Recombinant vaccine shows promise against dengue fever.

Recombinant vaccine shows promise against dengue fever 

Scientists this week reported progress in genetically engineering a 'vaccine for dengue fever, a severe viral disease of global significance that is beginning to spread to North America. Public health officials in the United States and abroad have expressed increasing concern about the mosquito-borne disease, which is endemic to much of Asia, Africa and South and Central America. Development of a vaccine has been hampered, however, by a peculiar characteristic of the dengue virus: Antibodies against dengue tend to promote rather then prevent reinfection with closely related strains of the dengue virus.

Ching-Juh Lai, a researcher with the National Institute of Allergy and Infectious Diseases in Bethesda, Md., reported at a National Institutes of Health seminar that a novel approach to vaccine development has so far conferred complete protection against dengue in mice. The vaccine is now being tested on rhesus monkeys.

Most viral antibodies -- whether naturally occurring or vaccine induced recognize and bind to the outer envelope of a target virus. But strains of the dengue virus can bind to such antibodies and subvert them to enhance the virus's ability to infect human monocytes, a kind of white blood cell. Moreover, such antibody-enhanced infections tend to be much more severe than the original infection, which is characterized by fever, headache and joint pain. Antibody-enhanced infection can lead to a potentially fatal syndrome involving internal bleeding, severe dehydration and shock.

Lai's approach is based on work by scientists at the University of Rochester (N.Y.), who found that antibodies against a so-called nonstructural protein, produced inside the monocytes to help assemble new viruses, can protect against dengue without enhancing re-infection later. The nonstructural protein, dubbed NS-1, is produced in monocytes after a dengue virus "hijacks" the cells' genetic machinery. It is critical to virus replication but is never actually incorporated into new viral offspring. Although the mechanism of protection is not well understood, there is evidence that NS-1 antibodies recognize dengue-infected monocytes and destroy them before the virus has a chance to reproduce.

Anti-NS-1 antibodies have proved effective against dengue in mice and against yellow fever, a closely related disease, in mice and monkeys, according to Jacob Schlesinger and Michael Brandriss, who performed those experiments at the University of Rochester. The production of those antibodies was cumbersome, however, because it required the culturing and purification of large volumes of live virus. In contrast, Lai is splicing relevant parts of the dengue genome into other viruses that can be used to mass produce NS-1.

"The recombinant approach is nicer both in practice and in theory," Brandriss told SCIENCE NEWS. However, he says, it is difficult to predict the vaccine's efficacy in humans because the dengue virus behaves differently in monkeys and mice than it does in people. Because of the lack of good animal models, says Schlesinger, "you're probably going to have to consider doing human trials sooner than you would normally."

More than 100 million cases of dengue fever and its more severe form, dengue hemorrhagic fever, are estimated to occur each year worldwide. Few cases have occurred in the United States to date, but severe epidemics have occurred in the past few years both in Asia and in the Americas. Concern about its spread to the North American continent was spurred by the recent introduction into 17 states of Aedes albopictus, a mosquito that can transmit the disease very efficiently (SN: 8/23/86,p. 119). R. Weiss