Safety and immunogenicity of a tetravalent dengue vaccine in healthy children aged 2-11 years in Malaysia: A randomized, placebo-controlled, Phase III study

Department of Pediatrics, Hospital Raja Permaisuri Bainun, Jalan Hospital, Ipoh, Perak, Malaysia. Electronic address: .
Vaccine (Impact Factor: 3.62). 10/2013; 31(49). DOI: 10.1016/j.vaccine.2013.10.013
Source: PubMed


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 candidate vaccine (CYD-TDV) in children in Malaysia.
In this observer-blind, placebo-controlled, Phase III study, children aged 2-11 years were randomized (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.
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).
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.

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Available from: Yanee Hutagalung, Dec 19, 2013
    • "In this regard, an additional challenge was to ensure that there was appropriate clinical trial infrastructure in place across these various sites. As mentioned previously, the CYD-TDV candidate had a satisfactory safety profile and good immunogenicity in initial phase I and phase II trials, and in subsequent phase III trials [4] [5] [32]. These trials were conducted over ten years on several continents in children, adolescents and adults with a diverse flavivirus infection and vaccination history, as a prelude to the efficacy trials. "
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    ABSTRACT: Sanofi Pasteur has developed a recombinant, live-attenuated, tetravalent dengue vaccine (CYD-TDV) that is in late-stage development. The present review summarizes the different steps in the development of this dengue vaccine, with a particular focus on the clinical data from three efficacy trials, which includes one proof-of-concept phase IIb (NCT00842530) and two pivotal phase III efficacy trials (NCT01373281 and NCT01374516). Earlier studies showed that the CYD-TDV candidate had a satisfactory safety profile and was immunogenic across the four vaccine serotypes in both in vitro and in vivo preclinical tests, as well as in initial phase I to phase II clinical trials in both flavivirus-naïve and seropositive individuals. Data from the 25 months (after the first injection) active phase of the two pivotal phase III efficacy studies shows that CYD-TDV (administered at 0, 6, and 12 months) is efficacious against virologically-confirmed disease (primary endpoint) and has a good safety profile. Secondary analyses also showed efficacy against all four dengue serotypes and protection against severe disease and hospitalization. The end of the active phases in these studies completes more than a decade of development of CYD-TDV, but considerable activities and efforts remain to address outstanding scientific, clinical, and immunological questions, while preparing for the introduction and use of CYD-TDV. Additional safety observations were recently reported from the first complete year of hospital phase longer term surveillance for two phase 3 studies and the first and second completed years for one phase 2b study, demonstrating the optimal age for intervention from 9 years. Dengue is a complex disease, and both short-term and long-term safety and efficacy will continue to be addressed by ongoing long-term follow-up and future post-licensure studies.
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    • "The overall antibody geometric mean titer (GMT) was higher in participants who were dengue seropositive at baseline compared to participants who were dengue seronegative at baseline [18]. A trend of higher seroconversion and GMT antibody response in baseline Flavivirus seropositive participants has also been seen in phase II studies in Brazil [19], Malaysia [20], and Latin America (Colombia, Honduras, Mexico, Puerto Rico) [21]. A phase IIb proofof-concept trial was conducted in 4002 Thai children aged 4–11. "
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