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Refined efficacy estimates of the Sanofi Pasteur dengue vaccine CYD-TDV using machine learning.

ABSTRACT: CYD-TDV is the first licensed dengue vaccine for individuals 9-45 (or 60) years of age. Using 12% of the subjects enroled in phase-2b and phase-3 trials for which baseline serostatus was measured, the vaccine-induced protection against virologically confirmed dengue during active surveillance (0-25 months) was found to vary with prior exposure to dengue. Because age and dengue exposure are highly correlated in endemic settings, refined insight into how efficacy varies by serostatus and age is essential to understand the increased risk of hospitalisation observed among vaccinated individuals during the long-term follow-up and to develop safe and effective vaccination strategies. Here we apply machine learning to impute the baseline serostatus for subjects with post-dose 3 titres but missing baseline serostatus. We find evidence for age dependence in efficacy independent of serostatus and estimate that among 9-16 year olds, CYD-TDV is protective against serotypes 1, 3 and 4 regardless of baseline serostatus.

SUBMITTER: Dorigatti I

PROVIDER: S-EPMC6128884 | biostudies-literature | 2018 Sep

REPOSITORIES: biostudies-literature

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Refined efficacy estimates of the Sanofi Pasteur dengue vaccine CYD-TDV using machine learning.

Dorigatti I I Donnelly C A CA Laydon D J DJ Small R R Jackson N N Coudeville L L Ferguson N M NM

Nature communications 20180907 1

CYD-TDV is the first licensed dengue vaccine for individuals 9-45 (or 60) years of age. Using 12% of the subjects enroled in phase-2b and phase-3 trials for which baseline serostatus was measured, the vaccine-induced protection against virologically confirmed dengue during active surveillance (0-25 months) was found to vary with prior exposure to dengue. Because age and dengue exposure are highly correlated in endemic settings, refined insight into how efficacy varies by serostatus and age is es ...[more]

PMID: 30194294

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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: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.

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Refined efficacy estimates of the Sanofi Pasteur dengue vaccine CYD-TDV using machine learning.

Publications

Refined efficacy estimates of the Sanofi Pasteur dengue vaccine CYD-TDV using machine learning.

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