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

Abstract

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.

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

“…2 Although this potential risk was observed, the vaccine demonstrated a good safety and efficacy profile in pooled analyses of clinical trials in the indicated age group of ≥9 years. [3][4][5] The safety and immunogenicity of CYD-TDV was previously investigated in two phase II studies in Vietnam and Singapore, countries with high and low dengue endemicity, respectively. 6,7 We present here the four-year follow-up of these participants (aged <9 and ≥9 years) after the third vaccine dose in two study populations to assess the persistence of immunogenicity and safety of CYD-TDV.…”

Safety and immunogenicity of the rVSV∆G-ZEBOV-GP Ebola virus vaccine candidate in healthy adults: a phase 1b randomised, multicentre, double-blind, placebo-controlled, dose-response study

“…The consistent pattern of transient, early-onset (<24 h) local arm pain and tenderness accompanied by systemic symptoms is commensurate with that of other live attenuated viral vaccines. [18][19][20] When examined by dose group or grouped dichotomously, a dose-related increase was observed in the incidence and, in some cases, severity of solicited local and systemic adverse events. The early acute phase reactogenicity was associated with low-level viraemia, which peaked on days 1-2.…”

Immune correlates of protection for dengue: State of the art and research agenda

“…Unpublished exploratory analyses of vaccinated cases from the Dengvaxia Phase 2b trials suggest a relationship between nAb titers and probability of disease [45]. Further, the Phase 3 clinical trials showed an overall positive efficacy (protection against having a dengue case) of the vaccine during the initial 25 months of the trial, but evidence of reduced protective immunity over the follow-up period, with more hospitalized dengue cases in vaccinees than placebos >1 year after the final vaccine dose in children <9 years old [46,47]. …”