NEW YORK, Sept. 19 (GenomeWeb News) - When anthrax spores floated out of envelopes at US media outlets, congressional offices and post offices two years ago, hundreds of people were exposed to the bacillus, but only an unlucky few developed infections.
Among other still-unsolved mysteries surrounding this wave of incidents is why so many of those exposed did not get sick -and how their immune system responses worked.
To gain a better understanding of human immune response to agents of bioterror such as anthrax, smallpox, and other pathogens, as well as to vaccines for these agents, the National Institutes of Allergy and Infectious Diseases awarded $85 million in grants on Sept. 17 to five research centers in the US, for Cooperative Centers for Translational Research on Human Immunology and Biodefense.
These centers are being established at Emory School of Medicine, which is receiving $16 million; Baylor Research Institute in Dallas, which is receiving $14.6 million; Dana-Farber Cancer Institute in Boston, which is receiving $15.1 million, Stanford University School of Medicine, which is receiving $16 million; and University of Massachusetts Medical School, which is also receiving $16 million. Researchers at the different centers will communicate through a biofefense research network, the NIAID said.
Part of the drive to establish the centers comes from the fact that existing data on immunological response comes from mouse models.
"The initiative of NIAID is both to understand immunology in humans, rather than extrapolating from mice the direct immune response to biological agents," said Alan Rothman, co-director of a center being established at UMMS. "But also, a significant component [of the program] is to develop improved technologies to continue further studies along those lines," he said.
In several of the research centers, genomics and proteomics technologies will take center stage in helping further the research on mechanisms of immunity.
Emory: T Cell Transcripts
Emory researchers are partnering with Alan Aderam at the Institute for Systems Biology in Seattle to study comparative gene expression in immune cells before and after exposure to pathogens, including yellow fever and anthrax, and their vaccines, Rafi Ahmed, director of the Emory Vaccine Center in Atlanta and a principal investigator on a grant to Emory, told GenomeWeb News.
This work is based somewhat on earlier research published last year (Cell 2002 Dec 13;111 (6):837-51), in which Ahmed and co-authors performed a time-course study of gene expression as well as functional changes, in antigen-specific T cells during viral infection, in order to understand how memory CD8 T cells develop, he said.
"The end goal here is to define what are the genes that make a memory cells behave like a memory cell," he said. While the initial work was done on mouse, "what we are hoping -and this is an ambitious goal-is to try and mimic some of this in humans."
The group is planning to use a combination of Affymetrix chips and the ISB's in-house chips in the work. The ISB researchers will analyze data. "We ourselves don't have much experience in the bioinformatics aspects of things, and we really need to have good bioinformatics, said Ahmed, to make sense of gene expression data.
In another project, the group plans to look at dendritic cells, which are activated by a vaccine - what kinds of dendritic cells get activated, and genomic profiles of the dendritic cells that get activated, Ahmed said. "Our real goal is to find some real correlates between what happens early on [after vaccination] and the end result," he said. A third projects looks at responses to the anthrax vaccine in the elderly vs. younger patients
In the projects, the Emory and ISB researchers will also do some proteomics, although on a much more limited scale than the gene expression work.
The UMass Medical School Center, which will be led by Francis Ennis, director of the university's Center for Infectious Disease Vaccine Research, also plans to use genomic and proteomic technologies to look at T cell responses - but in response to viral pathogens including poxviruses, hantaviruses, and flaviviruses.
This center will include a Technical Development Component (TDC), to be led by Lawrence Stern, of the university's department of pathology. Researchers in this part of the program will develop solid-phase array technology along with proteomics methods.
"We will be looking at improved technology to detect antigen-specific T cells and their function," said Rothman. Additionally, the technology will aim at identifying biomarkers that indicate a protective or pathological T cell response, the university said.
This technological development addresses what Helen Quill, of the NIAID's Division of Allergy, Immunology and Transplantation has called "a significant barrier in human immune function research." Improved techniques for detection of response at the single-cell level, and imaging techniques for viewing the body's response to infection, could aid in helping researchers to figure out what immune responses are responsible for weak and strong vaccine responses, Quill said.
Ultimately, this could lead to development of improved vaccines for agents of bioterrorism--one of the major goals set by NIAID in the Strategic Plan for Biodefense Research unveiled in 2002, (along with the development of improved diagnostics and therapeutics for these agents).
"We need to understand both the positive and negative aspects of immunity so that we can manipulate it," said Rothman. "This can come in several ways: one is designing newer vaccines that take advantage of the body's ability to develop a protective response," he said. "I also believe that in these cases where the immune system contributes to disease ... manipulating the system may influence the disease as well."
Stanford Gets the Flu
In the effort, the Stanford center will focus on the human immune response to influenza.
The influenza virus is not a Category A pathogen--a member of the US Centers for Disease control's list of most dangerous agents that includes anthrax, botulism, plague, smallpox, tularemia, and viral hemorrhagic fevers - but it does have characteristics that make it a potential bioweapon, according to the investigators in the study.
"Three times in the last century, it has played a particularly nasty trick and changed into a virus to which no one had immunity and caused a worldwide pandemic that killed millions," said Harry Greenberg, co-director of the study and a professor of microbiology and immunology, in a statement. "No one knows exactly how to reproduce a pandemic, but we are really close to knowing how to reproduce the sequence of the virus that caused the 1919 pandemic," which is a frightening prospect in the wrong hands."
The flu study, to be conducted by Ann Arvin, a professor of pediatrics and microbiology and immunology at Stanford, along with Greenberg and others, will involve studying the immunity that follows vaccination as a model for analyzing immune response in the respiratory response.
Stanford's center also will involve a genomics component, with microarray pioneer Pat Brown collaborating with Mark Davis, a professor of immunology and Howard Hughes Medical Institute investigator, according to a university spokeswoman.
Dana-Farber and Baylor
The grant to the Dana-Farber Institute will be led by Ellis Reinherz, a professor of medicine at Harvard Medical school. The studies under this grant will examine the human immune response to the virus in the current smallpox vaccine, as well as other viruses that may be safer for vaccination.
Baylor's effort, led by Jacques Banchereau, director of the BRI Institute for Immunology Research, will be concentrated on study of immune response to emerging pathogens, including West Nile virus, SARS, and other agents, and will focus on developing vaccines against them.
As with part of the Emory research, the Baylor centers will study dendritic cells, according to a university statement. This work will play into Banchereau's prior research using injections dendritic cells as therapeutics for melanoma.
"This award will permit investigators at the Baylor Institute for Immunology Research to further develop their studies aimed at harnessing dendritic cells to induce protective immunity against emerging pathogens, whether they are released deliberately or arise naturally in the environment," Michael Ramsay, president, of Baylor Research Institute, said in a statement.
This round of grants is part of a larger slate of programs that NIAID is expanding and introducing in FY 2004. In addition to this program and the $350 million in grants to establish Regional Centers of Excellence for Biodefense and Emerging Infectious Diseases, announced Sept. 4, the institute has said in its FY 2004 budget that it plans to expand the Biodefense and Emerging Infectious Diseases Research Resources Program "to acquire, authenticate, store, and ship reagents, standardized microarray panels, and other materials related to the study of Category A, B, and C priority pathogens; expand its Large-Scale B and T Cell Epitope Discovery Program; expand support of its Pathogen Functional Genomics Resource Center; and expand its Vaccine Treatment and Evaluation Units.
The Cooperative Centers for Translational Research on Human Immunology expect to receive their funding by the end of this month, according to investigators.