influenza is an acute viral illness of the respiratory tract , and constitutes a substantial public health burden in terms of morbidity , mortality and related costs . about 3 - 5 million cases of severe illness occur each year worldwide , resulting in about 250,000 to 500,000 deaths per year , high hospitalization and mortality rates , and considerable loss of productivity [ 1 - 3 ] . from a microbiologic point of view , type a and type b influenza viruses differ markedly in terms of their hosts and epidemiology . influenza a viruses have other animal reservoirs , in addition to humans , and display high antigenic variability , which mainly involves their surface glycoproteins : hemagglutinin ( ha ) and neuroaminidase ( na ) . antigenic shift and antigenic drift are the two well - known mechanisms responsible for major and minor variations ; antigenic shift is the main cause of the appearance of new influenza a strains with pandemic potential . influenza b viruses , for which humans are the sole host of epidemiological relevance , do not undergo antigenic shift , but they can undergo antigenic drift . since at least 1983 , two parallel evolutionary b pathways with little antigenic cross - reactivity have been recognized , thus allowing two distinct genetic lineages to be identified : the b / victoria/2/1987 ( victoria ) and b / yamagata/16/1988 ( yamagata ) strains [ 5- 6 ] . since 2002 , the two distinct influenza b lineages have frequently co - circulated , with one of the two predominating over the other in each season . from 2003 - 2004 to 2012 - 2013  variations in the prevalence of circulating b lineages were reported : in 2007/2008 and 2012/2013 , b viruses accounted for 47.7% and 58% , respectively , of viruses isolated , while in other seasons b viruses co - circulated with virus a , although with a lower prevalence . vaccination is the most effective means of reducing the number of influenza cases and related complications . annual influenza immunization is , in particular , recommended in elderly subjects , children aged six months or more , pregnant women and individuals with chronic conditions , such as respiratory / heart/ liver diseases , diabetes , or a weakened immune system . indeed , these categories are at heightened risk of influenza - related complications and mortality . in italy , the national ministry of health annually publishes influenza prevention recommendations , specifying the groups to whom vaccination is offered free of charge . in addition , the ministry sets a minimum target of vaccination coverage of 75% and an optimal target of 95% . the world health organization ( who ) annually recommends vaccine composition on the basis of global virological surveillance . annual trivalent influenza vaccines ( tivs ) contain two influenza a strains ( h1n1 and h3n2 ) and only one influenza b virus . the effectiveness of tivs therefore depends on the degree of matching between the vaccine strain and circulating viral strains . in the last two decades , four major and at least eight minor mismatches between vaccine and circulating b viruses have occurred in the northern hemisphere , thus impairing the performances of tivs ( tab . ambrose cs and colleagues observed that , in europe , a b - mismatch between vaccine and circulating strains occurred in 5 of 10 seasons between 2001 and 2011 . the effect of antigenic mismatching between vaccine and circulating strains on vaccine effectiveness has emerged from observational and experimental studies [ 6 , 11 - 14 ] . a recent meta - analysis by the centers for disease control and prevention ( cdc ) and the marshfield foundation reported that trivalent subunit or split influenza vaccines displayed good effectiveness in preventing lab - confirmed influenza illness when matching was good , but that vaccine effectiveness decreased when a drifted strain dominated the epidemiological picture . therefore , inaccurate prediction of the predominant influenza b lineage leaves many vaccinated individuals with suboptimal protection against influenza b disease caused by the influenza b lineage not included in the licensed trivalent vaccine . influenza vaccination strains and viruses circulating in the northern hemisphere in the seasons from 1995/96 to 2015/2016 . legend : in yellow : minor mismatches ; in red : major mismatches ; in green : new influenza a strains with pandemic potential . to minimize the impact of b - mismatch on vaccine effectiveness , in february 2009 the food and drug administration ( fda ) , for the first time , considered the inclusion of an additional influenza b strain in the antigenic composition of seasonal influenza vaccines . subsequently , in february 2012 , the who recommended the production of quadrivalent influenza vaccines ( qivs ) for seasonal immunization . in 2012 , the european medicines agency ( ema ) also highlighted the need for a quadrivalent vaccine that could overcome the lack of protection against the influenza b lineage not present in the trivalent vaccine . finally , in february 2013 , the who issued its first guidelines recommending that both expected b - strains be included in the vaccine composition [ 17 - 18 ] . in recent years , scientific research has addressed this need , and two quadrivalent influenza vaccines ( qivs ) have been developed : a live - attenuated quadrivalent influenza vaccine ( q / laiv ) and a split inactivated quadrivalent influenza vaccine ( i / qiv ) . the immunogenicity , safety and tolerability of quadrivalent influenza vaccines have been evaluated in children , adults and the elderly in several clinical trials . a phase- iii , randomized , double - blind study performed on 2,312 children aged 2 - 17 years demonstrated that the immunogenicity of an investigational q / laiv was non - inferior to that of two licensed t / laivs , one containing a b strain from the yamagata lineage and the other containing a strain from the victoria lineage . moreover , this q / laiv proved safe and well tolerated . 
  since 2014/2015 , q / laiv has been used in a universal pediatric vaccination programme in the united kingdom ( uk ) . in this real - life scenario , the vaccine was seen to provide significant protection against drifted circulating influenza b viruses . with respect to i / qiv , a phase ii study was conducted in two groups of children aged 18 - 47 months : the first group was constituted by children who had received two doses of tiv in the previous season and who received one dose of tiv or i / qiv in the study season ; the second group was composed of unprimed children who received two doses of i / qiv or tiv 28 days apart during the study season . in comparison with the tiv , the i / qiv displayed superior immunogenicity towards the alternative - lineage b strain , without impairing the immune responses to shared strains . these results were confirmed in a randomized phase iii study conducted by domachowske jb and colleagues in healthy children aged 3 - 17 years . langley and colleagues also investigated the immunogenicity and safety of a i / qiv candidate versus tivs , in a phase - iii randomized controlled trial involving 3,094 children aged 3 - 17 years . the i / qiv was non - inferior to the tivs in terms of immunogenicity towards the shared strains ( a / h3n2 and a / h1n1 ) , and , in comparison with tiv controls , elicited superior responses to the added b strains . solicited reactions , unsolicited adverse events and serious adverse events were similar in the i / qiv and pooled tiv groups . the promising results obtaining with i / qiv in children were also confirmed in clinical trials performed in adult populations . in a phase - iii clinical trial comparing i / qiv with tiv/ victoria and tiv / yamagata vaccines , 4,659 adult volunteers received one vaccine dose . overall , the i / qiv was highly immunogenic and , on day 21 , displayed greater immunogenicity towards the additional b strain than tiv , without interfering with the antibody responses to the three shared antigens . the i / qiv candidate was also tested in 1,565 adults aged  18 years in a phase iii , randomized , active - controlled , multicenter trial during the 2011/2012 influenza season . for all four vaccine strains , antibody responses to the i / qiv were non - inferior to those elicited by the tiv for matched strains . for both b strains , antibody responses to the i / qiv were non - inferior to the response to the tiv for the matched strains , and were superior to the responses elicited by the tivs that lacked the corresponding b strain . the safety of i / qiv was investigated through a routine surveillance system in western australia in 2015 in a sample of 1,685 healthcare workers ( hcws ) . the results indicated little difference between the reactogenicity of i / qiv and that of tiv ; the percentage of hcws reporting pain or swelling at the injection site was slightly higher among those who had received i / qiv than those who had received tiv ( 6.9% vs 4.2% , respectively ; p = 0.02 ) . the safety of i / qivs was verified in a review of data from the vaccine adverse event reporting system ( vaers ) in the us from 7/1/2013 to 5/31/2015 . the most frequent non - fatal serious adverse events were : injection site reactions , such as pain and erythema , constitutional symptoms , guillain - barr syndrome , seizures , and anaphylaxis , though these were rare or very rare . adverse events reported to the vaers following i / qivs were similar to those following tivs . on the basis of this evidence , the two quadrivalent influenza vaccines have recently been licensed in many countries , and have been gradually replacing tivs in the immunization programs of these countries . a phase- iii , randomized , double - blind study performed on 2,312 children aged 2 - 17 years demonstrated that the immunogenicity of an investigational q / laiv was non - inferior to that of two licensed t / laivs , one containing a b strain from the yamagata lineage and the other containing a strain from the victoria lineage . moreover , this q / laiv proved safe and well tolerated . 
  since 2014/2015 , q / laiv has been used in a universal pediatric vaccination programme in the united kingdom ( uk ) . in this real - life scenario , with respect to i / qiv , a phase ii study was conducted in two groups of children aged 18 - 47 months : the first group was constituted by children who had received two doses of tiv in the previous season and who received one dose of tiv or i / qiv in the study season ; the second group was composed of unprimed children who received two doses of i / qiv or tiv 28 days apart during the study season . in comparison with the tiv , the i / qiv displayed superior immunogenicity towards the alternative - lineage b strain , without impairing the immune responses to shared strains . these results were confirmed in a randomized phase iii study conducted by domachowske jb and colleagues in healthy children aged 3 - 17 years . langley and colleagues also investigated the immunogenicity and safety of a i / qiv candidate versus tivs , in a phase - iii randomized controlled trial involving 3,094 children aged 3 - 17 years . the i / qiv was non - inferior to the tivs in terms of immunogenicity towards the shared strains ( a / h3n2 and a / h1n1 ) , and , in comparison with tiv controls , elicited superior responses to the added b strains . solicited reactions , unsolicited adverse events and serious adverse events were similar in the i / qiv and pooled tiv groups . the promising results obtaining with i / qiv in children were also confirmed in clinical trials performed in adult populations . in a phase - iii clinical trial comparing i / qiv with tiv/ victoria and tiv / yamagata vaccines , 4,659 adult volunteers received one vaccine dose . overall , the i / qiv was highly immunogenic and , on day 21 , displayed greater immunogenicity towards the additional b strain than tiv , without interfering with the antibody responses to the three shared antigens . the i / qiv candidate was also tested in 1,565 adults aged  18 years in a phase iii , randomized , active - controlled , multicenter trial during the 2011/2012 influenza season . for all four vaccine strains , antibody responses to the i / qiv were non - inferior to those elicited by the tiv for matched strains . for both b strains , antibody responses to the i / qiv were non - inferior to the response to the tiv for the matched strains , and were superior to the responses elicited by the tivs that lacked the corresponding b strain . the safety of i / qiv was investigated through a routine surveillance system in western australia in 2015 in a sample of 1,685 healthcare workers ( hcws ) . the results indicated little difference between the reactogenicity of i / qiv and that of tiv ; the percentage of hcws reporting pain or swelling at the injection site was slightly higher among those who had received i / qiv than those who had received tiv ( 6.9% vs 4.2% , respectively ; p = 0.02 ) . the safety of i / qivs was verified in a review of data from the vaccine adverse event reporting system ( vaers ) in the us from 7/1/2013 to 5/31/2015 . the most frequent non - fatal serious adverse events were : injection site reactions , such as pain and erythema , constitutional symptoms , guillain - barr syndrome , seizures , and anaphylaxis , though these were rare or very rare . adverse events reported to the vaers following i / qivs were similar to those following tivs . on the basis of this evidence , the two quadrivalent influenza vaccines have recently been licensed in many countries , and have been gradually replacing tivs in the immunization programs of these countries . with respect to i / qiv , a phase ii study was conducted in two groups of children aged 18 - 47 months : the first group was constituted by children who had received two doses of tiv in the previous season and who received one dose of tiv or i / qiv in the study season ; the second group was composed of unprimed children who received two doses of i / qiv or tiv 28 days apart during the study season . in comparison with the tiv , the i / qiv displayed superior immunogenicity towards the alternative - lineage b strain , without impairing the immune responses to shared strains . these results were confirmed in a randomized phase iii study conducted by domachowske jb and colleagues in healthy children aged 3 - 17 years . langley and colleagues also investigated the immunogenicity and safety of a i / qiv candidate versus tivs , in a phase - iii randomized controlled trial involving 3,094 children aged 3 - 17 years . the i / qiv was non - inferior to the tivs in terms of immunogenicity towards the shared strains ( a / h3n2 and a / h1n1 ) , and , in comparison with tiv controls , elicited superior responses to the added b strains . solicited reactions , unsolicited adverse events and serious adverse events were similar in the i / qiv and pooled tiv groups . the promising results obtaining with i / qiv in children were also confirmed in clinical trials performed in adult populations . in a phase - iii clinical trial comparing i / qiv with tiv/ victoria and tiv / yamagata vaccines , 4,659 adult volunteers received one vaccine dose . overall , the i / qiv was highly immunogenic and , on day 21 , displayed greater immunogenicity towards the additional b strain than tiv , without interfering with the antibody responses to the three shared antigens . the i / qiv candidate was also tested in 1,565 adults aged  18 years in a phase iii , randomized , active - controlled , multicenter trial during the 2011/2012 influenza season . for all four vaccine strains , antibody responses to the i / qiv were non - inferior to those elicited by the tiv for matched strains . for both b strains , antibody responses to the i / qiv were non - inferior to the response to the tiv for the matched strains , and were superior to the responses elicited by the tivs that lacked the corresponding b strain . the safety of i / qiv was investigated through a routine surveillance system in western australia in 2015 in a sample of 1,685 healthcare workers ( hcws ) . the results indicated little difference between the reactogenicity of i / qiv and that of tiv ; the percentage of hcws reporting pain or swelling at the injection site was slightly higher among those who had received i / qiv than those who had received tiv ( 6.9% vs 4.2% , respectively ; p = 0.02 ) . the safety of i / qivs was verified in a review of data from the vaccine adverse event reporting system ( vaers ) in the us from 7/1/2013 to 5/31/2015 . the most frequent non - fatal serious adverse events were : injection site reactions , such as pain and erythema , constitutional symptoms , guillain - barr syndrome , seizures , and anaphylaxis , though these were rare or very rare . adverse events reported to the vaers following i / qivs were similar to those following tivs . on the basis of this evidence , the two quadrivalent influenza vaccines have recently been licensed in many countries , and have been gradually replacing tivs in the immunization programs of these countries . as mentioned above , two different influenza b strains may co - circulate during an influenza season . therefore , adding a second b strain to influenza vaccines increases the likelihood of achieving adequate protection against influenza b disease . some recent studies have evaluated the expected benefits of including qivs in national immunization programs . for instance , eichner et al . compared the effects of qivs and tivs on influenza incidence by using an individual simulation model in which the concomitant transmission of four influenza strains , maternal protection , boosting of existing immunity , loss of immunity and cross - immunizing events between the b lineages over 50 years were considered as variables . their study found that qiv administration could prevent 11.2% of all influenza b infections which still occur with tiv , thus reducing the influenza burden on the community . the public health impact of qivs in the united states was analyzed in a model by crpey and colleagues in a dynamic retrospective framework with real - life vaccine mismatch . assuming 70% cross - protection of the efficacy of a matching vaccine , the model predicted that qiv would have prevented , on average , about 16% more b lineage cases than tiv over the period 2000 - 2013 . the elderly (  65 years ) and adults aged 50 - 64 years were seen to benefit most from qiv , with 21% and 18% reductions , respectively , in b lineage cases . van bellinghen et al . conducted a lifetime economic evaluation of qivs in comparison with tivs in elderly people and clinical risk groups in the uk . using a multicohort markov model , they estimated that quadrivalent influenza vaccination could further reduce the disease burden of influenza . the qivs would be expected to result in substantial health benefits , reducing the number of symptomatic influenza cases , medical visits , complications , hospitalizations for complications and deaths , in comparison with tivs . in the uk , another study by meier et al . applied a lifetime , multi - cohort static markov model involving seven age - groups , and obtained analogous findings . thommes ew and colleagues used an age - stratified , dynamic four - strain transmission model which incorporated strain interaction , transmission - rate seasonality and agespecific mixing in the population , in order to demonstrate the cost - effectiveness of quadrivalent influenza vaccines in canada and the united kingdom . the results of this analysis revealed that switching from trivalent to quadrivalent vaccines would be a cost - effective means of further reducing the burden of influenza in both countries . you jh and colleagues simulated the outcomes of qiv vs. tiv in 6 age - groups : 0 - 4 years , 5 - 9 years , 10- 14 years , 15 - 64 years , 65 - 79 years and  80 years . direct cost alone , direct and indirect costs , and loss of qualityadjusted life - years ( qalys ) due to tiv - unmatched influenza b infection were simulated for each study arm . in the base - case analysis , qiv was more effective than tiv in all age - groups , and proved to be cost - effective from the societal perspective in all age - groups , except for those aged 15 - 64 years . from the healthcare provider 's perspective , qiv seemed to be cost - effective in very young ( 6 months  9 years ) and older (  80 years ) age - groups . in italy , a lifetime , multi - cohort , static markov model was constructed , and was run in one - year cycles for a lifetime ( maximum age : 100 years ) . specifically , qiv would be expected to reduce the number of influenza cases ( by about 1,413.887 ) , complications ( by about 169,638 ) , hospitalizations for complications ( by about 41,862 ) and influenza deaths ( by about 20,905 ) . the incremental cost - effectiveness ratio ( icer ) was  18,883/qaly for the base case . influenza b viruses have a considerable public health burden , particularly among children and at - risk subjects . the belief that influenza b illness is less severe than influenza a leads to underestimation of its real impact . however , the type b influenza virus causes 20% to 25% of influenza infections worldwide . since the mid-1980s , surveillance data have shown frequent co - circulation of both influenza b lineages , b / victoria - like and b/ yamagata - like , during influenza seasons . the conventional tivs , containing only a single b strain , showed limited ability to induce effective protection when major or minor mismatches between the influenza b vaccine component and the circulating strains occurred , thus substantially reducing the clinical effectiveness of the trivalent influenza vaccine . the availability of qivs may contribute to overcoming the well - known difficulties of predicting the circulating b lineage and choosing the right influenza b vaccine component in trivalent influenza vaccines ( tivs ) . in recent years , two qivs , an inactivated vaccine and a live - attenuated vaccine , have been developed and licensed for human use on the basis of the good safety , tolerability and immunogenicity profiles demonstrated during the entire pre - marketing research process . in some countries , such as canada , national guidelines now recommend qivs in preference to trivalent vaccines for use in children and young people . available models simulating the inclusion of qivs in influenza immunization programs support the benefits of this new preventive tool in terms of reductions in symptomatic influenza cases and related complications . indeed , qivs could reduce both direct costs in term of medical visits , hospitalizations and antibiotic prescriptions , and indirect costs related to working days lost by affected people and their caregivers . however , some issues need to be addressed in the near future . in particular , estimations from simulation models should be confirmed by effectiveness studies in the field and more cost - effectiveness analyses should be conducted in order to verify the expected advantages in different epidemiological scenarios .
summaryinfluenza illness is caused by influenza a and influenza b strains . 
 although influenza a viruses are perceived to carry greater risk because they account for the majority of influenza cases in most seasons and have been responsible for influenza pandemics , influenza b viruses also impose a substantial public health burden , particularly among children and at - risk subjects . 
 furthermore , since the 2001 - 2002 influenza season , both influenza b lineages , b / victoria - like viruses and b / yamagata - like viruses have co - circulated in europe.the conventional trivalent influenza vaccines have shown a limited ability to induce effective protection when major or minor mismatches between the influenza b vaccine component and circulating strains occur . 
 for this reason , the inclusion of a second b strain in influenza vaccines may help to overcome the well - known difficulties of predicting the circulating b lineage and choosing the influenza b vaccine component.two quadrivalent influenza vaccines , a live - attenuated quadrivalent influenza vaccine ( q / laiv ) and a split inactivated quadrivalent influenza vaccine ( i / qiv ) , were first licensed in the us in 2012 . 
 since their introduction , models simulating the inclusion of qiv in influenza immunization programs have demonstrated the substantial health benefits , in terms of reducing the number of influenza cases , their complications and mortality.in the near future , evaluations from simulation models should be confirmed by effectiveness studies in the field , and more costeffectiveness analyses should be conducted in order to verify the expected benefits .