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Daniel Rotrosen, M.D., Director, DAIT, NIAID & George Curlin, M.D., Acting Director, DMID
This joint meeting represents the first time that the Division of Microbiology and Infectious Diseases (DMID) and the Division of Allergy and Immunology and Transplantation (DAIT) have joined together for a combined Council session. The purpose of the joint session was to bring together experts in areas related to the immunological basis of vaccine adjuvants, a topic of overlapping interest to the two Divisions. Prior to the presentations, Drs. Daniel Rotrosen, Director of DAIT, and George Curlin, Acting Director of DMID, made brief opening remarks.
Dr. Rotrosen described the enthusiasm he and others were feeling for the upcoming session and referred to three rapidly advancing areas where basic immunology and vaccinology are mutually supportive: 1) the application of genomics and the ability to identify protein antigens; 2) the ability to track and characterize antigen-specific immune responses to antigen-specific immune responses to antigens in animal models and man; and 3) the major advances in understanding how vaccine adjuvants work and the potential to capitalize on such findings for future vaccine development. He emphasized that one of the goal's of the day's discussion was to put a "framework" on what are the immunologic principles underlying vaccine adjuvants and to explore the question of whether the NIAID should be making a greater effort to solicit and target research in this area.
In his comments, Dr. Curlin indicated that he was encouraged the two Divisions were jointly discussing this issue, and emphasized that the science in this area was advancing rapidly along "congruent" paths for both Divisions. He closed by thanking the organizers of the joint session, Drs. Lee Hall and Chuck Hackett, for their efforts.
The presentations were as follows:
- Bridging Innate and Adaptive Immunity (General Overview)
Giorgio Trinchieri, MD, The Wistar Institute
Dr. Trinchieri discussed how the initial alarm signals provided by the innate immune system serves to establish the immunological environment needed for appropriate T and B cell responses to infection. The function of the cytokine interleukin-12 as a mediator of adjuvant stimulation for inflammatory responses was reviewed. In addition to serving as a strong stimulus for TH1 responses, new data show that, in some situations, IL-12 can promote a compensatory response that inhibits lymphocyte activation. This recognition that IL-12 has both positive and negative regulatory effects needs to be considered in vaccination approaches.
- Receptors for Bacterial Cell Wall Lipopolysaccharide (LPS)
Paul J. Godowski Ph.D., Genentech
Vertebrates have evolved a complex system for responding to bacterial infection via receptors for LPS. Recently, Dr. Godowski and associates have shown that the Toll-like receptor 2 molecule is the direct mediator of signaling by LPS, and that it functions jointly with LPS binding protein and CD14 in this process. Currently at least 10 human Toll-like receptors have been identified, and are being studied for their role in innate immunity to infection. These may be targets for novel adjuvant approaches.
- Initiating T Cell Responses
Dr. Lindsay Whitton, Ph.D., Scripps Institute
Presentation of antigens to T cells requires the proteolytic degradation of foreign proteins to peptides that are displayed on the surface of antigen presenting cells in the context of self Major Histocompatibility Complex Molecules. Dr. Whitton presented an approach to target vaccine antigens for efficient proteolytic degradation, resulting in enhanced cytotoxic T cell responses to the antigens. Antibody responses, however, were not induced by this strategy, suggesting that its application alone may be limited to diseases where CTL responses are sufficient for protection, or alternatively, that it may need to be combined with other approaches for diseases where protective immunity requires a multifaceted immune response.
- Immune Amplification - Complement
Douglas Fearon, MD, University of Cambridge
Complement component C3 covalently tags microbial antigens, marking them for recognition by the adaptive immune system. Dr. Fearon addressed the mechanisms by which immune responses are enhanced by this endogenous adjuvant system. Because the C3-tagged antigen is recognized simultaneously by the appropriate B cell antigen receptor molecule and the molecules CD19/CR2 involved in complement recognition, strong stimulatory signals are delivered to the B cell for antibody production. Very low amounts of C3-complexed antigen, therefore, can effectively stimulate strong antibody production. Dr. Fearon also discussed the role that chemical modifications, such as the introduction of aldehyde groups into proteins or carbohydrates, may have on enhancing immunogenicity.
- CpG motifs
Heather Davis, Ph.D., University of Ottawa
Short stretches of DNA that contain neighboring bases of cytosine and guanine (CpG) can directly activate mammalian antigen-presenting cells such as B cells, macrophages, and dendritic cells. Such activation indirectly stimulates T cells responding to antigen, resulting in an exceptionally strong adjuvant effect, particularly for TH1 cells. The mechanistic basis by which CpG motifs exert their effects is being studied. These potentially useful adjuvant and immunomodulatory agents are being tested in both preclinical and clinical trials.
- Parasite Sugars
Donald A. Harn, Ph.D., Harvard University
Dr. Harn described recent studies of immune responses in schistosomiasis that led to the recognition that specific sugars could modulate the balance of TH1 and TH2 responses. Dr. Harn reviewed the mechanisms of immunomodulation, and discussed how these sugars are now being developed as Th2-driving adjuvants.
- Bacterial Toxins as Mucosal Vaccine Adjuvants
John Clements, Ph.D., Tulane
Dr. Clements discussed the mechanisms of toxicity, immunogenicity and adjuvanticity of toxins of enteric pathogens, and reviewed recent results obtained in experimental systems where mutagenized recombinant toxins have been used as adjuvants.
- General Discussion - Adjuvants in Humans
W. Ripley Ballou, M.D., Walter Reed Army Institute of Research
Using examples drawn from malaria and hepatitis B, Dr. Ballou provided an overview of clinical development strategies for vaccines formulated with novel adjuvants. He discussed how research on the adjuvant system had supported development of novel vaccines and improved the immunogenicity of existing vaccines. Dr. Ballou also provided a cogent discussion of the regulatory and safety issues surrounding the introduction of novel vaccines into target populations, especially vulnerable populations such as children.
These scientific presentations provided the Subcommittees with important information on the immunological basis of vaccine adjuvants. NIAID staff will take the findings presented at the meeting into consideration when developing future initiatives. back to top |