Persistence of Th1/Tc1 responses one year after tetravalent dengue vaccination in adults and adolescents in Singapore Efficacy of a tetravalent dengue vaccine in children in Latin America. Safety and Immunogenicity of a Recombinant Tetravalent Dengue Vaccine in 9–16 Year Olds: A Randomized, Controlled, Phase II Trial in Latin America The Cochrane Collaboration’s tool for assessing risk of bias in randomised trials Immunogenicity and Safety of a Recombinant Tetravalent Dengue Vaccine in Children and Adolescents Ages 9–16 Years in Brazil Immunogenicity and safety of tetravalent dengue vaccine in 2-11 year-olds previously vaccinated against yellow fever: randomized, controlled, phase II study in Piura, Peru. Protective efficacy of the recombinant, live-attenuated, CYD tetravalent dengue vaccine in Thai schoolchildren: a randomised, controlled phase 2b trial Efficacy and Long-Term Safety of a Dengue Vaccine in Regions of Endemic Disease. Live attenuated tetravalent dengue vaccine. Clinical efficacy and safety of a novel tetravalent dengue vaccine in healthy children in Asia: a phase 3, randomised, observer-masked, placebo-controlled trial Immunogenicity and safety of recombinant tetravalent dengue vaccine (CYD-TDV) in individuals aged 2-45 y: Phase II randomized controlled trial in Singapore. Safety and immunogenicity of a tetravalent dengue vaccine in healthy children aged 2-11 years in Malaysia: a randomized, placebo-controlled, Phase III study.
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 9 years , and 0.50 ( 95 % CI , 0.29 to 0.86 ) among those 9 years of age or older . During year 3 , hospitalization for severe dengue , as defined by the independent data monitoring committee criteria , occurred in 18 of 22,177 participants in the vaccine group and 6 of 11,089 participants in the control group . Pooled rates of efficacy for symptomatic dengue during the first 25 months were 60.3 % ( 95 % CI , 55.7 to 64.5 ) for all participants , 65.6 % ( 95 % CI , 60.7 to 69.9 ) for those 9 years of age or older , and 44.6 % ( 95 % CI , 31.6 to 55.0 ) for those younger than 9 years of age . CONCLUSIONS Although the unexplained higher incidence of hospitalization for dengue in year 3 among children younger than 9 years of age needs to be carefully monitored during long-term follow-up , the risk among children 2 to 16 years of age was lower in the vaccine group than in the control group . ( Funded by Sanofi Pasteur ; Clinical Trials.gov numbers , NCT00842530 , NCT01983553 , NCT01373281 , and NCT01374516 . ) The development of a live attenuated tetravalent dengue vaccine is currently the best strategy to obtain a vaccine against dengue viruses . The Mahidol University group developed c and i date live attenuated vaccines by attenuation through serial passages in certified primary cell cultures . Dengue serotype 1 , 2 and 4 viruses were developed in primary dog kidney cells , whereas dengue serotype 3 was serially passaged in primary African green monkey kidney cells . Tissue culture passaged strain viruses were subjected to biological marker studies . C and i date vaccines have been tested as monovalent ( single virus ) , bivalent ( two viruses ) , trivalent ( three viruses ) and tetravalent ( all four serotype viruses ) vaccines in Thai volunteers . They were found to be safe and immunogenic in both adults and children . The Mahidol live attenuated dengue 2 virus was also tested in American volunteers and result ed in good immune response indistinguishable from those induced in Thai volunteers . The master seeds from the four live attenuated virus strains developed were provided to Pasteur Merieux Connaught of France for production on an industrial scale following good manufacturing practice guidelines BACKGROUND An estimated 100 million people have symptomatic dengue infection every year . This is the first report of a phase 3 vaccine efficacy trial of a c and i date dengue vaccine . We aim ed to assess the efficacy of the CYD dengue vaccine against symptomatic , virologically confirmed dengue in children . METHODS We did an observer-masked , r and omised controlled , multicentre , phase 3 trial in five countries in the Asia-Pacific region . Between June 3 , and Dec 1 , 2011 , healthy children aged 2 - 14 years were r and omly assigned ( 2:1 ) , by computer-generated permuted blocks of six with an interactive voice or web response system , to receive three injections of a recombinant , live , attenuated , tetravalent dengue vaccine ( CYD-TDV ) , or placebo , at months 0 , 6 , and 12 . R and omisation was stratified by age and site . Participants were followed up until month 25 . Trial staff responsible for the preparation and administration of injections were unmasked to group allocation , but were not included in the follow-up of the participants ; allocation was concealed from the study sponsor , investigators , and parents and guardians . Our primary objective was to assess protective efficacy against symptomatic , virologically confirmed dengue , irrespective of disease severity or serotype , that took place more than 28 days after the third injection . The primary endpoint was for the lower bound of the 95 % CI of vaccine efficacy to be greater than 25 % . Analysis was by intention to treat and per procotol . This trial is registered with Clinical Trials.gov , number NCT01373281 . FINDINGS We r and omly assigned 10,275 children to receive either vaccine ( n=6851 ) or placebo ( n=3424 ) , of whom 6710 ( 98 % ) and 3350 ( 98 % ) , respectively , were included in the primary analysis . 250 cases of virologically confirmed dengue took place more than 28 days after the third injection ( 117 [ 47 % ] in the vaccine group and 133 [ 53 % ] in the control group ) . The primary endpoint was achieved with 56·5 % ( 95 % CI 43·8 - 66·4 ) efficacy . We recorded 647 serious adverse events ( 402 [ 62 % ] in the vaccine group and 245 [ 38 % ] in the control group ) . 54 ( 1 % ) children in the vaccine group and 33 ( 1 % ) of those in the control group had serious adverse events that happened within 28 days of vaccination . Serious adverse events were consistent with medical disorders in this age group and were mainly infections and injuries . INTERPRETATION Our findings show that dengue vaccine is efficacious when given as three injections at months 0 , 6 , and 12 to children aged 2 - 14 years in endemic areas in Asia , and has a good safety profile . Vaccination could reduce the incidence of symptomatic infection and hospital admission and has the potential to provide an important public health benefit . FUNDING Sanofi Pasteur This was a multicenter , blinded , Phase II study ( NCT00880893 ) conducted in Singapore . The primary objectives were to evaluate the safety of a tetravalent dengue vaccine ( TDV ) comprising four recombinant , live , attenuated viruses ( CYD-TDV ) and the dengue virus serotype-specific antibody responses before and 28 d after each vaccination . Participants were r and omized 3:1 to receive three doses of CYD-TDV or a control vaccine at 0 , 6 and 12 mo . Control vaccine was placebo for the first dose ( all ages ) and for subsequent doses , licensed hepatitis-A for children ( aged 2 - 11 y ) or  influenza vaccine for adolescents ( 12 - 17 y ) and adults ( 18 - 45 y ) . Between April and October 2009 , 317 children , 187 adolescents and 696 adults were enrolled . In all age groups , reactogenicity was higher after the first injection of CYD-TDV than after placebo control . Reactogenicity after subsequent CYD-TDV doses was no higher than after the first dose , and tended to be lower or similar to that seen after active control vaccination . Seropositivity rates and geometric mean neutralizing antibody titers ( GMTs ; 1/dil ) against all four dengue virus serotypes increased in all age groups after each of the three CYD-TDV doses . Post-dose 3 , 66.5 % of all participants were seropositive to all four serotypes , and 87.2 % were seropositive to ≥ 3 serotypes ; GMTs for all participants ranged from 43.0 against dengue virus serotype 1 to 100 against dengue virus serotype 4 . GMTs were higher in children than in adolescents . These results support the continued development of CYD-TDV for the prevention of dengue disease BACKGROUND Dengue disease is a major public health problem across the Asia-Pacific region for which there is no licensed vaccine or treatment . We evaluated the safety and immunogenicity of Phase III lots of a c and i date vaccine ( CYD-TDV ) in children in Malaysia . METHODS In this observer-blind , placebo-controlled , Phase III study , children aged 2 - 11 years were r and omized ( 4:1 ) to receive CYD-TDV or placebo at 0 , 6 and 12 months . Primary endpoints included assessment of reactogenicity following each dose , adverse events ( AEs ) and serious AEs ( SAEs ) reported throughout the study , and immunogenicity expressed as geometric mean titres ( GMTs ) and distribution of dengue virus ( DENV ) neutralizing antibody titres . RESULTS 250 participants enrolled in the study ( CYD-TDV : n=199 ; placebo : n=51 ) . There was a trend for reactogenicity to be higher with CYD-TDV than with placebo post-dose 1 ( 75.4 % versus 68.6 % ) and post-dose 2 ( 71.6 % versus 62.0 % ) and slightly lower post-dose 3 ( 57.9 % versus 64.0 % ) . Unsolicited AEs declined in frequency with each subsequent dose and were similar overall between groups ( CYD-TDV : 53.8 % ; placebo : 49.0 % ) . Most AEs were of Grade 1 intensity and were transient . SAEs were reported by 5.5 % and 11.8 % of participants in the CYD-TDV and placebo groups , respectively . No deaths were reported . Baseline seropositivity against each of the four DENV serotypes was similar between groups , ranging from 24.0 % ( DENV-4 ) to 36.7 % ( DENV-3 ) . In the CYD-TDV group , GMTs increased post-dose 2 for all serotypes compared with baseline , ranging from 4.8 ( DENV-1 ) to 8.1-fold ( DENV-3 ) . GMTs further increased post-dose 3 for DENV-1 and DENV-2 . Compared with baseline , individual titre increases ranged from 6.1-fold ( DENV-1 ) to 7.96-fold ( DENV-3 ) . CONCLUSIONS This study demonstrated a satisfactory safety profile and a balanced humoral immune response against all four DENV serotypes for CYD-TDV administered via a three-dose regimen to children in Malaysia
Background R and omised controlled trials have evaluated the recombinant tetravalent dengue vaccine ( CYD-TDV ) .
However , individual results may have little power to identify differences among the population s studied .
Objective To evaluate efficacy , immunogenicity and safety of CYD-TDV in the prevention of dengue in children aged 2–17 years .