Inclusion Criteria:
1. Male or non-pregnant female, age ≥18 to ≤75 years
2. Awaiting a primary heart transplant (listed for heart transplant only)
3. Epstein-Barr virus (EBV) IgG seropositive
4. Able to take oral medication and willing to adhere to the belatacept infusion regimen
5. No desensitization therapy prior to transplant
6. Vaccinations should be up to date for hepatitis B, influenza pneumococcal, haemophilus, varicella zoster virus (VZV), measles, mumps and rubella (MMR), and Human Papilloma Virus (HPV) (for participants \< 45 years of age) when available
7. Female subjects of childbearing potential must have a negative pregnancy test (serum or urine) prior to randomization
8. Mechanical support or investigational drug trials where the intervention ends at the time of transplantation are permitted
9. Negative virtual crossmatch
Exclusion Criteria:
1. Candidates awaiting multiorgan transplant
2. Estimated glomerular filtration rate (eGFR) \< 45 ml/min/m2
3. Candidates with prior organ transplant
4. Candidates actively being treated with immunosuppressive therapies
5. Candidates who have a history of treatment with cytolytic therapy (e.g. anti-thymocyte globulin)
6. Candidates who are intended to be treated with cytolytic therapy in the post-transplant period as induction therapy
7. EBV (IgG) seronegative
8. Active or prior infection with human immunodeficiency virus (HIV), Hepatitis C (HCV), Hepatitis B (HBV)
9. Untreated latent tuberculosis (TB)
10. All potential candidates will be screened prior to enrolment for a history of tuberculosis (chest radiograph and tuberculosis-Interferon Gamma Release Assay (TB-IGRA) or tuberculin skin tests (TST)). Potential candidates with latent TB must be treated prior to study enrolment
11. Prior history of active tuberculosis
12. Prior history of central nervous system infection
13. Known active current viral, fungal, mycobacterial, or other infections excluding driveline infections - potential participants from endemic areas will additionally be screened for histoplasmosis, blastomycosis, coccidioidomycosis, and strongyloidiasis
14. Vaccination with a live vaccine within the past 30 days
15. Malignancy within the last 5 years
16. Any previous treatment with alkylating agents or total lymphoid irradiation
17. Sensitized heart transplant candidates with panel-reactive antibodies (PRA) \>50% or those receiving desensitization treatment
18. Prior treatment with belatacept or abatacept
19. History of severe allergic anaphylactic reactions to humanized or murine monoclonal antibodies
20. Treatment with a disease modifying anti-rheumatic drug (DMARD) or other biologic agent (monoclonal antibody) within the past year
21. Treatment with another investigational drug or other intervention at the time of transplant (excluding device or intervention mechanical support or investigational drug trials where the intervention ends at the time of transplant)
22. Potential candidates for whom a calcineurin inhibitor other than tacrolimus (Prograf®) is anticipated after transplant. If during the course of the study, a participant is transitioned to another calcineurin inhibitor due to side effects or inability to achieve stable therapeutic trough levels, they may continue in the study at the discretion of the investigator
23. Any potential participant who remains on mechanical circulatory support for \> 72 hours post-transplant will be excluded from the study
24. The need for ongoing high dose vasopressor support \> 72 hours post-transplant
25. The need or anticipated need for post-transplant dialysis
26. Platelet count \<75,000/mm (within 24 hours prior to transplant)
27. Absolute neutrophil count (ANC) of less than 2000/mm3 within 24 hours prior to transplant
28. Any past or current medical problems or findings on history, physical examination, or laboratory testing, not listed above, that in the opinion of the investigator, may pose additional risk to participation, may interfere with the participant's ability to comply with study requirements, or that may impact the quality or interpretation of study results
