You are sitting on the beach in Colombia, taking a weekend break from your hospital and outpatient duties, where you have seen a broad spectrum of illness resulting from dengue – mild fever to Dengue Hemorrhagic Shock Syndrome. You think to yourself: “if only there was a vaccine that could reduce the morbidity and mortality associated with dengue”. You marvel at the time and effort it takes to create a safe, efficacious vaccine, and reflect on the complex path to product licensure, mentally noting the need for a vaccine that would ideally provide long-lasting immunity to all serotypes, both in those with and without prior dengue infection. Immunity that’s not long-standing enough could potentially result in increased risk of infection, particularly in a dengue endemic setting.
CDY-TDV is a live attenuated chimeric vaccine with the yellow fever virus as a backbone that carries the structural proteins of the dengue virus. The schedule was 3 doses administered over a 12-month period, with encouraging short-term safety and efficacy. Results of previously published work by Villar et al. published in NEJM showed a 67-80% reduction in dengue hospitalizations among vaccinees. Efficacy was higher in vaccinees with previous dengue infection compared to those who were seronegative at baseline, and efficacy varied across the 4 dengue serotypes.
The recently published article by Hadinegoro et al. in NEJM summarizes the efficacy and longer-term safety data of the CYD-TDV Dengue Vaccine. 35,000 children aged between 2-16 years were enrolled in 3 studies – two phase III trials, CYD14 and CYD15, and a phase IIb trial, CYD23/57. A safety endpoint was assessed – incidence of hospitalization with new dengue infection in years 3-6 post vaccine in the 3 studies. During year 3 in the CYD14, CYD15 and CYD57 trials, there was a lower risk of hospitalization for dengue among participants in the vaccine group compared to controls in those ≥9 years, but was higher in those <9 years. Pooled relative risks of hospitalizations for dengue were 0.84 among all participants, 1.58 in those <9 years, and 0.5 in those ≥9 years.
As described in the accompanying editorial, by Dr. Cameron Simmons, vaccination appears to be associated with an elevated risk of hospitalization in vaccinated children <9 years, most markedly in those 2-5 years of age, likely following natural infection in the 3rd year post vaccination. It’s hypothesized that vaccination of some young children may elicit transient immunity, with subsequent waning and pre-disposition to more serious infections that result in hospitalization. Surveillance was limited to hospital-based only – it remains unknown whether the <9 years subgroup experiences a higher incidence of symptomatic infection outside of the hospital setting also. Notably, vaccination did not increase the frequency of severe, life-threatening complications.
Vaccine efficacy was assessed using pooled data from the first 25 months of CYD14 and CYD15. Children between 9-16 years continue to benefit, likely due to vaccine-induced pan-serotype immunity in many recipients who were previously naturally infected; benefits are far less clear in children <9 years. Pooled rates of efficacy for symptomatic dengue during the first 25 months were 60.3% for all participants, 44.6% for those <9 years, and 65.6% for those ≥9 years. Longer-term efficacy will continue to be assessed, informing the need for booster doses.
Deputy Editor Lindsey Baden, MD comments “There is a tremendous need for a vaccine to prevent dengue associated illness, especially severe disease. A major challenge to developing such a vaccine has been the concern for disease enhancement associated with serotype-specific partial immunity. Longer term studies of dengue vaccine safety, such as this one, are critical for our understanding vaccine safety and for the development of a successful vaccine.”
You slap another Aedes mosquito away from your leg, resigned to the idea that while certainly closer, programmatic vaccination with CYD-TDV may not be available by the end of your weekend holiday, particularly for those aged <9 years.