Inclusion Criteria: * Male, aged 18 to 75 years at the time of screening. * Established severe or moderately severe hemophilia B (plasma FIX activity lesser than or equal to \[\<=\] 2 percent (%) measured following greater than or equal to \[\>=\] 5 half-lives of most recent exposure to exogenous FIX) and either \>= 3 hemorrhages per year requiring treatment with exogenous FIX or use of prophylactic therapy. * History of greater than (\>) 50 exposure days to exogenously administered FIX concentrates or cryoprecipitates. * Sexually active men must agree to use barrier contraception (combination of a condom and spermicide) or limit sexual intercourse to post-menopausal, surgically sterilized, or contraception-practicing partners for a minimum of 6 months after administration of SHP648, or until SHP648 genomes are no longer detected in the semen (whichever is sooner). * Signed informed consent. Exclusion Criteria: * Bleeding disorder(s) other than hemophilia B. * Documented laboratory evidence of having developed inhibitors (\>= 0.6 Bethesda Units \[BU\] on any single test) to FIX proteins at any time. * Documented prior allergic reaction to any FIX product. * Anti-AAV8 neutralizing antibody titer \>= 1:5. * Known hypersensitivity to prednisolone or prednisone, or to any of the excipients. * Having a disease in which treatment with prednisolone or prednisone is not tolerated (including, but not limited to osteoporosis with vertebral fractures, severe labile hypertension, and brittle diabetes). * Evidence of markers of potential underlying risk for autoimmune mediated hepatic disease: * Anti-smooth muscle antibody (ASMA) titer \>= 1:40. Values of 1:31 to 1:39 will be flagged as possibly abnormal and the Investigator and Medical Monitor will evaluate the participant for eligibility * Elevated anti-liver-kidney microsomal antibody type 1 (LKM1) titers * Total Immunoglobulin G (IgG) \> 1.5x upper limit of normal (ULN) * Antinuclear antibody (ANA) titer \> 1:320 OR ANA titer \> 1:80 if demonstrated concurrently with alanine aminotransferase (ALT) that is \> ULN * Active Hepatitis C: as indicated by detectable hepatitis C virus ribonucleic acid (HCV RNA) by polymerase chain reaction (PCR). * Hepatitis B: If surface hepatitis B virus (HBV) antigen is positive. * Receiving chronic systemic antiviral and/or interferon therapy within 4 weeks prior to enrollment. * Clinically significant infections (e.g., systemic fungal infections) requiring systemic treatment. * Known immune disorder (including myeloma and lymphoma). * Concurrent chemotherapy or biological therapy for treatment of neoplastic disease or other disorders. * An absolute neutrophil count lesser than \< 1000 cells per cubic millimetre (cells/mm\^3). * Markers of hepatic inflammation or cirrhosis as evidenced by 1 or more of the following: * Platelet count \< 150,000/microliter (μL) * Albumin \<= 3.5 gram per deciliter (g/dL) * Total bilirubin \> 1.5x ULN and direct bilirubin \>= 0.5 milligram per deciliter (mg/dL) * ALT or Aspartate aminotransferase (AST) \> 1.0x ULN * Alkaline phosphatase \> 2.0x ULN * History of liver biopsy or imaging indicating moderate or severe fibrosis (Metavir staging of F2 or greater) * History of ascites, varices, variceal hemorrhage, or hepatic encephalopathy * FibroSURE Score \>= 0.4 * Prothrombin time international normalized ratio (INR) \>= 1.4 * Serum creatinine \> 1.5 mg/dL. * Human immunodeficiency virus (HIV) if cluster of differentiation 4 (CD4)+ cell count \<= 200 mm\^3 and/or viral load \> 20 copies per milliliter (copies/mL). * Urine protein \> 30 mg/dL. * Body mass index \> 38. * Orthopedic or other major surgery planned within 6 months after enrollment. * Acute or chronic disease that, in the opinion of the Investigator, would adversely affect participant safety or compliance or interpretation of study results. * Received an AAV vector previously or any other gene transfer agent in the previous 12 months prior to Study Day 0. * Significant cardiovascular disease (such as New York Heart Association Class III or IV cardiac disease, congestive heart failure, myocardial infarction within the previous 6 months, unstable arrhythmias, or unstable angina) or significant pulmonary disease (including obstructive pulmonary disease). * History of arterial or venous thrombosis / thromboembolism, or a known pro-thrombotic condition. * Recent history of psychiatric illness or cognitive dysfunction (including drug or alcohol abuse) that, in the opinion of the Investigator, is likely to impair participants ability to comply with protocol mandated procedures. * Participation in another study involved with an investigational agent. * Participant is family member or employee of the Investigator.