Institute to identify new vaccine targets for tuberculosis, malaria, dengue virus and smallpox
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.