MultiPathogen Vaccine Project – PI: Anne S. De Groot, M.D.

The immunoinformatics team has completed a full Burkholderia genome analysis for conserved, immunogenic sequences. This was the first time that as many bacterial genomes (31 in total) have been analyzed using the TRIAD Immunoinformatics toolkit, and the first time that as many (more than 2,800) high quality targets for Burkholderia vaccine development have been identified. Performing HLA binding assays on the peptides will validate the approach, after which we will begin to select the best candidates for inclusion in the vaccine constructs. The highest quality vaccine candidates include some epitopes that are highly conserved in B. cepaciae, a causative agent of lung infections in patients with cystic fibrosis, allowing for further validation studies using human PBMC from individuals exposed to B. cepaciae. This will be the subject of a pilot proposal in Year 2, in collaboration with Joanna Goldberg (VA) a Burkholderia expert. HLA binding will be complete by end of Year 1, and in vivo screening will be completed by the end of year 2. The proposed addition of collaborations for human PBMC validation through the pilot projects mechanism is expected to yield high quality vaccine candidates for Year 3-5. The completed informatics work resulted in a short paper submission to the Immunoinformatics and Computational Immunology Workshop (ICIW 2010), which will take place in conjunction with the ACM International Conference on Bioinformatics and Computational Biology in Niagara Falls, NY in August 2-4, 2010

Dendritic-cell Pulsed HCV Vaccine Project  - PI: Steve Gregory, Ph.D.

Genetic diversity and the existence of multiple Hepatitis C virus (HCV) genotypes and subtypes represent one of the greatest barriers to the development of an effective vaccine. Computational and immunoinformatics tools were used to predict 25 highly conserved, highly immunogenic MHC class II (DRB1)-restricted epitopes expressed by HCV genotype 1. Six of these predicted epitopes are also conserved and expressed by HCV genotypes 2 and 3. These 25 epitopes, and 10 additional epitopes expressed by genotypes 2 and/or 3 but not 1, were synthesized as peptides. In addition, computer analysis and immunoinformatics tools enabled the prediction of 30 HLA class I-restricted epitopes that are both highly conserved and immunogenic. The validity of these predicted peptides will be determined by demonstrating the response of T cells obtained in the peripheral blood of individuals previously infected with HCV. Preliminary studies using the peptides and stored PBMC are underway at the CMI core laboratory.

Tick Vaccine Project - PI: Thomas N. Mather, Ph.D.

The anti-tick vaccine program team completed EpiMatrix analyses of tick salivary metalloproteases and identified for the first time potential T cell epitopes in tick salivary proteins. The fact that just 4 analyzed tick genes yielded 15 peptides with significant predicted immunogenic potential suggests promising outcomes for this project; as our genes-to-vaccines approach has identified over 500 putatively secreted salivary molecules in the blacklegged tick's salivome that could be similarly analyzed. Moreover, we are beginning to apply this approach to other tick vectors worldwide: One related project in Pakistan is developing tick salivary transcriptomics for the central Asian vector of Congo Hemorrhagic Fever virus, a level 4 potential biowarfare agent. In the coming years, Pakistani scientists will train with us in tick transcriptomics, immunoinformatics, and cell mediated immune assays. These synergistic projects provide an exceptional opportunity to consider an anti-tick vaccine based on conserved tick epitopes instead of focusing on microbial agents, so by focusing on the vector rather than the pathogens,  such a vaccine holds great potential for providing broad-spectrum protection against a wide variety of tick-transmitted agents.

H. pylori Therapeutic Vaccine Project-PIs: Lenny Moise, Ph.D. (URI), Steven Moss, M.D. (Lifespan)