Immunogenicity, reactogenicity, and safety of inactivated quadrivalent influenza vaccine candidate versus inactivated trivalent influenza vaccine in healthy adults aged ≥18 years: a phase III, randomized trial. Safety and immunogenicity of a quadrivalent inactivated influenza vaccine compared to licensed trivalent inactivated influenza vaccines in adults. 4Flu - an individual based simulation tool to study the effects of quadrivalent vaccination on seasonal influenza in Germany Influenza Vaccine Effectiveness in the United States During 2012–2013: Variable Protection by Age and Virus Type The Cochrane Collaboration’s tool for assessing risk of bias in randomised trials Immunogenicity and safety of quadrivalent versus trivalent inactivated influenza vaccine: a randomized, controlled trial in adults Immunogenicity, reactogenicity and safety of an inactivated quadrivalent influenza vaccine candidate versus inactivated trivalent influenza vaccine: a phase III, randomized trial in adults aged ≥18 years A Randomized Trial of Candidate Inactivated Quadrivalent Influenza Vaccine versus Trivalent Influenza Vaccines in Children Aged 3–17 Years Immune response to inactivated influenza virus vaccine: antibody reactivity with epidemic influenza B viruses of two highly distinct evolutionary lineages. Safety and immunogenicity of a quadrivalent inactivated influenza vaccine in adults. Immunogenicity and Safety of Inactivated Quadrivalent and Trivalent Influenza Vaccines in Children 18–47 Months of Age
BACKGROUND Two influenza B lineages have been co-circulating since the 1980s , and because inactivated trivalent influenza vaccine ( TIV ) contains only one B strain , it provides little/no protection against the alternate B-lineage . We assessed a c and i date inactivated quadrivalent influenza vaccine ( QIV ) containing both B lineages versus TIV in healthy adults . METHODS Subjects received one dose of QIV ( lot 1 , 2 , or 3 ) or one of two TIVs ( B strain from Victoria or Yamagata lineage ) ; r and omization was 2:2:2:1:1 . Hemagglutination-inhibition assays were performed 21-days post-vaccination ; superiority of QIV versus TIV for the alternate B-lineage was demonstrated if the 95 % confidence interval ( CI ) lower limit for the GMT ratio was ≥1.5 , and non-inferiority against the shared strains was demonstrated if the 95 % CI upper limit for the GMT ratio was ≤1.5 . Reactogenicity and safety were assessed during the post-vaccination period . NCT01196975 . RESULTS Immunogenicity of QIV lots was consistent , QIV was superior to TIV for the alternate B-lineage strain , and QIV was non-inferior versus TIVs for shared strains ( A/H1N1 , A/H3N2 , B-strain ) . Reactogenicity and safety profile of the QIV was consistent with seasonal influenza vaccines . CONCLUSION QIV provided superior immunogenicity for the added B strain without affecting the antibody response to the TIV strains , and without compromising safety PURPOSE To evaluate the safety and immunogenicity of a prototype quadrivalent inactivated influenza vaccine ( QIV ) containing two influenza B strains , one of each lineage , compared with licensed trivalent inactivated influenza vaccines ( TIVs ) containing either a Victoria B-lineage strain ( 2009 - 2010 TIV ) or a Yamagata B-lineage strain ( 2008 - 2009 TIV ) . METHODS Healthy adults ≥18 years of age were eligible to participate in this phase II , open-label , r and omized , controlled , multicenter study conducted in the US . Participants received a single dose of 2009 - 2010 TIV , 2008 - 2009 TIV , or QIV . Sera were collected before and 21 days after vaccine administration to test for hemagglutination inhibition ( HAI ) antibodies to each of the four influenza strains . Immunogenicity endpoints included geometric mean HAI antibody titers ( GMTs ) and rates of seroprotection ( titer ≥1:40 ) and seroconversion ( 4-fold rise pre- to post-vaccination ) . Safety endpoints included frequency of solicited injection-site and systemic reactions occurring within 3 days of vaccination , and unsolicited non-serious adverse events ( AEs ) and serious AEs ( SAEs ) within 21 days of vaccination . RESULTS One hundred and ninety participants were enrolled to each vaccine group . QIV induced GMTs to each A and B strain that were noninferior to those induced by the 2009 - 2010 and 2008 - 2009 TIVs ( i.e. , lower limit of the two-sided 95 % confidence interval of the ratio of GMT(QIV)/GMT(TIV)>0.66 for each strain ) . Rates of seroprotection and seroconversion were similar in all groups . Incidence and severity of solicited injection-site and systemic reactions , AEs , and SAEs were similar among groups . CONCLUSION QIV , containing two B strains ( one from each B lineage ) , was as safe and immunogenic as licensed TIV . QIV has the potential to be a useful alternative to TIV and offer protection against both B lineages Background Influenza vaccines contain Influenza A and B antigens and are adjusted annually to match the characteristics of circulating viruses . In Germany , Influenza B viruses belonged to the B/Yamagata lineage , but since 2001 , the antigenically distinct B/Victoria lineage has been co-circulating . Trivalent influenza vaccines ( TIV ) contain antigens of the two A subtypes A(H3N2 ) and A(H1N1 ) , yet of only one B lineage , result ing in frequent vaccine mismatches . Since 2012 , the WHO has been recommending vaccine strains from both B lineages , paving the way for quadrivalent influenza vaccines ( QIV ) . Methods Using an individual-based simulation tool , we simulate the concomitant transmission of four influenza strains , and compare the effects of TIV and QIV on the infection incidence .  Individuals are connected in a dynamically evolving age-dependent contact network based on the POLYMOD matrix ; their age-distribution reproduces German demographic data and predictions . The model considers maternal protection , boosting of existing immunity , loss of immunity , and cross-immunizing events between the B lineages . Calibration to the observed annual infection incidence of 10.6 % among young adults yielded a basic reproduction number of 1.575 . Vaccinations are performed annually in October and November , whereby coverage depends on the vaccinees ’ age , their risk status and previous vaccination status . New drift variants are introduced at r and om time points , leading to a sudden loss of protective immunity for part of the population and occasionally to reduced vaccine efficacy . Simulations run for 50 years , the first 30 of which are used for initialization . During the final 20 years , individuals receive TIV or QIV , using a mirrored simulation approach . Results Using QIV , the mean annual infection incidence can be reduced from 8,943,000 to 8,548,000 , i.e. by 395,000 infections , preventing 11.2 % of all Influenza B infections which still occur with TIV ( 95 % CI : 10.7 - 11.8 % ) . Using a lower B lineage cross protection than the baseline 60 % , the number of Influenza B infections increases and the number additionally prevented by QIV can be 5.5 times as high . Conclusions Vaccination with TIV substantially reduces the Influenza incidence compared to no vaccination . Depending on the assumed degree of B lineage cross protection , QIV further reduces Influenza B incidence by 11 - 33 % Background . During the 2012–2013 influenza season , there was cocirculation of influenza A(H3N2 ) and 2 influenza B lineage viruses in the United States . Methods . Patients with acute cough illness for ≤7 days were prospect ively enrolled and had swab sample s obtained at outpatient clinics in 5 states .  Influenza vaccination date s were confirmed by medical records . The vaccine effectiveness ( VE ) was estimated as [ 100 % × ( 1 − adjusted odds ratio ) ] for vaccination in cases versus test-negative controls . Results . Influenza was detected in 2307 of 6452 patients ( 36 % ) ; 1292 ( 56 % ) had influenza A(H3N2 ) , 582 ( 25 % ) had influenza B/Yamagata , and 303 ( 13 % ) had influenza B/Victoria . VE was 49 % ( 95 % confidence interval [ CI ] , 43%–55 % ) overall , 39 % ( 95 % CI , 29%–47 % ) against influenza A(H3N2 ) , 66 % ( 95 % CI , 58%–73 % ) against influenza B/Yamagata ( vaccine lineage ) , and 51 % ( 95 % CI , 36%–63 % ) against influenza B/Victoria . VE against influenza A(H3N2 ) was highest among persons aged 50–64 years ( 52 % ; 95 % CI , 33%–65 % ) and persons aged 6 months–8 years ( 51 % ; 95 % CI , 32%–64 % ) and lowest among persons aged ≥65 years ( 11 % ; 95 % CI , −41 % to 43 % ) . In younger age groups , there was evidence of residual protection from receipt of the 2011–2012 vaccine 1 year earlier . Conclusions . The 2012–2013 vaccines were moderately effective in most age groups . Cross-lineage protection and residual effects from prior vaccination were observed and warrant further investigation Flaws in the design , conduct , analysis , and reporting of r and omised trials can cause the effect of an intervention to be underestimated or overestimated . The Cochrane Collaboration ’s tool for assessing risk of bias aims to make the process clearer and more Background Two phylogenetic lineages of influenza B virus coexist and circulate in the human population ( B/Yamagata and B/Victoria ) but only one B-strain is included in each seasonal vaccine . Mismatch regularly occurs between the recommended and circulating B-strain . Inclusion of both lineages in vaccines may offer better protection against influenza . Methods This study ( NCT00714285 ) assessed the immunogenicity and safety of two c and i date quadrivalent influenza vaccines ( QIV ) containing two A- and two B-strains ( one from each lineage ) in adults ( 18–60 years ) . Subjects were r and omized and stratified by age to receive either QIV ( non-adjuvanted or low-dose adjuvanted [ LD QIV-AS ] ) or trivalent influenza vaccine ( TIV , non-adjuvanted or low-dose adjuvanted [ LD TIV-AS ] ) , N = 105 in all treatment groups . The study evaluated the statistical non-inferiority of the immunological response elicited by QIV and LD QIV-AS versus TIV and LD TIV-AS and the statistical superiority of the response elicited by the quadrivalent vaccines against the B-strain ( B/Jiangsu ) not included in the TIV . Results Pre-defined non-inferiority and superiority criteria were reached for both QIVs compared to the TIVs . On Day 21 in all vaccine groups SCRs were ≥54.8 % , SPRs ≥88.5 % and SCFs ≥5.4 for the A strains and B strain included in all vaccines ( B/Malaysia ) . This fulfilled the European ( CHMP ) and the US ( CBER ) licensing criteria for the assessment of influenza vaccines in adults ( CHMP criteria : SCR > 40 % , SPR > 70 % , SCF > 2 ; CBER criteria : LL of 95 % CI for SPR ≥ 70 % or SCR ≥ 40 % ) . Only the QIVs met the CHMP and CBER criteria for the B/Jiangsu strain . In the QIV and LD-QIV-AS groups , the SCFs were 9.1 and 8.1 , respectively and the SPRs were 98.1 % and 95.2 % , whereas for the TIV and LD-TIV-AS groups , the SCFs were 2.3 and 2.5 , respectively , and the SPRs were 75.0 % and 63.8 % , with the LLs of the 95 % CI < 70 % for SPR and < 40 % for SCR . Conclusions Addition of a fourth strain did not impact the immune response elicited by the three original strains contained in the TIV . A clear immunological benefit was seen with the QIV formulation for the second B-strain , indicating that quadrivalent vaccines could provide broader protection against influenza . Trial registration Clinical Trials.gov : Background Two antigenically distinct influenza B lineages have co-circulated since the 1980s , yet inactivated trivalent influenza vaccines ( TIVs ) include strains of influenza A/H1N1 , A/H3N2 , and only one influenza B from either the Victoria or Yamagata lineage . This means that exposure to B-lineage viruses mismatched to the TIV is frequent , reducing vaccine protection . Formulations including both influenza B lineages could improve protection against circulating influenza B viruses . We assessed a c and i date inactivated quadrivalent influenza vaccine ( QIV ) containing both B lineages versus TIV in adults in stable health . Methods A total of 4659 adults were r and omized 5:5:5:5:3 to receive one dose of QIV ( one of three lots ) or a TIV containing either a B/Victoria or B/Yamagata strain . Hemagglutination-inhibition assays were performed pre-vaccination and 21-days after vaccination . Lot-to-lot consistency of QIV was assessed based on geometric mean titers ( GMT ) . For QIV versus TIV , non-inferiority against the three shared strains was demonstrated if the 95 % confidence interval ( CI ) upper limit for the GMT ratio was ≤1.5 and for the seroconversion difference was ≤10.0 % ; superiority of QIV versus TIV for the alternate B lineage was demonstrated if the 95 % CI lower limit for the GMT ratio was > 1.0 and for the seroconversion difference was > 0 % . Reactogenicity and safety profile of each vaccine were assessed . Clinical trials.gov : NCT01204671 . Results Consistent immunogenicity was demonstrated for the three QIV lots . QIV was non-inferior to TIV for the shared vaccine strains , and was superior for the added alternate-lineage B strains . QIV elicited robust immune responses against all four vaccine strains ; the seroconversion rates were 77.5 % ( A/H1N1 ) , 71.5 % ( A/H3N2 ) , 58.1 % ( B/Victoria ) , and 61.7 % ( B/Yamagata ) . The reactogenicity and safety profile of QIV was consistent with TIV . Conclusions QIV provided superior immunogenicity for the additional B strain compared with TIV , without interfering with antibody responses to the three shared antigens . The additional antigen did not appear to alter the safety profile of QIV compared with TIV . This suggests that the c and i date QIV is a viable alternative to TIV for use in adults , and could potentially improve protection against influenza B.Trial registration Clinical Trials.gov : Background . Two antigenically distinct influenza B lineages have cocirculated since 2001 , yet trivalent influenza vaccines ( TIVs ) contain 1 influenza B antigen , meaning lineage mismatch with the vaccine is frequent . We assessed a c and i date inactivated quadrivalent influenza vaccine ( QIV ) containing both B lineages vs TIV in healthy children aged 3–17 years . Methods . Children were r and omized 1:1:1 to receive QIV or 1 of 2 TIVs ( either B/Victoria or B/Yamagata lineage ; N = 2738 ) .  Hemagglutination-inhibition assays were performed 28 days after 1 or 2 doses in primed and unprimed children , respectively . Immunological noninferiority of QIV vs TIV against shared strains , and superiority against alternate-lineage B strains was based on geometric mean titers ( GMTs ) and seroconversion rates . Reactogenicity and safety were also assessed ( Clinical trials.gov NCT01196988 ) . Results . Noninferiority against shared strains and superiority against alternate-lineage B strains was demonstrated for QIV vs TIV . QIV was highly immunogenic ; seroconversion rates were 91.4 % , 72.3 % , 70.0 % , and 72.5 % against A/H1N1 , A/H3N2 , B/Victoria , and B/Yamagata , respectively . Reactogenicity and safety of QIV was consistent with TIV . Conclusions . QIV vs TIV showed superior immunogenicity for the additional B strain without interfering with immune responses to shared strains . QIV may offer improved protection against influenza B in children compared with current trivalent vaccines Vaccination of adults ( healthy female employees potentially capable of transmitting influenza to high-risk persons ; n = 104 ) in autumn 1990 with a trivalent influenza virus vaccine containing B/Yamagata/16/88 induced a low antibody response to B/Finl and /150/90 , a recent variant of B/Victoria/2/87-like viruses , as compared with the antibody response to B/Finl and /172/91 , a current variant in the lineage of B/Yamagata/16/88-like viruses . Up to the end of the epidemic season , the antibody status declined but was still significantly better than before the vaccination . The results suggest that the vaccine strain was appropriate for the outbreak of 1990 to 1991 in Finl and , but may provide unsatisfactory protection against B/Victoria/2/87-like viruses . Evidence is given that use of Madin-Darby canine kidney (MDCK)-grown virus as an antigen in the haemagglutination inhibition test ( HI ) may provide more reliable information about the protective antibodies than use of untreated or ether-treated egg-grown viruses . Significantly higher postvaccination and postepidemic antibody titres were recorded among subjects who exhibited the antibody before vaccination than among seronegative subjects . A significantly higher response rate among initially seronegative people than among seropositive people was recorded for antibody to B/Finl and /150/90 , but no clear evidence was obtained that the pre-existing antibody could have had a negative effect on the antibody production BACKGROUND AND AIMS Although two antigenically distinct B strain lineages of influenza have co-circulated globally since the mid-1980s , trivalent influenza vaccines ( TIVs ) contain only one , result ing in frequent mismatches . This study examined the safety and immunogenicity of an inactivated quadrivalent influenza vaccine ( QIV ) c and i date . METHODS This was a phase III , r and omized , active-controlled , multicenter trial in adults during the 2011/2012 influenza season . Enrollment was stratified to include equal numbers of subjects 18 - 60 and > 60 years of age . Subjects were r and omized 5:1:1 to be vaccinated with the QIV , the licensed TIV , or an investigational TIV containing the alternate B strain lineage .  Hemagglutinin inhibition antibody titers were assessed pre-vaccination and 21 days post-vaccination . RESULTS 1116 subjects were vaccinated with QIV , 226 with the licensed TIV , and 223 with the investigational TIV . For all four vaccine strains , antibody responses to the QIV were non-inferior to the response to the TIV for the matched strains . For both B strains , post-vaccination antibody responses to the QIV were superior to the responses to the TIVs lacking the corresponding B strain . The QIV met all European Medicines Agency criteria for all four vaccine strains . Solicited reactions , unsolicited adverse events , and serious adverse events were similar for the QIV and pooled TIV groups . The most commonly reported solicited reactions were injection-site pain , headache , and myalgia , and most solicited reactions were mild or moderate and appeared and resolved within 3 days of vaccination . No treatment-related serious adverse events or deaths were reported . CONCLUSIONS The inactivated QIV was well tolerated without any safety concerns . For all four vaccine strains , antibody responses to the QIV were superior to the responses to TIV for the unmatched strains and non-inferior for the matched strains . QIV could therefore help address an unmet need due to mismatched B strains in previous influenza vaccines . CLINICAL TRIAL REGISTRY NUMBER EudraCT : 2011 - 001976 - 21 Background : Because inactivated trivalent influenza vaccines ( TIVs ) contain 1 influenza B strain , whereas 2 lineages may co-circulate , B lineage mismatch is frequent . We assessed an inactivated quadrivalent influenza vaccine ( QIV ) containing both B lineages versus TIV in young children . Methods : Children aged 18−47 months who had received 2 doses of TIV in a study during the previous season ( primed cohort , n = 192 ) were r and omized 1:1 to receive 1 dose of TIV or QIV  , and a further 407 children ( unprimed cohort ) were r and omized 1:1 to receive 2 doses of TIV or QIV 28 days apart  . Immunogenicity was assessed by hemagglutination-inhibition ( HI ) prevaccination and 28 days after each vaccination . Immunogenic non-inferiority QIV versus TIV for shared strains , and superiority against the alternate-lineage B strain were based on HI geometric mean titers ( pooled analyses of primed and half of unprimed cohort with Day 56 immunogenicity assessment ) . Solicited and unsolicited adverse events were assessed during each 7- and 28-day postvaccination period , respectively ( NCT00985790 ) . Results : Non-inferiority for shared strains and superiority for the alternate-lineage B strain unique to QIV was demonstrated for QIV versus TIV . QIV was immunogenic against all 4 vaccine strains and 87.0 % , 88.6 % , 69.8 % and 97.9 % of children had postvaccination titers of ≥1:40 against A/H1N1 , A/H3N2 , B/Victoria and B/Yamagata , respectively . Reactogenicity and safety of QIV was consistent with TIV . Conclusions : QIV provided superior immunogenicity for the alternate-lineage B strain compared with TIV without interfering with immune responses to shared strains . Further studies are warranted to assess QIVs in children and to establish the clinical benefits of QIV versus TIV
BACKGROUND A quadrivalent influenza vaccine ( QIV ) includes two A strains ( A/H1N1 , A/H3N2 ) and two B lineages ( B/Victoria , B/Yamagata ) .
The presence of both B lineages eliminate potential B lineage mismatch of trivalent influenza vaccine ( TIV ) with the circulating strain .