Researchers from the La Jolla Institute for Allergy & Immunology (LIAI) announced today the results of a first of its kind study analyzing all published data worldwide on influenza A virus antibody and T cell epitopes. Antibody and T cell epitopes are small sites on a virus that are the targets of the immune response, and they are critical for developing therapies and vaccines to combat infectious disease. The study, using information from a worldwide research database funded by the National Institute of Allergy and Infectious Diseases (NIAID), one of the National Institutes of Health (NIH), provides an important tool for scientists seeking to develop vaccines and therapies against both seasonal and pandemic influenza strains, including the deadly H5N1 avian flu.
"This study shows what is currently known about influenza A virus epitopes -- what are the areas that are well covered in the current research and where are the holes in our knowledge," said Alessandro Sette, Ph.D., director of LIAI's Center for Infectious Disease and one of the study's authors. "From this information, the scientific community can determine areas where focus is needed going forward."
The findings are being published online this week in a paper, "Antibody and T Cell Epitopes of Influenza A Virus – Knowledge and Opportunities" in the journal Proceedings of the National Academy of Sciences USA. LIAI researcher Huynh-Hoa Bui, Ph.D., was lead author on the paper.
The study looked at all scientific data on influenza A virus antibody and T cell epitopes published to date worldwide, drawing from the NIAID's Immune Epitope Database, a new worldwide scientific resource that went public last summer. LIAI researchers developed the database – which is the world's largest repository of scientific data on how the body's immune system responds to infectious agents -- under a $25 million contract awarded by the NIAID in 2004.
The database places particular emphasis on emerging infectious diseases, such as West Nile virus, along with those diseases considered potential bioterrorist threats. The database's influenza research was analyzed first due to the continuing problem of seasonal influenza and public health concerns over the possible spread of the H5N1 avian flu.
"The database marks the first time that all known antibody and T cell epitope information has been compiled in one place," said Sette, noting the searchable online database is freely available to scientists around the globe. "It gives researchers ways of sharing knowledge and information never available before. Previously, everyone did their own study, but would have no way of knowing if a particular epitope had been used one time, for example by a single individual responding to a single virus, or 100 different times. Now, scientists can search the database and find out all existing information on their particular topic. This will enable them to avoid unnecessary repetition and make faster progress toward new therapies and vaccines."
The database, publicly accessible at http://immuneEPITOPE.org, includes information culled from more than 100,000 separate research articles published over several decades, with the influenza information representing only a portion of the massive data set. "The influenza data shows that people have done a lot of work that gives important information as to how we respond to influenza virus," said Stephen Wilson, Ph.D., LIAI chief technology officer and project director of the database. "It also highlights those critical areas where we need to look further. The fact that we don't have a comprehensive vaccine for flu shows we have more work to do. This study shows us where we need to focus going forward."
For the influenza study, LIAI researchers analyzed information from 58 different influenza A virus strains, involving 600 different antibody and T cell epitopes. In particular, the LIAI scientists identified epitopes that were similar in many influenza strains. "This is important because the influenza virus continually changes requiring scientists to develop a new vaccine every year," Sette said. "If we can find shared epitopes, it may be possible to develop an influenza vaccine with greater cross protection for many different viruses." Sette said the study found hundreds of similar epitopes among the different virus strains. However, it remains to be seen whether these epitopes are similar enough to enable the successful development of a highly cross reactive influenza vaccine that would protect against many viruses. And, in fact, the study found only one epitope that has been published, which appears to be an ideal candidate for creating a multi-strain influenza vaccine.
Regarding gaps in knowledge of the way people respond to influenza, Wilson said two significant points emerged. "One concern is that most of the current influenza research is based on strains maintained in the lab, rather than wild influenza strains. Since we know the virus mutates, research needs to be done using influenza strains currently circulating in the population, so-called 'wild' strains, rather than using strains propagated in the lab. "
Secondly, Wilson noted that the analysis showed that most of the detailed studies were done in animal models, primarily mice, with very little data coming from studies with humans or birds. Only one of the antibody epitopes came from a human. "This is understandable given the ethical and health issues of testing a potential pathogen in humans," Wilson said. "However, based on this information, I think the research community will pursue data directly relevant to human immunity to influenza virus to close those critical gaps."
Regarding the dreaded H5N1 avian flu specifically, the information showed some important H5N1 epitopes currently being investigated. However, the number represented only a few of the 600 influenza virus epitopes in the database. "Given the concerns among the worldwide health community about this virus, I think this data gives timely assistance to much needed research in this area," Wilson said. He noted that such information is extremely valuable and shows how important the database can be for all researchers in determining their future research plans. "This study focused on influenza because it is a major illness that kills 36,000 Americans each year and global concerns over the possible spread of the H5N1 avian flu. In the future, database information on other infectious diseases can also be analyzed and used to good effect."