Enhanced Immunogenicity of Seasonal Influenza Vaccines in Young Children Using MF59 Adjuvant Relative Efficacy of AS03-Adjuvanted Pandemic Influenza A(H1N1) Vaccine in Children: Results of a Controlled, Randomized Efficacy Trial Safety and immunogenicity of AS03B adjuvanted split virion versus non-adjuvanted whole virion H1N1 influenza vaccine in UK children aged 6 months-12 years: open label, randomised, parallel group, multicentre study MF59-adjuvanted influenza vaccine (FLUAD®) elicits higher immune responses than a non-adjuvanted influenza vaccine (Fluzone®): A randomized, multicenter, Phase III pediatric trial in Mexico AMSTAR 2: a critical appraisal tool for systematic reviews that include randomised or non-randomised studies of healthcare interventions, or both Immunogenicity and reactogenicity of 1 versus 2 doses of trivalent inactivated influenza vaccine in vaccine-naive 5-8-year-old children. Randomized, Multicenter Trial of a Single Dose of AS03-adjuvanted or Unadjuvanted H1N1 2009 Pandemic Influenza Vaccine in Children 6 Months to <9 Years of Age: Safety and Immunogenicity A dose- and schedule-finding study of darbepoetin alpha for the treatment of chronic anaemia of cancer The efficacy of live attenuated, cold-adapted, trivalent, intranasal influenzavirus vaccine in children. Enhanced and persistent antibody response against homologous and heterologous strains elicited by a MF59-adjuvanted influenza vaccine in infants and young children. Dissecting the Immune Response to MF59-adjuvanted and Nonadjuvanted Seasonal Influenza Vaccines in Children Less Than Three Years of Age Dose-range Study of MF59-adjuvanted Versus Nonadjuvanted Monovalent A/H1N1 Pandemic Influenza Vaccine in Six- to Less Than Thirty-Six-month-old Children Antibodies to influenza nucleoprotein cross-react with human hypocretin receptor 2 Influenza vaccination in children primed with MF59®-adjuvanted or non-adjuvanted seasonal influenza vaccine AS03-adjuvanted versus non-adjuvanted inactivated trivalent influenza vaccine against seasonal influenza in elderly people: a phase 3 randomised trial. Immunogenicity and safety of cell-derived MF59®-adjuvanted A/H1N1 influenza vaccine for children Open-label, randomised, parallel-group, multicentre study to evaluate the safety, tolerability and immunogenicity of an AS03(B)/oil-in-water emulsion-adjuvanted (AS03(B)) split-virion versus non-adjuvanted whole-virion H1N1 influenza vaccine in UK children 6 months to 12 years of age. Assessment of the safety, tolerability and kinetics of the immune response to A/H1N1v vaccine formulations with and without adjuvant in healthy pediatric subjects from 3 through 17 years of age Immunogenicity and safety of MF59-adjuvanted and full-dose unadjuvanted trivalent inactivated influenza vaccines among vaccine-naïve children in a randomized clinical trial in rural Senegal. Oil-in-water emulsion adjuvant with influenza vaccine in young children.
Background : Children have high morbidity and hospitalization rates from seasonal influenza . Meta-analyses suggest that conventional inactivated influenza vaccines are of low efficacy in young children , making vaccines that induce greater and broader immune protection in this vulnerable population a medical priority . Adjuvanted influenza vaccines may offer a solution . Subjects and Methods : Unprimed healthy children ( 6 to < 36 months ) were enrolled in an observer-blinded study and r and omly assigned to receive 2 doses of MF59-adjuvanted vaccine ( Sub/MF59 , n = 130 ) or nonadjuvanted split vaccine ( split , n = 139 ) ; subgroups of these ( n = 43 and 46 , respectively ) received a booster dose 1 year later . Safety and clinical tolerability were assessed after each dose . Hemagglutination inhibition antibody titers were measured against influenza A and B strains included in the formulation of the vaccines and against mismatched strains . Results : Clinical tolerability and safety were generally comparable between vaccine groups , though some transient , mild solicited reactions were more frequent in the Sub/MF59 group . Postvaccination hemagglutination inhibition antibody titers to all 3 vaccine strains were significantly higher with Sub/MF59 than with split vaccine ( all comparisons P < 0.001 ) after each of the 3 vaccine doses . In addition , Sub/MF59 induced significantly higher cross-reactivity against A/H3N2 and A/H1N1 mismatched strains . Conclusion : MF59-adjuvanted influenza vaccine was well tolerated in healthy young children after each of 3 doses and induced greater , longer-lasting , and broader immune responses than a nonadjuvanted split vaccine . The enhanced immunogenicity of the adjuvanted vaccine was most evident in very young children and for the B vaccine strain Abstract Background . The vaccine efficacy ( VE ) of 1 or 2 doses of AS03-adjuvanted influenza A(H1N1 ) vaccine relative to that of 2 doses of nonadjuvanted influenza A(H1N1 ) vaccine in children 6 months to < 10 years of age in a multinational study conducted during 2010–2011 . Methods . A total of 6145 children were r and omly assigned at a ratio of 1:1:1 to receive 2 injections 21 days apart of A/California/7/2009(H1N1)-AS03 vaccine at dose 1 and saline placebo at dose 2 , 2 doses 21 days apart of A/California/7/2009(H1N1)-AS03 vaccine ( the Ad2 group ) , or 2 doses 21 days apart of nonadjuvanted A/California/7/2009(H1N1 ) vaccine ( the NAd2 group ) . Active surveillance for influenza-like illnesses continued from days 14 to 385 . Nose and throat sample s obtained during influenza-like illnesses were tested for A/California/7/2009(H1N1 ) , using reverse-transcriptase polymerase chain reaction . Immunogenicity , reactogenicity , and safety were assessed . Results . There were 23 cases of confirmed 2009 p and emic influenza A(H1N1 ) ( A[H1N1]pdm09 ) infection for the primary relative VE analysis . The VE in the Ad2 group relative to that in the NAd2 group was 76.8 % ( 95 % confidence interval , 18.5%–93.4 % ) . The benefit of the AS03 adjuvant was demonstrated in terms of the greater immunogenicity observed in the Ad2 group , compared with the NAd2 group . Conclusion . The 4–8-fold antigen-sparing adjuvanted p and emic influenza vaccine demonstrated superior and clinical ly important prevention of A(H1N1)pdm09 infection , compared with nonadjuvanted vaccine , with no observed increase in medically attended or serious adverse events . These data support the use of adjuvanted influenza vaccines during influenza p and emics . Clinical Trials Registration . NCT01051661 Objectives To compare the safety , reactogenicity , and immunogenicity of an adjuvanted split virion H1N1 vaccine and a non-adjuvanted whole virion vaccine used in the p and emic immunisation programme in the United Kingdom . Design Open label , r and omised , parallel group , phase II study . Setting Five UK centres ( Oxford , Southampton , Bristol , Exeter , and London ) . Participants Children aged 6 months to less than 13 years for whom a parent or guardian had provided written informed consent and who were able to comply with study procedures were eligible . Those with laboratory confirmed p and emic H1N1 influenza or clinical ly diagnosed disease meriting antiviral treatment , allergy to egg or any other vaccine components , or coagulation defects , or who were severely immunocompromised or had recently received blood products were excluded . Children were grouped by age : 6 months-<3 years ( younger group ) and 3-<13 years ( older group ) . Recruitment was by media advertising and direct mailing . Recruitment visits were attended by 949 participants , of whom 943 were enrolled and 937 included in the per protocol analysis . Interventions Participants were r and omised 1:1 to receive AS03B ( tocopherol based oil in water emulsion ) adjuvanted split virion vaccine derived from egg culture or non-adjuvanted whole virion vaccine derived from cell culture . Both were given as two doses 21 days apart . Reactogenicity data were collected for one week after immunisation by diary card . Serum sample s were collected at baseline and after the second dose . Main outcome measures Primary reactogenicity end points were frequency and severity of fever , tenderness , swelling , and erythema after vaccination . Immunogenicity was measured by microneutralisation and haemagglutination inhibition assays . The primary immunogenicity objective was a comparison between vaccines of the percentage of participants showing seroconversion by the microneutralisation assay ( fourfold rise to a titre of ≥1:40 from before vaccination to three weeks after the second dose ) . Results Seroconversion rates were higher after the adjuvanted split virion vaccine than after the whole virion vaccine , most notably in the youngest children ( 163 of 166 participants with paired serum sample s ( 98.2 % , 95 % confidence interval 94.8 % to 99.6 % ) v 157 of 196 ( 80.1 % , 73.8 % to 85.5 % ) , P<0.001 ) in children under 3 years and 226 of 228 ( 99.1 % , 96.9 % to 99.9 % ) v 95.9 % , 92.4 % to 98.1 % , P=0.03 ) in those over 3 years ) . The adjuvanted split virion vaccine was more reactogenic than the whole virion vaccine , with more frequent systemic reactions and severe local reactions in children aged over 5 years after dose one ( 13 ( 7.2 % , 3.9 % to 12 % ) v 2 ( 1.1 % , 0.1 % to 3.9 % ) , P<0.001 ) and dose two ( 15 ( 8.5 % , 4.8 % to 13.7 % ) v 2 ( 1.1 % , 0.1 % to 4.1 % ) , P<0.002 ) and after dose two in those under 5 years ( 15 ( 5.9 % , 3.3 % to 9.6 % ) v 0 ( 0.0 % , 0 % to 1.4 % ) , P<0.001 ) . Dose two of the adjuvanted split virion vaccine was more reactogenic than dose one , especially for fever ≥38ºC in those aged under 5 ( 24 ( 8.9 % , 5.8 % to 12.9 % ) v 57 ( 22.4 % , 17.5 % to 28.1 % ) , P<0.001 ) . Conclusions In this first direct comparison of an AS03B adjuvanted split virion versus whole virion non-adjuvanted H1N1 vaccine , the adjuvanted vaccine , while more reactogenic , was more immunogenic and , importantly , achieved high seroconversion rates in children aged less than 3 years . This indicates the potential for improved immunogenicity of influenza vaccines in this age group . Trial registration Clinical trials.gov NCT00980850 ; IS RCT N89141709 ABSTRACT The poor immune response elicited by trivalent influenza vaccines ( TIVs )  in children can be enhanced by the addition of adjuvants . This observer-blind , r and omized Phase III trial assessed the immunogenicity and safety of the MF59-adjuvanted trivalent influenza vaccine FLUAD ® ( aTIV ) and a non-adjuvanted TIV , in healthy children ( aged 6 to < 72 months ) from 3 centers in Mexico , during the 2014–2015 season . The primary objectives were to assess the non-inferiority of aTIV to TIV  , measured by geometric mean titers ( GMTs ) , and the safety of aTIV and  TIV . Seroconversion was one of several secondary objectives . In total , 287 children were enrolled . The non-inferiority criteria for GMTs and seroconversion were met for aTIV for all 3 vaccine strains . Lower bounds of the 95 % confidence intervals for all 3 aTIV : TIV vaccine ratios were > 2 , showing that the immunogenicity of aTIV was superior to that of TIV for all 3 strains . Solicited adverse events ( AEs ) were experienced more frequently with aTIV than TIV by younger children ( aged 6 to < 36 months ) , but were more frequent with TIV than aTIV in older children ( aged 36 to < 72 months ) who had been vaccinated previously . More unsolicited AEs were associated with aTIV than the TIV . All AEs were of mild or moderate severity . No deaths , serious AEs , or AEs leading to premature withdrawal were reported . Overall , aTIV was highly immunogenic and was well tolerated in healthy children 6 to < 72 months of age . These results indicate that aTIV may be a beneficial addition to national pediatric vaccination programs The number of published systematic review s of studies of healthcare interventions has increased rapidly and these are used extensively for clinical and policy decisions . Systematic review s are subject to a range of biases and increasingly include non-r and omised studies of interventions . It is important that users can distinguish high quality review s. Many instruments have been design ed to evaluate different aspects of review s , but there are few comprehensive critical appraisal instruments . AMSTAR was developed to evaluate systematic review s of r and omised trials . In this paper , we report on the updating of AMSTAR and its adaptation to enable more detailed assessment of systematic review s that include r and omised or non-r and omised studies of healthcare interventions , or both . With moves to base more decisions on real world observational evidence we believe that AMSTAR 2 will assist decision makers in the identification of high quality systematic review s , including those based on non-r and omised studies of healthcare interventions BACKGROUND Two doses of trivalent inactivated influenza vaccine ( TIV ) are recommended for children < 9 years old receiving vaccine for the first time , but compliance is suboptimal . This study assessed the need for a second dose of TIV in this age group . METHODS In this prospect i ve , open-label study , 232 influenza vaccine-naive 5 - 8-year-olds enrolled in a health maintenance organization received 2 doses of TIV in fall 2004 .  Serum for antibody titer measurement was obtained at 3 time points ( n = 222 ) . Parents completed diaries for 5 days . RESULTS Both doses of vaccine were well tolerated . The strongest predictor of a protective antibody response ( > or = 1 : 40 ) after 1 dose of TIV was baseline seropositive status . In multivariate analysis adjusting for age , sex , and baseline serostatus , the proportion of children with protective antibody responses was significantly higher after 2 doses than after 1 dose of TIV for each antigen ( P < .001 , for A/H1N1 ; P = .01 , for A/H3N2 ; P < .001 , for B ) . Age and sex were not independently predictive of a protective antibody response . Over one-third of children had antibody responses < 1:40 for the type B vaccine component , even after 2 doses . CONCLUSIONS The present study supports the need for 2 doses of TIV in 5 - 8-year-olds receiving TIV for the first time . Efforts to increase compliance with the 2-dose recommendation are warranted Background : During the 2009–2010 influenza p and emic , we evaluated the immunogenicity and safety of different H1N1 2009 p and emic influenza vaccines delivering various viral hemagglutinin ( HA ) doses with or without AS03 ( a tocopherol oil-in-water emulsion – based adjuvant system ) in children ( NCT00976820 ) . Methods : Three hundred twenty-two healthy children 6 months to < 9 years of age were r and omized to receive 2 doses of nonadjuvanted ( 15 µg or 7.5 µg HA ) or adjuvanted vaccine ( 3.75 µg HA/AS03A or 1.9 µg HA/AS03B ) , 21 days apart . Blood sample s before and after each dose were tested for immune responses using hemagglutination inhibition and microneutralization assays . Safety assessment s were done up to day 385 . Results : The first dose of both AS03-adjuvanted vaccines elicited strong immune responses ( seroprotection rates : 98.3%/99.0 % ; seroconversion rates : 94.9%/97.0 % ; geometric mean fold rises : 36.2/33.6 ) , which were higher post-dose 2 ( seroprotection rate : 100.0%/100 % ; seroconversion rate : 100.0%/98.8 % ; geometric mean fold rise : 157.1/151.6 ) , meeting European regulatory criteria on days 21 and 42 . The nonadjuvanted 15 µg HA vaccine also met the regulatory criteria after each dose ; the 7.5 µg HA vaccine met them only post-dose 2 . Six months post-dose 1 , all vaccines except the nonadjuvanted 7.5 µg HA vaccine met European regulatory criteria . Neutralizing antibody response paralleled the hemagglutination inhibition immune response after each dose . Pain at the injection site , lasting 2–3 days , was more common following adjuvanted than nonadjuvanted vaccination . Conclusions : AS03-adjuvanted H1N1 2009 p and emic influenza vaccine ( 3.75 µg or 1.9 µg HA ) , administered as 2 doses , was highly immunogenic , induced long-term immune response to 6 months , with a clinical ly acceptable safety profile in children aged 6 months to < 9 years of age A multicentre study evaluated the efficacy and safety of darbepoetin alpha administered weekly ( QW ) , every 3 weeks ( Q3W ) , and every 4 weeks ( Q4W ) to anaemic patients with cancer not concurrently receiving chemotherapy or radiotherapy . The QW portion ( n=102 ) was an open-label , sequential , dose-escalation design ; cohorts received darbepoetin alpha QW by subcutaneous ( s.c . ) injection at 0.5 , 1.0 , 2.25 , or 4.5 μg kg−1 week−1 for 12 weeks . The 12-week placebo-controlled , double – blind Q3W ( 6.75 μg kg−1 ) and Q4W ( 6.75 or 10.0 μg kg−1 ) schedules ( n=86 ) , which enrolled different patients , took place after the QW schedule and were followed by a 12-week , open-label phase . Patients were evaluated for change in haemoglobin end points and red blood cell transfusions , serum darbepoetin alpha concentration , and safety . Selected domains of health-related quality of life ( HRQOL ) were measured . With QW dosing , at least 70 % of each cohort had a haemoglobin increase from baseline of ⩾2 g dl−1 or a concentration ⩾12 g dl−1 ( haematopoietic response ) . In the 4.5 μg kg−1 QW cohort , all patients achieved a haematopoietic response ( 100 % ; 95 % confidence interval (CI)=100 , 100 ) . In the Q3W and Q4W schedules , all cohorts had at least 60 % of patients who achieved a haematopoietic response .  Darbepoetin alpha effectively increases haemoglobin concentration when given QW , Q3W , or Q4W . Less-frequent administration may benefit patients with chronic anaemia of cancer and their caregivers alike BACKGROUND Influenzavirus vaccine is used infrequently in healthy children , even though the rates of influenza in this group are high . We conducted a multicenter , double-blind , placebo-controlled trial of a live attenuated , cold-adapted , trivalent influenzavirus vaccine in children 15 to 71 months old . METHODS Two hundred eighty-eight children were assigned to receive one dose of vaccine or placebo given by intranasal spray , and 1314 were assigned to receive two doses approximately 60 days apart . The strains included in the vaccine were antigenically equivalent to those in the inactivated influenzavirus vaccine in use at the time . The subjects were monitored with viral cultures for influenza during the subsequent influenza season . A case of influenza was defined as an illness associated with the isolation of wild-type influenzavirus from respiratory secretions . RESULTS The intranasal vaccine was accepted and well tolerated . Among children who were initially seronegative , antibody titers increased by a factor of four in 61 to 96 percent , depending on the influenza strain . Culture-positive influenza was significantly less common in the vaccine group ( 14 cases among 1070 subjects ) than the placebo group ( 95 cases among 532 subjects ) . The vaccine efficacy was 93 percent ( 95 percent confidence interval , 88 to 96 percent ) against culture-confirmed influenza . Both the one-dose regimen ( 89 percent efficacy ) and the two-dose regimen ( 94 percent efficacy ) were efficacious , and the vaccine was efficacious against both strains of influenza circulating in 1996 - 1997 , A(H3N2 ) and B. The vaccinated children had significantly fewer febrile illnesses , including 30 percent fewer episodes of febrile otitis media ( 95 percent confidence interval , 18 to 45 percent ; P<0.001 ) . CONCLUSIONS A live attenuated , cold-adapted influenzavirus vaccine was safe , immunogenic , and effective against influenza A(H3N2 ) and B in healthy children BACKGROUND Non-adjuvanted seasonal influenza vaccines show only modest efficacy in young children . This study compared the immunogenicity , reactogenicity and safety of the MF59-adjuvanted trivalent subunit vaccine ( aTIV ) with two non-adjuvanted trivalent vaccines , TIV-1 , the non-adjuvanted version of aTIV , and TIV-2 , a split virion vaccine . METHODS 6078 children received two doses of aTIV ( n=3125 ) , TIV-1 ( n=1479 ) , or TIV-2 ( n=1474 ) four weeks apart ( Days 1 and 29 ) . Children aged 6 to < 36 months and 36 to < 72 months received 0.25 mL and 0.50 mL doses , respectively . Immunogenicity was assessed by hemagglutination inhibition ( HI ) assay ( n=2435 ) on Days 1 , 29 , 50 and 209 . Safety was assessed up to Day 394 . RESULTS After the second vaccination ( Day 50 ) , the aTIV group showed significantly higher geometric mean HI titers and seroconversion rates than the TIV-1 or TIV-2 groups against all homologous and heterologous strains . The difference was enhanced at HI titers ≥110 . aTIV elicited a faster , more persistent antibody response , with significantly higher titers in the aTIV group after one vaccination ( Day 29 ) and after six months ( Day 209 ) than in either TIV group . aTIV was more reactogenic than were TIV-1 and TIV-2 but rates of severe adverse events were very low for all three vaccines . CONCLUSION In infants and young children , the MF59-adjuvanted vaccine induced substantially faster ( after one dose ) , higher , persistent HI titers than the non-adjuvanted vaccines , with consistently higher seroprotection rates at increased threshold HI titers . This trial is registered at clinical trials.gov : NCT01346592 Introduction : Annual seasonal influenza epidemics are particularly dangerous for the very young , the elderly and chronically ill individuals , in whom infection can cause severe morbidity , hospitalization and death . Existing , nonadjuvanted influenza vaccines exhibit a suboptimal immunogenicity and efficacy in immunologically naive subjects such as young children . Methods : This phase II , r and omized clinical trial was conducted to evaluate the antibody and cell-mediated responses to a trivalent influenza vaccine administered without adjuvant ( TIV ) or adjuvanted with MF59 ( ATIV ) in previously nonvaccinated children less than 3 years of age . Results : The MF59-adjuvanted vaccine was well tolerated , and induced higher titers of hemagglutination inhibition antibodies able to recognize strains different from the one used in the vaccine ( heterovariant ) than TIV . The presence of the adjuvant MF59 induced a larger expansion of vaccine-specific CD4 + T cells . Interestingly , the adjuvant MF59 did not modify the cytokine profile of the elicited T cells , characterized by the production of IL-2 and TNF-&agr ; , and did not bias the response toward either Th1 or Th2 . The advantage of ATIV over TIV was more pronounced for the virus strains that had not circulated in the years that preceded this study and for the heterovariant strains . Conclusion : These data highlight the relevant role played by the oil-in-water adjuvant MF59 in enhancing the immunogenicity of inactivated influenza vaccines in immunologically naive individuals Background : The successful vaccination of children 6 to 36 months of age against 2009 A/H1N1 influenza was essential to help reduce the burden of p and emic disease in both the pediatric and adult population s. Objectives : We compared the immunogenicity and safety of 4 alternative monovalent vaccine formulations to identify which provided optimal levels of seroprotection according to the US and European Union ( EU ) licensure criteria . Subjects and Methods : A total of 654 healthy subjects ( 6 to < 36 months old ) were given 2 vaccine doses 3 weeks apart . Participants were assigned to 1 of the 4 immunization groups , receiving MF59-adjuvanted ( Novartis Vaccines , Marburg , Germany ) vaccine either containing 3.75 & mgr;g or 7.5 & mgr;g of A/H1N1 California/7/2009 antigen , or nonadjuvanted vaccine containing 7.5 & mgr;g or 15 & mgr;g of antigen .  Antibody titers were assessed by hemagglutination inhibition assay 3 weeks , 3 months and 1 year after immunization . Vaccine safety was monitored throughout the study . Results : After 1 dose , both adjuvanted formulations met the US and EU criteria for seroconversion ; the 15 & mgr;g nonadjuvanted vaccine met the EU criterion for seroconversion alone . The US and EU criteria for seroprotection were only met by adjuvanted groups . MF59-adjuvanted formulations alone result ed in clinical ly significant persisting antibody titers after 12 months . All vaccines were well tolerated . Conclusions : A single dose of MF59-adjuvanted vaccine containing 3.75 & mgr;g A/H1N1 antigen was highly immunogenic , met both the US and EU licensure criteria and was well tolerated . These data support the suitability of this monovalent vaccine formulation for p and emic use in children 6 to < 36 months of age Similarity between influenza nucleoprotein and hypocretin receptor 2 may trigger vaccine-associated narcolepsy . Immunological mistaken identity New reports of narcolepsy increased after the vaccination campaign against the 2009 A(H1N1 ) influenza p and emic in some countries but not others . Now Ahmed et al. examine differences between the vaccines used and find a potential mechanistic explanation for the vaccine-specific effect . They found a peptide in influenza nucleopeptide A that shared protein residues with human hypocretin receptor 2 , which has been linked to narcolepsy . The vaccine used in unaffected countries contained less influenza nucleoprotein . Indeed , patients with putative vaccine-associated narcolepsy produced antibodies that cross-reacted to both the influenza and the hypocretin receptor 2 epitopes . Although these data do not demonstrate causation , they provide a possible explanation for the association of this particular influenza vaccination with increased reports of narcolepsy . The sleep disorder narcolepsy is linked to the HLA-DQB1 * 0602 haplotype and dysregulation of the hypocretin lig and -hypocretin receptor pathway . Narcolepsy was associated with P and emrix vaccination ( an adjuvanted , influenza p and emic vaccine ) and also with infection by influenza virus during the 2009 A(H1N1 ) influenza p and emic . In contrast , very few cases were reported after Focetria vaccination ( a differently manufactured adjuvanted influenza p and emic vaccine ) . We hypothesized that differences between these vaccines ( which are derived from inactivated influenza viral proteins ) explain the association of narcolepsy with P and emrix-vaccinated subjects . A mimic peptide was identified from a surface-exposed region of influenza nucleoprotein A that shared protein residues in common with a fragment of the first extracellular domain of hypocretin receptor 2 . A significant proportion of sera from HLA-DQB1 * 0602 haplotype – positive narcoleptic Finnish patients with a history of P and emrix vaccination  ( vaccine-associated narcolepsy ) contained antibodies to hypocretin receptor 2 compared to sera from nonnarcoleptic individuals with either 2009 A(H1N1 ) p and emic influenza infection or history of Focetria vaccination . Antibodies from vaccine-associated narcolepsy sera cross-reacted with both influenza nucleoprotein and hypocretin receptor 2 , which was demonstrated by competitive binding using 21-mer peptide ( containing the identified nucleoprotein mimic ) and 55-mer recombinant peptide ( first extracellular domain of hypocretin receptor 2 ) on cell lines expressing human hypocretin receptor 2 . Mass spectrometry indicated that relative to P and emrix , Focetria contained 72.7 % less influenza nucleoprotein . In accord , no durable antibody responses to nucleoprotein were detected in sera from Focetria-vaccinated nonnarcoleptic subjects . Thus , differences in vaccine nucleoprotein content and respective immune response may explain the narcolepsy association with P and emrix Routine annual influenza immunization is increasingly recommended in young children . We compared the safety and immunogenicity of vaccination with trivalent inactivated influenza vaccine ( TIV ) versus MF59-adjuvanted TIV ( aTIV ) in children who received 2 half or full doses of aTIV or TIV , or non-influenza control vaccine  , in an efficacy trial conducted 2 years earlier . 197 healthy children aged 30–96 months were r and omized to receive vaccination with aTIV or TIV in 2010 . To evaluate responses to the first follow-up seasonal vaccination after priming we excluded children who received influenza vaccine(s ) in the 2009 p and emic year leaving 40 children vaccinated with aTIV , 26 children with TIV and 10 children with aTIV after a control vaccine in the parent study .  Hemagglutination inhibiting antibodies were assayed on Days 1 , 22 and 181 . aTIV vaccination produced 6.9 to 8.0-fold higher antibody responses than the reference TIV-TIV regimen against A/H3N2 and B strains , which remained higher 6 months following vaccination . The response to the B/Victoria lineage antigen in the second year 's vaccine ( the first vaccine contained a B/Yamagata lineage antigen ) demonstrated that aTIV primed for an adequate response after a single dose on Day 22 ( GMTs 160 , 95 to antigens in the 2 lineages , respectively ) , whereas TIV did not ( GMTs 38 , 20 ) . Vaccination with aTIV produced slightly higher but acceptable local and systemic reactogenicity compared to TIV-TIV and TIV-aTIV mixed regimens . Within the limitations of a small study , the strong immune responses support the use of aTIV for vaccination in young children BACKGROUND We aim ed to compare AS03-adjuvanted inactivated trivalent influenza vaccine ( TIV ) with non-adjuvanted TIV for seasonal influenza prevention in elderly people . METHODS We did a r and omised trial in 15 countries worldwide during the 2008 - 09 ( year 1 ) and 2009 - 10 ( year 2 ) influenza seasons . Eligible participants aged at least 65 years who were not in hospital or bedridden and were without acute illness were r and omly assigned ( 1:1 ) to receive either AS03-adjuvanted TIV or non-adjuvanted TIV . R and omisation was done in an internet-based system , with a blocking scheme and stratification by age ( 65 - 74 years and 75 years or older ) . Participants were scheduled to receive one vaccine in each year , and remained in the same group in years 1 and 2 . Unmasked personnel prepared and gave the vaccines , but participants and individuals assessing any study endpoint were masked . The co primary objectives were to assess the relative efficacy of the vaccines and lot-to-lot consistency of the AS03-adjuvanted TIV ( to be reported elsewhere ) . For the first objective , the primary endpoint was relative efficacy of the vaccines for prevention of influenza A ( excluding A H1N1 pdm09 ) or B , or both , that was confirmed by PCR analysis in year 1 ( lower limit of two-sided 95 % CI had to be greater than zero to establish superiority ) . From Nov 15 , to April 30 , in both years , participants were monitored by telephone or site contact and home visits every week or 2 weeks to identify cases of influenza-like illness . After onset of suspected cases , we obtained nasal and throat swabs to identify influenza RNA with real-time PCR . Efficacy analyses were done per protocol . This trial is registered with Clinical Trials.gov , number NCT00753272 . FINDINGS We enrolled 43 802 participants , of whom 21 893 were assigned to and received the AS03-adjuvanted TIV and 21 802 the non-adjuvanted TIV in year 1 . In the year 1 efficacy cohort , fewer participants given AS03-adjuvanted than non-adjuvanted TIV were infected with influenza A or B , or both ( 274 [ 1·27 % , 95 % CI 1·12 - 1·43 ] of 21 573 vs 310 [ 1·44 % , 1·29 - 1·61 ] of 21 482 ; relative efficacy 12·11 % , 95 % CI -3·40 to 25·29 ; superiority not established ) . Fewer participants in the year 1 efficacy cohort given AS03-adjuvanted TIV than non-adjuvanted TIV were infected with influenza A ( 224 [ 1·04 % , 95 % CI 0·91 - 1·18 ] vs 270 [ 1·26 , 1·11 - 1·41 ] ; relative efficacy 17·53 % , 95 % CI 1·55 - 30·92 ) and influenza A H3N2 ( 170 [ 0·79 , 0·67 - 0·92 ] vs 205 [ 0·95 , 0·83 - 1·09 ] ; post-hoc analysis relative efficacy 22·0 % , 95 % CI 5·68 - 35·49 ) . INTERPRETATION AS03-adjuvanted TIV has a higher efficacy for prevention of some subtypes of influenza than does a non-adjuvanted TIV . Future influenza vaccine studies in elderly people should be based on subtype or lineage-specific endpoints . FUNDING GlaxoSmithKline Biologicals SA Mass immunization of children has the potential to decrease infection rates and prevent the transmission of influenza . We evaluated the immunogenicity , safety , and tolerability of different formulations of cell-derived MF59-adjuvanted and nonadjuvanted A/H1N1 influenza vaccine in children and adolescents . This was a r and omized , single-blind , multicenter study with a total of 666 healthy subjects aged 6 months–17 y in one of 3 vaccination groups , each receiving formulations containing different amounts of influenza A/H1N1 antigen with or without MF59 . A booster trivalent seasonal MF59 vaccine was administered one year after primary vaccinations . Antibody titers were assessed by hemagglutination inhibition ( HI ) and microneutralization assays obtained on days 1 , 22 , 43 , 366 , and 387 ( 3 weeks post booster ) . Safety was monitored throughout the study . One vaccination with 3.75 μg of A/H1N1 antigen formulated with 50 % MF59 ( 3.75_halfMF59 ) or 7.5 μg of A/H1N1 antigen formulated with 100 % MF59 ( 7.5_fullMF59 ) induced an HI titer ≥1:40 in > 70 % of children in the 1–<3 , 3–8 , and 9–17 y cohorts ; however , 2 vaccinations with nonadjuvanted 15 μg A/H1N1 antigen were needed to achieve this response in the 1–<3 and 3–8 y cohorts . Among children aged 6–11 months , 1 dose of 7.5_fullMF59 result ed in an HI titer ≥1:40 in > 70 % while 2 doses of 3.75_halfMF59 were required to achieve this result . All vaccines were well tolerated . Our findings support the immunogenicity and safety of the 3.75_halfMF59 ( 2 doses for children < 12 months ) and 7.5_fullMF59 vaccine formulations for use in children and adolescents aged 6 months to 17 y The use of the 3.75_halfMF59 could have the benefit of antigen and adjuvant sparing , increasing the available vaccine doses allowing vaccination of more people OBJECTIVE To evaluate the safety , tolerability and immunogenicity of an AS03(B)/oil-in-water emulsion-adjuvanted ( AS03(B ) ) split-virion versus non-adjuvanted whole-virion H1N1 influenza vaccine in UK children aged 6 months to 12 years . DESIGN Multicentre , r and omised , head-to-head , open-label trial . SETTING Five UK sites ( Oxford , Bristol , Southampton , Exeter and London ) . PARTICIPANTS Children aged 6 months to < 13 years , for whom a parent or guardian had provided written informed consent and who were able to comply with study procedures , were eligible for inclusion . INTERVENTIONS A tocopherol/oil-in-water emulsion-adjuvanted ( AS03(B ) ) egg culture-derived split-virion H1N1 vaccine and a non-adjuvanted cell culture-derived whole-virion vaccine , given as a two-dose schedule , 21 days apart , were compared . Participants were grouped into those aged 6 months to < 3 years ( younger group ) and 3 years to < 13 years of age ( older group ) and were r and omised by study investigators ( 1 : 1 ratio ) to receive one of the two vaccines . Vaccines were administered by intramuscular injection ( deltoid or anterior-lateral thigh , depending on age and muscle bulk ) . Local reactions and systemic symptoms were collected for 1 week post immunisation , and serum was collected at baseline and after the second dose . To assess safety and tolerability , parents or guardians recorded the following information in diary cards from days 0 - 7 post vaccination : axillary temperature , injection site reactions , solicited and unsolicited systemic symptoms , and medications . MAIN OUTCOME MEASURE Comparison between vaccines of the percentage of participants demonstrating seroconversion by microneutralisation assay . RESULTS Among 937 children receiving vaccine , per- protocol seroconversion rates were higher after the AS03(B)-adjuvanted vaccine than after the whole-virion vaccine ( 98.2 % vs 80.1 % in children < 3 years , 99.1 % vs 95.9 % among those aged 3 - 12 years ) , as were severe local reactions ( 3.6 % vs 0.0 % in those under 5 years , 7.8 % vs 1.1 % in those aged 5 - 12 years ) , irritability in children < 5 years ( 46.7 % vs 32.0 % ) , and muscle pain in older children ( 28.9 % vs 13.2 % ) . The second dose of the adjuvanted vaccine was more reactogenic than the first , especially for fever > 38.0 ° C in those under 5 years of age ( 8.9 % vs 22.4 % ) . CONCLUSION The adjuvanted vaccine , although reactogenic , was more immunogenic , especially in younger children , indicating the potential for improved immunogenicity of influenza vaccines in this age group . TRIAL REGISTRATION NUMBER IS RCT N89141709 Background : The recent global A/H1N1v p and emic led to major efforts to develop effective vaccines against the novel virus , while global dem and and limited production capacity focused attention on dose sparing and schedules . Methods : An open-label phase III study of immunogenicity and safety of novel A/H1N1v vaccines included 392 Costa Rican children in two pediatric cohorts ( 3–8 and 9–17 years ) . They received two doses , of either an MF59 ® -adjuvanted formulation containing 7.5 μg antigen or non-adjuvanted formulations containing 15 or 30 μg antigen , three weeks apart . Immunogenicity was assessed as hemagglutination inhibition ( HI ) titers using the CBER licensure criteria . Results : All three vaccines elicited immune responses in 9–17 year-olds meeting CBER criteria three weeks after one dose ; responses were not enhanced by second dose . In 3–8 year-olds only the adjuvanted vaccine met the CBER criteria after one dose , but all three vaccines met criteria after second dose . All vaccines were well tolerated ; no related Serious Adverse Events ( SAE ) and few severe solicited reactions were reported . MF59-adjuvanted vaccine was associated with more reports of injection site pain and tenderness and overall systemic solicited reactions , most notably in older subjects , all of which decreased after the second dose . Conclusion : One dose of non-adjuvanted A/H1N1v vaccine is adequate in 9–17 year-olds , but younger children require either one dose of MF59-adjuvanted vaccine or two doses of non-adjuvanted vaccine to achieve protective titers . Enhanced immunogenicity with MF59 is associated with a small increase in reactogenicity , but no safety issues INTRODUCTION Effective , programmatically suitable influenza vaccines are needed for low-re source countries . MATERIAL S AND METHODS This phase II , placebo-controlled , r and omized safety and immunogenicity trial ( NCT01819155 ) was conducted in Senegal using the 2012 - 2013 Northern Hemisphere trivalent influenza vaccine ( TIV ) formulation . Participants were allocated in a 2:2:1 ratio to receive TIV ( full-dose for all age groups ) , adjuvanted TIV ( aTIV ) , or placebo .  Participants were stratified into age groups : 6 - 11 , 12 - 35 , and 36 - 71 months . All participants were vaccine-naïve and received two doses of study vaccine 4 weeks apart . The two independent primary objectives were to estimate the immunogenicity of TIV and of aTIV as the proportion of children with a hemagglutination inhibition ( HI ) antibody titer of ≥1:40 to each vaccine strain at 28 days post-dose two . Safety was evaluated by solicited local and systemic reactions , unsolicited adverse events , and serious adverse events . RESULTS 296 children received TIV , aTIV , or placebo , and 235 were included in the final analysis . After two doses , children aged 6 - 11 , 12 - 35 , and 36 - 71 months receiving TIV had HI titers ≥1:40 against A/H1N1 ( 73.1 % , 94.1 % , and 97.0 % ) , A/H3N2 ( 96.2 % , 100.0 % , and 100.0 % ) , and B ( 80.8 % , 97.1 % , and 97.0 % ) , respectively . After two doses , 100 % children aged 6 - 11 , 12 - 35 , and 36 - 71 months receiving aTIV had ≥1:40 titers against A/H1N1 , A/H3N2 , and B. After a single dose , the aTIV response was comparable to or greater than the TIV response for all vaccine strains . TIV and aTIV reactogenicity were similar , except for mild elevation in temperature ( 37.5 - 38.4 ° C ) which occurred more frequently in aTIV than TIV after each vaccine dose . TIV and aTIV had similarly increased pain/tenderness at the injection site compared to placebo . CONCLUSIONS Both aTIV and full-dose TIV were well-tolerated and immunogenic in children aged 6 - 71 months . These vaccines may play a role in programmatically suitable strategies to prevent influenza in low-re source setting BACKGROUND The efficacy of inactivated influenza vaccines is known to be poor in infants and young children . METHODS We studied the effect of the adjuvant MF59 , an oil-in-water emulsion , on the efficacy of trivalent inactivated influenza vaccine ( TIV ) in 4707 healthy children 6 to less than 72 months of age who had not previously been vaccinated against influenza . The children were r and omly assigned to three study groups , each of which received the assigned vaccines in two doses , 28 days apart , during two consecutive influenza seasons . Two of the groups were given age-appropriate doses of TIV either with or without the MF59 adjuvant , and the third group was given control ( noninfluenza ) vaccines to assess their absolute and relative efficacy against influenza-like illness , as confirmed by means of polymerase-chain-reaction ( PCR ) assay . RESULTS Attack rates of influenza-like illness across both influenza seasons were 0.7 % , 2.8 % , and 4.7 % in the adjuvant , nonadjuvant , and control vaccine groups , respectively . The absolute vaccine efficacy rates against all influenza strains ( 94 of 110 cases were due to vaccine-matched H3N2 viruses ) were 86 % ( 95 % confidence interval [ CI ] , 74 to 93 ) for the MF59-adjuvant vaccine ( ATIV ) and 43 % ( 95 % CI , 15 to 61 ) for the vaccine without the adjuvant ( TIV ) ; the relative vaccine efficacy rate for ATIV versus TIV was 75 % ( 95 % CI , 55 to 87 ) . The efficacy rates for ATIV were 79 % ( 95 % CI , 55 to 90 ) in children 6 to less than 36 months of age and 92 % ( 95 % CI , 77 to 97 ) in those 36 to less than 72 months of age , as compared with 40 % ( 95 % CI , -6 to 66 ) and 45 % ( 95 % CI , 6 to 68 ) , respectively , for TIV . Antibody responses were higher with ATIV and remained so through day 181 . The rates of systemic and local reactions to the influenza vaccines with and without the adjuvant were similar in the younger age group ( relative risk , 1.04 ; 95 % CI , 0.98 to 1.09 ) , but systemic events in the older age group were more frequent after administration of ATIV ( 63 % ) than after administration of TIV ( 44 % ) or the control vaccine ( 50 % ) . Serious adverse events were distributed evenly across the three vaccine groups . CONCLUSIONS Influenza vaccine with the MF59 adjuvant is efficacious against PCR-confirmed influenza in infants and young children . ( Funded by Novartis Vaccines and Diagnostics ; Clinical Trials.gov number , NCT00644059 . )
St and ard inactivated influenza vaccines are poorly immunogenic in immunologically naive healthy young children , who are particularly vulnerable to complications from influenza .
For them , there is an unmet need for better influenza vaccines .
Oil-in-water emulsion-adjuvanted influenza vaccines are promising c and i date s , but clinical trials yielded inconsistent results .