Inclusion Criteria:
- Considered legally an adult, as defined by country regulations.
- Has congenital hemophilia B with known severe or moderately severe FIX deficiency (less than or equal to \[<=\] 2% of normal circulating FIX) for which the participant is on continuous routine FIX prophylaxis.
- Has 2 consecutive detectable AAV5 NAb titer results between Screening and Visit L-Final using a validated AAV5 NAb assay (based on central laboratory results).
- Has greater than (>) 150 previous exposure days to FIX replacement therapy.
- Has been on stable FIX prophylaxis for at least 2 months before Screening.
- Has demonstrated capability to independently, accurately, and in a timely manner complete the eDiary during the Lead-in Period, as judged by the investigator.
- Acceptance to adhere to contraception guidelines.
- Able to provide informed consent after receipt of verbal and written information about the study.
- Investigator believes that the participant (or the participant's legally acceptable representative\[s\]) understands the nature, scope, and possible consequences of the study and is able to adhere to the study procedures.
Exclusion Criteria:
- History of FIX inhibitors or positive FIX inhibitor test at Prescreening, Screening or Visit L-Final (based on central laboratory results).
- Screening or Visit L-Final laboratory values (based on central laboratory results) of total bilirubin > 2 × the upper limit of normal (ULN) (except if caused by Gilbert's syndrome).
- Screening or Visit L-Final laboratory values (based on central laboratory results) of any of the following laboratory abnormalities:
1. ALT > 2 × the ULN
2. AST > 2 × the ULN
3. Alkaline phosphatase > 2 × the ULN
4. Serum creatinine > 2 × the ULN
5. Hemoglobin less than (<) 8 g/dL
- Any condition other than hemophilia B resulting in an increased bleeding tendency.
- Thrombocytopenia, defined as a platelet count <50 × 10\^9/L, at Screening or Visit L Final (based on central laboratory results).
- Any uncontrolled or untreated infection (human immunodeficiency virus \[HIV\], hepatitis B virus \[HBV\] and hepatitis C virus \[HCV\], or any other significant concurrent, uncontrolled medical condition including, but not limited to, renal, hepatic, cardiovascular, hematological, gastrointestinal, endocrine, pulmonary, neurological, cerebral or psychiatric disease, alcoholism, drug dependency, or any other psychological disorder evaluated by the investigator to interfere with adherence to the clinical study protocol procedures or with the degree of tolerance to CSL222.
- Known history of allergy to corticosteroids or known medical condition that would require chronic administration of oral corticosteroids.
- Known uncontrolled allergic conditions or allergy / hypersensitivity to any component of the CSL222 excipients (ie, sucrose, potassium chloride, potassium dihydrogen phosphate, sodium chloride, and disodium hydrogen phosphate).
- Previous AAV5 gene therapy treatment.
- Receipt of an experimental agent or device within 60 days before Screening until the end of the study.