Drug Evaluation Expert Influvac, a trivalent inactivated Opinion subunit influenza vaccine Gian Vincenzo Zuccotti' & Valentina Fabiano nis’ degli Sri dl Milan, Lag Sacco Hora, Daparonent of Pada, aly 1. Introduction 2 Overview of sessonal influenza ‘Importance of the field: Influenza represents a major sanitary and socio aes economic burden and vaccination is universally considered the most effective strategy for preventing the disease and its complications. Traditional influ tenza vaccines have been on the market since the late 1940s, with million of doses administered annually worldwide, and demonstrated a substantial efficacy and safety ‘Areas covered in this review: The trivalent inactivated subunit vaccine has been available for more than 25 years and has been studied in healthy chil dren, adults and the elderly and in people affected by underlying chronic medical conditions. We describe vaccine technology focusing on subunit Expert opinion vaccine production procedures and mode of action’ and provide updated information on efficacy and safety available data, What the reader will gain: A review of efficacy and safety data in healthy subjects and in high risk populations from major sponsor- and investigator-driven studies. Take home message: The vaccine showed 9 good immunogenicity and a favorable safety profile in all target groups. In the panorama of actually avail able influenza vaccines, trivalent inactivated subunit vaccine represents a ‘well-established tool for preventing flu and the associated complications 3. The trivalent inactivated subunit formulation: composition and mechanisms of immune response 4 Influvac: efficacy and safety studies Conclusions Keywords chien, influensa vain fic, influnad vaccine safe, Inflac, trivlne subi influenza vaccine For persona ase Bxpert Opin. Bil Thr. (2011) 111):89-98 1. Introduction Inti Ot exes sual Bae eterna Be a ws parece Fant gl aeral polly ihe ddaty indiiaregel =? pasendn poopie wid Riuaifledeving meilal enditon, sch w Gone tpi, {erbrocariorscab and meatedacaes an pinay or aque immune, devin hl ceegneteuseeeibfucorierposutpemals naples ‘The Word Heath Ongannation (WHO) exited anal fom ect ve milion influenza cases of severe illness with 250,000 — 500,000 deaths worldwide (3). Influenza ita devant pb heth mater et ner neat or heat ye team duce intend mumber af hopaliaon and tupac vts 2 and 4 tee-conamic burden, seanday oped quality of cand oof product all resulting in increased direct and indirect healtheare costs (s]. The most effective strat- fay tinprecniiy de dsenrsadieroapesontcemen eainadoy, oder Skates sdelcnpaepeatien soning wcamalgensioe aihtiown 8 snsand on sean Bocuse of amici of auenea iy, the compo: “ion ofnleno cin as oe updated a commended bythe WHOon the bass of worldwide trlnce to and mathe oling Aer dhe . 2009 influenza A (HIN1) pandemic, health authorities recommendations for the informa 2010-2011 inBscna som ave ben plat snd vacinaon ib eommende here feral peonsaped> Granth Thndeion shed on hee major reson, Fly the obtenaon that morbid nd may even revo heakby young sale Expt Opin. Bil. Ther, Dwslosed frm nformacalthar com by Abst Laboratories on 01/244 "1597/47 )2588 219 541436 © 2011 rma UK, Le BSN 14712588 8 ‘A nhs eee proc ne orn pt not persed nigureureksExpt ino. Tet Downlond fm informs com by AB Laborers on 244 or pete se oly Influvac Box 1. Drug summary. Drug name inflvae® Phase rH Indeation Influenza Pharmacology description Irnmunostimulant Route of administration Parenteral Pivotal tals) [eh388.7) armapojets epyght to Caine Drug negenc (ance ‘snes Rasdes a eed opine stirs pgsine icin com) and Ctelne tepstiermsceine con) ‘occurs in every influenza season; secondly the unawareness of being at risk of influenza complications and lastly a higher rik of influenza complications among adults < 50 years because of the predicted pandemic 2009 A (HIN1 like virus circulation in the 2010 ~ 2011 influenza season (6) together with the evidence that a great proportion of young adults do not yer have natural immunity against the virus 9. Strong recommen- dlation is however provided for children and adolescents aged 6 months ~ 18 years, patients with underlying chronic diseases, all persons aged ® 50 yeas, pregnant and breastfeeding women, household and close contacts with high risk people and hhealehcare personnel ‘Annual vaccination is a cost-effective strategy, in the elderly 1011 in healthy adolescents and adults 1213) and in working settings 10. Eficacy and cost-effectiveness of influ- enva vaccination in healthy children is discussion. Although influenza in children is a benign- course disease, it ha been considered responsible either for a significant disease burden even in the absence of high risk conditions 4) or for a social and economic effect‘ Some studies suggested that annual influenza vaccination of healthy children would resu in health benefits and be cost~ saving for the whole community (1%171, in contrast, other studies raised doubts 18) or stated that modest or even no effects on morality, serious complications and community transmission of the disease would result from influenza ‘vaccination of healthy children 1. ater of current 2. Overview of seasonal influenza vaccines market Inactivated influenza vaccines have been available since the 1940s (2 and ther production underwent a constant increase 0 that in the 2004 ~ 2007 period an estimated 408 million doses had been distributed worldwide fn. There are curently three available inactivated influenza vaccine types: subunit inactivated vaccines, made up only of surface haemagglutinin (HA) and neuraminidase (NA) antigens; split-virion inaci- vated vaccines, which contain both surface and internal anti- gens: and whole-virion inactivated vaccines. The seasonal version of whole-virion inactivated vaccine is manufactured by Baxter and will be available in Auseria and the Czech Republic in the 2010 ~ 2011 influenza season. Both subunit and split-virion ae egg-derived inactivated vaccines. The pro- duction process stars with the amplification of influenza viruses in embryonated chicken eggs and i followed by afrag- mentation of the vir lipid membrane through the use of decergents, obtaining split influenza vaccines, or by the sepa ration ofthe surfice HA and NA antigens through a puriica- tion process, obtaining the subunit vaccines. Although initially considered less immunogenic than the whole-vition vaccines (229, a subsequent review by Beyer etal. showed ‘qual immunogenicity of the three vaccine types 24. Cute rently available wivalent subunit and splivirion influenza vaccines demonstrated a substantial efficacy, offering protec- tion against the citculating stains in 70 ~ 90% of healthy adule< 65 years of age 2520, in 60 ~ 90% and in 50 ~ 60% of healthy children and elderly adults, respectively 27. Trivax Jen inactivated influenca vaccines (TIV) provide significant health benefits in people with underlying medical conditions, such as the elderly with chronic heart diseases i, patients with chronic obstructive pulmonary disease 291 or HIV- infeced individuals (0), Since the immune response to TIV is suboptimal in certain people such as older adults 1s), new approaches to enhance influenza vaccine immunogeniciey ate currently being evaluated, including the use of adjuvants ‘Two adjuvanted seasonal influenza vaccines were firstly aval able in several countries since lare 1990s an MF59-adjue ‘vanted subunit vaccine (Fluad®, Novartis Vaccines, Siena, Tealy) and a virosomal-adjuvanted subunit vaccine (Inflesal V®, Berna Biotech Ltd, Berne, Switzerland). MF-59, a submi ‘ron squalene oil-in-water emulsion capable of activating ntigen-presenting cells (APCs) jx, has been used in infa- ‘naa vaccine formulations, showing 2 good immunogenic effect even in target groups such asthe elderly ss and people at risk of influenza complications 3435). Enhanced immuno- enicity of MF59-adjuvanced influenza vaccines has been ‘observed in healthy infants and young children, 00 (3637). Moreover, recent studies suggested chat MF59-adjuvanted subunit influenza vaccines could offer cross protection against antigenically drifted. influenaa. virus stains, 100 382). MF59-adjuvanted vaccines show a good safety profile with only a higher rate of local side eects, due (0 the local pro-inflammatory response induced by the squalene ermusion ‘when injeted in the muse (2 Another strategy isthe novel virosomal antigen presenta- tion (1) dhrough which che viral surface glycoproteins ae pre- lar to that of the intact virus, by ‘mimicking and maintaining the cell-entry and membrane- fusion properties and acting s antigen delivery and presenting system 2}, thus resulting in good vaccine immune response (44) even in high-risk populations, such as che cldenly (6) or asthmatic (4, diabetic tr1 and. HIV-infected children and adolescents 4840 In 2003 the FDA approved the use of Flumist® (Medimmune, Gaitherburg, MD, USA) (so, a ctvalent liveawenuated cold-adapted temperatute-snstive influenza sented ina manner si 30 ‘er Opi al her (2011) 1) RiguTsLExpert Opin, Biol, Ther. Downloaded from infomshellcae som by Abbot Labortories on 01 For persona ee (CAIV-T), administered intranasally, in which the live vius can only mulsiply in che lower temperatures of nasal passages stimulating both mucosal ancibody and celular responses with potential efficacy against variane circulating stains (1) This vaccine is available for healthy children and non-pregnant adults berween 2 and 49 years of age. Live- attenuated influenza vaccines seem to be less efficacious than conventional wivalent inactivated vaccines in healthy adults 50, in contrat, they are capable of eliciting a good immune fesponse in children (aged 6 ~ 59 months) (9, ceven if safery data about hospitalization rates for any cause, including wheezing, are contrasting 31.54. Tneradermally administered influenza vaccines are available, 100, The skin shows unique immunological properties. Inthe skin, two types of dendritic ells (DCS), which act as patent antigen-presenting cells, are present: the Langerhans els (LCS) in the epidermis and dermal DCs (4DC8) in the der. mis. Intradermal vaccination targets direedly APCs, which, bby migrating tothe draining lymph nodes, ate able o crigget T- and Becell activation (51. Moreover, intradermal vaccina- tion could favour lymphatic drainage of free antigens and ther subsequent capture by DCs in the Iymph nodes 6. Sev- cal major studies evaluated immunogenicity and safery of intradermally administered influenza vaccines, which demon- strated is similar immunogenicity and safery co the intarmus- colar ones in adule subjects 1578). Few studies evaluated intradermal vaccine administration in children; however, available data suggested a good immunogenicity. Local eac- tions were mote common in intradermally. immunized children, but all adverse events were mild and transient 60.6, ‘A recent new horizon of influenza vaecine manufacturing is the one of cell-culture-grown vaccines. Despite the undeniable success of eggederived vaccine production, the increased demand for seasonal influenza vaccination, the reduced and/or variable vaccine supply, and the cheat of avian HINS pandemic influenza and the subsequent need for mil- lions of rapidly available vaccine doses are reasons for which ‘manufacturer are pursuing alternative approaches for influ- wa vaccine production. The use of tissue cell-culure lines could eliminate che long lead times and the limited flesbiliry of egg-based production, overcome potential sterility probe lems and enable production of avian stsins influenza vac- cines, which generally poorly grow in eggs. Mammalian cell lines, PER.C6, Madin Darbin Canine Kidney (MDCK), Vero cells and insect cell lines are being in use in Europe and the USA for seasonal and pandemic influenza vaccines manufacture (65) Tn 1993 Ulmer era: reported for the iste that a DNA vaccine can prevent influenza infection in mice sand subse- {quent preclinical studies demonstrated that DNA-technology- based influenza vaccination is successful in enhancing both a humoral and a cellular immune response against influenza antigens in various animal models (6). In humans, after some disappointing initial results, a Phase I study by Drape and colleagues has demonstrated the induction of protective Zuccotti & Fabiano cs after DNA influenza vaccination {67}. A new influenza vaccine strategy targeting highly conserved viral proteins NP, MI and M2 is under development 5.9 antibody ‘universal 3. The trivalent inactivated subur formulation: composition and mechanisms of immune response Influvac® (Abbott, Chicago, USA) has been on the market since the eatly 1980s and is a trivalent subunie inactivated influenza vaccine made up of surface antigens haemagglutinin and neuraminidase of the A/HIN1, A/H3N2 and B virus stcains acording to annual WHO recommendations for the upcoming influenza season. Inflavac is one of the leading influenza vaccines worldwide with more than 250 million doses manufactured so far (Box 1). Every year in February for the northern hemisphere, in August for the southern hemisphere, each of the primary seed virus strains is separately propagated in chicken eggs (0 produce secondary seed virwies. These are inoculated in mil- lions of 10 ~ 11-day old embryonated eggs and, after a three-day incubation period, virus particles are extracted from the eggs. Viral RNA is inactivated and viral particles ae uleracenrifuged to obtain a highly purified vieus suspen sion. ‘These viruses are dead and cannot replicate anymore NA and HA antigens the subunits, are removed ftom viral membrane using acerytrimethylammonium bromide deter- gent. A second ulracentfugation is than necessary for separating the subunits from the viral membrane and viral core, Finally, the components are combined in the correct proportion in 0,5 ml pre-filled syringes for intramuscular or leepsubcutancous injection containing 15 yg HA and 7.5 pg NA per seain. From 2004 onwards, Influvac has nor contained thimerosal as preservative, Protection against influenza infection is achieved through the production, by Belymphocytes, of specific antibodies, scram haemagglutintion inhibiion antibodies and neuraliz~ ing antibodies (7, Specific anibody response starts to appear scaly as 2~ 6 days after immunization (172, and by 2 weeks jon, 9096 of subjects have protective anbody ). The majority of healthy adults and children have high antibody cues after vaecination 479, typically defined asthe achieverent of 1:40 haemagglatnation tee threshold. Serum immune response is characterized principally by influenza-specifc IgG antibodies (mainly IgG1) with a lower concentration of IgA and IgM i. Although postaccination antbody response is typespecific 73, eros-reaction towards newer vil strains is posible. Afer trivalent inactivated infu cnza vaccination, a local immune response is induced in the tonsils and saliva. In the tonsillar tise and in the peripheral blood, IgG and IgA influcnza-specific antibody secreting cells (ASCs) can be predominandy detected, in the oral fluid, the Jmmune response is dominated by serum IgA (SIgA1) and, 10 less extent, SIgA2 (7. In young, influnza-infection-naive ‘ort Opin. Bi Ter 2010) 10) m RIGHTS KeTor personal Expert Opin. il. Ther: ownloaded from informahealincsre com by Abbot Laborstriss on 01/2414 Influvac children immune response is mainly characterized by IgM, with lower IgA tives and no or very litle salivary SigA (7. Specific immunity persists usually from 6 t 12 months after vaccination, even if some studies suggest thar vaccination-induced immunity could last even longer 1479 4, Influvac: efficacy and safety studies Since Inluvac has been available on the market from 1982 10 2006, 76 clinical efficacy and safery studies in healthy adults and in the elderly, including the annual update studies required by European Union regulations jo), have been performed giving a sample of more than 6400 vaccinated ssubjecs (6), Influvac has been studied in children, too 41 Immunogenicity in healthy adults, in the elderly and in at-risk populations ‘Targee population of the majority of the above mentioned studies were healthy adults and older subjects; 23 were rando- mised double- oF single-blind studies, 2 studies were per- formed in subjects at risk of influenza complications and 2 in mursing home residents. All studies were performed in accordance with the Good Clinical Practice Guidelines of the International Conference on Harmonization standards and with the Declaration of Helsinki, Study design was more of less identical. Subjects were immunized with the inramuscuasly administered vaccine Influvac. Blood samples were collected at baseline, before receiving vaccination and 2 ~ 4 weeks afterwards, According to the citeris established by the Committee on Proprietary “Medicinal Products (CPMP) 0), immunogenicity of Influvac was assesed considering the seroprotection rate, defined as the proportion of subjects with an_ haemo inhibition (HI) antibody titre ® 40; the seroconversion! fourfold increase rate, defined as the proportion of subjects with a pre-vaccination HI tire < 10 and a postvaccination titre 2 40, ofa last a fourfold post-vaccination HI antibody relative increase; and the mean fold increase, defined as the {geometric mean of che inea-individual fold inczeaes in HI tite (GMT). For healthy adults aged 18 - 60 yeas, seropro- tection rate must exceed 70%, seroconversion rate 40% and the mean fold increase 2.5, 60%, 30% and 2.0 are the respee~ tive targets for the over 60 yeats old subjects. Based on these criteria, vaccination with Influvac-was immunogenic both in hnealthy adults and in the eldely, with seroprotecion rates cof 80 ~ 90% forall the three virus stains in the ones and of more than 70% in the later. Seroconversion rate targets vwete aso largely achieved, both in healthy adults and in the elderly. Mean fold increase was more than 10.0 forall ehrce virus strains in adults and more than 6.0 in the older subjects Immunogenicity of Influvac was confirmed in nursing home residents and, even if postvaccination antibody ttre in the avis population was lower, all the requested criteria were met inthis subject group, too (21 Comparative studies of Influvae and other influenza vaccines have been published. In a randomized, observ blind, three-arms, parallel group, multicentre trial, immun genicity and safety of Influvac, 2 virosomal subunit vaccine Alnvivac®, Solvay Pharmaceuticals, Brussels, Belgium), and a ME59-adjuvanted subunit vaccine (Fluad) were studied in nearly 400 elderly subjects in four countries 1s. Immuno- geniciy was similar, with 84.1 ~ 100% seroprotection rates, indicating 2 good humoral immune response for all three vaccines. In a randomized, controlled study conducted in Chin immunogenicity and safety of Influvae and of another inati- vated subunit influenza vaccine (Agrippal®, Novartis Vac- «ines, Siena, Italy) were compared in healthy adults and the elderly 0. Both Inflvac and Agrippal proved ro be highly immunogenic, with seroproteetion rates > 85% and serocon- version rate > 70% for both vaccines in both age groups. In this study, post-vaccination GMT were higher in the Influvac-vacinated subjects than in those who received Agrip- pal, with an average of nearly 50% higher teres in the Fest ‘up, in all age groups and forall che three virus strains ‘A comparative study has been conducted in eldely people in Russia. Immunogenicity was asesed for Influvac and four other inactivated influenza vaccines licensed in Rusia, three spli-virion vaccines, Begrivac® (Novartis Vaccines and Diagnostics GmbH & Co., Marburg, Getmany), Vaxigrip® (Sanofi Pasteur SA, Lyon, France) and Fluarix® (Glaxos- rmithkline Spa, Rixensart, Belgium); and an inactivated subunit vaccine Grippol® (Petrovax, Moscow, Russia and Solvay Pharmaceuticals, Brussels, Belgium). All influenza vaccines demonstrated similar high immunogenicity in che elderly. ‘The presence of chronic underlying medical ‘conditions did not affect immunogenicity in all vaccines (5 42 Effectiveness in healthy and at-risk children Influvac has been studied in both healthy and high- risk children, resulting in a substantial efficacy and safety. In a recent field study (s4, a mas immunization programme was catied out in Russia, in the Moscow area, in kindergat~ ten children aged 3~ 6 years and in schoolchildren and ado- lescents from 7 t0 17 years. A total of 28,309 children of both age groups were vaccinated with Influvae before the onset of the 2001 ~ 2002 influenza season. Compared with a neatly 61,000 aged-matched subjects ofthe control group, cfcacy of children influenza mass-vaccinacion wih Tnfla- vc, evaluated as reduction of influenza-like illnesses (ILD), ‘was 60.9% in kindergartner children and 68.8% in school children and adolescents. Moreover, mass childhood infla- eza immunization with Influvae resulted in a significane reduction of ILI and influenza-complications in. unvace nated non-institutionalized elderly showing favourable Influvac effect on public health. Zim. and colleagues (8s) evaluated immunogenicity. and safety of Influvae compared with Agrippal in healthy children aged 3 — 12 years. In this study wo age subgroups were 2 ‘pet Opin Ba Thar BOTH) 1) RIGHTS LINKEDExper Opa, Bil, Ter. Downloaded frm infomnaheatcare om by Abt Laboratories om 01/2414 For personal use on. considered: 56 children aged 3 ~ 5 years and 217 children from 6 to 12 years of age. Children of both subgroups were randomized to receive Influvac or Agrippal. In both younger and older children, Influvac and Agrippal resulted in good immunogenicity. GMTs were higher for Inluvac especially in the 6 ~ 12 years old children subgroup, in which GMT ratios for Influvac:Agrippal were becween 1.44 and 1.70, Influenza vaccination is always recommended in children at risk of complications, che ones with chronic underlying med- ical eonditions such as respiratory or cardiac diseases. Immu- nogenicity and tolerability of Influvac have been studied in high-risk children beeween 6 months and 4 years of age, with chronic lung disease or congenital hear disease (1 In this open study, 52 high-risk children (48% with chronic lung disease, 469% with congenital heart disease and 6% with both condicions) were vaccinated with two 0.25 ml doses of Influvac, administered 4 weeks apart, Immunogenicity was assessed by dosage, three weeks after administration of the sec ‘ond vaccine dose, of Hl-antibody tits. Influvac proved to be strongly immunogenic against all three virus stains in this population with an efficacy similar to that in healthy adults Vaccination in asthmatic children is recommended however, influenca vaccination coverage in this highrise group, although variable, is generally lower than in asthmatic adults, Influenza vaccination with Tafluvac in. asthmatic children has been found to have a moderate beneficial effect con quality of life (i, but scarce effects on reduction of the ‘number, severity and duration of asthma exacerbations related ¢o influenza infection pon, However, in a randomized, double- blind, placebo-contelled stud, influenza vaccination did not prove co be associated with asthma exacerbations ‘A comparative study of Influvac and Inflexal V was conducted in children and adolescents with eystic fibrosis (CE). In these patients, both vaccines were effciendy immunogenic pa. TInfluvac and Inflexal V have been also compared in a study in diabetic children, adolescents and young adults 71. Both vaccines resulted immunogenic but a beter long-asi immune response was assessed in patients vaccinated. with Inilexal V, especially those withoue pre-existing antibodies to influenza strains Efficacy of Inflvac has been assessed in severely ill chil dren, such as those affeced by acute lymphoblastic leukemia idren Influyac proved wo be efficiently immuno- genic, both in previously vaccinated and in unprimed individuals 9. In these 43 Safety and tolerability In clinical trials and annual update studies in adults and che elderly, safety and tolerability of Influvac were assessed by subjects recording of local and systemic reactions and general ‘onvenience on a standard questionnaire for three oF more days after vaccination. Local vaccine reactions are the jones thar typically occur at the vaccination site, namely redness, induration, pain, bruises, warmth, swelling and arm Zuccotti & Fabiano movement impairment. Systemic reactions are instead caused by immunological reaction to the vaccine, represented gener- ally by headache, malaise, fever, insomnia, increase sweating and coughing. Both local and systemic reactions were scored 2 present of not present. If present, general inconvenience was scored as slight, moderate or severe TInfluvac showed a good safety profile, with the majority of reported reactions being local and mostly represented by pain atthe vaccination site. Other more frequentty reported local reactions were redness, warmth and induration at the vaccina- tion ste. The most frequently reported systemic reaction was headache, followed by malaise and increased sweating. For both local and systemic reactions, there was an age- dependent trend wich fewer events reported by the elderly The population at rsk of influenza complications showed a lice higher incidence of systemic reactions, the most frequent of which were always headache and malaise. The degree of inconvenience was reported as absent or mild by the majoricy ofthe subjects, both adults and elderly. Serious adverse events were collected only in the more recent studies and che ones possibly related to vaccination were three eases of dizzines, ‘nausea and pneumonia respectively i. These data were con firmed by postmarketing surveillance. As regard nervous sys tem disorders apart from headache, the most commonly ported events were acute polyneuropathy, paraesthesia ot ddysasthesia, paralysis and dizziness. In more than 25 years ‘experience with Influvac, only 46 cases of Guillain-Barré Syn- drome have been reported isan. Comparative studies con- firmed safety and tolerability of Influvac. In study by De Bruijn and colleagues Influvac, Invivac and Fluad were all safe and substantially well-tolerated and a higher incidence ‘of local and systemic reactions inthe MF59-adjuvanted group ‘vas reported (46 and 3290 respectively forthe adjuvanted vae- ine versus approximately 20% for the other two vaccine types) isl, Comparison with Agrippal demonstrated. that both vaccines presented a good safety profile in all age g10ups ios. Low reactogenicity in the elderly was observed in the comparative Russian study, too In children, Influvac showed 2 good safety profile in all studies. Compatson with Agrippal resulted in good tolera Billy in both vaccines. The most frequently reported local reactions were pain and itching/pruritus at site of injection (wine children in the Influvae group). Systemic reactions were mainly mild and represented above all by headache. Fever after vaccination was observed in nine children in the Influvac group and four children in the Agrippal group. Sys temic temperature inerease was mild in all subjets and lasted no longer than 1 day. No serious adverse reaction was ‘observed in lage population mass vaccination [) In children with underlying chronie respiratory or cardiac diseases, most frequently reported local reactions were redness a the injection site (12% out ofa total local reactions rate of 2366) whereas fever and increased irvtabiliy were the most common systemic ones (27 and 25% of reported systemic reactions respectively). In all cases, systemic reactions were ‘xp Onin, Bt. Ther QOH) 3 RIGHTS|Eps Opin Bik. Ther, Dolo fm ina com by Ao Laborato 01204 Foeperona ase ony Influvac described as mild and resolution was observed within a few days (71 Tn asthmatic children and adolescents the most frequently reported local reactions were redness and pain at injection site, whereas sneezing and runny and/or stuffed nose were the most frequent systemic ones (74 and 47% respectively). Both local and. syste 2~ 3 days, and no serious adverse event, including asthma exacerbations, was observed 1 In children affected by cystic fibrosis, local reactions were more frequently reported by Influvacvaccinated patients (57) than Inflexal V-vaccinated ones (449%). In this study, incidence of reported systemic reactions was higher than that reported inthe literature, with 15 (719%) of children vac- cinated with Influvac reporting one or more systemic adverse event. In cis case however, incidence of systemic reactions in Inflavac-vaccinated children was lower than. in Infiexal Vevaccinated ones (36 vaccinees, 8496). Most of che events were represented by headache, fatigue, cough and coryza and classified as mild or moderate; there was no case of fever. ‘These data were in contrast with the general tolerance of vaccination, judged as ‘very good’ or ‘good’ 4 weeks after and can be explained by difficlty in distinguishing between vaccine reactions and underlying CF sympromatology (2) Tnfluvac has been well tolerated in diabetic children and adolescents, without any sgnifcane difference of the severity ‘of any local or systemic reaction compared with Inflexal V7, ic reactions lasted no more than Conclusions ‘The analysis of data from annual update studies, clinical eval and postemarketing suneillance demonstrates the substantial immunogenicity and the Favorable safety profile of the inact vated subunic influenza vaccine Inflavac i949. These obser- line with lteraare data on efficacy and safety of influenza vaccines in children 60s), in healthy, working adults 252790, and in the elderly 27,100,001. Seroprotection rates in healthy adults vaccinated with Inflwvac consistently met the CPMP serological criteria for immunogenicity and were beeween 80 and 90% in all studies. These data are in accordance wi xe reports, in which iaceivated influenza vaccines are estimated to prevent the dis- casein 70 ~ 90% of healthy adults 27.200, Since serological HI antibody vitr is considered « well-accepted correlate of pro tection [103], Influvac proved to be substantially effica in all studies. Seroresponses to vaccination with Influyac the elderly were somewhat lower than in younger adults ‘This has been largely reported in the literature: ageing of the {immune system is responsible for lower responsiveness to vac ination in general. However, Influvac seroprotection rate in the ler subject was over 70% in the majority ofthe scudies, proving co be even better than the estimated 30 - 70% eff cacy inthis subject group i). Immunogenicity of Inluvac is in accordance with literature data about comparisons of literature and surveil inactivated subunit vaccines with other inactivated vaccine types (241 or with cold-adapred live influenea vaccines (104 even ifthe later have been found being able to elci a long- lasting, broader immune humoral and cellular response in heathy adults and children but not inthe eldest 1. In all suis, vaccination with Influvae was found eo be safe and well-tolerated, with an extremely low prevalence of serious adverse evens. The favorable safety profile of Influvac con- firms what is reported for other erivalene inactivated influenza vaccines (9). In children from 6 wo 23 months of age, a large population-based study reported safer of trivalent inactivated vaccines. In a eohore of more chan 45,000 vaccinated ch dren, very few medically atended events significantly aso ated to the vaccine have been reported. None of these was serious p51. Moreover, efficacy and safety of Influvac has been confirmed in high-risk children, to. 6. Expert opinion Influenza vaceination is overall considered the best way to pre- ‘yen the infection and related complications, Asa result, ree- ‘ommendations for immunization have been regularly updated to meet the constantly increasing need for influenza protection, both from an individual and a societal poine of view. With their long-lasting presence on the marker and. their ‘worldwide distribuxion, raditional trivalent inactivated influ- ‘naa vaccines represent actually the mainstay of influenza pre- vention, More recently, adjuvanted influenza vaccines, virosomal and MP59-adjuvanted vaccines have demonstrated to be particularly immunogenic in elderly people 3439, Recent head-to-head comparative studies with conventional subunit, virosoma-adjuvanted, and MFS9-adjuvanted influenza vac munogeniciyy of che three vaccine ypes 3.06. MF59 vaccine resulted in a greater reactogenicity than inactivated and viosome-adjuvanted ones. Seasonal influensa vaccines are safe and suficiently immuno- {genic in children, virosome-adjuvanted vaecines show a greater immunogeniiry than inacivated ones, especially in unprimed children 107, Liveatenvated intranasally administered infha- cnza vaccine showed a higher immunogenicity in children than conventional inactivated vaccines not only for well matched stains but also for antigenically drifted ones. How ever, data on safey are actually already contrasting, Influenza immunization is nt licensed in infants aged les than 6 months, ‘because of searceimmunogeniciy, typical ofthis age. However, recent studies evaluated immunogenicity and safety of conven tional trivalent inactivated influenza vaccines in infancs less than 6 months old. TIV proved 10 be safe and well tolerated and showed a moderate immunogenicity particulasy in infants ‘without pre-existing macerally acquired antibodies 08.0 ‘Considering all available literature data together with the long-lasting post-marketing experience, TIV continue represent a valid and safe choice for influenza immunization in children, adults and the elderly even in the presence of undelying chronic medical conditions. Influvac has been on ines have shown however a similar 3a ‘per Opn. Bal Ther GOT) HY RIGHTS.Expert Opin. Bil, Ther. Downes frm infommabealtcare com by Abt Laboratories on 01/2414 Forres we nls the market for more chan 25 years and millions of doses have been administered worldwide, [ts efficacy and safery in all ra get populations have been demonstrated by several studies and post-markering surveillance. Bibliography ‘Gene for Disses Cone and Prevention, Prevention and contol infuenaa with vaccines Recommendtions of the Advisory (Commis on Inmaniton Pitt ACIP). 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MD & Yalesina Fabiano MD "author for comespondence Universi dep Sead i Mian, Lagi Saco Hp, Deparmeas of Palins, Via GB Gras, 74, 20187, Mi Tay Tel «390239082255 Fax «390039042254 El: ianvinceno succori@unimie ‘sper Opi Bik Ther (2039) #1) RIGHTS Lin Ke