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Immunogenicity and safety of recombinant tetravalent dengue vaccine (CYD-TDV) in individuals aged 2-45 y: Phase II randomized controlled trial in Singapore.

ABSTRACT: 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 randomized 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.

SUBMITTER: Leo YS

PROVIDER: S-EPMC3579907 | biostudies-literature | 2012 Sep

REPOSITORIES: biostudies-literature

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Immunogenicity and safety of recombinant tetravalent dengue vaccine (CYD-TDV) in individuals aged 2-45 y: Phase II randomized controlled trial in Singapore.

Leo Yee Sin YS Wilder-Smith Anneliese A Archuleta Sophia S Shek Lynette P LP Chong Chia-Yin CY Leong Hoe Nam HN Low Chian Yong CY Oh May-Lin Helen ML Bouckenooghe Alain A Wartel T Anh TA Crevat Denis D

Human vaccines & immunotherapeutics 20120816 9

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 randomized 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 ...[more]

PMID: 22894958

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Project description:BackgroundRandomised controlled trials have evaluated the recombinant tetravalent dengue vaccine (CYD-TDV). However, individual results may have little power to identify differences among the populations studied.ObjectiveTo evaluate efficacy, immunogenicity and safety of CYD-TDV in the prevention of dengue in children aged 2-17 years.DesignSystematic review and meta-analysis.Data sourcesMEDLINE (from 1950 to 5 December 2018), EMBASE (from 1947 to 5 December 2018) and Cochrane (from 1993 to 5 December 2018).Eligibility criteria of studiesRandomised trials comparing efficacy, immunogenicity and safety of CYD-TDV with placebo or other vaccines for preventing dengue cases in children aged 2-17 years.Outcome measuresEfficacy, immunogenicity and safety of CYD-TDV.Study appraisal and methodsCalculations were made of relative risk (RR) and mean difference (MD) for dichotomous and continuous outcomes, respectively. All estimates were calculated considering a 95% CI estimate. A p<0.05 was considered statistically significant.ResultsNine studies involving 34 248 participants were included. The overall efficacy of CYD-TDV was 60% (RR 0.40 (0.30 to 0.54)). Serotype-specific efficacy of the vaccine was 51% for dengue virus type-1 (DENV-1) (RR 0.49 (0.39 to 0.63)); 34% for DENV-2 (RR 0.66 (0.50 to 0.86)); 75% for DENV-3 (RR 0.25 (0.18 to 0.35)) and 77% for DENV-4 (RR 0.23 (0.15 to 0.34)). Overall immunogenicity (MD) of CYD-TDV was 225.13 (190.34 to 259.93). Serotype-specific immunogenicity was: DENV-1: 176.59 (123.36 to 229.83); DENV-2: 294.21 (181.98 to 406.45); DENV-3: 258.78 (146.72 to 370.84) and DENV-4: 189.35 (141.11 to 237.59). The most common adverse events were headache and pain at the injection site.LimitationsThe main limitation of this study was unclear or incomplete data.Conclusions and implications of key findingsCYD-TDV is considered safe and able to partially protect children and adolescents against four serotypes of DENV for a 1-year period. Despite this, research should prioritise improvements in vaccine efficacy, thus proving higher long-term protection against all virus serotypes.Prospero registration numberCRD42016043628.

Project description:BackgroundDengue hemorrhagic fever is the leading cause of hospitalization and death in children living in Asia and Latin America. There is an urgent need for an effective and safe dengue vaccine to reduce morbidity and mortality in this high-risk population given the lack of dengue specific treatment at present. This review aims to determine the efficacy, safety, and immunogenicity of CYD-TDV vaccine in children.MethodsThis is a systematic review including meta-analysis of randomized controlled clinical trial data from Embase, Medline, the Cochrane Library, Web of Science, and ClinicalTrials.gov. Studies that assessed CYD-TDV vaccine efficacy [(1 - RR)*100], safety (RR), and immunogenicity (weighted mean difference) in children were included in this study. Random effects model was employed to analyze patient-level data extracted from primary studies.ResultsThe overall efficacy of CYD-TDV vaccine was 54% (40-64), while serotype-specific efficacy was 77% (66-85) for DENV4, 75% (65-82) for DENV3, 50% (36-61) for DENV1, and 34% (14-49) for DENV2. 15% (-174-74) vaccine efficacy was obtained for the unknown serotype. Meta-analysis of included studies with longer follow-up time (25 months) revealed that CYD-TDV vaccine significantly increased the risk of injection site reactions (RR = 1.1: 1.04-1.17; p-value = 0.001). Immunogenicity (expressed as geometric mean titers) in descending order was 439.7 (331.7-547.7), 323 (247 - 398.7), 144.1 (117.9-170.2), and 105 (88.7-122.8) for DENV3, DENV2, DENV1, and DENV4, respectively.ConclusionCYD-TDV vaccine is effective and immunogenic in children overall. Reduced efficacy of CYD-TDV vaccine against DENV2 notoriously known for causing severe dengue infection and dengue outbreaks cause for serious concern. Post hoc meta-analysis of long-term follow-up data (≥25 months) from children previously vaccinated with CYD-TDV vaccine is needed to make a conclusion regarding CYD-TDV vaccine safety in children. However, CYD-TDV vaccine should be considered for use in regions where DENV2 is not endemic as currently there is no specific treatment for dengue infection.

Project description:BackgroundThe live attenuated tetravalent dengue vaccine (CYD-TDV) is licensed using a 0-, 6- and 12-month schedule in dengue-endemic areas. An effective shorter schedule may provide more rapid, optimal protection of targeted populations during vaccine campaigns in dengue-endemic countries. We compared immune responses to two schedules of CYD-TDV in a non-endemic population. We also evaluated the impact of yellow fever (YF) co-administration.MethodsThis phase II, open-label, multicentre study enrolled 390 healthy 18-45-year-olds in the USA with no prior exposure to dengue. Participants were randomised (4:4:4:1) to four treatment groups stratified by prior YF vaccine status: Group 1, CYD-TDV standard 0-6-12 months schedule; Group 2, CYD-TDV accelerated 0-2-6 months schedule; Group 3, CYD-TDV accelerated schedule with YF co-administered (dose 1); Group 4, YF vaccination only. Neutralising antibody geometric mean titres (GMTs) and percentages of seropositive participants (antibody titres ≥10 [1/dil]) were measured against each dengue serotype using a 50% plaque reduction neutralisation test.ResultsOn D28 post-CYD-TDV dose 3, there were no marked differences in seropositivity rates and GMTs between Groups 1 and 2. In Groups 1 and 2 respectively, 73.4 and 82.4% were dengue seropositive for ≥3 serotypes, with 50.0 and 42.6% seropositive against all four serotypes. Flavivirus status (FV+ or FV-) at baseline did not markedly affect GMTs and seropositivity rates with either schedule. In Groups 1 and 2, GMTs measured 6 months after the third dose decreased against all serotypes, except for a small increase in GMT for serotype 4 in Group 1. In addition, dengue seropositivity remained above 70% for serotypes 2, 3 and 4 in Groups 1 and 2. Co-administration with YF did not affect antibody responses against dengue and YF or impact vaccine safety following completion of the compressed schedule, compared to dengue or YF vaccination alone.ConclusionsThe live attenuated CYD-TDV vaccine given in a compressed schedule in a non-endemic setting can elicit similar antibody responses to the licensed CYD-TDV schedule.Trial registrationThis trial was registered on cinicaltrials.gov, NCT01488890 (December 8, 2011).

Dataset Information

Immunogenicity and safety of recombinant tetravalent dengue vaccine (CYD-TDV) in individuals aged 2-45 y: Phase II randomized controlled trial in Singapore.

Publications

Immunogenicity and safety of recombinant tetravalent dengue vaccine (CYD-TDV) in individuals aged 2-45 y: Phase II randomized controlled trial in Singapore.

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