Immunization, Vaccines and Biologicals

Questions and Answers on Dengue Vaccines

What is the current status of dengue vaccine development?

There is a growing public health need for effective preventive interventions against dengue, a disease caused by four viruses, termed serotypes 1-4. A safe, effective and affordable dengue vaccine against the four strains would represent a major advance for the control of the disease and could be an important tool for reaching the WHO goal of reducing dengue morbidity by at least 25% and mortality by at least 50% by 2020. One dengue vaccine has been licensed, Dengvaxia® (CYD-TDV), developed by Sanofi Pasteur. Approximately five additional dengue vaccine candidates are in clinical development, with two candidates (developed by Butantan and Takeda) expected to begin Phase III trials in early 2016.

What is Dengvaxia® (CYD-TDV)?

CYD-TDV is the first dengue vaccine to be licensed. It was first licensed in Mexico in December 2015 for use in individuals 9-45 years of age living in endemic areas. CYD-TDV is a live recombinant tetravalent dengue vaccine developed by Sanofi Pasteur (CYD-TDV), given as a 3-dose series on a 0/6/12 month schedule.

What are the results from the Phase 3 trials?

CYD-TDV has been evaluated in two Phase 3 clinical trials (CYD14 in five countries in Asia and CYD15 in five countries in Latin America). Together, these trials included over 35,000 participants aged 2 to 16 years: ages at first vaccination were 2 to 14 years in CYD14, 9 to 16 years in CYD15. In each of these trials, participants were randomized to vaccine and placebo in a 2:1 ratio. The study protocols included an active phase of follow-up for one year after the last dose of vaccine in the series (25 months from dose 1) and include a hospital-based follow-up period of four additional years, which is ongoing.

Results have been published for each trial separately, as well as pooled. Trial results include children aged <9 years old, which is an age group that is not included in the current indication. This is due to results that were observed during the Phase 3 trials in the youngest age group in the CYD14 Phase 3 trial.

Vaccine efficacy against confirmed dengue pooled across both trials was 59.2% in the year following the primary series (per protocol analysis). During this initial time period, pooled vaccine efficacy against severe dengue was 79.1%. Efficacy varied by serotype: vaccine efficacy was higher against serotypes 3 and 4 (71.6% and 76.9%, respectively) than for serotypes 1 and 2 (54.7% and 43.0%). Vaccine efficacy also varied by age at vaccination and serostatus at baseline (i.e., previous exposure to dengue prior to vaccination).

When limited to older age groups (ages included in the current licensure), pooled vaccine efficacy amongst all participants aged 9 years or over was 65.6%, and in participants aged <9 years it was 44%.

Within the randomized subset of participants for whom pre-vaccination blood samples were collected, pooled vaccine efficacy against VCD in those seropositive for a prior exposure to dengue virus was 78.2%, while in those seronegative at baseline it was 38.1% (not statistically significant). In a post-hoc analysis in those ≥9 years of age, vaccine efficacy in those seronegative at baseline was 52.5% (95% CI 5.9%, 76.1%).

While efficacy was reported against hospitalized and severe dengue in Years 1 and 2 post-dose 1, an excess of cases of hospitalized and severe dengue cases in those receiving CYD-TDV was seen in Year 3 in some subgroups, although it is based on relatively small numbers of cases. The excess was mostly observed in those vaccinated aged 2-5 years in CYD14 in Asia, for which the relative risk of hospitalized dengue in vaccinees was 7.45 (95% CI 1.15, 313.80) in Year 3, based on 15 cases in the CYD-TDV group and 1 case in the control group. This younger age group has not been included in the age indication of the vaccine. No safety signals were reported in the older age groups.

What are WHO’s recommendations related to CYD-TDV?

WHO recommends that countries should consider introduction of the dengue vaccine CYD-TDV only in geographic settings (national or subnational) where epidemiological data indicate a high burden of disease. Complete recommendations may be found in the WHO position paper on dengue vaccines.

Has the vaccine been prequalified by WHO?

CYD-TDV is currently not prequalified. Prequalification requires an NRA of record, which is typically the NRA in the manufacturing country (in this case, EMA). WHO is awaiting a submission of an application from the manufacturer for prequalification of this vaccine.

What other interventions exist for dengue control?

Vector control has been the key strategy to control or prevent the transmission of dengue virus. Strategies include:

  • preventing mosquitoes from accessing egg-laying habitats by environmental management and modification;
  • disposing of solid waste properly and removing artificial man-made habitats;
  • covering, emptying and cleaning of domestic water storage containers on a weekly basis;
  • applying appropriate insecticides to water storage outdoor containers;
  • using of personal household protection such as window screens, long-sleeved clothes, insecticide treated materials, coils and vaporizers;
  • improving community participation and mobilization for sustained vector control;
  • applying insecticides as space spraying during outbreaks as one of the emergency vector-control measures
  • active monitoring and surveillance of vectors should be carried out to determine effectiveness of control interventions.

Questions and answers on previous clinical trial results of CYD-TDV

Results from the pooled Phase 3 trials for efficacy and longer-term safety of CYD-TDV have been published in July 2015.

Results from a phase III multicentric efficacy study in Latin America have been published in November 2014.

Results from a phase III multicentric efficacy study in Asia have been published in July 2014.

Results from a phase IIb efficacy study in Thailand have been published in September 2012.