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Vaccine 27 (2009) 4381–4387

Contents lists available at ScienceDirect

Vaccine

journa l homepage: www.e lsev ier .com/ locate /vacc ine

eview

leven years of Inflexal® V—a virosomal adjuvanted influenza vaccine

hristian Herzog ∗, Katharina Hartmann, Valérie Künzi, Oliver Kürsteiner, Robert Mischler,edvika Lazar1, Reinhard Glück

erna Biotech AG, Rehhagstrasse 79, 3018 Berne, Switzerland

r t i c l e i n f o

rticle history:eceived 16 December 2008eceived in revised form 23 April 2009

a b s t r a c t

Since the introduction to the Swiss market in 1997, Crucell (former Berna Biotech Ltd.), has sold over41 million doses worldwide of the virosomal adjuvanted influenza vaccine, Inflexal® V. Since 1992, 29company sponsored clinical studies investigating the efficacy and safety of Inflexal® V have been com-

ccepted 10 May 2009vailable online 29 May 2009

eywords:nfluenza vaccineirosomes

pleted in which 3920 subjects participated. During its decade on the market, Inflexal® V has shown anexcellent tolerability profile due to its biocompatibility and purity. The vaccine contains no thiomersal orformaldehyde and its purity is reflected in the low ovalbumin content. By mimicking natural infection,the vaccine is highly efficacious. Inflexal® V is the only adjuvanted influenza vaccine licensed for all agegroups and shows a good immunogenicity in both healthy and immunocompromised elderly, adults and

®

djuvant

nflexal® V

children. This review presents and discusses the experience with Inflexal V during the past decade.© 2009 Elsevier Ltd. All rights reserved.

ontents

1. Influenza viruses and epidemics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 43812. Impact of influenza vaccination on health economics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 43823. Virosomes as an adjuvant system . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 43824. Immunogenicity of Inflexal® V . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 43825. Safety of Inflexal® V . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 43836. Clinical experience with Inflexal® V . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4383

6.1. Children . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 43846.2. Adults . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4385

6.3. The elderly . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4385

. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4385

. . . .. . . . .

enome segments between viruses [3]. Antigenic drift is the grad-al evolution of viral strains, due to frequent mutations of theurface glycoproteins hemagglutinin and neuraminidase [4,5]. Con-equently, infecting viruses can no longer be neutralized effectively

∗ Corresponding author. Tel.: +41 980 62 51; fax: +41 980 67 72.E-mail address: christian.herzog@crucell.ch (C. Herzog).

1 Current address: Kenta Biotech AG, Rehhagstrasse 79, 3018 Berne, Switzerland.

264-410X/$ – see front matter © 2009 Elsevier Ltd. All rights reserved.oi:10.1016/j.vaccine.2009.05.029

. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4386. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4386

by the antibodies raised against previously circulating strains,allowing the virus to spread rapidly among the population [6,7].In case of antigenic shift, an influenza virus emerges to which thehuman population is immunologically naïve, resulting in devastat-ing pandemics [8]. Outbreaks of influenza are therefore an ongoingpublic health threat and require global pandemic preparedness.

Recent findings from an extensive research collaboration on pre-diction of the evolution of influenza viruses suggest that seasonalinfluenza strains constantly evolve in overlapping epidemics in Asiabefore sweeping the rest of the world every year [9]. In Europe, theaverage length of an influenza season is 12–19 weeks, and during

7. Conclusion. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .Acknowledgement . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

1. Influenza viruses and epidemics

Influenza is one of the most important respiratory infections ofhumans, responsible for 300,000–500,000 annual deaths world-wide [1,2]. The influenza viruses are capable of genetic variation,both by continuous, gradual mutation and by reassortment of

the last 7 years there was a west–east and south–north peak ofactivity [10]. Several hypotheses exist why influenza viruses tendto strike in cold weather. Recently, it was suggested that lipid order-ing in the virus envelope may contribute to virus stability at lower

4 cine 27

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emperatures which is important for airborne transmission [11].his theory does, however, not explain influenza epidemics in theropical areas and other factors are likely to come into play.

In order to deal with the seasonal disease burden caused bynfluenza, the World Health Organization (WHO) established thelobal Influenza Network in 1952. The network involves a numberf collaborative centres around the world and is able to monitorntigenic drift and emerging virus strains. Based on these data,HO recommends the content of the influenza vaccine for the

ubsequent influenza season [12].

. Impact of influenza vaccination on health economics

Louis Pasteur, who developed the first vaccine against rabies,stablished in 1881 the basic paradigm for vaccine development,hich included the isolation, inactivation and injection of the

ausative pathogen. These basic principles have guided vaccineevelopment during the twentieth century [13]. The use of wholeirus influenza vaccines has discontinued, primarily due to theigh level of reactogenicity associated. Influenza vaccines on thearket are either split virus or subunit inactivated vaccines, com-

osed of two influenza A strains and one B strain. In addition to thenactivated vaccines, live attenuated influenza vaccines using cold-dapted strains for intranasal administration have been developed14].

Currently licensed influenza vaccines are safe and highly effec-ive in prevention of disease. The efficacy of inactivated influenzaaccine in healthy adults varies between 70 and 90% in influenzaeasons with a good match between circulating strains and thetrains included in the vaccine. In contrast, the efficacy of currentnactivated influenza vaccines in the elderly is approximately 60%15]. In addition to providing substantial health benefits, vaccina-ion may also be associated with significant economic benefits.ecent reviews of the cost-effectiveness of influenza vaccinationupport immunisation of children and the elderly, as well as work-ng adults [16,17]. Health economic studies involving Inflexal® V areisted in Table 1.

National recommendations for influenza vaccination vary, par-icularly for children.

In the United States, the recommended age range of children

or annual influenza immunisation includes all healthy childrenged 6 months or above [18,19]. The preschool-aged cohort rep-esents an important potential source of transmission of influenzao household members and others in the community. Influenza vac-ination is also recommended by the WHO for healthy children

able 1ealth economic studies involving Inflexal® V.

uthor Study type Subject age No. receiv

asparini et al. (2001) Cost benefit analysiscomparison

>65 years 100

sposito et al. (2006) Randomised study comparingvaccinated and non-vaccinatedsubjects

2–5 years 202

alleras et al. (2006) Cohort study comparingvaccinated and non-vaccinatedsubjects

3–14 years 966

archetti et al. (2007) Markov model simulatedcohort study

6–60 months 3 millionb

avas et al. (2007) Cost-effectiveness compared tocurrent non-routinevaccination policy

3–14 years 1000

a Calculation based on a simulation using a cohort of 100 subjects.b Simulated cohort over 5 influenza seasons.c Cost benefit to Italian society per influenza season.d Theoretical cohort.

(2009) 4381–4387

aged 6–23 months and for all children aged 6 months or above withchronic conditions [20]. Influenza vaccination of children is not arecent approach. In Japan, influenza vaccination of children wasmandatory from 1977 to 1987, resulting in a decrease of the excessmortality rate among older persons [21]. Several studies have sug-gested that universal vaccination of children against influenza couldhave health benefits and be cost-saving to the whole community[22–25].

3. Virosomes as an adjuvant system

Novel and increasingly safer vaccines use well-characterizedantigens. However, these antigens are often too small to be highlyimmunogenic and would benefit from administration of a suitableadjuvant [26–28].

Virosomes demonstrate the characteristics of an adjuvantsystem and are biodegradable, non-toxic and do not induce anti-bodies against themselves [29]. The virosomes are reconstitutedinfluenza virus envelopes devoid of inner core and genetic infor-mation. During the production process, the influenza virus surfaceantigens neuraminidase and hemagglutinin are integrated intophosphatidylcholine bilayer liposomes, yielding unilamellar viro-somes with an average diameter of 150 nm [30]. The particulatestructure and the function of the surface hemagglutinin protein ofbinding to the cell receptor, mediating pH-dependent fusion withendosomes and stimulating the immune system are responsible forthe adjuvant function (Fig. 1) [31]. Virosomal adjuvant system allowantigen presentation in the context of both major histocompabilitycomplex (MHC) I and MHC II and in this way, virosomes are able toinduce both B- and T-cell responses [31–35].

The composition of Inflexal® V consists of a mixture of threemonovalent virosome pools, each formed with one influenzastrain’s specific hemagglutinin and neuraminidase glycoproteins[30,36]. The influenza strains are chosen according to the annualrecommendations of the WHO and the European Medicines Agency(EMEA) [12]. Inflexal® V is approved as a vaccine for immunisa-tion against influenza in 38 countries, and is the only adjuvantedinfluenza vaccine licensed for all age groups. Inflexal® V is also mar-keted under the trade name InfectoVac® Flu in Germany, as Isiflu®

V in Italy and as Viroflu® in the United Kingdom.

4. Immunogenicity of Inflexal® V

Due to the virosomal technology, Inflexal® V is highly effica-cious by mimicking natural viral infection. The use of virosomes to

ing Inflexal® V Outcome Cost benefit Ref.

a Inflexal® V more cost-effectivethan comparator

∼D 15 per subject [64]

Net savings in vaccinated group D 131.43 per subject [22]

Reduced illness incidence,school absenteeism, antibioticuse and parental work loss invaccinated group.

Not calculated [23]

Estimated increase in quality oflife for children and theirfamilies

D 12.6 millionc [65]

d Substantial socioeconomic andhealth benefits

D 7.59 per child [24]

C. Herzog et al. / Vaccine 27 (2009) 4381–4387 4383

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ig. 1. Virosomes are reconstituted influenza virus envelopes devoid of inner corehe cell entry and membrane-fusion properties that allow presentation to the MHC

eliver influenza antigens stimulates a strong immune response ofmmunocompetent cells [31,35].

For influenza vaccines to be accepted throughout the Europeannion (EU), annual clinical trials must demonstrate immunogenic-

ty and safety in at least 50 subjects between 18 and 60 years andn 50 subjects over 60 years. Vaccines must fulfil at least one ofhe three EMEA criteria (Table 2) for each influenza strain con-ained in the vaccine for both age groups [37]. In addition, the EMEAtates that for EU acceptance, an influenza vaccine must complyith European Pharmacopoeia requirements and contain at least

5 �g of A/H1N1-, A/H3N2-, and B-virus hemagglutinin antigenser dose. In the annual re-licensing trials, Inflexal® V has demon-trated an excellent humoral immune response according to theMEA immunogenicity criteria regarding seroconversion, geomet-ic mean titer (GMT) fold increase and seroprotection and has methe EMEA efficacy criteria for annual re-licensing in both age groupsvery year from 1997 onwards in a total of approximately 1100ubjects (data not shown). In addition, Inflexal® V proofed to bemmunogenic and safe in various pre- and post-licensing clinicalrials performed in all age groups of healthy, as well as in immuno-ompromised subjects (Sections 5 and 6).

. Safety of Inflexal® V

The purity and biocompatible nature of the virosomal con-tituents result in a significantly reduced rate of unwanted sideffects as confirmed in a clinical study comparing a commerciallyvailable non-virosomal adjuvanted vaccine with Inflexal® V [38].

able 2MEA criteria for assessment of influenza vaccine immunogenicity in serum.

18–60 years >60 years

eroconversion (SC) rate % >40 >30eroprotection rate (SP) % >70 >60MT fold increase >2.5 >2.0

C = ≥4-fold increase and achievement of ≥1:40 in HI antibody titer, SP = HI anti-ody titer ≥1:40 and GMT = geometric mean titer. To meet the EMEA re-licensingequirements, at least one of the three parameters has to be met for each strain.

netic information. By mimicking native influenza viruses, the virosomes maintainI and class II pathway.

Inflexal® V contains no thiomersal or formaldehyde and is com-pletely biodegradable. The purity of the vaccine is reflected in itslow ovalbumin content, an indication of the amount of residualegg protein. In a survey of several influenza vaccines, Inflexal® Vcontained less than 10 ng of ovalbumin per dose, satisfying theEuropean Pharmacopoeia requirements for virosomal influenzavaccines by far [39]. In contrast, conventional influenza vaccines arepermitted to contain up to 1 �g ovalbumin per dose. An influenzavaccine with this low ovalbumin content is expected to induceless allergic reactions. This hypothesis is supported by data gath-ered in asthmatic children with mild to severe egg allergy showingthat the administration of a single dose of Inflexal® V was safeand well tolerated [40]. Clinical trials have demonstrated a trendtowards an improved safety profile in terms of systemic and localadverse events after immunisation with Inflexal® V comparedwith administration of whole virus and subunit influenza vaccines[38,41,42]. Published clinical trials involving Inflexal® V are listedin Tables 3 and 4.

Since the introduction to the Swiss market in 1997, more than 41million doses of Inflexal® V have been sold worldwide. During thisperiod, 695 spontaneously reported adverse drug reactions (ADRs)were reported in 364 cases for 41.1 million doses distributed. Thisresults in a spontaneous reporting rate of 0.89 cases per 100,000immunisations [43]. Of the 364 subjects reporting spontaneousADRs, 151 subjects were elderly (>60 years), 36 were children (<15years), and eight were adolescents (15 to <18 years).

6. Clinical experience with Inflexal® V

Since 1992, 29 company sponsored clinical studies investigatingthe efficacy and safety of Inflexal® V have been completed in which3920 subjects participated and 2205 subjects received the final for-mulation of Inflexal® V. Of these, 906 were adults (18–60 years),

948 were elderly (>60 years), and 351 were children or adolescents(0.5 to <18 years). Two post-marketing surveillance studies includ-ing 1,127 adults and adolescents (>16 years) and 405 children (≥6months to ≤6 years), respectively have been conducted. The earlyclinical trials in healthy adults, the elderly and children at risk havebeen reviewed by Holm and Goa [44].

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.1. Children

Influenza epidemics are known to be a significant sourcef morbidity and mortality among young children, the elderly,nd subjects with underlying chronic diseases [45–47]. In veryoung children, influenza is a potentially serious disease dueo low or lacking background immunity [48,49]. There are cur-ently no EMEA immunogenicity guidelines for children. In aontrolled study of 453 healthy children aged 6–71 months,nflexal® V fulfilled the EMEA criteria given for adults for sero-onversion, seroprotection and increases in GMT for all threenfluenza strains. The vaccine was found to be safe and wellolerated. Furthermore, Inflexal® V showed significantly greatermmunogenicity in unprimed children over the comparator splitnfluenza vaccine used in the study for the A/H1N1 strain50].

Children with HIV are particularly susceptible to influenza-elated complications. In order to evaluate the immunogenicitynd safety of influenza vaccination, children with HIV were immu-

ised with Inflexal® V. Although the vaccine was, as expected, less

mmunogenic in children infected with HIV than in healthy sub-ects, it was immunogenic in most cases and the results overall wereomparable with the results from studies in healthy children [51].

able 3ublished comparator-controlled studies involving Inflexal® V.

uthor Age N Study design Title

hildrenSchaad et al. (2000) ≤6 years, >6 years 64 open, mc, r Comparison o

safety of a viroinfluenza vaccwith cystic fib

Kanra et al. (2004) 6–71 months 453 open, mc, r Comparison otolerability ofand a split infl

dultsde Bernardi di Valserra et

al. (2002)23–100 years 88 open, mc, r An open-label

immunogenicintranasal andformulations ovaccine in hea

lderlyGlück et al. (1994) 63–102 years 126 open, r Immunogenic

influenza vaccConne et al. (1997) 60–98 years 76 db, r Immunogenic

versus virosomvaccines in ge

Baldo et al. (1999) 56–99 years 163 db, r Vaccination agelderly. Expervaccines

Baldo et al. (2001) 65–100 years 300 db, r Comparison ovaccines in ins

Mensi et al. (2001) 65–87 years 51 open, r Humoral andresponse to avaccine in hea

Pregliasco et al. (2001) >64 years 635 ob, mc, r Immunogeniccommercial ininstitutionaliz

Ruf et al. (2004) ≥60 years 827 open, mc, r Open, randomthe immunogeof an influenzMF59-adjuvana virosome-baelderly

Zamparo et al. (2004) Mean 76 years 533 db, mc, r Comparison oimmunogenicinfluenza vacc

de Bruijn et al. (2005)a ≥60 years 287 review Clinical expervirosomal infl

= subjects enrolled, db = double-blind, ob = observed blind, mc = multi-centre and r = rana Review article on 3 studies involving subjects aged >18 years, 287 of which were “eld

(2009) 4381–4387

Vaccination did not induce viral replication or T-cell activation, thussupporting the use of Inflexal® V in such patients [52,53].

In another study of children and adolescents with cystic fibrosis,Inflexal® V was found to be safe and induced an efficient immuneresponse against all three viral strains in both children and adoles-cents [54].

A prospective study was conducted to evaluate long-termimmunogenicity of Inflexal® V in children with asthma. In unvac-cinated children, vaccination with a single dose of Inflexal® V waseffective and well tolerated. However, while immune response andpersistence were excellent in children with pre-existing antibodies,the immune parameters were lower 6 months after vaccination inchildren naïve for the antigens, but still fulfilling the EMEA require-ments for re-licensing of influenza vaccines [55].

Data assessing the safety of trivalent inactivated influenza vac-cines in children are limited. Analysis of adverse events reported tothe Vaccine Adverse Event Reporting System (VAERS) after vaccina-tion of children aged <2 years with trivalent inactivated influenzavaccine, alone or in combination with other vaccines, showed

that relatively few adverse events were reported between 1990and 2003 [56]. To better address the safety of administration ofInflexal® V to children, a post marketing study was performedincluding 405 children aged ≥6 months to ≤6 years. The vaccine

Comparator Ref.

f immunogenicity andsome with subunitine in pediatric patientsrosis

Subunit (Influvac®) [54]

f immunogenicity anda virosome-adjuvanteduenza vaccine in children

Split (Fluarix®) [50]

comparison of theity and tolerability ofintramuscularf virosomal influenza

lthy adults

Virosome (NasalFlu®) [66]

ity of new virosomeine in elderly people

Whole (Inflexal®), subunit (Influvac®) [42]

ity of trivalent subunite-formulated influenza

riatric patients

Subunit (Influvac®) [41]

ainst influenza in theience with adjuvant

Subunit (Fluad®) [67]

f three different influenzatitutional elderly

Subunit (Fluad®), split (Mutagrip®) [68]

cell-mediated immunevirosomal influenzalthy elderly

Whole (Inflexal®) [69]

ity and safety of threefluenza vaccines ined elderly

Whole (Inflexal®), subunit (Fluad®) [70]

ised study to comparenicity and reactogenicity

a split vaccine with anted subunit vaccine andsed subunit vaccine in

Split (Fluarix®), subunit (Fluad®) [63]

f the safety andity of two adjuvantedines in elderly subjects

Subunit (Fluad®) [38]

ience with inactivated,uenza vaccine

Virosome (Influvac Plus®, Invivac®), subunit(Influvac®), split (Vaxigrip®)

[62]

domised.erly” (aged ≥60 years).

C. Herzog et al. / Vaccine 27 (2009) 4381–4387 4385

Table 4Published uncontrolled studies involving Inflexal® V.

Author Age N Title Ref.

ChildrenHerzog et al. (2002)a 1–12 years 200 Virosome influenza vaccine in children [71]Zuccotti et al. (2002) 2–17 years 23 Immunogenicity and safety of a virosomal influenza vaccine in HIV

infected children[53]

Zuccotti et al. (2004) 2–17 years 23 Immunogenicity and tolerability of a trivalent virosomal influenzavaccine in a cohort of HIV-infected children

[51]

Tanzi et al. (2006) Mean 10.3 years 29 Immunogenicity and effect of a virosomal influenza vaccine on viralreplication and T-cell activation in HIV-infected children receivinghighly active antiretroviral therapy

[52]

Zuccotti et al. (2007) 3–9 years 106 Long-term immunogenicity of a virosomal subunit inactivatedinfluenza vaccine in children with asthma

[55]

Esposito et al. (2008) Mean 6.2 years 88 Safe administration of an inactivated virosomal adjuvanted influenzavaccine in asthmatic children with egg allergy

[40]

Künzi et al. (2009) 6 months–6 years 405 Safe vaccination of children with a virosomal adjuvanted influenzavaccine

[57]

Vigano et al. (2008) Median 11.9 years 38 Humoral and cellular response to influenza vaccine in HIV-infectedchildren with full viroimmunologic response to antiretroviral therapy

[72]

AdultsAmendola et al. (2001) 18–57 years 409 Influenza vaccination of HIV-1-positive and HIV-1-negative former

intravenous drug users[58]

Gaeta et al. (2002) Mean 62.6 yearsb 28 Immunogenicity and safety of an adjuvanted influenza vaccine inpatients with decompensated cirrhosis

[59]

Zanetti et al. (2002)c NA NA Safety and immunogenicity of influenza vaccination in individualsinfected with HIV

[73]

ElderlyPregliasco et al. (2002)d – – Protective efficacy of Inflexal® V in elderly [74]Consonni et al. (2004) 65–94 years 374 Tolerability and efficacy of anti-influenza vaccination alone and

associated with antipneumococcal vaccination in an elderlyambulatory population and adherence to the vaccination campaign

[75]

Frech et al. (2005) 18–>60 years 166 Improved immune responses to influenza vaccination in the elderlyusing an immunostimulant patch

[76]

a

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6

ec(wpnsaibiwipstbwi

6

cn

Cumulative data from 4 studies.b Mean age of study group. Mean age of control group = 59.5 years.c Review of 2 studiesd Conference proceedings, age range and number enrolled not available.

as found to be safe, well tolerated and widely accepted by parents57].

.2. Adults

The immunogenicity and safety of Inflexal® V in adults and thelderly is monitored annually in the re-licensing trials. The vac-ine is highly immunogenic and well tolerated in healthy adultsSection 4). In a study of 409 former intravenous drug users, ofhich 72 subjects were seropositive for HIV-1 antibodies [58], theercentage of subjects with protective antibody titers increased sig-ificantly after vaccination with Inflexal® V, also in HIV-1 infectedubjects. Immunisation did not activate the replication of HIV-1, andlthough the immune response to vaccination was lower in compar-son to immunocompetent individuals, influenza vaccination mayenefit HIV-1 infected persons. In another study, the immunogenic-

ty and safety of Inflexal® V in 20 patients (mean age 62.6 years)ith decompensated cirrhosis due to chronic hepatitis B or C virus

nfections was evaluated [59]. One month after immunisation, theercentage of subjects who seroconverted was 75% for the A/H1N1train, 80% for the A/H3N2 strain and 85% for the B strain. In addi-ion, the GMTs were significantly higher compared to baseline inoth groups of vaccinees. The vaccine was also found to be safe,ith five patients reporting mild erythema and swelling at the

noculation site.

.3. The elderly

The elderly are among the groups at highest risk for the seriousomplications of influenza such as secondary bacterial pneumo-ia and exacerbations of underlying chronic medical conditions.

Vaccination of the elderly presents a number of challenges relatedto decreased immune responses with increasing age. Immunose-nescence seems to be primarily related to loss of naïve T cells,diminishing T-cell activity, and thymic involution, thus requiringnovel vaccine candidates to induce both cytotoxic T-cell activity aswell as antibody response [60]. Since virosomes have the capacityto induce the cellular immune response in addition to antibodies,virosomal adjuvanted vaccines appear to be a suitable candidate foran improved vaccine in the elderly [61,62].

Safety and superior immunogenicity of Inflexal® V were demon-strated in a randomised trial involving 126 elderly nursing homeresidents aged 63–102 [42]. In another controlled study where 76elderly subjects were enrolled, Inflexal® V was found to possess sig-nificantly enhanced immunogenicity for two of the three vaccinestrains [41]. Its greatest benefit was, however, found to be in sub-jects who possessed non-protective antibody levels at baseline. Asthe vaccine technology has improved, the immunogenicity of mod-ern vaccines is in general comparable, and more attention must begiven to reactogenicity. The safety profile of Inflexal® V in a double-blind, randomised, multi-centre study of 533 elderly subjects wasfound to be significantly better than the comparator using MF59 asan adjuvant regarding pain, systemic reactions and additional med-ication to treat vaccine-related AEs [38]. Similar results were foundin a controlled study involving 840 subjects aged 60 years or older[63].

7. Conclusion

Inflexal® V is the only virosomal adjuvanted influenza vaccinelicensed for all age groups. During its 11 years on the market,Inflexal® V has shown an excellent tolerability profile due to its

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iocompatibility and purity. The vaccine contains no thiomersal orormaldehyde and very low levels of ovalbumin. It is completelyiodegradable and highly efficacious by mimicking natural infec-ion. Inflexal® V has a good immunogenicity in both healthy andmmunocompromised elderly, adults and children.

cknowledgement

We thank Marie Lovoll for her contribution in writing theanuscript.

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