Researchers from the La Jolla Institute for Allergy & Immunology will take aim at several of the world's most dangerous infectious diseases - tuberculosis, malaria and dengue virus -- in a five-year, $18.8 million federally-funded set of projects seeking to make new inroads toward vaccines against the disorders.

The Institute received four project awards totaling $18.8 million from the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health, to fund the study. The study also includes a component on smallpox, a deadly infectious disease eradicated worldwide, which remains a focus due to bioterrorism concerns.

Alessandro Sette, Ph.D., a world-renowned expert on vaccine development and director of the La Jolla Institute's Center for Infectious Disease, will lead the study, which focuses on identifying epitopes -- pieces of a virus or microbe that cause the body's immune system to launch an attack. Epitopes are important for protective immunity and are key to developing new and more effective vaccines.

Several prominent immunology researchers from around the country praised the projects as promising and timely. "A recent NIH workshop identified the lack of epitope information as a key "missing link" in the search for effective malaria vaccines," said John T. Harty, Ph.D, an endowed professor in Microbial Immunology at the University of Iowa, who studies basic immunology that can inform vaccine design. "This new support for Dr. Sette and colleagues, based on their proven track record in epitope identification, is timely and addresses major knowledge gaps in the design of effective vaccines."

Steven A. Porcelli, M.D., a professor in the Department of Microbiology and Immunology at the Albert Einstein College of Medicine in New York, emphasized the importance of the work of the La Jolla Institute team in narrowing down the list of epitopes so that vaccines can be constructed that will focus the immune response in the correct way. "For many of the major infections for which we lack an effective vaccine, the causative microbes are extremely complex and contain hundreds or even thousands of potential individual targets or epitopes," said Dr. Porcelli. "The efforts being undertaken by the La Jolla Institute group are going to help sort out this complex mixture of good and bad (epitope) targets, and will help many researchers working toward development of vaccines against some of the most deadly infections in the world today."

Dr. Sette said significant advances in bioinformatics and genomic sequencing over the last 10 years will enable the La Jolla Institute team to seek more comprehensive epitope identification than ever before. "The genomes of microbes of very large sizes are now available," he said, referring to biomedical advances that have allowed the entire molecular blueprint of many viruses and microbes to be mapped. In addition, bioinformatic prediction, which uses computer modeling and algorithms for disease research, has been greatly refined, he said.

"It is now technologically possible to tackle some of the biggest pathogens, such as malaria and TB (tuberculosis), with a truly unbiased screen that could reveal many exciting new vaccine and diagnostic candidates," said Dr. Sette, who is principal investigator on the tuberculosis and dengue virus contracts and co-investigator on the malaria contract.

Shane Crotty, Ph.D., co-investigator on the tuberculosis contract, described epitopes as what the immune system "sees" on an infected cell and which causes it to attack and eliminate the cell. "By understanding which epitopes cause an immune attack, scientists can conceivably use those epitopes to develop a vaccine to ward off illness - in this case to tuberculosis." Researchers from UC San Diego and FIOCRUZ, a health institute in Brazil, will also collaborate on the tuberculosis study, providing clinical samples from a diverse patient group reflecting the diversity of tuberculosis exposures and of patient ethnic backgrounds worldwide. "Using samples from a diverse patient population will enable us to ensure that the immune responses we're measuring will be universally protective," said Dr. Sette.

Joel Ernst, M.D., director of Infectious Diseases at New York University and a leader in the field of tuberculosis immunology, said the La Jolla Institute study may lead to an improved approach to tuberculosis vaccine development. "The scientific community's knowledge of T cell epitopes in TB is currently very limited," he said, noting that scientists are aware of a number of tuberculosis epitopes, but know little about those that have been identified.

"We're gradually coming to understand the complexity of the immune response in TB, and as we appreciate that complexity, we have to know what the targets of T cells are at various stages of infection and in people who have different outcomes," he said, adding that the La Jolla Institute study will be valuable in illuminating how tuberculosis epitopes trigger the immune system's T cells to launch an attack in a broad cross-section of patients.

According to the World Health Organization, about 1.6 million people die from tuberculosis each year and another nearly one million deaths are caused by malaria. In both diseases, people living in the poorest countries are the most vulnerable, with the majority of deaths occurring in the developing world. Currently, no vaccine exists for malaria. The World Health Organizations states that about 3.3 billion people - half of the world's population - are at risk for malaria. For tuberculosis, the only vaccine available, BCG, has varying degrees of efficacy. These factors, coupled with the emergence of multi-drug-resistant strains for both tuberculosis and malaria, have made the search for new, more effective counter-measures a major public health concern.

For the malaria component, Dr. Sette and his research team will work with Denise Doolan, principal investigator on the malaria contract, and her team at the Queensland Institute of Medical Research in Australia, who are collecting blood samples from people exposed to the disease in Papua New Guinea, in collaboration with colleagues at the Papua New Guinea Institute for Medical Research.

Dr. Sette's team will provide key epitope information that the Queensland group can use in testing the blood samples. "We've looked at the malaria genome and have made bioinformatics predictions on which epitopes we think the immune system may recognize in malaria," said Dr. Sette. "Since the Queensland researchers are using blood samples from people previously infected, their immune systems' will have "memory" of the malaria parasite and will react to synthesized epitope pieces from it. It will become apparent, based on various body indicators, which epitopes triggered a defensive reaction from the immune system. We think this will provide some very exciting data that we hope may be useful in developing a first-ever malaria vaccine."

Institute researchers used the expansive resources of the Immune Epitope Database (IEDB), a major public health tool developed and hosted by the La Jolla Institute under a contract with the NIAID, to develop the malaria epitope predictions. The IEDB contains epitope data on a multitude of diseases, including malaria.

Regarding the dengue virus study, Dr. Sette said the Institute's research will be propelled by key advances in animal modeling made by researcher Sujan Shresta, Ph.D., who is co-investigator on the dengue study. In 2008, Dr. Shresta developed the world's first dengue virus mouse model showing key aspects of human infection. "For a long time, the central question in the field was, "Do the T cells protect or do they contribute to dengue virus disease?'" said Dr. Shresta, referring to the body's white blood cells that typically fight disease. Using mouse models, Dr. Shresta recently proved that T cells play a protective role. "Now we will explore whether they can also contribute to causing dengue disease symptoms," she said. The information will provide another important piece of the puzzle that Institute researchers say will move the world closer to a vaccine.

Now categorized by the U.S. Centers for Disease Control as an emerging disease threat, dengue virus infects an estimated 50 to 100 million people worldwide annually, with 250,000 cases of the severest form reported each year. Primarily found in Southeast Asia and Latin America, dengue cases have now been reported in Mexico and mosquitoes capable of transmitting the virus have been found recently in the U.S.

Regarding the smallpox component, Bjoern Peters, Ph.D., principal investigator on the study, said he will analyze the body's antibody response to the vaccinia virus, a close, but non-dangerous relative of the smallpox virus, which is the basis of the smallpox vaccine. "B cells make antibodies, which are the parts of the immune system that keep us from getting sick," he said. "The smallpox vaccine is the most successful vaccine ever developed," added Dr. Peters, noting that it led to the worldwide eradication of the disease. "By analyzing in detail which mechanisms make the smallpox vaccine work, we will develop better vaccines for other diseases in the future."

In addition, smallpox remains of research interest due to bioterrorism concerns that the virus could one day be reintroduced, said Dr. Peters. "Understanding the key aspects of viral protection against smallpox is important from this perspective as well."

Source: Bonnie Ward
La Jolla Institute for Allergy and Immunology

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