Immunology is a branch of biomedical science that covers the study of all aspects of the immune system in all organisms. It deals with, among other things, the physiological functioning of the immune system in both healthy and diseased states; malfunctions of the immune system in immunological disorders such as autoimmune diseases, hypersensitivities, immune deficiency and transplant rejection; the physical, chemical and physiological characteristics of the components of the immune system in vitro, in situ, and in vivo.
The availability of immunome-mining tools has fueled the design and development of vaccines by a process that was at first called “vaccinomics” by Brusic and Petrovsky in 2002, “reverse vaccinology” by Rappuoli in 2003 and, more recently, “immunome-derived or genome-derived vaccine design” by Pederson; De Groot and Martin; and Doytchinova, Taylor, and Flower.
The theory behind these descriptors is that a minimal set of antigens that induce a competent immune response to a pathogen or neoplasm can be discovered using immunoinformatics, and that administration of these epitopes, in the right delivery vehicle and with the correct adjuvant, will result in a degree of protection against infection by the pathogen. In its most minimalist form, an IDV would contain only adjuvanted B-cell and T-cell epitopes in delivery vehicles such as liposomes. When these minimal components are packaged in an appropriate delivery vehicle, the complete package comprises an immunome-derived vaccine.
Compared to traditional vaccines, immunome-derived vaccines (IDVs) have the potential to be safer and more effective since they focus the protective immune response on the most essential antigenic elements of the pathogen/neoplasm, while eliminating potentially cross-reactive and deleterious or simply inert components, reducing the potential for adverse outcomes. Despite these advantages, immunome derived vaccines are only now beginning to enter clinical trials.
One reason for the relative paucity of IDV in clinical development is that the immunoinformatics tools for developing these vaccines have matured only in the last ten to fifteen years, while the average length of time to develop a vaccine is typically twenty years or more. While immunoinformatics tools are now more commonly used for antigen discovery, testing vaccines in animal models and developing clinical trials is a lengthy process.
It is likely that IDV and epitope-based IDV will begin to enter clinical trials and emerge on the market in greater numbers in five to ten years.
Selected Research Areas
Multipathogen Vaccine Project for Biodefence
Biodefense vaccines against Category B bioterror agents Burkholderia pseudomallei (BPM) and Burkholderia mallei (BM) are needed, as they are both easily accessible to terrorists and have strong weaponization potential. Burkholderia cepaciae (BC), a related pathogen, causes chronic lung infections in cystic fibrosis patients. Since BPM, BM and BC are intracellular bacteria, they are excellent targets for T cell-based vaccines. However, the sheer volume of available genomic data requires the aid of immunoinformatics for vaccine design. Recent results show it is possible to rapidly identify promiscuous T helper epitopes conserved across multiple Burkholderia species and test their binding to HLA in vitro. The next step in our process will be to test the epitopes ex vivo using peripheral leukocytes from BC, BPM infected humans and for immunogenicity in human HLA transgenic mice.
The Immunome Project
Tools available to map T cell epitopes in whole virus and bacterial vaccines are of interest because of the potential for cross-protection against like pathogens, or, alternatively, deleterious cross-reactive immune responses to autologous proteins or the human microbiome. Our ability to differentiate between adaptive immune responses elicited by vaccines that are both protective and also pathogen-specific and responses to host or host-associated sequences is critical to foster the development of better vaccines in the future. Thus the laboratories of De Groot and Moise (TRIAD CCHI at URI) collaborating with Rothman (URI) and Selin (UMass) and Sztein are collaborating to explore the role of cross-reactive T cell responses in vaccination. Thus we propose to (i) measure the modulation of immune responses to common vaccines due to pre-existing T cell responses to common viral pathogens (Epstein Barr and influenza) and (ii) delineate cross-reactive T cell responses between a bacterial vaccine (S. Typhi) and the human microbiome. Exploration of the intersecting T-cell epitope and TCR specificities between vaccines, self, commensals, and common human pathogens is critically important to building better vaccines for human use. Likewise, better understanding of vaccine-induced immune responses that could jeopardize self-tolerance and/or human microbiome homeostasis is critical to effective vaccine design.