The future of dengue vaccines

Abstract

Every year there are several hundred thousand acres of dengue hemorrhagic fever/dengue shock syndrome (DHF/DSS) resulting in thousands of deaths. The only method currently available to prevent dengue infections is the control of Aedes aegypti the mosquito vector. This approach has proved expensive and mostly unworkable. Serial infection occurs in most areas of the world where multiple dengue viruses circulate. A small percentage of second dengue infections result in DHF/DSS. Dengue vaccines must provide solid and long-lasting protection against all four dengue viruses or in dengue-endemic countries there is the risk of sensitizing recipients to severe disease. Many candidate dengue vaccines are moving towards clinical trials in human beings. These vaccines include several based on the formation of live-attenuated chimeric viruses. Yellow fever (YF) Japanese encephalitis (JE) and the four dengue viruses are all small single-strand positive-sense ribonucleic acid flaviviruses with similar genetic organization and replication strategies. Evidence that dengue vaccines should succeed comes from encouraging experience with attenuated vaccines against related viruses such as YF and JE and from a recent successful phase 1 trial of a chimera of these two viruses. This progress is timely because global dengue morbidity achieved an all time high during 2001-02. Thomas Monath and colleagues developed a live-attenuated chimeric vaccine against JE virus by replacing the premembrane (prM) and envelope (E) genes of the YF 17D vaccine with the corresponding genes from SA 14-14-2 an attenuated JE virus strain to produce YF-JE chimera. No unusual side-effects were seen in the phase 1 study and high titers of neutralizing antibodies to JE virus were found 3-4 weeks after inoculation of doses of 100000 and 1000. plaque-forming units. Similar methodology has been used to make chimera vaccines with YF virus for all four dengue viruses. Hence to ensure the introduction of safe and effective dengue vaccines for the worlds children ways must be found to accelerate phase 3 trials of tetravalent dengue vaccines in suitable people. Only testing in man can answer questions of safety and efficacy. A parallel effort is needed to understand protective mechanisms in dengue-infections especially those mediated by antibodies. The largest constraint to the solution of these problems is adequate funding which is now being addressed by a new international consortium. (authors)