Efficacy of a tetravalent dengue vaccine in children in Latin America. Dengue Virus Neutralizing Antibody Levels Associated with Protection from Infection in Thai Cluster Studies Safety and Immunogenicity of a Recombinant Tetravalent Dengue Vaccine in 9–16 Year Olds: A Randomized, Controlled, Phase II Trial in Latin America Factors Associated with Findings of Published Trials of Drug–Drug Comparisons: Why Some Statins Appear More Efficacious than Others Immunogenicity and safety of recombinant tetravalent dengue vaccine (CYD-TDV) in individuals aged 2–45 years Safety and immunogenicity of three tetravalent dengue vaccine formulations in healthy adults in the USA. Immunogenicity and Safety of a Recombinant Tetravalent Dengue Vaccine in Children and Adolescents Ages 9–16 Years in Brazil Safety Overview of a Recombinant Live-Attenuated Tetravalent Dengue Vaccine: Pooled Analysis of Data from 18 Clinical Trials 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.
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 Long-term homologous and temporary heterologous protection from dengue virus ( DENV ) infection may be mediated by neutralizing antibodies . However , neutralizing antibody titers ( NTs ) have not been clearly associated with protection from infection . Methodology /Principal Findings Data from two geographic cluster studies conducted in Kamphaeng Phet , Thail and were used for this analysis . In the first study ( 2004–2007 ) , cluster investigations of 100-meter radius were triggered by DENV-infected index cases from a concurrent prospect i ve cohort . Subjects between 6 months and 15 years old were evaluated for DENV infection at days 0 and 15 by DENV PCR and IgM ELISA . In the second study ( 2009–2012 ) , clusters of 200-meter radius were triggered by DENV-infected index cases admitted to the provincial hospital . Subjects of any age ≥6 months were evaluated for DENV infection at days 0 and 14 . In both studies , subjects who were DENV PCR positive at day 14/15 were considered to have been “ susceptible ” on day 0 . Comparison subjects from houses in which someone had documented DENV infection , but the subject remained DENV negative at days 0 and 14/15 , were considered “ non-susceptible . ” Day 0 sample s were presumed to be from just before virus exposure , and underwent plaque reduction neutralization testing ( PRNT ) . Seventeen “ susceptible ” ( six DENV-1 , five DENV-2 , and six DENV-4 ) , and 32 “ non-susceptible ” ( 13 exposed to DENV-1 , 10 DENV-2 , and 9 DENV-4 ) subjects were evaluated . Comparing subjects exposed to the same serotype , receiver operating characteristic ( ROC ) curves identified homotypic PRNT titers of 11 , 323 and 16 for DENV-1 , -2 and -4 , respectively , to differentiate “ susceptible ” from “ non-susceptible ” subjects . Conclusions / Significance PRNT titers were associated with protection from infection by DENV-1 , -2 and -4 . Protective NTs appeared to be serotype-dependent and may be higher for DENV-2 than other serotypes . These findings are relevant for both dengue epidemiology studies and vaccine development efforts 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 Background Published pharmaceutical industry – sponsored trials are more likely than non-industry-sponsored trials to report results and conclusions that favor drug over placebo . Little is known about potential biases in drug – drug comparisons . This study examined associations between research funding source , study design characteristics aim ed at reducing bias , and other factors that potentially influence results and conclusions in r and omized controlled trials ( RCTs ) of statin – drug comparisons . Methods and Findings This is a cross-sectional study of 192 published RCTs comparing a statin drug to another statin drug or non-statin drug .  Data on concealment of allocation , selection bias , blinding , sample size , disclosed funding source , financial ties of authors , results for primary outcomes , and author conclusions were extracted by two coders ( weighted kappa 0.80 to 0.97 ) . Univariate and multivariate logistic regression identified associations between independent variables and favorable results and conclusions . Of the RCTs , 50 % ( 95/192 ) were funded by industry , and 37 % ( 70/192 ) did not disclose any funding source . Looking at the totality of available evidence , we found that almost all studies ( 98 % , 189/192 ) used only surrogate outcome measures . Moreover , study design weaknesses common to published statin – drug comparisons included inadequate blinding , lack of concealment of allocation , poor follow-up , and lack of intention-to-treat analyses . In multivariate analysis of the full sample , trials with adequate blinding were less likely to report results favoring the test drug , and sample size was associated with favorable conclusions when controlling for other factors . In multivariate analysis of industry-funded RCTs , funding from the test drug company was associated with results ( odds ratio = 20.16 [ 95 % confidence interval 4.37–92.98 ] , p < 0.001 ) and conclusions ( odds ratio = 34.55 [ 95 % confidence interval 7.09–168.4 ] , p < 0.001 ) that favor the test drug when controlling for other factors . Studies with adequate blinding were less likely to report statistically significant results favoring the test drug . Conclusions RCTs of head-to-head comparisons of statins with other drugs are more likely to report results and conclusions favoring the sponsor 's product compared to the comparator drug . This bias in drug – drug comparison trials should be considered when making decisions regarding drug choice 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 years ) or  influenza vaccine for adolescents ( 12–17 years ) and adults ( 18–45 years ) . 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 A c and i date recombinant , live-attenuated , CYD tetravalent dengue vaccine ( CYD-TDV ) has recently demonstrated immunogenicity , efficacy and good tolerability . This study was performed to evaluate three CYD-TDV  formulations in adults . METHODS This was a r and omized , double-blind , multicenter , phase II trial . The vaccine formulations were : CYD-TDV 5555 ( ≈5log10 tissue culture infectious dose 50 % [ TCID50 ] of serotypes 1 - 4 ) ; CYD-TDV 5553 ( ≈5log10 TCID50 of serotypes 1 - 3 and ≈3log10 TCID50 of serotype 4 ) ; and CYD-TDV 4444 ( ≈4log10 TCID50 of serotypes 1 - 4 ) . Vaccinations were administered at 0 , 6 and 12 months . Immunogenicity was assessed using the plaque reduction neutralization test . RESULTS In total , 260 individuals were enrolled . The 5555 formulation elicited a superior serotype 4 response versus the 5553 formulation , with seropositivity rates of 89.7 % and 58.3 % , respectively , after the second dose ( between-group difference 31.4 % ; 95 % confidence interval 18.2 - 43.2 ) . After each of the three doses , seropositivity rates for serotypes 1 - 3 were numerically highest with CYD-TDV 5553 and lowest with the 4444 formulation ; seropositivity rates for serotype 4 were similar with the 5555 and 4444 formulations , and much lower among recipients of CYD-TDV 5553 . Geometric mean titers followed the same pattern as that seen with seropositivity rates . Safety/reactogenicity results were similar for all three vaccine formulations , although the percentage of participants reporting solicited injection site reactions was lower with CYD-TDV 4444 than with the other two formulations . All serious adverse events were unrelated to vaccination . CONCLUSIONS Reducing the dose of serotype 4 antigen ( 5553 formulation ) creates an imbalance in the immune response to CYD-TDV . Immune responses to CYD-TDV 5555 were slightly higher than to the 4444 formulation . Development of CYD-TDV 5555 has subsequently been pursued 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 A recombinant live attenuated tetravalent dengue vaccine ( CYD-TDV ) has been shown to be efficacious in preventing virologically-confirmed dengue disease , severe dengue disease and dengue hospitalization in children aged 2–16 years in Asia and Latin America . We analyzed pooled safety data from 18 phase I , II and III clinical trials in which the dengue vaccine was administered to participants aged 2–60 years , including long-term safety follow-up in three efficacy trials . The participants were analyzed according to their age at enrollment . The percentage of participants aged 2–60 years reporting ≥1 solicited injection-site or systemic reactions  was slightly higher in the CYD-TDV  group than in the placebo group . The most common solicited injection-site reactions were pain . Headache and malaise were the most common solicited systemic reactions . In both groups 0.3 % of participants discontinued for safety reasons . The most common unsolicited adverse events were injection-site reactions , gastrointestinal disorders , and infections . Reactogenicity did not increase with successive doses of CYD-TDV . The frequency and nature of SAEs occurring within 28 days of any dose were similar in the CYD-TDV and placebo groups and were common medical conditions that could be expected as a function of age . Baseline dengue virus serostatus did not appear to influence the safety profile . No vaccine-related anaphylactic reactions , neurotropic events or viscerotropic events were reported . In year 3 after dose 1 , an imbalance for dengue hospitalization , including for severe dengue , observed in participants aged < 9 years in the CYD-TDV group compared with the placebo group was not observed for participants aged ≥9 years . In Year 4 , this imbalance in participants aged < 9 years was less marked , giving an overall lower risk of dengue hospitalization or severe dengue from dose 1 to Year 4 in the CYD-TDV group . These results have contributed to the definition of the target population for vaccination ( ≥9 years old ) for which CYD-TDV has a satisfactory safety profile . Long-term safety will continue to be monitored in the ongoing follow-up of efficacy trials . Safety and effectiveness in real-life setting s will be assessed through post-licensure studies 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 . )
INTRODUCTION Dengue virus ( DENV ) is a serious global health problem .
CYD-TDC ( Dengvaxia ® ) was the first vaccine to gain regulatory approval to try and address this problem .
AIM Summarize all available evidence on the immunogenicity , efficacy and safety of the CYD-TDV dengue vaccine .