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 . Highly pathogenic avian influenza H5N1 viruses remain a threat to human health , with potential to become p and emic agents . Methods . This phase III , placebo-controlled , observer-blinded study evaluated the immunogenicity , cross-reactivity , safety , and lot consistency of 2 doses of oil-in-water ( AS03A ) adjuvanted H5N1 A/Indonesia/05/2005 ( 3.75 μg hemagglutinin antigen ) prep and emic c and i date vaccine in 4561 adults aged 18–91 years . Results . Humoral antibody responses in the H5N1 vaccine groups fulfilled US and European immunogenicity licensure criteria for p and emic vaccines in all age strata 21 days after the second dose . At 6 months after the administration of the primary dose , serum antibody seroconversion rates continued to fulfill licensure criteria . Neutralizing cross-clade immune responses were demonstrated against clade 1 A/Vietnam/1194/2004 . Consistency was demonstrated for 3 consecutive H5N1 vaccine lots . Temporary injection-site pain was more frequent with H5N1 vaccine than placebo ( 89.3 % and 70.7 % in the 18–64 and ≥65 years strata vs 22.2 % and 14.4 % in the placebo groups ) . Unsolicited adverse event frequency , including medically attended and serious events , was similar between groups through day 364 . Conclusions . In adults and elderly adults  , AS03A-adjuvanted H5N1 c and i date vaccine was highly immunogenic for A/Indonesia/05/2005 , with cross-reactivity against A/Vietnam/1194/2004 . Temporary injection site reactions were more frequent with H5N1 vaccine than placebo , although the H5N1 vaccine was well tolerated overall . Clinical Trials Registration . NCT00616928 BACKGROUND AS03-adjuvanted H5N1 p and emic influenza vaccines have been assessed in an extensive clinical development program conducted in North America , Europe , and Asia including children from 6 months of age , adults , and elderly adults . We evaluated AS03-H5N1 in Korean adults 18 through 60 years of age . METHODS This Phase IV , r and omized , study was conducted to assess the immunogenicity , reactogenicity , and safety of two doses ( 3.75μg of hemagglutinin antigen ) of A/Indonesia/5/2005 ( H5N1 ) adjuvanted with AS03 given 21 days apart in Korean adults . Antibody responses were assessed using hemagglutination-inhibition ( HI ) assays against the vaccine strain and a vaccine-heterologous strain ( A/Vietnam/1194/2004 ) 21 days after the second dose . A control group ( safety ) received a licensed seasonal inactivated trivalent influenza vaccine ( TIV ) . Reactogenicity was assessed for 7 days after each vaccination , and unsolicited adverse events were assessed for 182 days following vaccination in both study groups ( NCT01730378 ) . RESULTS AS03-H5N1 was immunogenic and elicited robust HI antibody responses with seroconversion rates of 100 % for the vaccine strain and 69.1 % for the heterologous strain ( N=81 ) . HI antibody responses fulfilled the European licensure criteria for immunogenicity ( primary endpoint ) . The incidence of local and systemic solicited adverse events ( reactogenicity ) was higher with AS03-H5N1 than TIV . There was no apparent difference in the rate of unsolicited adverse events in the AS03-H5N1 and TIV groups . CONCLUSION The results indicate that AS03-H5N1 vaccine is immunogenic with reactogenicity and safety findings that are consistent with the established profile of AS03-H5N1 vaccine BACKGROUND Effective planning and preparedness against a possible future A/H5N1 influenza p and emic is a major global challenge . Because dose sparing strategies are required to meet the global dem and for vaccine , efforts have focused on the development of adjuvanted vaccine formulations of relatively lower antigen content . AIM This study aim ed to demonstrate the non-inferiority of a low-antigen-dose ( 3.75 μ ) [ DOSAGE ERROR CORRECTED ] A/H5N1 pre-p and emic vaccine compared with a licensed , higher-dose ( 7.5 mg ) formulation in adult and elderly subjects . Immunogenicity was assessed according to European and U.S. licensure criteria . METHODS A total of 722 subjects were r and omized in equal numbers to receive either the licensed or low-dose formulation . All subjects received two vaccine doses administered three weeks apart . Immunogenicity was assessed three weeks after the administration of each vaccine dose by hemagglutination inhibition ( HI ) , single radial haemolysis ( SRH ) and microneutralization assays ( MN ) . Local and systemic reactions were assessed over a seven day period post-vaccination . Adverse events were recorded throughout . RESULTS The low-dose vaccine was demonstrated to be non-inferior to the licensed formulation in terms of antibody titres against the vaccine strain . All three European licensure criteria were met by adult subjects in response to the low-dose vaccine ; two criteria were met by the elderly age group  . Cross-reactive antibodies were detected against the heterologous A/H5N1 antigen strains A/Indonesia/05/05 and A/turkeyTurkey/01/05 . Both vaccines were generally well tolerated by both age groups . CONCLUSION These data demonstrate that a low antigen dose in combination with MF59 adjuvant is adequate for the routine pre-p and emic immunization of adult and elderly subjects Background The availability of H5N1 vaccines that can elicit a broad cross-protective immunity against different currently circulating clade 2 H5N1 viruses is a pre-requisite for the development of a successful pre-p and emic vaccination strategy . In this regard , it has recently been shown that adjuvantation of a recombinant clade 1 H5N1 inactivated split-virion vaccine with an oil-in-water emulsion-based adjuvant system also promoted cross-immunity against a recent clade 2 H5N1 isolate ( A/Indonesia/5/2005 , subclade 2.1 ) . Here we further analyse the cross-protective potential of the vaccine against two other recent clade 2 isolates ( A/turkey/Turkey/1/2005 and A/Anhui/1/2005 which are , as defined by WHO , representatives of subclades 2.2 and 2.3 respectively ) . Methods and Findings Two doses of the recombinant A/Vietnam/1194/2004 ( H5N1 , clade 1 ) vaccine were administered 21 days apart to volunteers aged 18–60 years . We studied the cross-clade immunogenicity of the lowest antigen dose ( 3.8 µg haemagglutinin ) given with ( N = 20 ) or without adjuvant ( N = 20 ) . Immune responses were assessed at 21 days following the first and second vaccine doses and at 6 months following first vaccination . Vaccination with two doses of 3.8 µg of the adjuvanted vaccine induced four-fold neutralising seroconversion rates in 85 % of subjects against A/turkey/Turkey/1/2005 ( subclade 2.2 ) and 75 % of subjects against A/Anhui/1/2005 ( subclade 2.3 ) recombinant strains . There was no response induced against these strains in the non-adjuvanted group . At 6 months following vaccination , 70 % and 60 % of subjects retained neutralising antibodies against the recombinant subclade 2.2 and 2.3 strains , respectively and 40 % of subjects retained antibodies against the recombinant subclade 2.1 A/Indonesia/5/2005 strain . Conclusions In addition to antigen dose-sparing , adjuvantation of inactivated split H5N1 vaccine promotes broad and persistent cross-clade immunity which is a pre-requisite for a pre-p and emic vaccine . Trial Registration Clinical Trials.gov The immunogenicity and lot-to-lot consistency of an AS03-adjuvanted H5N1 vaccine were evaluated in 1206 Asian adults , r and omised to receive two doses of adjuvanted ( 3.75 microg haemagglutinin ) or diluent-mixed vaccines , 21 days apart . Post-Dose 2 , 96.0 % of vaccinees in the H5N1-AS03 group demonstrated a four-fold increase in neutralising antibody titres against the vaccine strain A/Vietnam/1194/2004 and 91.4 % against strain A/Indonesia/05/2005 . Haemagglutination-inhibiting antibodies ( titre > or = 1:40 ) against A/Vietnam/1194/2004 and A/Indonesia/05/2005 strains were observed in 94.3 % and 50.2 % of subjects , respectively . Lot-to-lot consistency of the AS03-adjuvanted vaccine combinations was demonstrated . The AS03-adjuvanted vaccine was well tolerated , induced a high frequency of immune responses to the vaccine strain , allowed antigen sparing and promoted cross-clade immunity . These characteristics make it suitable for presumptive use if an H5N1 p and emic were considered to be imminent Proactive priming before the next p and emic could induce immune memory responses to novel influenza antigens . In an open-label study , we analyzed  B cell memory and antibody responses of 54 adults who received 2 7.5-μg doses of MF59-adjuvanted A/Vietnam/1194/2004 clade 1 ( H5N1 ) vaccine . Twenty-four subjects had been previously primed with MF59-adjuvanted or plain clade 0-like A/duck/Singapore/1997 ( H5N3 ) vaccine during 1999–2001 . The prevaccination frequency of circulating memory B cells reactive to A/Vietnam/1194/2004 was low in both primed and unprimed individuals . However , at day 21 after boosting , MF59-adjuvanted primed subjects displayed a higher frequency of H5N1-specific memory B cells than plain-primed or unprimed subjects . The immune memory was rapidly mobilized by a single vaccine administration and result ed in high titers of neutralizing antibodies to antigenically diverse clade 0 , 1 , and 2 H5N1 viruses already at day 7 . In general , postvaccination antibody titers were significantly higher in primed subjects than in unprimed subjects . Subjects primed with MF59-adjuvanted vaccine responded significantly better than those primed with plain vaccine , most notably in early induction and duration of cross-reacting antibody responses . After 6 months , high titers of cross-reactive antibody remained detectable among MF59-primed subjects . We conclude that distant priming with clade 0-like H5N3 induces a pool of cross-reactive memory B cells that can be boosted rapidly years afterward by a mismatched MF59-adjuvanted vaccine to generate high titers of cross-reactive neutralizing antibodies rapidly . These results suggest that pre-p and emic vaccination strategies should be considered Background . Accelerated immunization schedules may help gain early control of influenza p and emics . We investigated different schedules of an AS03A-adjuvanted H5N1 vaccine . Methods . This phase II , open-label , 6-month study r and omized participants ( aged 18–64 years ) to 2 vaccine doses administered 21 ( st and ard schedule ) , 14 , or 7 days apart , or on the same day . Co primary end points were that the lower limit of the 98.75 % confidence interval 14 days after the last dose must be ( 1 ) > 40 % for seroconversion rate ( SCR ) ( Center for Biologics Evaluation and Research [ CBER ] criterion ) and ( 2 ) > 50 % for seroprotection rate ( SPR ) ( attainment rate for reciprocal hemagglutination inhibition titers ≥40 , protocol -defined criterion ) for the vaccine homologous strain ( A/Indonesia/5/2005 ) . European Committee for Human Medicinal Products ( CHMP ) immunogenicity criteria were also evaluated . Results . Co primary end points were achieved ( lower 98.75 % confidence intervals exceeded defined values ) . Titers were highest with the st and ard schedule . Nevertheless , CBER SCR , protocol -defined SPR , and CHMP criteria were met with all schedules for the A/Indonesia/5/2005 strain . There were no significant differences between age groups ( 18–40 vs 41–64 years ) . Immune response was robust against drift variants A/turkey/Turkey/1/2005 and A/Vietnam/1194/2004 . 
    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 . Highly pathogenic avian influenza H5N1 viruses remain a threat to human health , with potential to become p and emic agents . Methods . This phase III , placebo-controlled , observer-blinded study evaluated the immunogenicity , cross-reactivity , safety , and lot consistency of 2 doses of oil-in-water ( AS03A ) adjuvanted H5N1 A/Indonesia/05/2005 ( 3.75 μg hemagglutinin antigen ) prep and emic c and i date vaccine in 4561 adults aged 18–91 years . Results . Humoral antibody responses in the H5N1 vaccine groups fulfilled US and European immunogenicity licensure criteria for p and emic vaccines in all age strata 21 days after the second dose . At 6 months after the administration of the primary dose , serum antibody seroconversion rates continued to fulfill licensure criteria . Neutralizing cross-clade immune responses were demonstrated against clade 1 A/Vietnam/1194/2004 . Consistency was demonstrated for 3 consecutive H5N1 vaccine lots . Temporary injection-site pain was more frequent with H5N1 vaccine than placebo ( 89.3 % and 70.7 % in the 18–64 and ≥65 years strata vs 22.2 % and 14.4 % in the placebo groups ) . Unsolicited adverse event frequency , including medically attended and serious events , was similar between groups through day 364 . Conclusions . In adults and elderly adults  , AS03A-adjuvanted H5N1 c and i date vaccine was highly immunogenic for A/Indonesia/05/2005 , with cross-reactivity against A/Vietnam/1194/2004 . Temporary injection site reactions were more frequent with H5N1 vaccine than placebo , although the H5N1 vaccine was well tolerated overall . Clinical Trials Registration . NCT00616928 BACKGROUND AS03-adjuvanted H5N1 p and emic influenza vaccines have been assessed in an extensive clinical development program conducted in North America , Europe , and Asia including children from 6 months of age , adults , and elderly adults . We evaluated AS03-H5N1 in Korean adults 18 through 60 years of age . METHODS This Phase IV , r and omized , study was conducted to assess the immunogenicity , reactogenicity , and safety of two doses ( 3.75μg of hemagglutinin antigen ) of A/Indonesia/5/2005 ( H5N1 ) adjuvanted with AS03 given 21 days apart in Korean adults . Antibody responses were assessed using hemagglutination-inhibition ( HI ) assays against the vaccine strain and a vaccine-heterologous strain ( A/Vietnam/1194/2004 ) 21 days after the second dose . A control group ( safety ) received a licensed seasonal inactivated trivalent influenza vaccine ( TIV ) . Reactogenicity was assessed for 7 days after each vaccination , and unsolicited adverse events were assessed for 182 days following vaccination in both study groups ( NCT01730378 ) . RESULTS AS03-H5N1 was immunogenic and elicited robust HI antibody responses with seroconversion rates of 100 % for the vaccine strain and 69.1 % for the heterologous strain ( N=81 ) . HI antibody responses fulfilled the European licensure criteria for immunogenicity ( primary endpoint ) . The incidence of local and systemic solicited adverse events ( reactogenicity ) was higher with AS03-H5N1 than TIV . There was no apparent difference in the rate of unsolicited adverse events in the AS03-H5N1 and TIV groups . CONCLUSION The results indicate that AS03-H5N1 vaccine is immunogenic with reactogenicity and safety findings that are consistent with the established profile of AS03-H5N1 vaccine BACKGROUND Effective planning and preparedness against a possible future A/H5N1 influenza p and emic is a major global challenge . Because dose sparing strategies are required to meet the global dem and for vaccine , efforts have focused on the development of adjuvanted vaccine formulations of relatively lower antigen content . AIM This study aim ed to demonstrate the non-inferiority of a low-antigen-dose ( 3.75 μ ) [ DOSAGE ERROR CORRECTED ] A/H5N1 pre-p and emic vaccine compared with a licensed , higher-dose ( 7.5 mg ) formulation in adult and elderly subjects . Immunogenicity was assessed according to European and U.S. licensure criteria . METHODS A total of 722 subjects were r and omized in equal numbers to receive either the licensed or low-dose formulation . All subjects received two vaccine doses administered three weeks apart . Immunogenicity was assessed three weeks after the administration of each vaccine dose by hemagglutination inhibition ( HI ) , single radial haemolysis ( SRH ) and microneutralization assays ( MN ) . Local and systemic reactions were assessed over a seven day period post-vaccination . Adverse events were recorded throughout . RESULTS The low-dose vaccine was demonstrated to be non-inferior to the licensed formulation in terms of antibody titres against the vaccine strain . All three European licensure criteria were met by adult subjects in response to the low-dose vaccine ; two criteria were met by the elderly age group  . Cross-reactive antibodies were detected against the heterologous A/H5N1 antigen strains A/Indonesia/05/05 and A/turkeyTurkey/01/05 . Both vaccines were generally well tolerated by both age groups . CONCLUSION These data demonstrate that a low antigen dose in combination with MF59 adjuvant is adequate for the routine pre-p and emic immunization of adult and elderly subjects Background The availability of H5N1 vaccines that can elicit a broad cross-protective immunity against different currently circulating clade 2 H5N1 viruses is a pre-requisite for the development of a successful pre-p and emic vaccination strategy . In this regard , it has recently been shown that adjuvantation of a recombinant clade 1 H5N1 inactivated split-virion vaccine with an oil-in-water emulsion-based adjuvant system also promoted cross-immunity against a recent clade 2 H5N1 isolate ( A/Indonesia/5/2005 , subclade 2.1 ) . Here we further analyse the cross-protective potential of the vaccine against two other recent clade 2 isolates ( A/turkey/Turkey/1/2005 and A/Anhui/1/2005 which are , as defined by WHO , representatives of subclades 2.2 and 2.3 respectively ) . Methods and Findings Two doses of the recombinant A/Vietnam/1194/2004 ( H5N1 , clade 1 ) vaccine were administered 21 days apart to volunteers aged 18–60 years . We studied the cross-clade immunogenicity of the lowest antigen dose ( 3.8 µg haemagglutinin ) given with ( N = 20 ) or without adjuvant ( N = 20 ) . Immune responses were assessed at 21 days following the first and second vaccine doses and at 6 months following first vaccination . Vaccination with two doses of 3.8 µg of the adjuvanted vaccine induced four-fold neutralising seroconversion rates in 85 % of subjects against A/turkey/Turkey/1/2005 ( subclade 2.2 ) and 75 % of subjects against A/Anhui/1/2005 ( subclade 2.3 ) recombinant strains . There was no response induced against these strains in the non-adjuvanted group . At 6 months following vaccination , 70 % and 60 % of subjects retained neutralising antibodies against the recombinant subclade 2.2 and 2.3 strains , respectively and 40 % of subjects retained antibodies against the recombinant subclade 2.1 A/Indonesia/5/2005 strain . Conclusions In addition to antigen dose-sparing , adjuvantation of inactivated split H5N1 vaccine promotes broad and persistent cross-clade immunity which is a pre-requisite for a pre-p and emic vaccine . Trial Registration Clinical Trials.gov The immunogenicity and lot-to-lot consistency of an AS03-adjuvanted H5N1 vaccine were evaluated in 1206 Asian adults , r and omised to receive two doses of adjuvanted ( 3.75 microg haemagglutinin ) or diluent-mixed vaccines , 21 days apart . Post-Dose 2 , 96.0 % of vaccinees in the H5N1-AS03 group demonstrated a four-fold increase in neutralising antibody titres against the vaccine strain A/Vietnam/1194/2004 and 91.4 % against strain A/Indonesia/05/2005 . Haemagglutination-inhibiting antibodies ( titre > or = 1:40 ) against A/Vietnam/1194/2004 and A/Indonesia/05/2005 strains were observed in 94.3 % and 50.2 % of subjects , respectively . Lot-to-lot consistency of the AS03-adjuvanted vaccine combinations was demonstrated . The AS03-adjuvanted vaccine was well tolerated , induced a high frequency of immune responses to the vaccine strain , allowed antigen sparing and promoted cross-clade immunity . These characteristics make it suitable for presumptive use if an H5N1 p and emic were considered to be imminent Proactive priming before the next p and emic could induce immune memory responses to novel influenza antigens . In an open-label study , we analyzed  B cell memory and antibody responses of 54 adults who received 2 7.5-μg doses of MF59-adjuvanted A/Vietnam/1194/2004 clade 1 ( H5N1 ) vaccine . Twenty-four subjects had been previously primed with MF59-adjuvanted or plain clade 0-like A/duck/Singapore/1997 ( H5N3 ) vaccine during 1999–2001 . The prevaccination frequency of circulating memory B cells reactive to A/Vietnam/1194/2004 was low in both primed and unprimed individuals . However , at day 21 after boosting , MF59-adjuvanted primed subjects displayed a higher frequency of H5N1-specific memory B cells than plain-primed or unprimed subjects . The immune memory was rapidly mobilized by a single vaccine administration and result ed in high titers of neutralizing antibodies to antigenically diverse clade 0 , 1 , and 2 H5N1 viruses already at day 7 . In general , postvaccination antibody titers were significantly higher in primed subjects than in unprimed subjects . Subjects primed with MF59-adjuvanted vaccine responded significantly better than those primed with plain vaccine , most notably in early induction and duration of cross-reacting antibody responses . After 6 months , high titers of cross-reactive antibody remained detectable among MF59-primed subjects . We conclude that distant priming with clade 0-like H5N3 induces a pool of cross-reactive memory B cells that can be boosted rapidly years afterward by a mismatched MF59-adjuvanted vaccine to generate high titers of cross-reactive neutralizing antibodies rapidly . These results suggest that pre-p and emic vaccination strategies should be considered Background . Accelerated immunization schedules may help gain early control of influenza p and emics . We investigated different schedules of an AS03A-adjuvanted H5N1 vaccine . Methods . This phase II , open-label , 6-month study r and omized participants ( aged 18–64 years ) to 2 vaccine doses administered 21 ( st and ard schedule ) , 14 , or 7 days apart , or on the same day . Co primary end points were that the lower limit of the 98.75 % confidence interval 14 days after the last dose must be ( 1 ) > 40 % for seroconversion rate ( SCR ) ( Center for Biologics Evaluation and Research [ CBER ] criterion ) and ( 2 ) > 50 % for seroprotection rate ( SPR ) ( attainment rate for reciprocal hemagglutination inhibition titers ≥40 , protocol -defined criterion ) for the vaccine homologous strain ( A/Indonesia/5/2005 ) . European Committee for Human Medicinal Products ( CHMP ) immunogenicity criteria were also evaluated . Results . Co primary end points were achieved ( lower 98.75 % confidence intervals exceeded defined values ) . Titers were highest with the st and ard schedule . Nevertheless , CBER SCR , protocol -defined SPR , and CHMP criteria were met with all schedules for the A/Indonesia/5/2005 strain . There were no significant differences between age groups ( 18–40 vs 41–64 years ) . Immune response was robust against drift variants A/turkey/Turkey/1/2005 and A/Vietnam/1194/2004 . 
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