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HPV-related OPSCC occurs in younger patients, has a significantly better prognosis, and is most often caused by HPV subtype 16. There is a 90% overall survival for HPV+/p16+ OPSCC (40% for HPV-/p16- OPSCC), which can be cured with multimodality care. For patients with R/M disease, treatment with pembrolizumab (P) +/- chemotherapy is palliative, with a median OS of approximately 12 months for patients with PD-L1 combined positive score (cps) >1 treated with pembrolizumab (P) alone. Heterologous prime boost with DNA priming followed by vaccinia-based boosting against HPV16 viral antigens will be studied using the priming of pBI-11 DNA [pNGVL4a DNA construct encoding HPV16 E7(detox)/ HPV18 E7(detox)/HPV16 E6(detox)/HPV18 E6(detox) fusion protein linked to mycobacteria tuberculosis heat shock protein 70] followed by boosting of TA-HPV (recombinant vaccinia-human papillomavirus (denoted TA-HPV) derived from the Wyeth strain of vaccinia which carries modified E6 and E7 genes from HPV types 16 and 18). This study is approved by the Vanderbilt University IRB and is open (NCT NCT05799144). Additional sites will include the University of Michigan, Mayo Clinic Scottsdale and Mount Sinai Medical Center Miami Beach Patients with R/M, HPV positive OPSCC without prior therapy for R/M disease, without contraindications to immunotherapy and with a PD-L1 cps > 1 will be screened. There is a 6 patient safety run-in. Treatment with pBI-11 vaccine (2 IM injections on weeks 1 and 4) plus one IM administration of TA-HPV on week 7 will be given in combination with P IV on weeks 1, 4, and 7). Following restaging, all patients will continue (including those with PD) with 3 more cycles of P followed by restaging. The primary clinical outcome is RR to addition of vaccine in the 50% of predicted P non-responders (NR) who proceed to Part II (ie conversion to responders). All responders will continue to receive P until progression. Approximately 54 patients with be enrolled. Two research tumor biopsies and blood draws will be obtained pre- and on treatment (week7-9). Tumor tissue cores will be utilized for immunohistochemical and molecular tests (e.g., expression of immune cell and viral markers, TCR sequencing and total transcripts). Blood with be tested for HPV16/18 E6, E7 antibodies and vaccinia virus neutralizing antibodies; proliferative responses of peripheral blood lymphocytes to stimulation by HPV16/18 E6 and E7; HPV16/18 E6- and E7-Specific T cells; and HPV DNA in plasma. 2 patients enrolled. Accrual ongoing. [ABSTRACT FROM AUTHOR]