Dengue is an emerging and reemerging arboviral disease of great global public health importance. Increased transmission and disease outbreaks are being driven by population growth, urbanization, international travel, and unchecked vector populations. Southeast Asia, Central and South America, and parts of the Caribbean experience endemic and hyperendemic dengue virus (DENV) transmission while indigenous transmission is being increasingly recognized in areas of Africa, the Middle East and South Asia. Reports indicate that southern US border-states and Hawaii can support episodic DENV transmission. Dengue poses a risk to traveler and military populations, especially those originating from non-dengue endemic regions.
Millions of DENV infections, hundreds of thousands of hospitalizations, and tens of thousands of deaths related to dengue occur annually. There is no specific, licensed anti-DENV therapeutic or preventative vaccine. The financial, social and individual cost of dengue is significant, underestimated, and underappreciated. The strategic administration of a safe and efficacious dengue vaccine, in coordination with efforts to educate about personal protective measures and sustained vector control, is the best hope to reduce the global dengue burden.
There are numerous dengue vaccine candidates in clinical development. Early efforts to develop a dengue vaccine date back more than 70 years, with attempts to prevent virus transmission using infectious human plasma treated with ox bile or virus grown in live mosquitoes and inactivated with formalin. Schelsinger and Sabin undertook the first attempts to immunize using mouse-passaged live-attenuated DENV-1 and -2 viruses. Halstead and colleagues discovered DENVs were attenuated following passage in primary dog kidney (PDK) cell culture. Mahidol University and Sanofi Pasteur attempted to codevelop live attenuated virus dengue vaccine candidates using PDK cell passage; the Walter Reed Army Institute of Research and GlaxoSmithKline Biologicals also used PDK passage to attenuate vaccine virus strain candidates. The US National Institutes of Allergy and Infectious Diseases attenuate DENV strains by targeted mutagenesis; the resulting attenuated DENV strains may constitute stand-alone vaccine candidates or serve as chimeric backbones. The US Naval Medical Research Center has completed a phase 1 trial testing a DENV-1 pre-Membrane/Envelope DNA vaccine; explorations of different vector and/or adjuvant combinations continue. Hawaii Biotech/Merck & Company is completing a phase 1 trial testing a DENV-1 recombinant Envelope protein candidate. Sanofi Pasteur is in advanced clinical development (phase 3) of a chimeric-Yellow fever-dengue (CYD) vaccine candidate using a construct created at the St. Louis University Health Sciences Center and Acambis Inc. The CYD candidate is the first candidate to enter clinical endpoint trials.