Dengue fever is a mounting global public health problem driven by population growth, urbanization, and vastly augmented regional and international travel. 1 Since vector control programs have been difficult to sustain, public health authorities have called for development of a dengue virus (DENV) vaccine. Vaccination is a proven method of infectious disease control. The successful development of a liveattenuated vaccine for yellow fever in the mid-20th century encouraged many that a live-attenuated vaccine for dengue fever, which is caused by a complex of four viruses in the same family (Flaviviridae) as yellow fever virus, could be developed. For several decades, the public health vision has been that control of endemic dengue fever could be achieved by routine administration of a live-attenuated DENV vaccine to children residing in affected countries. Because dengue fever is an important disease in some travelers, 2 and infected travelers appear to be major means by which DENV spreads between countries, additional disease control could be achieved by vaccination of non-immune travelers to and within the tropics.

Historically, dengue fever has adversely affected military forces deployed from temperate to tropical or sub-tropical locales. Much early research on dengue was conducted or funded by the United States Army, which saw operational effectiveness degraded by epidemic dengue during troop deployments in almost every decade of the 20th century. 3− 7 Following the successful propagation of dengue virus type 1 (DENV-1) and DENV-2 in mouse brains, the United States Army sponsored more than a decade of research to develop live-attenuated DENV vaccines manufactured in mouse brains. 8 This work culminated in a field efficacy trial in Puerto Rico in 1962 in which partial protection of subjects administered DENV-1 vaccine was observed during an outbreak of predominantly DENV-3. 9 Ultimately, the United States Army halted development of the DENV mouse brain vaccine when propagation of DENV in cell cultures, a theoretically safer production substrate, was achieved. Bolstered by the preliminary evidence of vaccine efficacy in Puerto Rico, and the observation that low-passage DENV-2 isolates that produced small plaques in cell monolayers were also temperature sensitive and less pathogenic for suckling mice, the United States Army Medical Research and Development Command in 1971 launched a program at the Walter Reed Army Institute of Research (WRAIR) to develop a cloned, temperature-sensitive, live-attenuated vaccine candidate for each DENV type.