Enhanced Immunogenicity of Seasonal Influenza Vaccines in Young Children Using MF59 Adjuvant Comparison of half and full doses of an MF59-adjuvanted cell culture-derived A/H1N1v vaccine in Japanese children A novel influenza A (H1N1) vaccine in various age groups. Assessment of the immunogenicity and safety of varying doses of an MF59®-adjuvanted cell culture-derived A/H1N1 pandemic influenza vaccine in Japanese paediatric, adult and elderly subjects. An early (3-6 weeks) active surveillance study to assess the safety of pandemic influenza vaccine Focetria in a province of Emilia-Romagna region, Italy - part one. Dose-range Study of MF59-adjuvanted Versus Nonadjuvanted Monovalent A/H1N1 Pandemic Influenza Vaccine in Six- to Less Than Thirty-Six-month-old Children Safety and immunogenicity of 2009 pandemic influenza A H1N1 vaccines in China: a multicentre, double-blind, randomised, placebo-controlled trial Safety and immunogenicity of an inactivated split-virus influenza A/H1N1 vaccine in healthy children from 6 months to <18 years of age: a prospective, open-label, multi-center trial. 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 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 Introduction The substantial p and emic ( A/H1N1v ) influenza disease burden in children highlights the need for effective vaccination . We report the results of modern cell culture technology , lower doses of antigen , and different doses of MF59 ® adjuvant ( Novartis Vaccines , Marburg , Germany ) , on the immunogenicity and safety profile in a healthy Japanese pediatric population . Methods A total of 123 children from 6 months to 19 years of age were r and omly assigned in a 1:1 ratio to receive , at 21-day intervals , two doses of either 3.75 μg antigen with 50 % of the st and ard MF59 dose ( group A ) or 7.5 μg antigen and 100 % st and ard MF59 dose ( group  B ) . Antibody levels were measured by hemagglutinin inhibition ( HI ) and microneutralization assays on day 1 and on days 22 and 43 ( 3 weeks after the first and second vaccinations , respectively ) . Solicited adverse events were reported for 7 days after each injection and spontaneous events were reported throughout the study period . Results At 3 weeks after the first vaccination , seroprotective HI antibodies ( titers ≥40 ) were observed in 56 % and 78 % of subjects from groups A and B , respectively ; 100 % in both groups exhibited HI titers ≥40 after the second dose . The reactogenicity profile was acceptable , with local and systemic reactions described as mainly mild to moderate in severity . Five serious adverse events were reported , but none related to the study vaccine . Conclusion One dose of cell culture-derived A/H1N1v vaccine containing 7.5 μ g antigen with the full MF59 adjuvant dose was immunogenic and well tolerated in healthy Japanese children , meeting all three European Union Committee for Medicinal Products for Human Use ( EU CHMP ) licensure criteria . Two doses of 3.75 μg antigen with 50 % of the st and ard MF59 dose fulfilled these licensure criteria BACKGROUND There is an urgent need for a vaccine that is effective against the 2009 p and emic influenza A ( H1N1 ) virus . METHODS A split-virus , inactivated c and i date vaccine against the 2009 H1N1 virus was manufactured , and we evaluated its safety and immunogenicity in a r and omized clinical trial . Subjects were between 3 and 77 years of age , stratified into four age groups . The immunization schedule consisted of two vaccinations , 21 days apart . Subjects were injected with placebo or with vaccine , with or without alum adjuvant , at doses of 7.5 microg , 15 microg , or 30 microg . Serologic analysis was performed at baseline and on days 21 and 35 . RESULTS A total of 2200 subjects received one dose , and 2103 ( 95.6 % ) received the second dose , of vaccine or placebo .  No severe adverse side effects associated with the vaccine were noted . In the nonadjuvanted-vaccine groups , injection-site or systemic reactions , most mild in nature , were noted in 5.5 to 15.9 % of subjects . Among the subjects receiving 15 microg of nonadjuvanted vaccine , a hemagglutination-inhibition titer of 1:40 or more was achieved by day 21 in 74.5 % of subjects between 3 and 11 years of age , 97.1 % of subjects between 12 and 17 years , 97.1 % of subjects between 18 and 60 years , and 79.1 % of subjects 61 years of age or older ; by day 35 , the titer had been achieved in 98.1 % , 100 % , 97.1 % , and 93.3 % of subjects , respectively . The proportion with a titer of 1:40 or more was generally highest among the subjects receiving 30 microg of vaccine , with or without adjuvant . Vaccine without adjuvant was associated with fewer local reactions and greater immune responses than was vaccine with adjuvant . CONCLUSIONS These data suggest that a single dose of 15 microg of hemagglutinin antigen without alum adjuvant induces a typically protective immune response in the majority of subjects between 12 and 60 years of age . Lesser immune responses were seen after a single dose of vaccine in younger and older subjects . ( Clinical Trials.gov number , NCT00975572 ) INTRODUCTION Effective vaccination strategies are required to combat future influenza p and emics . Here we report the results of three independent clinical trials performed in Japan to assess the immunogenicity , tolerability and safety of varying doses of a cell culture-derived MF59( ® )-adjuvanted A/H1N1 p and emic vaccine in healthy Japanese paediatric , adult and elderly subjects . METHODS One hundred and twenty-three children ( 6 months-18 years ) , and 200 adults ( 19 - 60 years ) were r and omly assigned in a 1:1 ratio to receive two doses of vaccine containing either 7.5 μg antigen with a full ( 9.75 mg ) adjuvant dose , or 3.75 μg antigen with a half ( 4.875 mg ) adjuvant dose . One hundred elderly ( ≥ 61 years ) subjects received only the low antigen/adjuvant vaccine formulation . Immunogenicity was assessed by haemagglutination inhibition assay at baseline and three weeks after the first and second vaccine doses on Days 22 and 43 , respectively . Solicited and unsolicited adverse reactions were recorded for seven and 21 days post-immunization , respectively . RESULTS In adult and elderly subjects , a single low antigen/adjuvant dose vaccination was sufficient to meet all of the three European licensure criteria established for influenza vaccines . One high , or two low antigen/adjuvant dose vaccinations were required to meet the licensure criteria in paediatric subjects . Both vaccine formulations were well tolerated , with the majority of adverse reactions mild to moderate in severity . None of the five serious adverse events reported throughout the three trials were considered to be vaccine-related by the investigators . CONCLUSION The use of MF59 adjuvant allows for much reduced vaccine antigen content , and a single dose administration schedule in adults and the elderly . The production of p and emic vaccine using modern cell culture techniques is highly advantageous in terms of the quantity , quality , and rapidity of antigen production ; these benefits , in combination with the use of MF59 , maximize manufacturing capacity and global vaccine supply . These data support the suitability of the investigational vaccine for use in the Japanese paediatric , adult , and elderly population INTRODUCTION An observational , non-comparative , prospect i ve , surveillance study of individuals vaccinated with the MF59-adjuvanted A/H1N1 influenza vaccine , Focetria , ( Novartis Vaccines & Diagnostics , Siena , Italy ) , was performed in Italy during the 2009 A/H1N1 influenza p and emic . METHOD This study assessed the short-term ( six-week ) safety profile of the investigational vaccine in real time . After vaccination ( N=7943 ) , adverse events ( AE ) were assessed using both active ( telephone ) and passive ( healthcare data base ) follow-up in enrolled vaccinated subjects , including infants ( 6 - 23 months ) , pregnant women , and the immunosuppressed . The treating physicians of all subjects experiencing AEs post-vaccination were consulted for clinical information on the conditions reported . All AEs were coded according to ICD-10 . RESULTS A total of 1583 AEs occurred during the study , 67 ( 4.2 % ) of which were serious adverse events ( SAEs ) . One SAE was considered to be possibly related to vaccination ( transitory and ill-defined neurologic disorder experienced by a 16-year-old asthmatic male ) . Three adverse events of special interest ( AESI ) were identified ( convulsions experienced by two epileptic subjects ) , none of which were considered to be vaccine-related . Six individuals died during the study period , in each case the cause of death was not related to vaccination ( four cases of severe underlying co-morbidity , one case of psychoactive drug misuse , and one case of acute myocardial infa rct ion ) . CONCLUSIONS No cases of clinical ly relevant AEs , SAEs , or AESI were observed within a six-week period of vaccine administration . In accordance with existing clinical and post-marketing safety data , the results of this active surveillance study demonstrate a good safety profile for the MF59-adjuvanted A/H1N1 vaccine , Focetria , within the general population 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 BACKGROUND The current influenza p and emic calls for a safe and effective vaccine . We assessed the safety and immunogenicity of eight formulations of 2009 p and emic influenza A H1N1 vaccine produced by ten Chinese manufacturers . METHODS In this multicentre , double-blind , r and omised trial , 12 691 people aged 3 years or older were recruited in ten centres in China . In each centre , participants were stratified by age and r and omly assigned by a r and om number table to receive one of several vaccine formulations or placebo . The study assessed eight formulations : split-virion formulation containing 7.5 microg , 15 microg , or 30 microg haemagglutinin per dose , with or without aluminium hydroxide adjuvant , and whole-virion formulation containing 5 microg or 10 microg haemagglutinin per dose , with adjuvant . All formulations were produced from the reassortant strain X-179A ( A/California/07/2009-A/PR/8/34 ) . We analysed the safety ( adverse events ) , immunogenicity ( geometric mean titre [ GMT ] of haemagglutination inhibition antibody ) , and seroprotection ( GMT > or=1:40 ) of the formulations . Analysis was by per protocol . Two sites registered their trial with Clinical Trials.gov , numbers NCT00956111 and NCT00975572 . The other eight studies were registered with the State Food and Drug Administration of China . FINDINGS 12 691 participants received the first dose on day 0 , and 12 348 participants received the second dose on day 21 . The seroprotection rate 21 days after the first dose of vaccine ranged from 69.5 % ( 95 % CI 65.9 - 72.8 ) for the 7.5 microg adjuvant split-virion formulation to 92.8 % ( 91.9 - 93.6 ) for the 30 microg non-adjuvant split-virion formulation . The seroprotection rate was 86.5 % ( 796 of 920 ; 84.1 - 88.7 ) in recipients of one dose of the 7.5 microg non-adjuvant split-virion vaccine compared with 9.8 % ( 140 of 1432 ; 8.3 - 11.4 ) in recipients of placebo ( p<0.0001 ) . One dose of the 7.5 microg non-adjuvant split-virion vaccine induced seroprotection in 178 of 232 children ( aged 3 years to < 12 years ; 76.7 % , 70.7 - 82.0 ) , 211 of 218 adolescents ( 12 years to < 18 years ; 96.8 % , 93.5 - 98.7 ) , 289 of 323 adults ( 18 - 60 years ; 89.5 % , 85.6 - 92.6 ) , and 118 of 147 adults older than 60 years ( 80.3 % , 72.9 - 86.4 ) , meeting the European Union 's licensure criteria for seroprotection in all age-groups . In children , a second dose of the 7.5 microg formulation increased the seroprotection rate to 97.7 % ( 215 of 220 , 94.8 - 99.3 ) . Adverse reactions were mostly mild or moderate , and self-limited . Severe adverse effects occurred in 69 ( 0.6 % , 0.5 - 0.8 ) recipients of vaccine compared with one recipient ( 0.1 % , 0 - 0.2 ) of placebo . The most common severe adverse reaction was fever , which occurred in 25 ( 0.22 % ; 0.14 - 0.33 ) recipients of vaccine after the first dose and four ( 0.04 % ; 0.01 - 0.09 ) recipients of vaccine after the second dose compared with no recipients of placebo after either dose . INTERPRETATION One dose of non-adjuvant split-virion vaccine containing 7.5 microg haemagglutinin could be promoted as the formulation of choice against 2009 p and emic influenza A H1N1 for people aged 12 years or older . In children ( aged < 12 years ) , two 7.5 mug doses might be needed . FUNDING Sinovac Biotech , Hualan Biological Bacterin , China National Biotec Group , Beijing Tiantan Biological Products , Changchun Institute of Biological Products , Changchun Changsheng Life Sciences , Jiangsu Yanshen Biological Technology Stock , Zhejiang Tianyuan Bio-Pharmaceutical , Lanzhou Institute of Biological Products , Shanghai Institute of Biological Products , and Dalian Aleph Biomedical This study was conducted to determine the immunogenicity and safety of an inactivated split-virus influenza A/H1N1 vaccine in healthy Korean children from 6 months to < 18 years of age . The immunization schedule consisted of two vaccinations , 21 days apart . The unadjuvanted vaccine contained 7.5microg ( subjects 6 months to <3 years of age ) or 15microg ( subjects 3 to < 18 years of age ) of hemagglutinin antigen per dose . A total of 251 subjects were enrolled and 248 and 242 subjects , respectively , were included in the post-first dose and post-second dose immunogenicity evaluations conducted on a per protocol basis . By day 21 , after the first dose , hemagglutination-inhibition titers of 1:40 or more were observed in 5.9 % of subjects 6 months to <3 years of age , 34.9 % of subjects 3 to < 9 years of age and 81.4 % of subjects 9 - 18 years of age . By day 21 after the second dose , the titer had been achieved 55.9 % , 69.5 % and 90.5 % , respectively . No vaccination-related serious adverse events were observed . A single 15-microg dose of vaccine was highly immunogenic in subjects equal to or more than 9 years of age . However , a two-dose regimen is needed to produce potentially protective antibody titers in younger children 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 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 . )
OBJECTIVE To assess the efficacy and safety of MF59-adjuvanted p and emic influenza A/H1N1 vaccine in children .