• Researchers are studying the role of E7 protease in inducing CTL response—for example, inducing CD8-positive T-cells—but it unclear whether these cells are effective in viral infection or in the treatment of existing human cancer.

• When these studies move into humans for efficacy testing, a logical clinical endpoint would be cytological abnormalities—not cervical cancer. Investigators could also monitor DNA in the cervix.

• There is as yet no data on mucosal routes of administration, although this will be an important issue in the future.

• There is as yet inadequate knowledge of the epitopes of the various papillomavirus subtypes to assess the possibility of making chimeric VLPs containing L1 proteins from multiple serotypes.

• The timetable is uncertain. Some pharmaceutical companies may try to go into Phase I clinical trials in the next couple of years, but it will take a period of time to demonstrate immunological reactivity and safety, and a longer time following women to demonstrate efficacy. Controlled Phase III trials might be completed in more than 5 but less than 10 years.

• The target population for a prophylactic vaccine would be women, hopefully before they become sexually active.

Pathobiology. Dengue is a positive-strand RNA virus, like HCV a member of the flavivirus family, and is transmitted by mosquitoes. There are four serotypes, and infection with one serotype results in long-lived immunity against that serotype, as well as sensitization to other serotypes. Dengue virus infection presents as two clinical syndromes: dengue fever (DF) and dengue hemorrhagic fever (DHF). Several days pass between transmission and the appearance of fever. In uncomplicated DF, the fever lasts for 3 or 4 days and then resolves successfully. In a few cases, however, as the fever is resolving, the patient develops capillary leak syndrome, which is a more serious illness commonly called DHF. There is little real hemorrhage but a lot of leakage from the capillaries, and hematocrit rises and body temperature falls. In its most severe form, DHF can result in shock and death. Depending on the speed of diagnosis and treatment, mortality can be anywhere from less than 1 percent to as high as 20 percent. Fortunately, most children respond well to aggressive volume expansion.

Incidence and Burden. Dengue fever (DF) is a frequent childhood infection in tropical and subtropical regions of the world where the mosquito Aetes aegypti is prevalent. There are an estimated 100 million cases per year,