Long-term immunogenicity and safety of tetravalent dengue vaccine (CYD-TDV) in healthy populations in Singapore and Vietnam: 4-year follow-up of randomized, controlled, phase II trials.

Dengue is prevalent in the Asia-Pacific region. Participants of two immunogenicity and safety phase II studies conducted in Singapore and Vietnam (NCT0088089 and NCT00875524, respectively) were followed for up to four years after third vaccine dose of a recombinant, live, attenuated, tetravalent dengue vaccine (CYD-TDV). Participants (2-45 years) received three doses of CYD-TDV or control at 0, 6, and 12 months. Dengue plaque reduction neutralization test (PRNT50) antibody titers were measured in both studies. Cytokine-producing antigen-specific CD4+ and CD8+ T-cells were quantified to assess cell-mediated immunity (CMI) in Singapore. Post-hoc analyses were carried out for participants aged <9 and ≥9 years old. Related and fatal serious adverse events (SAEs) were collected during long-term follow-up. Of participants who received ≥1 CYD-TDV injection in Singapore (n = 1198) and Vietnam (n = 180), 87% and 92% participants completed long-term follow-up, respectively. At four years, geometric mean titers (GMTs) in participants who received CYD-TDV ranged from 30.2 1/dil (95% CI 23.9-38.3) to 73.7 (49.3-110) 1/dil in Vietnam and 9.73 1/dil (95% CI 8.28-11.4) to 21.8 (18.9-25.1) 1/dil in Singapore. Interferon and interleukin-13 levels were lower at four years than one year post-vaccination but were still present. Tumor necrosis factor-α levels at four years were similar to those after the third vaccine dose. Seropositivity rates were higher at year four in participants who were seropositive vs. seronegative at baseline in both studies. No safety concerns were identified. CYD-TDV demonstrated long-term immunogenicity and was well-tolerated for four years after the third vaccine dose.

Immunogenicity of the CYD tetravalent dengue vaccine using an accelerated schedule: randomised phase II study in US adults.

BACKGROUND: The 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. METHODS: This 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. RESULTS: On 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. CONCLUSIONS: The 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 REGISTRATION: This trial was registered on cinicaltrials.gov, NCT01488890 (December 8, 2011).

Dengue vaccination during pregnancy - An overview of clinical trials data.

BACKGROUND: The live, attenuated, tetravalent dengue vaccine (CYD-TDV) is licensed in several endemic countries and contraindicated during pregnancy. Inadvertent vaccination during pregnancy may occur during clinical trials that include women of childbearing age. The potential risk associated with dengue vaccination in pregnancy remains unknown. We describe pregnancy outcomes following inadvertent dengue vaccination in pregnancy from CYD-TDV trial data. METHODS: Data were collected from trials conducted as part of the CYD-TDV clinical development. Women who received CYD-TDV or placebo during the pre-specified pregnancy risk window (from 30 days before the date of their last menstrual period to end of pregnancy) were considered as exposed; pregnancies occurring in non-risk periods during the trials were considered to be non-exposed. Pregnancy losses were defined as abortion (spontaneous or unspecified), death in utero, and stillbirth. RESULTS: 615 pregnancies were reported from 19 CYD-TDV trials: 404 in the CYD-TDV arm, and 211 in the placebo arm. Exposure could not be determined for 7 pregnancies (5, CYD-TDV; 2, placebo). In the CYD-TDV arm, 58 pregnancies were considered as exposed. Most of these (n = 47, 81%) had healthy live births; 6 (10.3%) had pregnancy losses; 3 underwent elective termination and 2 had unknown outcome. In the placebo group, 30 pregnancies were considered exposed. Most of these (n = 25, 83%) had healthy births; 4 (13.3%) had pregnancy losses; and 1 had elective termination. Among non-exposed pregnancies, most resulted in healthy live births; 23/341 (6.7%) in the CYD-TDV group and 17/179 (9.5%) in the placebo group had pregnancy losses. Most reported pregnancy losses were in women considered high-risk for adverse pregnancy outcome, primarily due to young age. CONCLUSION: In the small dataset assessed, no evidence of increased adverse pregnancy outcomes has been identified from inadvertent immunization of women in early pregnancy with CYD-TDV compared with the control group.

A recombinant live attenuated tetravalent vaccine for the prevention of dengue.

INTRODUCTION: Dengue is an important and still growing public health problem associated with substantial morbidity, as well as significant social and economic impact. The present review describes the main features and development of the first dengue vaccine (CYD-TDV, Dengvaxia®), which has been licensed by several dengue-endemic countries in Asia and Latin America for use in populations above 9 years of age. Areas covered: The review focuses on the large clinical development of CYD-TDV, which includes in particular two pivotal phase III efficacy trials conducted in Asia and Latin America and supported vaccine licensure. Based on these clinical data, the WHO Strategic Advisory Group of Experts (SAGE) on Immunization recommended considering introduction of the vaccine in geographic settings (national or subnational) with high burden of disease. Long-term safety follow-up studies of the efficacy trials are currently ongoing, and post-licensure studies will evaluate the vaccine effectiveness and safety in 'real-life' following vaccine introduction. Expert commentary: During vaccine development, a number of complexities were tackled, innovation pursued, and risk managed. These aspects, as well as the potential impact of CYD-TDV on public health are also discussed.

Safety Overview of a Recombinant Live-Attenuated Tetravalent Dengue Vaccine: Pooled Analysis of Data from 18 Clinical Trials.

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 settings will be assessed through post-licensure studies.