A Novel Strategy to Identify Protective T cell Epitopes for HPV Therapeutic Vaccine

I am a molecular immunologist fascinated by T cell immunology. My scientific interest is applying molecular and computational approaches to study the human T cell repertoire and antigenic epitopes during infection. In prior research, I acquired skills and knowledge that are highly aligned with my interests, which resulted in consecutive first-author publications in prestigious journals, including Immunity, Cell Reports, and Frontiers in Immunology. My short-term goal is to become an assistant professor and start my independent research. My long-term goal is to become a leading scientist in T cell recognition. Stanford University provides the best possible training environment through world-leading faculty, facilities and resources to fulfill my career goals. My postdoc mentor, Dr. Mark M Davis, has been a world-leading T cell immunologist since 1980s. He has mentored over 70 postdocs and most are on tenure-track positions at renowned universities. My career training will be under the close guidance of Dr. Davis as well as my Advisory Committee with five outstanding senior professors from Stanford, Yale and MIT, who are Drs. Calvin Kuo, Akiko Iwasaki, Darrell Irvine, Benjamin Pinsky, and Holden Maecker. Each of them and I have developed an individualized research training and career development plan. My training will focus on advanced methodologies and knowledge, academic activities, faculty job hunting, grant application, scientific publication, laboratory management, and long-term collaborations. This proposal will focus on the identification of protective T cell epitopes that have potential to formulate HPV therapeutic vaccine. Most vaccines prevent viral infection effectively by inducing neutralizing antibodies, but they fail to eliminate pathogens post-infection, one such example is the existing HPV vaccines. It’s striking that while most HPV-infected females clear the virus naturally, many do not and progress to cervical cancer. T cells are the complements of antibody responses to maintain host immune competence. We recently found that there is a small fraction of T cell specificity groups uniquely enriched in females who cleared HPV. It is worth noting that this pattern is similar to what our group found in the control of Mtb (Nat Med, 2023). Thus, I hypothesize that there are unique T cell specificity groups in HPV-infected females that correlate with HPV clearance, and T cells that contribute to clearance are subdominant during infection. This is a critical question as prior studies on protective T cells largely focus on dominant T cells. The identification of T cell epitopes is technically challenging, especially for those recognized by subdominant T cells. Moreover, as the T cell response is MHC restricted, it is a longstanding barrier to probing T cell epitopes with appropriate experimental models. I am proposing to tackle these problems with cutting-edge technologies, this study will comprehensively cover T cell receptor (TCR) sequencing, protective TCR discovery, T cell epitope identification and the establishment of probing models. The novel concepts and the knowledge generated in this study will pave a path to identify protective T cell epitopes for T cell-based vaccines, not only for combating HPV infection but also for viral infection in general. Project Number: 1K99AI185150-01A1 | Fiscal Year: 2025 | NIH Institute/Center: National Institute of Allergy and Infectious Diseases (NIAID) | Principal Investigator: Fei Gao | Institution: STANFORD UNIVERSITY, STANFORD, CA | Award Amount: $131,166 | Activity Code: K99 | Study Section: Microbiology and Infectious Diseases B Research Study Section[MID-B] View on NIH RePORTER: https://reporter.nih.gov/project-details/1K99AI18515001A1