* Signed and dated written informed consent * Male or female \>= 18 years of age on the day of signing informed consent * Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 * Having been diagnosed with R/M p16+ PD-L1 CPS \>= 1 OPC not previously treated for R/M disease. They must be eligible for, and planning to start therapy with pembrolizumab, according to standard of care * hrHPV(+) status (staining with p16 is adequate) and PD-L1 expression (CPS≥1) in tumor based on validated testing methods performed on FFPE tumor tissue (needle core biopsy or resection; fine needle aspiration/biopsy \[FNA\] cell blocks acceptable if with adequate tissue) at local labs or VUMC labs. \[This biopsy tissue will also be used for the pre-treatment tissue research correlate studies.\] For patients with neither existing tumor hrHPV and PD-L1 CPS test results nor adequate archived tissue available for PD-L1 and hrHPV testing, a biopsy performed during screening is necessary to obtain diagnostic tissue. If no tissue is available for PD-L1 and hrHPV testing on either archived or newly obtained tissue, the patient cannot be enrolled. * Evaluable tumor burden (measurable and/or non-measurable tumor lesion\[s\]) which can be followed by computed tomography (CT) scan or magnetic resonance imaging (MRI), based on Immune-Modified Response Evaluation Criteria in Solid Tumors (iRECIST) as assessed by the local site investigator/radiology. Tumors that are biopsied (for diagnosis and research use) will not be considered in the iRECIST version (v)1.1 assessment. However, if patient has only one evaluable tumor, patient may still be eligible for participation * Absolute neutrophil count (ANC) \>= 1,000/uL (resulted =\< 28 days prior to first dose of protocol-indicated treatment) * CD4 T cell count \> 200/uL (resulted =\< 28 days prior to first dose of protocol-indicated treatment) * Platelets \>= 75,000/uL (resulted =\< 28 days prior to first dose of protocol-indicated treatment) * Hemoglobin \>= 7.0 g/dL (resulted =\< 28 days prior to first dose of protocol-indicated treatment) * Estimated glomerular filtration rate (eGFR) \>= 45 mL/min (as calculated by the Cockcroft-Gault Formula or calculated/measured by an alternative established institutional standard consistently applied across participants at the site) (resulted =\< 28 days prior to first dose of protocol-indicated treatment) * Total bilirubin =\< 1.5 times institutional upper limit of normal (ULN), or direct bilirubin =\< ULN for participants with total bilirubin \> 1.5 x ULN (resulted =\< 28 days prior to first dose of protocol-indicated treatment) * Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase \[SGOT\]) and alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase \[SGPT\]) =\< 2.5 times institutional ULN (resulted =\< 28 days prior to first dose of protocol-indicated treatment) * Calcium =\< 11.5 mg/dL or =\< 2.9 mmol/L; in patients with albumin outside the normal range, calcium (corrected for albumin) must be =\< 11.5 mg/dL or =\< 2.9 mmol/L (resulted =\< 28 days prior to first dose of protocol-indicated treatment) * International normalized ratio (INR) or prothrombin time (PT) =\< 1.5 times institutional ULN; except for patients receiving anticoagulant therapy as long as PT in such patients per investigator judgment is within therapeutic range of intended use of anticoagulants (resulted =\< 28 days prior to first dose of protocol-indicated treatment) * Activated partial thromboplastin time (aPTT) preferred or partial thromboplastin time (PTT) =\< 1.5 times institutional ULN; except for patients receiving anticoagulant therapy as long as PTT in such patients per investigator judgment is within therapeutic range of intended use of anticoagulants (resulted =\< 28 days prior to first dose of protocol-indicated treatment) * Patients must not be breastfeeding and further agree to not breastfeed during study treatment; and for at least 120 days after patient's final dose of heterologous vaccination and pembrolizumab * A woman of childbearing potential (WOCBP) must have a negative serum or urine pregnancy test during screening within 28 days prior to receiving first dose of protocol-indicated treatment, and must agree to follow instructions for using acceptable contraception from the time of signing consent, and until at least 180 days after her final dose of heterologous vaccination and pembrolizumab. In order to be considered not of childbearing potential, women under the age of 62 must have a documented serum follicle stimulating hormone (FSH) level more than 40 mIU/mL (or within local laboratory reference range for postmenopausal women * Patients must refrain from donating blood or sperm throughout the duration of study treatment followed by at least 120 days after patients' final dose of heterologous vaccination or pembrolizumab * A patient able to father children who is sexually active with a WOCBP must agree to follow instructions for using acceptable contraception, from the time of signing consent, and until at least 120 days after his final dose of heterologous vaccination and pembrolizumab