A study now under way in the Philippines may help doctors understand why some babies get very sick after being infected by dengue virus while others do not. The information being gathered by NIAID grantee Daniel Libraty, M.D., and his American and Filipino collaborators could also help researchers design a vaccine to protect people from dengue fever, a mosquito-borne illness also known as break-bone fever.
They may be small and helpless, but newborns are not defenseless against disease. During pregnancy, infection-fighting proteins called antibodies pass from the woman’s body to the developing fetus through the placenta. These maternally acquired antibodies protect an infant for about 6 months or so, until the child’s own immune system becomes fully functional.
Infection by a virus, even if no disease results, stimulates the immune system to produce antibodies to the virus. In the Philippines and other parts of Asia, dengue virus is so common that essentially everyone has been infected at least once prior to adolescence. Thus, most babies born in the Philippines will have dengue antibodies from their mothers. In effect, says Dr. Libraty, maternal antibodies give infants a kind of short-lived immunization against dengue. However, because of unique aspects of dengue viruses and the way they cause disease, this early life “vaccine” may not always protect a newborn from illness.
The dengue viruses exist in four distinct forms or serotypes. In the Philippines, all four serotypes are present year-round, but a single serotype tends to predominate in each year’s dengue transmission season of June through October.
Among children and adults, serious illness following a first, or primary, dengue infection is rare. The trouble comes when a person gets infected a second time with a serotype that differs from the one he or she encountered originally. Then, immune responses generated following the primary infection can augment the severity of disease during the secondary infection. People suffering a secondary dengue infection are at increased risk of developing a severe and sometimes fatal form of disease called dengue hemorrhagic fever. Each year, some 22,000 people die of dengue hemorrhagic fever worldwide.
In contrast to the situation in older children, dengue hemorrhagic fever in infants occurs almost exclusively following a primary infection. The predominant hypothesis is that infants and older children both experience antibody-dependent enhancement of viral infection (ADE). In the case of infants, ADE is postulated to occur when maternally acquired anti dengue virus antibodies drop to low concentrations.
Dr. Libraty’s believes that severe dengue illness in infants results when the dengue antibodies acquired from the mother fall below some as-yet-undetermined protective level, leading to virus replication and anti viral primary immune responses that are different in infants than those in older children. To date, however, notes Dr. Libraty, there have been no large studies of dengue virus infecTtions in infants so the causes of severe disease and the role of ADE in this population remain unclear.
To answer the question, Dr. Libraty and his colleagues launched the current study, which will enroll approximately 10,000 infants over 4 years. Blood samples taken from infants soon after birth and again when they are between 4 and 6 months old will tell the researchers what levels of dengue-specific maternally acquired antibodies an enrolled child has at those two time points.
The investigators will also monitor area hospitals and health clinics to see if any infants come down with acute febrile illnesses at any time during the 16 months each child is in the study. If dengue infection is diagnosed, the team will collect blood samples during the baby’s illness and after he or she recovers. Comparing the amounts of maternally acquired antibodies in pre- and post-illness blood samples will allow the researchers to determine antibody levels that are associated with protection from symptomatic dengue virus infections, including dengue hemorrhagic fever. In addition to shedding light on factors contributing to development of dengue hemorrhagic fever in infants, this study will also generate data that will be useful in testing and implementing dengue vaccines to protect against infection by all four serotypes, a goal that has so far eluded researchers.
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Last Updated November 03, 2008