n engl j med
engue is an important hu-man viral disease transmit-ted by insects. Although nearly half the world’s population is at risk for infection and as many as100 million cases occur annual-ly,
we have no antiviral drugsto treat it and no vaccines to pre- vent it. A closely related but muchmore lethal mosquito-borne virus, yellow fever, used to be one of the great scourges among hu-mans. Although yellow fever isnow largely controlled by vacci-nation, many regions are suscep-tible to a reemergence if the dis-ease is introduced by travelers,and substantial recent problems with vaccine safety will no doubt change vaccination policy.Both dengue and yellow feverare single-stranded RNA virusesin the family Flaviviridae, whichincludes West Nile virus and ap-proximately 50 others. Substan-tial progress has been made inunderstanding the mechanism of the entry of these viruses intocells, the atomic structure of the viral envelope (see figure), the in-teractions between the moleculardeterminants and the host anti-body, and the mechanism under-lying the neutralization of the virus by antibodies.
The unravel-ing of virus–cell and virus–anti-body interactions at the molecularlevel may lead to the development of antiviral drugs, improved vac-cines, and tests for protective andpathological antibodies.Dengue and yellow fever areendemic to and epidemic in trop-ical regions (see map). Both arezoonoses maintained in natureby transmission to humans frommonkeys or mosquitoes that breedin tree holes. Infected humanshave high blood levels of virusand can therefore infect vectormosquitos. After an incubationperiod of about 10 days, during which the virus replicates in thesalivary-gland tissues of blood-feeding aedes mosquitoes, they can transmit the virus to anotherperson. Throughout the tropics,the principal vector for endemicand epidemic spread,
has adapted to living among hu-mans in domestic environments.Increasing human populationdensity, urbanization, poor sani-tation (creating breeding sites forlarval mosquitoes), reinfestation(in the 1970s) of South Americaby
after a successfuleradication campaign, and themovement of infected persons by airplanes have contributed to asubstantial increase in dengueincidence during the past 50 years.
mosquitoes areprevalent in the southern UnitedStates, which is therefore recep-tive to the introduction and spreadof both dengue and yellow fever(see map).In its classic form, dengue isan acute illness characterized by fever, headache, muscle and joint pain, and rash. There are fourserotypes, and neutralizing anti-bodies are serotype-specific, soin regions where multiple sero-types cocirculate, people may havesequential infections. Immunity against a specific serotype is life-long, but previous infection withone serotype is a risk factor for amore severe form of dengue — dengue hemorrhagic fever — upon subsequent infection withanother serotype. Dengue hem-orrhagic fever is characterizedby the capillary-leak syndrome,thrombocytopenia, hemorrhage,hypotension, and shock. Its inci-dence has increased dramatically during the past several decades,as multiple dengue serotypes in-troduced into new environmentsby air travelers with viremia havebecome endemic. Approximately 500,000 cases occur annually, witha case fatality rate ranging from1 to 3% to as high as 10 to 20%,depending on the sophisticationof the available fluid manage-ment and intensive care.Since we lack an animal mod-el of dengue hemorrhagic fever,our knowledge of pathogenicmechanisms relies on evidencefrom in vitro studies and pa-tients. Differences in virulenceamong dengue-virus strains as well as host factors — princi-pally antibody-mediated enhance-ment of dengue replication
— contribute to disease expression.Central to the immune-enhance-ment mechanism in dengue hem-orrhagic fever is the usurping of
Dengue and Yellow Fever — Challenges for the Development and Use of Vaccines
Dengue and Yellow Fever — Challenges for the Developmentand Use of Vaccines
Thomas P. Monath, M.D.
Structure of the Dengue Virus onCryoelectron Microscopy.
C o u r t e s y o f R i c h a r d K u h n , P u r d u e U n i v e r s i t y .
Downloaded from www.nejm.org on June 12, 2010 . Copyright © 2007 Massachusetts Medical Society. All rights reserved.