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Once an obscure pathogen, Zika virus (ZIKV) has emerged as a significant global public health concern. Several studies have linked ZIKV infection in pregnant women with the development of microcephaly and other neurological abnormalities, emphasizing the need for a safe and effective vaccine to combat the spread of this disease. Preclinical studies and vaccine development efforts have largely focused on the role of humoral immunity in disease protection. Consequently, relatively little is known in regard to cellular immunity against ZIKV, although an effective vaccine will likely need to engage both the humoral and cellular arms of the immune system. To that end, we utilized two-dimensional liquid chromatography coupled with tandem mass spectrometry to identify 90 ZIKV peptides that were naturally processed and presented on HLA class I and II molecules (HLA-A*02:01/HLA-DRB1*04:01) of an immortalized B cell line infected with ZIKV (strain PRVABC59). Sequence identity clustering was used to filter the number of candidate peptides prior to evaluating memory T cell recall responses in ZIKV convalescent subjects. Peptides that individually elicited broad (4 of 7 subjects) and narrow (1 of 7 subjects) T cell responses were further analyzed using a suite of predictive algorithms and in silico modeling to evaluate HLA binding and peptide structural properties. A subset of nine broadly reactive peptides was predicted to provide robust global population coverage (97.47% class I; 70.74% class II) and to possess stable structural properties amenable for vaccine formulation, highlighting the potential clinical benefit for including ZIKV T cell …