Dengue is the most frequent and rapidly spreading arboviral disease. The first dengue vaccine, CYD-TDV (Dengvaxia®) is licensed in twenty countries.
WHO issued its position on the use of CYD-TDV in July 2016 based on recommendations provided by SAGE in April 2016, principally, that countries interested in introducing the vaccine consider its use only in those aged 9 years and above, and in areas with a seroprevalence of ≥70%, and not in areas below 50%. SAGE noted that the evidence of the absence of a safety issue in seronegatives 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 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:
While overall population level benefit of vaccination is favourable, the vaccine performs differently in seropositive versus seronegative individuals. Vaccine efficacy (VE) against virologically confirmed symptomatic dengue was high among inferred baseline seropositive participants ≥9 years of age: 76% (95%CI: 63.9, to 84.0), but much lower among baseline seronegative participants: 38.8% (95%CI: –0.9 to 62.9%) in the first 25 months after the first dose of vaccine.
An increased risk of hospitalized and severe dengue in seronegative individuals was noted from year 3 onwards throughout the trial observation time of 66 months
These findings translate into the following: In areas of 70% dengue seroprevalence, over a 5-year follow-up, for every 4 severe cases prevented in seropositives there would be one excess severe case in seronegatives per 1,000 vaccinees; for every 13 hospitalizations prevented in seropositive vaccinees, there would be 1 excess hospitalization in seronegative vaccinees.
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.
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.