Elledge, Stephen JChen, Genghao2026-06-0920262026-05-122026Chen, Genghao. 2026. Epitope-level Dissection of Antibody and T Cell Immunity in Allergen Immunotherapy and Viral Vaccine Development. Doctoral Dissertation, Harvard University Graduate School of Arts and Sciences.32701067https://dash.harvard.edu/handle/1/42740522The adaptive immune system relies on highly specific recognition of discrete antigenic epitopes by B and T cells to mediate protection against pathogens while maintaining tolerance to innocuous or self-antigens. However, how epitope-level immune recognition shapes protective versus pathological outcomes, and how this knowledge can be harnessed for immunotherapy and vaccine design, remains underexplored. This dissertation investigates adaptive immune responses at epitope resolution across two disease-relevant contexts: IgE-mediated food allergy and antiviral T cell immunity. In the first part, I describe the development of AllerScan, a high-throughput phage display method that enables comprehensive, amino acid–resolution mapping of allergen-specific antibody responses. Applying AllerScan to sera from peanut-allergic individuals undergoing oral immunotherapy (OIT), I defined the landscape of IgE and IgG recognition across all major peanut allergens. This analysis revealed the presence of highly conserved “public” IgE epitopes shared among allergic individuals, with strikingly similar antibody footprints at the residue level. OIT induced a marked expansion and diversification of peanut-specific IgG responses, accompanied by a reduction in pre-existing IgE abundance in some instances but not in IgE epitope diversity. Notably, IgE and OIT-induced IgG antibodies targeting the same epitopes exhibited highly similar binding footprints within individuals, supporting epitope competition as a mechanism for IgG-mediated inhibition of allergic responses and a clonal or convergent relationship between IgE- and IgG-producing B cells. These findings provided mechanistic insight into how OIT reshapes antibody repertoires to promote desensitization and highlighted epitope-level information as a foundation for developing safer, more precise allergen immunotherapies. In the second part of the dissertation, I focused on the design and evaluation of vaccines targeting conserved CD8 T cell epitopes of SARS-CoV-2 in preclinical mouse models. Through a systematic epitope mapping effort, I identified conserved and variant-specific murine CD8 T cell epitopes within the Omicron BA.1 spike protein. I then developed carrier protein–fusion vaccines designed to elicit robust T cell responses in the absence of antibody induction, enabling direct evaluation of T cell–mediated protection. While subcutaneous vaccination with CD8 T cell epitopes significantly reduced lung viral load and protected against low-dose viral challenge, it failed to confer protection against high-dose viral challenge. In contrast, intranasal boosting—with or without adjuvant—induced durable lung-resident memory CD8 T cells and provided robust protection against disease and mortality, at levels comparable to spike mRNA vaccines which induced a combination of neutralizing antibody and T cell responses. These findings highlighted mucosal T cell immunity as a critical determinant of effective T cell–based protection against respiratory viral infection and supported the development of conserved T cell epitope-based vaccine design to provide broad, pan-variant protection against emerging viral threats. Together, this work demonstrates that epitopes constitute a fundamental unit of immune recognition that govern both pathological and protective immune outcomes. By resolving immune responses at epitope-level precision, this dissertation provides the bases for rational design of immunotherapies and vaccines that elicits protective immunity while minimizing pathogenic immune activation.application/pdfenAllergyantibodyMucosal ImmunitySARS-CoV-2T cellVaccineBiologyVirologyMolecular biologyThesis or Dissertation2026-06-090000-0002-8585-9943