Oct. 13, 2003 PHILADELPHIA -- In a new research study, two prototype oral vaccines have both been shown capable of inducing protection against a dangerous virus in newborn mice. If the new vaccines are able to do the same for human newborns, they might be able to address an important window of immunological vulnerability in the lives of infant children. Particularly in the developing world, where the threat of infectious diseases is generally greater than in the developed world, many lives might be saved with vaccines of this type.
The vaccines are based on human and chimpanzee adenoviruses that have been altered in the laboratory so that they are unable to replicate. In the current proof-of-principle study, the viruses were engineered to incorporate a gene from the rabies virus. Following oral administration of the vaccine, newborn mice developed antibodies that protected them from subsequent exposure to the rabies virus. By extension, the researchers say, the same vaccine strategy might also prove effective against other viral diseases, such as measles, viral respiratory infections, and viral diarrhea. A report on the study findings appears in the October 15 issue of the Journal of Immunology.
The potential significance of the new study lies in the effectiveness of the prototype vaccines in newborns. Although newborns are protected from most common viral infections immediately after birth by antibodies received from their mothers, these antibodies decline in the first weeks and months of life as the fledgling immune system grows in its capacity to generate its own antibody protections against viruses. Between the waning of maternal-antibody protection and the development of a fully functional immune system in the infant, a period of relatively poor defense against disease for infants is frequently seen. This is partly because the infant immune system is not yet sufficiently developed, but also because the maternal antibodies, while protecting the infant from infections, can interfere with the efficacy of traditional vaccines.
"These new vaccines we've developed trigger the production of protective antibodies in newborn mice during a time in their lives when traditional vaccines are commonly less than effective," says Hildegund C.J. Ertl, M.D., professor and head of the Immunology Program at Wistar and senior author on the study. "This has potentially important public-health implications, especially in the developing world. In addition, these are oral vaccines, which could make them easier to distribute and administer in those same areas."
One question the researchers wanted to answer was whether there would be response differences between the human and chimpanzee adenovirus vaccines due to so-called pre-existing immunity. In humans, adenoviruses are nearly ubiquitous, so much so that more than 45 percent of the population in the U.S., for example, has neutralizing antibodies circulating in the blood able to impair any vaccine based on a common human adenovirus. In essence, many people would be prevented by their own immune systems from realizing the benefits of a vaccine based on a human adenovirus.
For this reason, the researchers developed a version of the vaccine that uses a chimpanzee adenovirus as its basis. The hypothesis was that the chimpanzee adenovirus vaccine possesses the immunological advantages of a human adenovirus vaccine, but without the drawbacks of likely pre-existing immunity in its target population. Somewhat to their surprise, the researchers found that the human adenovirus vaccine was as effective as the chimpanzee adenovirus vaccine in the current study.
"Even in the presence of maternal antibodies against human adenovirus, the human adenovirus vaccine remained effective," Ertl says. "Although unexpected, this was good news, because it increases the repertoire of vaccine types potentially suitable for infant vaccination."
The lead author on the Journal of Immunology study is Zhi Quan Xiang, M.D., at The Wistar Institute. Yan Li, also at Wistar, is a coauthor, as are Guangping Gao, Ph.D., and James M. Wilson, M.D., Ph.D., of the University of Pennsylvania.
Primary funding for the research was provided by the National Institutes of Health. Additional support came from the Commonwealth of Pennsylvania.
The Wistar Institute is an independent nonprofit biomedical research institution dedicated to discovering the causes and cures for major diseases, including cancer, cardiovascular disease, autoimmune disorders, and infectious diseases. Founded in 1892 as the first institution of its kind in the nation, The Wistar Institute today is a National Cancer Institute-designated Cancer Center – one of only eight focused on basic research. Discoveries at Wistar have led to the development of vaccines for such diseases as rabies and rubella, the identification of genes associated with breast, lung, and prostate cancer, and the development of monoclonal antibodies and other significant research technologies and tools.
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