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: To characterize the cell mediated immunity ( CMI ) induced by the investigational CYD tetravalent dengue vaccine ( TDV ) , we developed a whole-blood , intracellular cytokine staining ( ICS ) assay and a multiplex assay , each requiring 3 mL of blood . We assessed CMI before and 28 d after a first and third injection of CYD-TDV and one year after the third injection in a subset of 80 adolescents and adults enrolled in a phase II trial in Singapore ( Clinical Trial.gov NCT NCT00880893 ) . CD4/IFNγ/TNFα responses specific to dengue NS3 were detected before vaccination . Vaccination induced YF-17D-NS3-specific CD8/IFNγ responses , without significant TNFα , and a CYD-specific Th1/Tc1 cellular response in all participants , which was characterized by predominant IFNγ secretion compared with TNFα , associated with low level IL-13 secretion in multiplex analysis of peripheral blood mononuclear cells ( P BMC ) supernatants after restimulation with each the CYD vaccine viruses . Responses were directed mainly against CYD-4 after the first vaccination , and were more balanced against all four serotypes after the third vaccination . The same qualitative profile was observed one year after the third vaccination , with approximately 2-fold lower NS3-specific responses , and 3-fold lower serotype-specific cellular responses . These findings confirm previous observations regarding both the nature and specificity of cellular responses induced by CYD-TDV , and for the first time demonstrate the persistence of cellular responses after one year . We also established the feasibility of analyzing CMI with small blood sample s , allowing such analysis to be considered for pediatric trials BACKGROUND In light of the increasing rate of dengue infections throughout the world despite vector-control measures , several dengue vaccine c and i date s are in development . METHODS In a phase 3 efficacy trial of a tetravalent dengue vaccine in five Latin American countries where dengue is endemic , we r and omly assigned healthy children between the ages of 9 and 16 years in a 2:1 ratio to receive three injections of recombinant , live , attenuated , tetravalent dengue vaccine ( CYD-TDV ) or placebo at months 0 , 6 , and 12 under blinded conditions . The children were then followed for 25 months . The primary outcome was vaccine efficacy against symptomatic , virologically confirmed dengue ( VCD ) , regardless of disease severity or serotype , occurring more than 28 days after the third injection . RESULTS A total of 20,869 healthy children received either vaccine or placebo . At baseline , 79.4 % of an immunogenicity subgroup of 1944 children had seropositive status for one or more dengue serotypes . In the per- protocol population , there were 176 VCD cases ( with 11,793 person-years at risk ) in the vaccine group and 221 VCD cases ( with 5809 person-years at risk ) in the control group , for a vaccine efficacy of 60.8 % ( 95 % confidence interval [ CI ] , 52.0 to 68.0 ) . In the intention-to-treat population ( those who received at least one injection ) , vaccine efficacy was 64.7 % ( 95 % CI , 58.7 to 69.8 ) . Serotype-specific vaccine efficacy was 50.3 % for serotype 1 , 42.3 % for serotype 2 , 74.0 % for serotype 3 , and 77.7 % for serotype 4 . Among the severe VCD cases , 1 of 12 was in the vaccine group , for an intention-to-treat vaccine efficacy of 95.5 % . Vaccine efficacy against hospitalization for dengue was 80.3 % . The safety profile for the CYD-TDV vaccine was similar to that for placebo , with no marked difference in rates of adverse events . CONCLUSIONS The CYD-TDV dengue vaccine was efficacious against VCD and severe VCD and led to fewer hospitalizations for VCD in five Latin American countries where dengue is endemic . ( Funded by Sanofi Pasteur ; Clinical Trials.gov number , NCT01374516 . ) Background : The dengue virus is a member of the Flavivirus ( FV ) genus , which also includes the yellow fever virus . Dengue disease is caused by any 1 of 4 dengue virus serotypes and is a serious public health concern in Latin America . This study evaluated the safety and immunogenicity of a c and i date recombinant , live-attenuated , tetravalent dengue vaccine ( CYD-TDV ) in 9–16 year olds in Latin America . Methods : In this r and omized , blinded , controlled study , volunteers received either 3 doses of CYD-TDV ( n = 401 )  or placebo as first and second injection and tetanus/diphtheria/acellular pertussis vaccine as third injection ( n = 199 ) at 0 , 6 and 12 months . Adverse events were documented . Plaque reduction neutralization test antibody titers against the 4 CYD-TDV parental strains were measured before and 28 days after each dose . Seropositivity was defined as antibody titers ≥10 1/dil . Results : The number of adverse reactions decreased after each successive CYD-TDV dose . After each CYD-TDV dose , antibody titers against all 4 serotypes were higher than baseline and respective predose titers . After the third dose of CYD-TDV , 100 % , 98.6 % and 93.4 % of participants were seropositive for at least 2 , at least 3 or all 4 serotypes , respectively . Higher antibody titers were observed in participants in the CYD-TDV group who were FV-seropositive at baseline compared with those who were FV-seronegative . Conclusions : CYD-TDV had a favorable safety profile and elicited antibody responses against all 4 dengue virus serotypes in 9–16 year olds in Latin America . These findings support the continued development of CYD-TDV Flaws in the design , conduct , analysis , and reporting of r and omised trials can cause the effect of an intervention to be underestimated or overestimated . The Cochrane Collaboration ’s tool for assessing risk of bias aims to make the process clearer and more Immunogenicity and safety of a recombinant , live-attenuated , tetravalent dengue disease vaccine ( CYD-TDV ) was evaluated in children/adolescents in Brazil . In this observer-blind , placebo-controlled , phase II single-center study , children/adolescents ( ages 9–16 years ) were r and omized to receive CYD-TDV or placebo at 0 , 6 , and 12 months . Immunogenicity was assessed using a 50 % plaque neutralization test . Overall , 150 participants were enrolled  ( CYD-TDV : N = 100 ; placebo : N = 50 ) . Injection site pain and headache were the most common solicited injection site and systemic reactions . Unsolicited adverse events ( AEs ) and serious AEs were similar between groups . No serious AEs were vaccine-related . Geometric mean titers against all dengue virus serotypes increased with CYD-TDV vaccination and were 267 , 544 , 741 , and 432 1/dil for serotypes 1–4 , respectively , after dose 3 , representing a mean fold increase from baseline of 5 , 6 , 6 , and 20 , respectively . CYD-TDV vaccination elicited a neutralizing antibody response against serotypes 1–4 and was well-tolerated in children/adolescents in a dengue-endemic region In a r and omized , placebo-controlled , monocenter , observer blinded study conducted in an area where dengue is endemic , we assessed the safety and immunogenicity of a recombinant , live , attenuated , tetravalent dengue vaccine c and i date ( CYD-TDV ) in 2 - 11 year-olds with varying levels of pre-existing yellow-fever immunity due to vaccination 1 - 7 years previously . 199 children received 3 injections of CYD-TDV  ( months 0 , 6 and 12 ) and 99 received placebo  ( months 0 and 6 ) or pneumococcal polysaccharide vaccine  ( month 12 ) . One month after the third dengue vaccination , serotype specific neutralizing antibody GMTs were in the range of 178 - 190 ( 1/dil ) ( versus 16.7 - 38.1 in the control group ) , a 10 - 20 fold-increase from baseline , and 94 % of vaccines were seropositive to all four serotypes ( versus 39 % in the control group ) . There were no vaccine-related SAEs . The observed reactogenicity profile was consistent with phase I studies , with severity grade 1 - 2 injection site pain , headache , malaise and fever most frequently reported and no increase after subsequent vaccinations . Virologically confirmed dengue cases were seen after completion of the 3 doses : 1 in the CYD-TDV group ( N=199 ) , and 3 in the control group ( N=99 ) . A 3-dose regimen of CYD-TDV had a good safety profile in 2 - 11 year olds with a history of YF vaccination and elicited robust antibody responses that were balanced against the four serotypes BACKGROUND Roughly half the world 's population live in dengue-endemic countries , but no vaccine is licensed . We investigated the efficacy of a recombinant , live , attenuated tetravalent dengue vaccine . METHODS In this observer-masked , r and omised , controlled , monocentre , phase 2b , proof-of-concept trial , healthy Thai schoolchildren aged 4 - 11 years were r and omly assigned ( 2:1 ) to receive three injections of dengue vaccine or control ( rabies vaccine or placebo ) at months 0 , 6 , and 12 . R and omisation was by computer-generated permuted blocks of six and participants were assigned with an interactive response system . Participants were actively followed up until month 25 . All acute febrile illnesses were investigated . Dengue viraemia was confirmed by serotype-specific RT-PCR and non-structural protein 1 ELISA . The primary objective was to assess protective efficacy against virologically confirmed , symptomatic dengue , irrespective of severity or serotype , occurring 1 month or longer after the third injection ( per- protocol analysis ) . This trial is registered at Clinical Trials.gov , NCT00842530 . FINDINGS 4002 participants were assigned to vaccine ( n=2669 ) or control ( n=1333 ) . 3673 were included in the primary analysis ( 2452 vaccine , 1221 control ) . 134 cases of virologically confirmed dengue occurred during the study . Efficacy was 30·2 % ( 95 % CI -13·4 to 56·6 ) , and differed by serotype . Dengue vaccine was well tolerated , with no safety signals after 2 years of follow-up after the first dose . INTERPRETATION These data show for the first time that a safe vaccine against dengue is possible . Ongoing large-scale phase 3 studies in various epidemiological setting s will provide pivotal data for the CYD dengue vaccine c and i date . FUNDING Sanofi Pasteur BACKGROUND A c and i date tetravalent dengue vaccine is being assessed in three clinical trials involving more than 35,000 children between the ages of 2 and 16 years in Asian-Pacific and Latin American countries . We report the results of long-term follow-up interim analyses and integrated efficacy analyses . METHODS We are assessing the incidence of hospitalization for virologically confirmed dengue as a surrogate safety end point during follow-up in years 3 to 6 of two phase 3 trials , CYD14 and CYD15 , and a phase 2b trial , CYD23/57 . We estimated vaccine efficacy using pooled data from the first 25 months of CYD14 and CYD15 . RESULTS Follow-up data were available for 10,165 of 10,275 participants ( 99 % ) in CYD14  and 19,898 of 20,869 participants ( 95 % ) in CYD15 . Data were available for 3203 of the 4002 participants ( 80 % ) in the CYD23 trial included in CYD57 . During year 3 in the CYD14 , CYD15 , and CYD57 trials combined , hospitalization for virologically confirmed dengue occurred in 65 of 22,177 participants in the vaccine group and 39 of 11,089 participants in the control group . Pooled relative risks of hospitalization for dengue were 0.84 ( 95 % confidence interval [ CI ] , 0.56 to 1.24 ) among all participants , 1.58 ( 95 % CI , 0.83 to 3.02 ) among those under the age of 
    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: To characterize the cell mediated immunity ( CMI ) induced by the investigational CYD tetravalent dengue vaccine ( TDV ) , we developed a whole-blood , intracellular cytokine staining ( ICS ) assay and a multiplex assay , each requiring 3 mL of blood . We assessed CMI before and 28 d after a first and third injection of CYD-TDV and one year after the third injection in a subset of 80 adolescents and adults enrolled in a phase II trial in Singapore ( Clinical Trial.gov NCT NCT00880893 ) . CD4/IFNγ/TNFα responses specific to dengue NS3 were detected before vaccination . Vaccination induced YF-17D-NS3-specific CD8/IFNγ responses , without significant TNFα , and a CYD-specific Th1/Tc1 cellular response in all participants , which was characterized by predominant IFNγ secretion compared with TNFα , associated with low level IL-13 secretion in multiplex analysis of peripheral blood mononuclear cells ( P BMC ) supernatants after restimulation with each the CYD vaccine viruses . Responses were directed mainly against CYD-4 after the first vaccination , and were more balanced against all four serotypes after the third vaccination . The same qualitative profile was observed one year after the third vaccination , with approximately 2-fold lower NS3-specific responses , and 3-fold lower serotype-specific cellular responses . These findings confirm previous observations regarding both the nature and specificity of cellular responses induced by CYD-TDV , and for the first time demonstrate the persistence of cellular responses after one year . We also established the feasibility of analyzing CMI with small blood sample s , allowing such analysis to be considered for pediatric trials BACKGROUND In light of the increasing rate of dengue infections throughout the world despite vector-control measures , several dengue vaccine c and i date s are in development . METHODS In a phase 3 efficacy trial of a tetravalent dengue vaccine in five Latin American countries where dengue is endemic , we r and omly assigned healthy children between the ages of 9 and 16 years in a 2:1 ratio to receive three injections of recombinant , live , attenuated , tetravalent dengue vaccine ( CYD-TDV ) or placebo at months 0 , 6 , and 12 under blinded conditions . The children were then followed for 25 months . The primary outcome was vaccine efficacy against symptomatic , virologically confirmed dengue ( VCD ) , regardless of disease severity or serotype , occurring more than 28 days after the third injection . RESULTS A total of 20,869 healthy children received either vaccine or placebo . At baseline , 79.4 % of an immunogenicity subgroup of 1944 children had seropositive status for one or more dengue serotypes . In the per- protocol population , there were 176 VCD cases ( with 11,793 person-years at risk ) in the vaccine group and 221 VCD cases ( with 5809 person-years at risk ) in the control group , for a vaccine efficacy of 60.8 % ( 95 % confidence interval [ CI ] , 52.0 to 68.0 ) . In the intention-to-treat population ( those who received at least one injection ) , vaccine efficacy was 64.7 % ( 95 % CI , 58.7 to 69.8 ) . Serotype-specific vaccine efficacy was 50.3 % for serotype 1 , 42.3 % for serotype 2 , 74.0 % for serotype 3 , and 77.7 % for serotype 4 . Among the severe VCD cases , 1 of 12 was in the vaccine group , for an intention-to-treat vaccine efficacy of 95.5 % . Vaccine efficacy against hospitalization for dengue was 80.3 % . The safety profile for the CYD-TDV vaccine was similar to that for placebo , with no marked difference in rates of adverse events . CONCLUSIONS The CYD-TDV dengue vaccine was efficacious against VCD and severe VCD and led to fewer hospitalizations for VCD in five Latin American countries where dengue is endemic . ( Funded by Sanofi Pasteur ; Clinical Trials.gov number , NCT01374516 . ) Background : The dengue virus is a member of the Flavivirus ( FV ) genus , which also includes the yellow fever virus . Dengue disease is caused by any 1 of 4 dengue virus serotypes and is a serious public health concern in Latin America . This study evaluated the safety and immunogenicity of a c and i date recombinant , live-attenuated , tetravalent dengue vaccine ( CYD-TDV ) in 9–16 year olds in Latin America . Methods : In this r and omized , blinded , controlled study , volunteers received either 3 doses of CYD-TDV ( n = 401 )  or placebo as first and second injection and tetanus/diphtheria/acellular pertussis vaccine as third injection ( n = 199 ) at 0 , 6 and 12 months . Adverse events were documented . Plaque reduction neutralization test antibody titers against the 4 CYD-TDV parental strains were measured before and 28 days after each dose . Seropositivity was defined as antibody titers ≥10 1/dil . Results : The number of adverse reactions decreased after each successive CYD-TDV dose . After each CYD-TDV dose , antibody titers against all 4 serotypes were higher than baseline and respective predose titers . After the third dose of CYD-TDV , 100 % , 98.6 % and 93.4 % of participants were seropositive for at least 2 , at least 3 or all 4 serotypes , respectively . Higher antibody titers were observed in participants in the CYD-TDV group who were FV-seropositive at baseline compared with those who were FV-seronegative . Conclusions : CYD-TDV had a favorable safety profile and elicited antibody responses against all 4 dengue virus serotypes in 9–16 year olds in Latin America . These findings support the continued development of CYD-TDV Flaws in the design , conduct , analysis , and reporting of r and omised trials can cause the effect of an intervention to be underestimated or overestimated . The Cochrane Collaboration ’s tool for assessing risk of bias aims to make the process clearer and more Immunogenicity and safety of a recombinant , live-attenuated , tetravalent dengue disease vaccine ( CYD-TDV ) was evaluated in children/adolescents in Brazil . In this observer-blind , placebo-controlled , phase II single-center study , children/adolescents ( ages 9–16 years ) were r and omized to receive CYD-TDV or placebo at 0 , 6 , and 12 months . Immunogenicity was assessed using a 50 % plaque neutralization test . Overall , 150 participants were enrolled  ( CYD-TDV : N = 100 ; placebo : N = 50 ) . Injection site pain and headache were the most common solicited injection site and systemic reactions . Unsolicited adverse events ( AEs ) and serious AEs were similar between groups . No serious AEs were vaccine-related . Geometric mean titers against all dengue virus serotypes increased with CYD-TDV vaccination and were 267 , 544 , 741 , and 432 1/dil for serotypes 1–4 , respectively , after dose 3 , representing a mean fold increase from baseline of 5 , 6 , 6 , and 20 , respectively . CYD-TDV vaccination elicited a neutralizing antibody response against serotypes 1–4 and was well-tolerated in children/adolescents in a dengue-endemic region In a r and omized , placebo-controlled , monocenter , observer blinded study conducted in an area where dengue is endemic , we assessed the safety and immunogenicity of a recombinant , live , attenuated , tetravalent dengue vaccine c and i date ( CYD-TDV ) in 2 - 11 year-olds with varying levels of pre-existing yellow-fever immunity due to vaccination 1 - 7 years previously . 199 children received 3 injections of CYD-TDV  ( months 0 , 6 and 12 ) and 99 received placebo  ( months 0 and 6 ) or pneumococcal polysaccharide vaccine  ( month 12 ) . One month after the third dengue vaccination , serotype specific neutralizing antibody GMTs were in the range of 178 - 190 ( 1/dil ) ( versus 16.7 - 38.1 in the control group ) , a 10 - 20 fold-increase from baseline , and 94 % of vaccines were seropositive to all four serotypes ( versus 39 % in the control group ) . There were no vaccine-related SAEs . The observed reactogenicity profile was consistent with phase I studies , with severity grade 1 - 2 injection site pain , headache , malaise and fever most frequently reported and no increase after subsequent vaccinations . Virologically confirmed dengue cases were seen after completion of the 3 doses : 1 in the CYD-TDV group ( N=199 ) , and 3 in the control group ( N=99 ) . A 3-dose regimen of CYD-TDV had a good safety profile in 2 - 11 year olds with a history of YF vaccination and elicited robust antibody responses that were balanced against the four serotypes BACKGROUND Roughly half the world 's population live in dengue-endemic countries , but no vaccine is licensed . We investigated the efficacy of a recombinant , live , attenuated tetravalent dengue vaccine . METHODS In this observer-masked , r and omised , controlled , monocentre , phase 2b , proof-of-concept trial , healthy Thai schoolchildren aged 4 - 11 years were r and omly assigned ( 2:1 ) to receive three injections of dengue vaccine or control ( rabies vaccine or placebo ) at months 0 , 6 , and 12 . R and omisation was by computer-generated permuted blocks of six and participants were assigned with an interactive response system . Participants were actively followed up until month 25 . All acute febrile illnesses were investigated . Dengue viraemia was confirmed by serotype-specific RT-PCR and non-structural protein 1 ELISA . The primary objective was to assess protective efficacy against virologically confirmed , symptomatic dengue , irrespective of severity or serotype , occurring 1 month or longer after the third injection ( per- protocol analysis ) . This trial is registered at Clinical Trials.gov , NCT00842530 . FINDINGS 4002 participants were assigned to vaccine ( n=2669 ) or control ( n=1333 ) . 3673 were included in the primary analysis ( 2452 vaccine , 1221 control ) . 134 cases of virologically confirmed dengue occurred during the study . Efficacy was 30·2 % ( 95 % CI -13·4 to 56·6 ) , and differed by serotype . Dengue vaccine was well tolerated , with no safety signals after 2 years of follow-up after the first dose . INTERPRETATION These data show for the first time that a safe vaccine against dengue is possible . Ongoing large-scale phase 3 studies in various epidemiological setting s will provide pivotal data for the CYD dengue vaccine c and i date . FUNDING Sanofi Pasteur BACKGROUND A c and i date tetravalent dengue vaccine is being assessed in three clinical trials involving more than 35,000 children between the ages of 2 and 16 years in Asian-Pacific and Latin American countries . We report the results of long-term follow-up interim analyses and integrated efficacy analyses . METHODS We are assessing the incidence of hospitalization for virologically confirmed dengue as a surrogate safety end point during follow-up in years 3 to 6 of two phase 3 trials , CYD14 and CYD15 , and a phase 2b trial , CYD23/57 . We estimated vaccine efficacy using pooled data from the first 25 months of CYD14 and CYD15 . RESULTS Follow-up data were available for 10,165 of 10,275 participants ( 99 % ) in CYD14  and 19,898 of 20,869 participants ( 95 % ) in CYD15 . Data were available for 3203 of the 4002 participants ( 80 % ) in the CYD23 trial included in CYD57 . During year 3 in the CYD14 , CYD15 , and CYD57 trials combined , hospitalization for virologically confirmed dengue occurred in 65 of 22,177 participants in the vaccine group and 39 of 11,089 participants in the control group . Pooled relative risks of hospitalization for dengue were 0.84 ( 95 % confidence interval [ CI ] , 0.56 to 1.24 ) among all participants , 1.58 ( 95 % CI , 0.83 to 3.02 ) among those under the age of 
    Output:
    