human
***TASK*** the task is to summarize an input biomedical literature in six sentences 
    ***INPUT*** the input is a biomedical literature 
    ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences 
    ***DOCUMENTATION*** 
    ***EXAMPLES*** 
    Input: 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 health 
    Output:
    
agent
***TASK*** the task is to summarize an input biomedical literature in six sentences 
    ***INPUT*** the input is a biomedical literature 
    ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences 
    ***DOCUMENTATION*** 
    ***EXAMPLES*** 
    Input: 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 health 
    Output:
    