Phase I Open-Label Safety Trial of Pembrolizumab for Neurological Post- Acute Sequelae of SARS-CoV-2 (PD1-PASC I)

Background: SARS-CoV-2 is the virus that causes COVID-19. Some people who recover from an acute COVID-19 infection may continue to have symptoms that persist for months or years. These can include neurological symptoms, such as headaches, loss of taste or smell, dizziness, or trouble walking. Pembrolizumab is a drug approved to treat certain cancers. Researchers think this drug might reduce long-term neurologic symptoms after a COVID-19 infection. Objective: To test pembrolizumab in people with ongoing neurologic symptoms of COVID-19. Eligibility: People aged 18 years or older who had COVID-19 at least 6 months ago and have ongoing neurologic symptoms. Design: Participants will have 7 clinic visits in 7 months. Participants will be screened. They will have a physical exam with blood tests. Swabs will be used to collect cells from inside the mouth and nose. They may opt to have an imaging scan. Participants will also have other tests before they are given the study drug. These include eye and skin exams; tests of their memory and thinking; and tests of involuntary body functions, such as heart rate, blood pressure, sweating, and digestion. Their grip strength and walking pace will be measured. They will wear a heart rate monitor for 24 hours. They will wear devices on a wrist and thigh to measure activity for 10 days. Participants will have a lumbar puncture (spinal tap): A thin needle will be inserted into their lower back to draw out a sample of the fluid around their spinal cord. Pembrolizumab is given through a needle inserted into a vein. Participants will receive 1 dose of the drug. Participants will have 4 follow-up visits over 6 months. Tests may be repeated during these visits.

* INCLUSION CRITERIA: To be eligible to participate in this study, an individual must meet all the following criteria: * Stated willingness to comply with all study procedures and availability for the duration of the study. * Male or female, aged at least 18 or older. --Documentation of the SARS-CoV-2 infection that led to development of PASC confirmed either by a positive testing by a commercial laboratory or a positive home test followed by confirmatory nucleocapsid antibody testing. * Previously diagnosed with mild-moderate COVID-19 (WHO Clinical Progression Scale between 2-5. Participants who had severe acute COVID-19 requiring hospitalization or ICU care are excluded. * If participants had multiple SARS-CoV-2 infections, they would need to be at least 6 months after the last infection. * All participants would need to have a negative SARS-CoV-2 nasal swab at the time of enrollment. * Exhibiting persistent neurologic symptoms evidenced by a self-reported illness narrative of the development of persistent PASC symptoms after recovering from a SARS-CoV-2 infection. These include symptoms such as fatigue, cognitive difficulties, sleep disturbances, orthostatic intolerance, and any ongoing issues with gait instability, vision, speech, swallowing, sensation, or strength. Symptoms must persist for at least 6 months after the diagnosis of acute COVID-19. * All participants will have PD-1 expression on CD8 T cells that is one SD above the mean value of normal controls as established in the SINS Lab and published previously. * Moderate to severe PASC symptom severity, as determined using PCFS (minimal score of 3). * Ability of participant to understand and sign a written informed consent document. * Prior completion of a clinical brain MRI after the diagnosis of COVID-19, or willingness to complete a brain MRI. * Agrees not to have vaccinations over the course of the study. * Participants of childbearing potential must agree to use a combination of contraception (defined as two forms of effective birth control) or have had surgical sterilization, from the time of enrollment until 4 months after the dose of study drug. * Participants capable of sperm donation must agree to not donate sperm from the time of enrollment until 4 months after the dose of study drug. EXCLUSION CRITERIA: An individual who meets any of the following criteria will be excluded from participation in this study: * For participants who have not completed a brain MRI since onset of symptoms: inability to complete brain MRI with gadolinium including contraindicated metal in the body, prior allergic reaction to gadolinium, eGFR \1.5 x ULN for the NIH Clinical Center, if risk of lumbar puncture is increased for other reasons such as space occupying lesion, skin infection at site of the puncture or otherwise inability to complete the procedure. * A condition that would significantly confound interpretation of the clinical and research tests as determined by the study investigators. This could include traumatic brain injury, substance use disorder, active malignancy, systemic immunologic disorders, current or previous long-term immune suppressive therapy. * Any premorbid medical condition that would potentially cause fatigue and exercise intolerance. This includes many chronic medical diseases, such as congestive heart failure, coronary artery disease, chronic obstructive pulmonary disease, severe arthritis, uncontrolled asthma, renal failure, fibromyalgia, and ME/CFS. * Symptom severity that makes it impossible for the participant to travel to NIH. * Received a SARS-CoV-2 vaccine dose within less than 4 weeks of enrollment or is planning for any additional vaccines during the study. * Prior treatment for PASC with immunomodulatory therapies such as check point inhibitors which in the opinion of the investigators could impact the outcome of this study. * Current medications include oral steroids or other immunosuppressive medications which in the opinion of the investigators could impact the outcome of this study. * Active participation in a clinical protocol which includes any intervention that may affect the results of the current study. * Abnormal anti-thyroid panel (anti-TPO and anti-TG) test at screening visit. * ANA titer of 1:80 or greater, positive anti-CCP. * Abnormal screening blood tests exceeding any of the limits defined below or as deemed exclusionary by the investigators on review at baseline: * Aspartate aminotransferase and alanine aminotransferase values \>2x upper limit of normal precluding the use of acetaminophen * Fasting triglyceride \> 300 mg/dL. * Total bilirubin \>2x upper limit of normal (unless participant has Gilbert syndrome) * Creatinine Clearance or eGFR \