Rochester Vaccine Fellowship
The Rochester Vaccine Fellowship is awarded annually to an outstanding postdoctoral fellow working in the area of vaccine-related research, who is mentored by a faculty member with a primary or secondary appointment in the Department of Microbiology and Immunology.
2011 Awardee
Eva-Stina Edholm
Research Summary
Cancer vaccine or immunotherapy is based on the activation of the immune response with the goal of either preventing a malignant cell from establishing or specifically target and eradicate existing tumor cells. This can be achieved through a variety of different mechanisms including vaccination with known tumor-associated antigens,
infusion of immune stimulating cytokines and/or distinct tumor specific effector cells. Although these approaches have achieved encouraging clinical results during the recent years there are still many questions and problems associated with cancer vaccination. For example, during tumorigenesis tumor progression is influenced by multiple, complex interactions between the malignant cell and the host immune system. In many cases tumor progression is strongly associated with immune evasion mechanisms that ultimately limit the success of tumor-associated antigen based vaccine strategies. For example, tumors often down-regulate classical MHC class Ia expression allowing the tumor cell to escape conventional T-cell mediated immune recognition. As a possible consequence many different types of tumors have been found to induce or upregulated expression of non-classical MHC class Ib genes, some of which are thought to serve as a mechanism to escape immune cell mediated elimination.
The comparative immuno-cancer model developed in the amphibian Xenopus laevis has been instrumental to explore novel approach for tumor vaccine. The high level of conservation of the Xenopus immune system with human, including anti-tumor immune effector cells, MHC class Ia and class Ib molecules, and the amenability of Xenopus to in vivo experimentation makes it a highly relevant non-mammalian model. We have focused our studies on the class Ib XNC10 molecule that we postulate to be critically involved in immune response against tumors that has downregulated class Ia antigens to escape immune recognition. Evidence from our lab suggests that XNC10 mediate the differentiation and activation of a subset of CD8+ innate α/βT cells that express an invariant TCR repertoire and that has anti-tumor activity.
To further characterize the function of these innate CD8+ T cells in anti-tumor response, we have generated XNC10 tetramers that specifically bind a population of innate like CD8dim+ cells in the spleen of adult frogs. We have also generated a soluble recombinant XNC10 molecule that can be produced by our tumor line, and that will allow us to identify putative tumor antigens. Our rational is that XNC10, since they are recognized by innate T cell, is likely to complex and present antigens that are of limited diversity and evolutionary conserved (e.g., pattern recognitions). We plan to further investigate the function of XNC10 in generating anti-tumor innate T cell effectors in vivo by transgenesis and tumor transplantation. Despite the fact that class Ib genes in humans and Xenopus are not homologs, their proposed function in tumor surveillance as well as the differentiation and activation of innate CD8+ T cells is likely to rely on conserved mechanisms. We aim to elucidate specific fundamental mechanisms underlying the observed role of class Ib molecules in tumor immunity with the ultimate goal of identifying suitable targets or antigens (likely to be structurally conserved) for novel tumor vaccine therapies.
2010 Awardee
Raychel Chambers
Research Summary
Influenza is a globally important respiratory pathogen that causes nearly annual epidemics and occasional pandemics, including the 2009 H1N1 swine virus pandemic. Because influenza virus is continuously evolving, the emergence of new antigenic variants (drift strains) is constantly occurring. In addition, because all subtypes of influenza A are found in the aquatic bird reservoir from which new viruses emerge, influenza is not eradicable. Thus, the only pragmatic goal is prevention. 
Production of a sufficient amount of flu vaccines, as well as a vaccine which is effective for various age ranges is essential to limiting an outbreak. The problem that prevents large scale vaccine production is the fact that most of the human influenza A viruses, as well as the novel H1N1 strain do not grow well in embryonated eggs or tissue culture. Furthermore, additional live-attenuated vaccines to protect young children and the elderly, the populations most at risk, need to be developed. In order to generate these vaccines, a better understanding of virus assembly is necessary. The lack of knowledge concerning the molecular mechanism of virion formation and release hampers efforts to quickly and sufficiently produce vaccines or to develop safe live vaccines.
An essential step in virion formation is the transport of the viral nucleocapsid to the assembly sites. As part of my PhD studies, I investigated how the Sendai virus (SeV) nucleocapsid is transported through the cytoplasm to plasma membrane assembly sites. I found that Rab11a, a regulator of the recycling endosome pathway was involved in the trafficking of viral nucleocapsid. Consistent with my findings, a recent study reported that Rab11 is necessary for influenza A budding and virus production. It is still unknown how Rab11 plays a role in influenza assembly and how the nucleocapsid travels through the cytoplasm to the plasma membrane. My research will elucidate host cellular proteins that mediate intracellular nucleocapsid transport, and their interactions with viral proteins. We expect the data to provide important clues for designing recombinant viruses which grow efficiently in cells or live-attenuated viruses which replicate well but have attenuated progeny virion production.
Education
University of Rochester School of Medicine and Dentistry, Rochester, NY
Department of Microbiology and Immunology
Postdoctoral Research Fellow, 2009-present
Mentor: Toru Takimoto, PhD
University of Rochester School of Medicine and Dentistry, Rochester, NY
Department of Microbiology and Immunology
Doctor of Philosophy, 2009
Mentor: Toru Takimoto, PhD
Texas State University, San Marcos, Texas
Department of Chemistry and Biochemistry
Master of Biochemistry, 2003
Mentor: Linda Watkins, Ph
D
Texas State University, San Marcos, Texas
Bachelor of Science, 2001
2009 Awardees
Michael Overstreet
Research Summary
Most immune responses to microbial infection are measured in the draining lymph node (mouse) or peripheral blood (human). A recent study from our laboratory demonstrated that early in Leishmania major infection in mice, the cytokine profile of CD4+ helper T cells in the infected tissue site did not reflect the cytokine profile of T cells in the draining lymph node. The concept that tissue resident pathogens may subvert the centrally generated cytokine repertoire by limiting the local recruitment or activation of specific effectors has important implications for the design and measurement of immune function in disease and vaccine settings. Where an immune response or vaccine, fails to control infection the host may nevertheless have generated a central pool of appropriate effectors with anti-microbial potential. We will thus test the hypothesis that Leishmania major exploits an intrinsic homing potential of IFN-γ-secreting (Th1) and IL-4 secreting (Th2) CD4+ T cells and modifies the infected tissue microenvironment so as to limit the ability of Th1 cells to migrate into that tissue. By flow cytometry, we will track the migration and accumulation of functionally-marked helper T cells into inflamed tissue (using fluorescent cytokine reporters), as well as evaluate complex surface marker expression on those cells that reach the tissue. By in vivo intravital multiphoton microscopy, we will compare the ability of Th1 and Th2 cells to extravasate into the inflamed tissue from the bloodstream, as well as their migratory characteristics within the tissue itself. With these tools in place, we will address biologically relevant settings on immune activation:
- Can the migratory potential of helper T cells be modulated by local changes induced by a pathogen?
- Can the migratory potential of helper T cells be modulated by altering inflammatory conditions at the time of immunization?
We highlight an emerging principle in pathogen-host interactions: that the lymph node-derived T cell cytokine repertoire can be edited by the pathogen at the infection site. Understanding pathogen-specific mechanisms of regulation at the tissue site becomes key to the design of appropriate therapeutics. Developing ways of harnessing a diverse LN repertoire to retune immune responses at the infection site, by manipulating the type of effectors generated and recruited to the site, has great therapeutic potential for many disease states.
Education
University of Rochester - School of Medicine and Dentistry - Rochester ,NY
David H. Smith Center for Vaccine Biology and Immunology
Postdoctoral Training, 2008 - Present
Mentor: Deborah Fowell, D.Phil
Johns Hopkins University - Bloomberg School of Public Health - Baltimore, MD
Department of Molecular Microbiology and Immunology
Doctor of Philosophy, 2008
Mentor: Fidel Zavala, MD
Johns Hopkins University - Whiting School of Engineering - Baltimore, MD
Department of Biomedical Engineering
Bachelor of Science, 2002 Grade Point Average: 3.7
Graduated with University Honors and Department Honors
Shanaka Rodrigo
Research Summary
The research I am doing in the lab of Prof. Luis Martinez-Sobrido involves members and proteins of the family Arenaviridae. Arenaviruses are emerging viruses with a 
worldwide distribution. They are enveloped with a bi-segmented negative stranded RNA genome. Arenaviruses cause chronic and asymptomatic infections in rodents and can be transmitted to humans causing infections and in some cases leading to severe conditions such as hemorrhagic fever (HF) with fatality rate up to 35%. These HF arenaviruses poses a public health problem, as well a potential bioterrorism threat in the endemic regions. There is no specific anti-arenaviral therapeutic or vaccine available. Also, the study of the HF arenaviruses require BSL-4 containment. We are using reverse genetics techniques to rescue prototypic BSL-2 arenavirus Lymphocytic choriomeningitis virus (LCMV) in which the surface glycoprotein (GP) gene is replaced with a reporter gene/RG using LCMV GP expressing stable cell lines, which we developed in our laboratory. The replication of GP-deficient rLCMVs is limited to a single cycle in non-GP expressing cell lines. Parallel, we have developed cell lines expressing GP of the HF Lassa fever virus (LASV), and planning to extend our studies to other HF arenaviruses such as Junin virus (JUNV) and Machupo virus (MACV). These HF GP expressing cell lines will allow us to generate the corresponding GP-pseudotyped rLCMVΔGP/RG allowing its use and study under BSL-2. Once rescued, these viruses can be used in;
- The development of sensitive and specific high-through-put screening assays to evaluate anti-virals against different steps of the arenavirus life cycle.
- To detect and quantify neutralizing antibodies.
- As mentioned in our current proposal, for the development as safe and effective vaccine candidates againt HF arenaviruses.
Education
Shanaka attended the University of Colombo, Faculty of Science, Sri Lanka from 1997 to 2001 on a “Mahapola higher education merit scholarship” and graduated with a Bachelor of Science (first class honors) in Biochemistry and Molecular Biology in December 2001. He carried out an undergraduate research project in isolation and characterization of banana streak virus for enzyme-linked immunosorbant assay and polymerase chain reaction identification, under the guidance of Professor W. Kumara Hirimburegama. He was at Unilever (Ceylon) Ltd., Colombo, Sri Lanka for industrial training as a part of his undergraduate training. After graduation he was appointed Assistant lecturer in Biochemistry, Molecular Biology and Pharmacy, in the Department of Chemistry, University of Colombo in 2001-2002. He was then appointed Research assistant in the same department in 2002-2003, to carryout research in “natural products chemistry”. Shanaka entered the Pathways of human disease (PWD) cluster on a graduate student fellowship, and began graduate studies in Pathology at the Department of Pathology and Laboratory Medicine at the University of Rochester School of Medicine and Dentistry, Rochester, NY, USA in the fall of 2003. He pursued research in the field of dengue virology under the guidance of Professor Robert C. Rose, Professor Jacob J. Schlesinger, and Professor Xia Jin. He investigated “the role of human Fcγ receptors in antibody-mediated dengue virus neutralization: implications for dengue disease pathogenesis”. Shanaka received his Master of Science degree in Pathology in the spring of 2006. He received the honor of being awarded for the outstanding research publication (2006-2007) of the year: Differential enhancement of dengue virus immune complex infectivity mediated by signaling-competent and signaling-incompetent human FcγRIA (CD64) or FcγRIIA (CD32). J. Virol. 2006 Oct; 80(20): 10128-38. He received the graduate student travel award (2007-2008) enabling him to present at the 57th American Society for Tropical Medicine and Hygiene annual meeting, New Orleans, LA, December 2008. He also received awards of achievement at the annual pathology research day poster sessions in 2007 and 2008. Shanaka received his Doctor of Philosophy degree in Pathology in the spring of 2009. Presently he is pursuing his post-doctoral fellowship under the mentorship of Professor Luis Martinez-Sobrido, at the Department of Microbiology and Immunology, University of Rochester School of Medicine and Dentistry, Rochester, NY, since April 2009. He is a member of American Society for Virology and a member of American Society for Tropical Medicine and Hygiene since 2006. He is also a life-time member of the Sri Lanka Association for the Advancement of Science.
