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 NIH/Butantan and Takeda) now in Phase III trials.
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, and is now licensed in 20 countries. 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.
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.
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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="">
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 at the time of the April 2016 SAGE recommendations. SAGE noted that the evidence of the absence of a safety issue in seronegative individuals aged 9 and above was based on the limited data set of 10%-20% of the trial population, and highlighted the urgent need to better describe the long-term benefit-risk ratio of CYD-TDV in seronegative individuals.
On 29 November 2017, Sanofi Pasteur announced the results of additional studies to better describe the benefit-risk in seronegative individuals. This was made possible through the use of a newly developed NS1-based antibody assay applied to blood samples taken 13 months after vaccination to retrospectively infer dengue serostatus at time of first vaccination.
The new analyses from the long-term safety follow-up indicated that:
Following the release of the long-term safety data stratified by serostatus on 29 November 2017, a SAGE working group on dengue vaccines was reconvened and a thorough review of the new data with the guidance of external experts such ethicists and modellers was conducted.
In light of the new evidence on the long-term safety issue in seronegative individuals, balanced against the documented efficacy and safety in seropositive individuals, SAGE carefully considered two strategies: population seroprevalence criteria versus pre-vaccination screening. SAGE weighed up the feasibility of population seroprevalence studies and individual pre-vaccination screening, heterogeneity of seroprevalence between and within countries, potential vaccine coverage rates, public confidence in national vaccination programmes, perceptions of ethical considerations with regard to population level benefit versus individual level risk, and communication issues.
SAGE concluded that for countries considering vaccination as part of their dengue control program, a “pre-vaccination screening strategy” would be the preferred option, in which only dengue-seropositive persons are vaccinated.
Serological testing for past dengue infection (e.g. dengue IgG ELISA) could be used to identify persons who have had previous dengue infections. Currently available rapid diagnostic tests, despite their lower sensitivity and specificity to detect past dengue infection compared with conventional dengue IgG ELISA, could be considered in high transmission settings until better tests are available. In settings with high seroprevalence, a test with lower specificity might be acceptable. In settings with low to moderate seroprevalence, a test with high specificity is needed.
Given that no test will be 100% specific, some truly seronegative individuals may be vaccinated due to a false positive test result. Furthermore, although the efficacy against dengue infections in seropositive individuals is high, it is still not complete. Hence, the limitations of CYD-TDV will need to be clearly communicated to those offered vaccination.
Decisions about implementing a pre-vaccination screening strategy will require careful assessment at the country level, including sensitivity and specificity of a screening, dengue hospitalization rates, and affordability of both CYD-TDV and tests. Vaccination should be considered as part of an integrated dengue prevention and control strategy together with well-executed and sustained vector control and the best evidence-based clinical care.
The vaccine should be used within the indicated age range, typically 9 to 45 years of age. The optimal age group to be targeted is the age at which the incidence of severe dengue is highest, and this can be ascertained from national and subnational routine hospital data.
In the absence of data on vaccine efficacy and safety with fewer than three doses, CYD-TDV is recommended as a three-dose series given 6 months apart.
SAGE highlighted that important research and implementation questions remain for CYD-TDV, in particular the development of a highly sensitive and specific rapid diagnostic test to determine serostatus, simplified immunization schedules, and assessment of the need for boosters.
WHO will publish a revised position paper in September 2018 based on the SAGE recommendations from 18 April 2018.
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.
Vector control has been the key strategy to control or prevent the transmission of dengue virus. Strategies include: