years. The advantage of LAIV over conventional, inactivated vaccines is that they not only induce humoral and cellular immunity, but also lead to the formation of secretory IgA, which exerts a direct protective effect at the portal of entry of influenza virus (29, 30, e25).
Multiple clinical studies have shown that LAIV is effective in children (31–34) and most effective in those up to age 7 (35). A study comparing LAIV to TIV showed that the former lowered the frequency of disease by 48% compared to the latter (4.2% versus 8.1%) (36). This effect was strongest against A/H1N1 infection (97%) and weakest against influenza B infection (32%). LAIV also protects well against influenza A virus variants (33, 37). The rate of influenza-associated otitis media in small children is lower after vaccination with LAIV than after vaccination with TIV (85% versus 54%) (38).
Children aged 2 years and above tolerate LAIV well. The vaccine sometimes induces a local reaction: about 10% of children vaccinated with LAIV have nasal congestion or coryza in the first ten days after vaccination, while fewer children develop these symptoms after vaccination with TIV or placebo (37). LAIV is not approved for use in children aged 6–23 months, because there is a higher frequency of acute wheezing in this age group from the 7th to the 28th day after the initial vaccination (39).
The optimal use of influenza vaccines
Influenza vaccines are still commonly used without any special attention to product-specific data on their efficacy and tolerability in different age and risk groups. This generic attitude is rooted in the past, a holdover from a previous era in which only high-dose, whole-virus vaccines were used and the clinical profiles of all available products were essentially the same—that is, they all had very high immunogenicity, combined with relatively high reactogeniticity (40). The occurrence of poorly tolerated side effects of whole-virus vaccines in seasonal use led at first to a reduction of their antigen content and then to the development of the better-tolerated split-virus vaccines and subunit vaccines. Markedly better tolerability was associated with markedly lower immunogenicity to the vaccine antigens.
Despite these major differences in product properties, it is commonly assumed that the products available today have exactly the same efficacy as the earlier ones. That this is not the case has been demonstrated by recent clinical studies on the development of so-called mock-up vaccines against viral strains that could cause a pandemic. It is questionable, for example, whether and under what circumstances (in terms of the dosage and number of required partial doses) the currently approved, non-adjuvanted, inactivated split-virus vaccines and subunit vaccines are suitable for the primary immunization of immunologically naive persons. In contrast, the suitability of adjuvanted and live attenuated influenza vaccines for this purpose is well documented. These findings clearly suggest that product specificity should be a major consideration in determining which vaccine is best for patients in the main risk groups (the elderly and the chronically ill) and what the optimal dosage and mode of administration should be.
It follows from the above that influenza vaccines should be selected individually for each target group. The most important conclusion of this review is that none of the currently available influenza vaccines has an identical risk/benefit profile in all age groups and risk groups. The optimal use of influenza vaccines in each age group and risk group is only possible on the basis of an individual risk/benefit analysis in the light of up-to-date scientific knowledge. A reasonable scheme for using the currently approved vaccines (and those now in advanced clinical testing) in various age groups and risk groups is given in Table 2. For some time now, reimbursement of the costs of influenza vaccination in Germany has been restricted to one or a few vaccines; this restriction is clearly an impediment to optimal evidence-based medical practice.
The authors thank PD Dr. M. Pfleiderer (Paul Ehrlich Institute, Langen) for giving us valuable information on the optimal use of influenza vaccines.
Conflict of interest statement
Prof. Wutzler has received payment for serving on advisory boards for AstraZeneca and Sanofi Pasteur as well as lecture honoraria from AstraZeneca, GSK, and Novartis.
Prof. Hardt has received lecture honoraria from Sanofi Pasteur MSD and has received payment for serving on its advisory board. He has also received research support (third-party funding) from the same company.
Prof. Knuf received lecture honoraria and payment for serving on advisory boards from the AstraZeneca, GSK, and Novartis companies until 1 April 2012. He has received research support (third-party funding) from Novartis and reimbursement of travel expenses from AstraZeneca and Novartis.
Prof. Wahle has received lecture honoraria from Sanofi Pasteur MSD and GSK.
Manuscript submitted on 19 October 2012, revised version accepted on 20 September 2013.
Translated from the original German by Ethan Taub, M.D.
Prof. Dr. med. Peter Wutzler
Universitätsklinikum Jena, Institut für Virologie und Antivirale Therapie
Hans-Knöll-Str. 2 (Beutenberg Campus), D-07745 Jena, Germany
@For eReferences please refer to:
Catholic Clinic Mainz, St. Hildegardis Hospital: Prof. Dr. med. Hardt
Department of Child and Adolescent Medicine, Dr. Horst Schmidt Clinic GmbH, Wiesbaden: Prof. Dr. med. Knuf
German Association of General Practitioners, Münster: Prof. Dr. med. Wahle
|1.||Pfleiderer M: Prävention/Impfen. In: Zepp F, Ruf BR (eds.): H1N1-Update 2009: Kompendium Influenza 2009. Wiesbaden: med update 2009.|
|2.||Belshe RB: The need for quadrivalent vaccine against seasonal influenza. Vaccine 2010; 28: 45–53. CrossRef MEDLINE|
|3.||Keitel WA, Atmar RL, Cate TR, et al.: Safety of high doses of influenza vaccine and effect on antibody responses in elderly persons. Arch Intern Med 2006: 166: 1121–7. CrossRef MEDLINE|
|4.||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. CrossRef MEDLINE PubMed Central|
|5.||Chen WH, Cross AS, Edelman R, Sztein MB, Blackwelder WC, Pasetti MF: Antibody and Th1-type cell-mediated immune responses in elderly and young adults immunized with the standard or a high dose influenza vaccine. Vaccine 2011; 29: 2865–73. CrossRef MEDLINE PubMed Central|
|6.||Centers for Disease Control and Prevention: Licensure of a high-dose inactivated influenza vaccine for persons aged > or = 65 years (Fluzone High-Dose) and guidance for use – United States, 2010. MMWR Morb Mortal Wkly Rep 2010; 59: 485–6. MEDLINE|
|7.||Heinonen S, Silvennoinen H, Lehtinen P, Vainionpää R, Ziegler T, Heikkinen: Effectiveness of inactivated influenza vaccine in children aged 9 months to 3 years: an observational cohort study. Lancet Infect Dis 2011; 11: 23–9. CrossRef MEDLINE|
|8.||Song JY, Cheong HJ, Seo YB, et al.: Comparison of the long-term immunogenicity of two pandemic influenza A/H1N1 2009 vaccines, the MF59-adjuvanted and unadjuvanted vaccines, in adults. Clin Vaccine Immunol 2012; 19: 638–41. CrossRef MEDLINE PubMed Central|
|9.||Hatz C, von Sonnenburg F, Casula D, Lattanzi M, Leroux-Roels G: |
A randomized clinical trial to identify the optimal antigen and MF59(®) adjuvant dose of a monovalent A/H1N1 pandemic influenza vaccine in healthy adult and elderly subjects. Vaccine 2012; 30: 70–7. CrossRef MEDLINE
|10.||Podda A: The adjuvanted influenza vaccines with novel adjuvants: experience with the MF59-adjuvanted vaccine. Vaccine 2001; 19: 2673–80. CrossRef MEDLINE|
|11.||Banzhoff A, Nacci P, Podda A: A new MF-59 adjuvanted vaccine enhances the immune response in the elderly with chronic diseases: results from an immunogenicity meta-analysis. Gerontology 2003; 49: 177–84. CrossRef MEDLINE|
|12.||Baldo V, Baldovin T, Floreani A, Carraro AM, Trivello R, Family Medicine Group of Pianiga: MF59-adjuvanted influenza vaccine confers superior immunogenicity in adult subjects (18–60 years of age) with chronic diseases who are at risk of post-influenza complications. Vaccine 2007; 25: 3955–61. CrossRef MEDLINE|
|13.||Del Giudice G, Hilbert AK, Bugarini R, et al.: An MF59-adjuvanted inactivated influenza vaccine containing A/Panama/1999 (H3N2) induced broader serological protection against heterovariant influenza virus strain A/Fujian/2002 than a subunit and a split influenza vaccine. Vaccine 2006; 24: 3063–5. CrossRef MEDLINE|
|14.||Baldo V, Baldovin T, Floreani A, Fragapane E, Trivello R: Response of influenza vaccines against heterovariant influenza virus strains in adults with chronic diseases. J Clin Immunol 2007; 27: 542–7. CrossRef MEDLINE|
|15.||Puig-Barberà J, Diez-Domingo J, Hoyos SP, Varea AB, Vidal DG: Effectiveness of the MF59-adjuvanted influenza vaccine in preventing emergency admissions for pneumonia in the elderly over 64 years of age. Vaccine 2004; 23: 283–9. CrossRef MEDLINE|
|16.||Puig-Barberà J, Díez-Domingo J, Varea AB, et al.: Effectiveness of MF59-adjuvanted subunit influenza vaccine in preventing hospitalisations for cardiovascular disease, cerebrovascular disease and pneumonia in the elderly. Vaccine 2007; 25: 7313–21. CrossRef MEDLINE|
|17.||Mannino S, Villa M, Apolone G, et al.: Effectiveness of adjuvanted influenza vaccination in elderly subjects in Northern Italy. Am J Epidemiol 2012; 176: 527–33. CrossRef MEDLINE PubMed Central|
|18.||Vesikari T, Pellegrini M, Karvonen A, et al.: Enhanced immunogenicity of seasonal influenza vaccines in young children using MF59 adjuvant. Pediatr Infect Dis J 2009; 28: 563–71. CrossRef MEDLINE|
|19.||Vesikari T, Knuf M, Wutzler P, et al.: Oil-in-water emulsion adjuvant with influenza vaccine in young children. N Engl J Med 2011; 365: 1406–16. CrossRef MEDLINE|
|20.||Huckriede A, Bungener L, Stegmann T, et al.: The virosome concept for influenza vaccines. Vaccine 2005; 23: 26–38. CrossRef MEDLINE|
|21.||Conne P, Gauthey L, Vernet P, et al.: Immunogenicity of trivalent subunit versus virosome-formulated influenza vaccines in geriatric patients. Vaccine 1997; 15: 1675–9. CrossRef MEDLINE|
|22.||de Bruijn IA, Nauta J, Gerez L, Palache A: Virosomal influenza vaccine: a safe and effective influenza vaccine with high efficacy in elderly and subjects with low pre-vaccination antibody titers. Virus Res 2004; 103: 139–45. CrossRef MEDLINE|
|23.||Herzog C, Metcalfe IC, Schaad UB: Virosome influenza vaccine in children. Vaccine 2002; 20: 24–8. CrossRef MEDLINE|
|24.||de Bruijn IA, Nauta J, Gerez L, Palache AM: The virosomal influenza vaccine Invivac: immunogenicity and tolerability compared to an adjuvanted influenza vaccine (Fluad) in elderly subjects. Vaccine 2006; 24: 6629–31. CrossRef MEDLINE|
|25.||Baldo V, Baldovin T, Pellegrini M, et al.: Immunogenicity of three different influenza vaccines against homologous and heterologous strains in nursing home elderly residents. Clin Dev Immunol 2010: 517198. MEDLINE PubMed Central|
|26.||Salleras L, Domínguez A, Pumarola T, et al.: Effectiveness of virosomal subunit influenza vaccine in preventing influenza-related illnesses and its social and economic consequences in children aged 3–14 years: a prospective cohort study. Vaccine 2006; 24: 6638–42. CrossRef MEDLINE|
|27.||van Damme P, Arnou R, Kafeja F, et al.: Evaluation of non-inferiority of intradermal versus adjuvanted seasonal influenza vaccine using two serological techniques: a randomised comparative study. BMC Infect Dis 2010; 10: 134. CrossRef MEDLINE PubMed Central|
|28.||Ansaldi F, Canepa P, Ceravolo A, et al.: Intanza(®) 15 mcg intradermal influenza vaccine elicits cross-reactive antibody responses against heterologous A(H3N2) influenza viruses. Vaccine 2012; 30: 2908–13. CrossRef MEDLINE|
|29.||Belshe RB, Gruber WC, Mendelman PM, et al.: Correlates of immune protection induced by live, attenuated, cold-adapted, trivalent, intranasal influenza virus vaccine. J Infect Dis 2000; 181: 1133–7. CrossRef MEDLINE|
|30.||Hoft DF, Babusis E, Worku S, et al.: Live and inactivated influenza vaccines induce similar humoral responses, but only live vaccines induce diverse T-cell responses in young children. J Infect Dis 2011; 204: 845–53. CrossRef MEDLINE PubMed Central|
|31.||Ashkenazi S, Vertruyen A, Arístegui J, et al.: CAIV-T Study Group. Superior relative efficacy of live attenuated influenza vaccine compared with inactivated influenza vaccine in young children with recurrent respiratory tract infections. Pediatr Infect Dis J 2006; 118: 2298–312. MEDLINE|
|32.||Fleming DM, Crovari P, Wahn U, et al.: Comparison of the efficacy and safety of live attenuated cold-adapted influenza vaccine, trivalent, with trivalent inactivated influenza virus vaccine in children and adolescents with asthma. Pediatr Infect Dis J 2006; 25: 860–9. CrossRef MEDLINE|
|33.||Belshe RB, Edwards KM, Vesikari, et al.: Live attenuated versus inactivated influenza vaccine in infants and young children. N Engl J Med 2007; 356: 685–96. CrossRef MEDLINE|
|34.||Belshe RB, Toback SL, Yi T, Ambrose CS: Efficacy of live attenuated influenza vaccine in children 6 months to 17 years of age. Influenza Other Respi Viruses 2010; 4: 141–5. CrossRef MEDLINE|
|35.||Osterholm MT, Kelley NS, Sommer A, Belongia EA: Efficacy and effectiveness of influenza vaccines: a systematic review and meta-analysis. Lancet Infect Dis 2012; 12: 36–44. CrossRef MEDLINE|
|36.||Ambrose CS, Wu X, Knuf M, Wutzler P: The efficacy of intranasal live attenuated influenza vaccine in children 2 through 17 years of age: A meta-analysis of 8 randomized controlled studies. Vaccine 2012; 30: 886–92. CrossRef MEDLINE|
|37.||Belshe RB, Gruber WC, Mendelman PM, et al.: Efficacy of vaccination with live attenuated, cold-adapted, trivalent, intranasal influenza virus vaccine against a variant (A/Sydney) not contained in the vaccine. J Pediatr 2000; 136: 168–75. CrossRef MEDLINE|
|38.||Block SL, Heikkinen T, Toback SL, Zheng W, Ambrose CS: The efficacy of live attenuated influenza vaccine against influenza-associated acute otitis media in children. Pediatr Infect Dis J 2011; 30: 203–7. CrossRef MEDLINE|
|39.||Belshe RB, Ambrose CS, Yi T: Safety and efficacy of live attenuated influenza vaccine in children 2–7 years of age. Vaccine 2008; 26: 10–6. CrossRef MEDLINE|
|40.||Hilleman MR: Realities and enigmas of human viral influenza: pathogenesis, epidemiology and control. Vaccine 2002; 20: 3068–87. CrossRef MEDLINE|
|e1.||Robert Koch-Institut: Empfehlungen der Ständigen Impfkommission (STIKO) am Robert Koch-Institut/Stand: Juli 2012. Epidem Bull 2012/30 .|
|e2.||Beyer WE, Palache AM, Osterhaus AD: Comparison of serology and reactogenicity between influenza subunit vaccines and whole virus or split vaccines: A review and meta-analysis of the literature. Clin Drug Investig 1998; 15: 1–12. CrossRef MEDLINE|
|e3.||Anonymus: Erster Quadrivalenter Grippeimpfstoff. Dtsch Arztebl 2013; 110(12): A 569. (Pharmainformation) VOLLTEXT|
|e4.||Uphoff H, Hauri AM, Schweiger B, et al.: Zur Schätzung der Schutzwirkung der Influenzaimpfung aus Surveillancedaten. Bundesgesundheitsblatt Gesundheitsforschung Gesundheitsschutz 2006; 49: 287–95. CrossRef MEDLINE|
|e5.||Jefferson T, Rivetti A, Harnden A, Di Pietrantonj C, Demicheli V: Vaccines for preventing influenza in healthy children. Cochrane Database Syst Rev 2008; 2: CD004879. MEDLINE|
|e6.||Michiels B, Govaerts F, Remmen R, Vermeire E, Coenen S: A systematic review of the evidence on the effectiveness and risks of inactivated influenza vaccines in different target groups. Vaccine 2011; 29: 9159–70. CrossRef MEDLINE|
|e7.||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. MEDLINE /td>|
|e8.||Jefferson T, Di Pietrantonj C, Al-Ansary LA, Ferroni E, Thorning S, Thomas RE: Vaccines for preventing influenza in the elderly. Cochrane Database Syst Rev 2010; 2: CD004876. MEDLINE|
|e9.||DiazGranados CA, Dunning AJ, Jordanov E, Landolfi V, Denis M, Talbot HK: High-dose trivalent influenza vaccine compared to standard dose vaccine in elderly adults: safety, immunogenicity and relative efficacy during the 2009–2010 season. Vaccine 2013; 31: 861–6. CrossRef MEDLINE|
|e10.||Leroux-Roels I, Borkowski A, Vanwolleghem T, et al.: Antigen sparing and cross-reactive immunity with an adjuvanted rH5N1 prototype pandemic influenza vaccine: a randomised controlled trial. Lancet 2007; 370: 580–9 CrossRef MEDLINE|
|e11.||Schwarz TF, Horacek T, Knuf M, et al.: Single dose vaccination with AS03-adjuvanted H5N1 vaccines in a randomized trial induces strong and broad immune responsiveness to booster vaccination in adults. Vaccine 2009; 27: 6284–90. CrossRef MEDLINE|
|e12.||Nohynek H, Jokinen J, Partinen M, et al.: AS03 adjuvanted AH1N1 vaccine associated with an abrupt increase in the incidence of childhood narcolepsy in Finland. PLoS One 2012; 7: e33536. MEDLINE|
|e13.||Partinen M, Saarenpää-Heikkilä O, Ilveskoski I, et al.:Increased incidence and clinical picture of childhood narcolepsy following the 2009 H1N1 pandemic vaccination campaign in Finland. PLoS ONE 2012; 7: e33723. MEDLINE|
|e14.||Miller E, Andrews N, Stellitano L, et al.: Risk of narcolepsy in children and young people receiving AS03 adjuvanted pandemic A/H1N1 2009 influenza vaccine: retrospective analysis. BMJ 2013; 346: 794. CrossRef MEDLINE|
|e15.||Tsai TF, Crucitti A, Nacci P, et al.: Explorations of clinical trials and pharmacovigilance databases of MF59®-adjuvanted influenza vaccines for associated cases of narcolepsy. Scand J Infect Dis 2011; 43: 702–6. MEDLINE|
|e16.||Choe YJ, Bae GR, Lee DH: No association between influenza A(H1N1)pdm09 vaccination and narcolepsy in South Korea: an ecological study. Vaccine 2012; 30: 7439–42. CrossRef MEDLINE|
|e17.||Esposito S, Marchisio P, Montinaro V, et al.:The immunogenicity and safety of a single 0.5 mL dose of virosomal subunit influenza vaccine administered to unprimed children aged ≥ 6 to <36 months: data from a randomized, Phase III study. Vaccine 2012; 30: 7005–12. CrossRef MEDLINE|
|e18.||Nicolas JF, Guy B: Intradermal, epidermal and transcutaneous vaccination: from immunology to clinical practice. Expert Rev Vaccines 2008; 7: 1201–14. CrossRef MEDLINE|
|e19.||Lambert PH, Laurent PE: Intradermal vaccine delivery: will new delivery systems transform vaccine administration? Vaccine 2008; 26: 3197–208. CrossRef MEDLINE|
|e20.||Leroux-Roels I, Vets E, Freese R, et al.: Seasonal influenza vaccine delivered by intradermal microinjection: a randomized controlled safety and immunogenicity trial in adults. Vaccine 2008; 26: 6614–9. CrossRef MEDLINE|
|e21.||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. CrossRef MEDLINE|
|e22.||Murphy BR, Coelingh K: Principles underlying the development and use of live attenuated cold-adapted influenza A and B virus vaccines. Viral Immunol 2002; 15: 295–323. CrossRef MEDLINE|
|e23.||Jin H, Lu B, Zhou H, et al.: Multiple amino acid residues confer temperature sensitivity to human influenza virus vaccine strains (FluMist) derived from cold-adapted A/Ann Arbor/6/60. Virology 2003; 306: 18–24. CrossRef MEDLINE|
|e24.||Vesikari T, Karvonen A, Korhonen T, et al.: A randomized, double-blind study of the safety, transmissibility and phenotypic and genotypic stability of cold-adapted influenza virus vaccine. Pediatr Infect Dis J 2006; 25: 590–5. CrossRef MEDLINE|
|e25.||Ambrose CS, Wu X, Jones T, Mallory RM: The role of nasal IgA |
in children vaccinated with live attenuated influenza vaccine.
Vaccine 2012; 30: 6794–801. CrossRef MEDLINE